Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone...Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone of treatment,they often fail to fully address certain symptoms.Additionally,treatment-resistant schizophrenia,affecting 30%-40%of patients,remains a substantial clinical challenge.Positive,negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic,serotonin,GABAergic,and muscarinic pathways in the brain.Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new,and reinforced prior,concepts on the genetic and neurological underpinnings of schizophrenia,including abnormalities in synaptic function,immune processes,and lipid metabolism.Concurrently,new therapeutics targeting different modalities,which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients,are currently being evaluated.Collectively,these efforts provide new momentum for the next phase of schizophrenia research and treatment.展开更多
The yam Dioscorea alata L.is widely cultivated globally.Purple-fleshed varieties of this important crop have enhanced market value due to their high anthocyanin contents,but how anthocyanin biosynthesis in D.alata tub...The yam Dioscorea alata L.is widely cultivated globally.Purple-fleshed varieties of this important crop have enhanced market value due to their high anthocyanin contents,but how anthocyanin biosynthesis in D.alata tubers is regulated remains poorly understood.In this study,we identified and functionally validated key transcription factors that regulate anthocyanin biosynthesis based on a comparative transcriptome and metabolome analysis of three D.alata cultivars with different colored tubers(dark purple,light purple,and white).The anthocyanin glycoside cyanidin-3-O-(2′′-O-glucosyl)glucoside was abundant during early tuber development,and we determined that its accumulation is regulated in opposite manners by two R2R3-MYB transcription factors:DaMYB75 and DaMYB56.Yeast two-hybrid and bimolecular fluorescence complementation assays in Nicotiana benthamiana and co-expression assays in D.alata demonstrated that DaMYB75 promotes anthocyanin biosynthesis by specifically activating the promoter of the late anthocyanin biosynthesis gene DaANS and enhancing its expression through an interaction with DabHLH72.By contrast,DaMYB56 is a negative regulator of anthocyanin biosynthesis that binds to the DaANS promoter together with DabHLH72.Furthermore,the methylation levels of the DaMYB75 promoter were significantly lower in purple tubers than in white tubers.These findings shed light on the regulation of anthocyanin biosynthesis by MYBs and provide the basis for genetically improving anthocyanin content in D.alata.展开更多
Ischemic stroke is one of the major causes of long-term disability and mortality worldwide.It results from an interruption in the cerebral blood flow,triggering a cascade of detrimental events like oxidative stress,mi...Ischemic stroke is one of the major causes of long-term disability and mortality worldwide.It results from an interruption in the cerebral blood flow,triggering a cascade of detrimental events like oxidative stress,mitochondrial dysfunction,neuroinflammation,excitotoxicity,and apoptosis,causing neuronal injury and cellular death.Melatonin,a pleiotropic indoleamine produced by the pineal gland,has multifaceted neuroprotective effects on stroke pathophysiology.Interestingly,the serum melatonin levels are associated with peroxidation and antioxidant status,along with mortality score in patients with severe middle cerebral artery infarction.Melatonin exhibits strong antioxidant,anti-inflammatory,and anti-apoptotic properties and preserves mitochondrial function and homeostasis.Several preclinical studies have shown that melatonin administration conserves blood-brain barrier integrity,reduces infarct size,and edema.These mechanisms contribute to minimizing tissue damage and improving the neurological outcomes following ischemic events.Therefore,the present review evaluates evidence from experimental studies furthered with limited clinical investigations and explores the mechanistic pathways ofmelatonin functions to establish its therapeutic potential in stroke management.展开更多
Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postn...Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postnatal neurogenesis remains unclear.In this study,to define the precise role of transforming growth factor-βsignaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo,we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-βsignaling in neural stem cells in(mGFAPcre-ALK5fl/fl-Ai9)or immature neuroblasts in(DCXcreERT2-ALK5fl/fl-Ai9).Our data showed that exogenous transforming growth factor-βtreatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration.These effects were abolished in activin-like kinase 5(ALK5)knockout primary neural stem cells.Consistent with this,inhibition of transforming growth factor-βsignaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells.Interestingly,deletion of transforming growth factor-βreceptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice,while abolishment of transforming growth factor-βsignaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus.In summary,our data supports a dual role of transforming growth factor-βsignaling in the proliferation and migration of neural stem cells in vitro.Moreover,our data provides novel insights on cell type-specific-dependent requirements of transforming growth factor-βsignaling on neural stem cell proliferation and migration in vivo.展开更多
Flower and fruit abscission reduce crop yield,so decreasing abscission is a significant agricultural issue.HAESA(HAE)and HAESA-like2(HSL2)kinases and their ligand,INFLORESCENCE DEFICIENT IN ABSCISSION(IDA)peptide,have...Flower and fruit abscission reduce crop yield,so decreasing abscission is a significant agricultural issue.HAESA(HAE)and HAESA-like2(HSL2)kinases and their ligand,INFLORESCENCE DEFICIENT IN ABSCISSION(IDA)peptide,have been confirmed to be the core elements regulating floral organ abscission in Arabidopsis thaliana.Our earlier research revealed that Sl IDL6,a homolog of IDA in tomato,functions similarly to At IDA,regulating the abscission of tomato flower organs.Here,we further isolated three HAESA-like homologs,Sl HSL1/2/3,which are involved in tomato flower abscission.Sl HSL1/2/3 are highly expressed in the abscission zone(AZ).The knockout mutant lines of Slhsl1,Slhsl2,and Slhsl3 showed lower flower pedicel abscission than wild type(WT).The double mutant of Slhsl1Slhsl2,Slhsl1Slhsl3,and Slhsl2Slhsl3 further depressed abscission than each of the single mutant lines,while triple mutants Slhsl1Slhsl2Slhsl3 exhibited the lowest abscission,indicating that Sl HSL1/2/3 mediated abscission is non-redundancy,at least partially.Treating tomato pedicel explants with Sl IDL6 peptide significantly accelerated pedicel abscission in WT.However,it had little effect on the abscission rate of Sl HSL1/2/3 knockout lines,indicating that Sl HSL1/2/3 are the receptors of Sl IDL6 in pedicel abscission.Ethylene action inhibitor 1-methylcyclopropene(1-MCP)can significantly depress the expression of Sl HSL1/2/3.Ethylene can significantly accelerate the abscission of WT,while less abscission was found in Sl HSL1/2/3 knockout lines.Our findings indicate that Sl HSL1/2/3 can act as receptors for Sl IDL6 to positively regulate tomato pedicel abscission,and the abscission regulated by Sl HSL1/2/3 was partially dependent on ethylene.展开更多
A growing global population and the increasing prevalence of diet-related health issues such as“hidden hunger”,obesity,hypertension,and diabetes necessitate a fundamental rethinking of crop design and breeding.Synth...A growing global population and the increasing prevalence of diet-related health issues such as“hidden hunger”,obesity,hypertension,and diabetes necessitate a fundamental rethinking of crop design and breeding.Synthetic metabolic engineering offers a method to modify and redesign metabolic pathways to increase the nutritional value of crops.We summarize recent advances in the biofortification of key nutrients including provitamin A,vitamin C,vitamin B9,iron,zinc,anthocyanins,flavonoids,and unsaturated fatty acids.We discuss the potential of multi-gene stacking,gene editing,enzyme engineering,and artificial intelligence in synthetic metabolic engineering.We propose future research directions and potential solutions centered on leveraging AI-driven systems biology,precision gene editing,enzyme engineering,agrobacterium-mediated genotype-independent transformation,and modular metabolic engineering strategies to develop next-generation nutritionally enhanced super crops and transform global food systems.展开更多
Dear Editor,Systemic sclerosis(SSc)is an autoimmune connective tissue disease in which there are vascular abnormalities,inflammation,and fibrosis[1].These three characteristics primarily affect the skin and lungs.Of a...Dear Editor,Systemic sclerosis(SSc)is an autoimmune connective tissue disease in which there are vascular abnormalities,inflammation,and fibrosis[1].These three characteristics primarily affect the skin and lungs.Of all the autoimmune rheumatic diseases,SSc has the highest all-cause mortality rate,and the underlying pathogenic processes that mediate disease are still obscure,with wide diff erences in presentation and progression[2,3].展开更多
The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the cent...The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the central determinant of the functional properties of neurons and neural circuits.The topological and structural morphology of axons and dendrites defines and determines how synapses are conformed.The morphological diversity of axon and dendrite arborization governs the neuron’s inputs,synaptic integration,neuronal computation,signal transmission,and network circuitry,hence defining the particular connectivity and function of the different brain areas.展开更多
Oral squamous cell carcinoma(OSCC)is a prevalent malignancy with high morbidity and mortality.Globally,about 400000 people are affected,often with a poor quality of life.Its high mortality is mainly due to its aggress...Oral squamous cell carcinoma(OSCC)is a prevalent malignancy with high morbidity and mortality.Globally,about 400000 people are affected,often with a poor quality of life.Its high mortality is mainly due to its aggressive growth and tendency to spread.Epithelial-mesenchymal transition(EMT)is a central regulatory hub driving tumor cell migration and invasion by enabling changes in cell characteristics.During EMT,epithelial cells gradually take on mesenchymal traits,gaining mobility and spreading mo re easily.Recent multi-omics studies show that many cancer cells exist in a hybrid or partial-EMT state,which lies between the full epithelial and mesenchymal forms.Cells in this state are especially invasive and metastatic,with high plasticity that promotes tumor progression.This review summarizes the role of partial-EMT in OSCC,with a focus on how it alters the tumor microenvironment(TME),promotes invasion and metastasis,and influences cancer stem cells(CSCs).We also highlight the link between partial-EMT and treatment resistance in OSCC.Based on these insights,we discuss therapeutic strategies targeting partial-EMT to improve outcomes.Targeting partial-EMT may offer promising strategies to enhance treatment effectiveness and improve patient survival and quality of life.展开更多
Backgroud Efficient communication between the embryo and the endometrium is essential for the successful establishment and maintenance of pregnancy.Uterine-derived extracellular vesicles(EVs)contribute to embryomatern...Backgroud Efficient communication between the embryo and the endometrium is essential for the successful establishment and maintenance of pregnancy.Uterine-derived extracellular vesicles(EVs)contribute to embryomaternal communication,supporting early embryonic development.This study aimed to:(i)compare the protein cargo of uterine fluid EVs(UF-EVs)from CYCLIC and PREGNANT heifers;(ii)characterize the protein profile of conditioned medium(CM)-EVs from endometrial explants cultured alone(EXPL)or co-cultured with five d 7 blastocysts(EXPL+EMB)in vitro;and(iii)compare the EV protein cargo between the in vivo and in vitro models(i.e.,EXPL vs.CYCLIC and EXPL+EMB vs.PREGNANT).Results We identified 1,459 and 1,752 proteins in the UF-EVs of CYCLIC and PREGNANT heifers,respectively.Among these,12 were exclusive to CYCLIC,and 18 were exclusive to PREGNANT.Among the 1,329 proteins identified in both groups,16 were differently abundant;ten were more abundant,and six were less abundant in UF-EVs from PREGNANT heifers.In vivo,the changes in UF-EV protein cargo induced by the presence of a blastocyst were related to inflammatory and immune responses,endometrial receptivity,and support of early embryonic development by promoting cell polarity,cell–cell adhesion,and stem cell differentiation.In vitro,we identified 1,501 proteins in the CM-EVs from EXPL,1,975 in the CM-EVs from EXPL+EMB,and 82 in the CM-EVs from EMB.Additionally,50 proteins were unique to EXPL+EMB,and another 33 were differentially abundant due to the synergistic interaction between the embryo and the endometrium.These proteins are involved in embryonic development,regulation of stem cell differentiation,establishment and maintenance of cell polarity,interferon tau(IFNT)-mediated cell signaling,endometrial receptivity,and immune modulation.Although there are qualitative and quantitative differences between in vivo and in vitro-derived EVs,UF-EVs from CYCLIC heifers compared to CM-EVs from EXPL,as well as UFEVs from PREGNANT heifers compared to CM-EVs from EXPL+EMB shared common proteins.Conclusions These findings highlight the pivotal role of EVs in embryo-maternal communication,suggesting that their protein cargo may actively contribute to the modulation of the uterine environment to support early embryonic development.Understanding these molecular interactions could provide valuable insights into the mechanisms of implantation and pregnancy establishment.展开更多
Background Fast-growing broilers are poorly adapted to heat.Adjusting feed composition may mitigate heat stress(HS)effects in temperate climates,while maintaining performance and health during cooler days.Methods One ...Background Fast-growing broilers are poorly adapted to heat.Adjusting feed composition may mitigate heat stress(HS)effects in temperate climates,while maintaining performance and health during cooler days.Methods One thousand nine hundred and twenty Ross 308 male broilers were housed in 64 pens in 4 climate-controlled rooms,2 under cyclical HS(d 28–43;32±2℃;60%–70%RH;09:30–15:30)and 2 under thermoneutral(TN)conditions.In the finisher phase,broilers were allocated to 4 dietary treatments,analyzed values are given except for metabolizable energy(ME):low crude protein(CP)and control fat(LowCP-ConF;17.0%CP,5.9%crude fat(CF),2,925 kcal/kg ME),low CP and high fat(LowCP-HighF;17.2%CP,7.9%CF,3,019 kcal/kg ME),control CP and high fat(ConCP-HighF;18.1%CP,8.0%CF,2,992 kcal/kg ME)and a basal control(ConCP-ConF;18.7%CP,6.3%CF,2,913 kcal/kg ME).LowCP diets contained control levels of digestible amino acids.Results During the finisher phase,compared to control CP levels,LowCP increased average daily feed intake(ADFI)(+2.15%;P=0.020)and affected average daily gain(ADG)and feed conversion ratio(FCR)negatively under TN(-3.77%and+6.49%;P=0.003 and P<0.001,respectively),but not during HS.Compared to control CF,HighF decreased ADFI during TN and HS(-3.16%and-3.17%;P<0.001 and P=0.022)and reduced ADG in TN groups(-3.17%;P=0.010),but not during HS.Mortality was higher in broilers receiving HighF during HS(P=0.040).Slaughter weights were unaffected.LowCP decreased plasma uric acid and lactate dehydrogenase levels during TN,but increased plasma glucose during HS.LowCP increased breast meat redness(a*)during TN and HS(P<0.05).HighF decreased fat(-1.68%;P=0.017),but increased protein levels(+1.53%;P<0.001)in breast meat of HS-broilers.Conclusion LowCP and HighF impaired performance under TN but not under HS.HighF increased mortality under HS,yet improved breast meat composition.These findings highlight the challenge of designing an optimal diet for both conditions and underscore the need to better understand amino acid needs and energy-to-protein ratios during HS.展开更多
Psoriasis is a hereditary,autoimmune,chronic illness that influences the immune system and can have both cutaneous and systemic symptoms.It can seriously impair a patient’s quality of life.Psoriasis affects 2.3 perce...Psoriasis is a hereditary,autoimmune,chronic illness that influences the immune system and can have both cutaneous and systemic symptoms.It can seriously impair a patient’s quality of life.Psoriasis affects 2.3 percent of people globally and has a significant financial cost for those who suffer from it.Genes and environmental factors are the primary etiological factors.Dendritic cells,T cells,human neutrophilic peptides,lipoprotein-2,galactosin-3,fractalkine,vaspin,and familial predispositions,among other factors,are characteristics of the pathophysiology of psoriasis.Conventional psoriasis treatments for patients include corticosteroids,biological agents,vitamin D3 analogs,acitretin,calcineurin inhibitors,cyclosporine,methotrexate,and phototherapy.Growing in popularity as a multidisciplinary field of study,nano dermatology is being used to treat psoriasis.Over the years,major advancements have been made in understanding its complex pathogenesis and developing more effective,targeted treatments.Medication delivery methods utilizing nanocarriers demonstrate promise in treating psoriasis because they improve medication penetration,reduce side effects,and provide targeted action at the afflicted areas.Because of their biological compatibility,adaptability,and capacity for carrying a variety of therapeutic substances,lipid-based and polymer-based nanocarriers have demonstrated exceptional promise among them.This article summarizes the pathogenesis,epidemiology,clinical diagnosis,and conventional psoriasis treatments.Furthermore,the review includes an overview of various nanotechnology-based psoriasis treatments.展开更多
Glymphatic flow has been proposed to clear brain waste while we sleep.Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma,with subsequent cerebrospinal fluid drainage to dural lymph...Glymphatic flow has been proposed to clear brain waste while we sleep.Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma,with subsequent cerebrospinal fluid drainage to dural lymphatics.Glymphatic disruption is associated with neurological conditions such as Alzheimer’s disease and traumatic brain injury.Therefore,investigating its structure and function may improve understanding of pathophysiology.The recent controversy on whether glymphatic flow increases or decreases during sleep demonstrates that the glymphatic hypothesis remains contentious.However,discrepancies between different studies could be due to limitations of the specific techniques used and confounding factors.Here,we review the methods used to study glymphatic function and provide a toolkit from which researchers can choose.We conclude that tracer analysis has been useful,ex vivo techniques are unreliable,and in vivo imaging is still limited.Finally,we explore the potential for future methods and highlight the need for in vitro models,such as microfluidic devices,which may address technique limitations and enable progression of the field.展开更多
Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,includi...Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).展开更多
The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitte...The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitter,plays a crucial role in coordinating synapse formation,neuronal proliferation,and migration during this time.展开更多
Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male m...Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male macaques aged 10-15 years underwent an 18-month HFD intervention.Physiological parameters(BMI,BP,hematology),liver fat fraction(evaluated by ultrasound/MRI),cardiac function(assessed by echocardiography),and histopathology(using liver biopsy)were measured before and after the intervention.Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.Results:Within 6 months,HFD induced dyslipidemia(elevated TG,TCHO,HDL-C,LDL-C).After 18 months,metabolic dysfunction-associated steatohepatitis(MASH)was confirmed by histopathology in 57.14%(16/28)of macaques,diabetes(elevated FPG/HbA1c)in 17.86%(5/28),and myocardial hypertrophy(elevated LVMass/LAD)in 46.43%(13/28).Proteomics identified Bile acid-CoA:amino acid N-acyltransferase(BAAT)as a MASH hallmark protein,the level of which was inversely correlated with the degree of fibrosis.For diabetes,citrate synthase(CS)and malate dehydrogenase 1(MDH1)impaired glucose oxidation via the TCA cycle,while hexose-6-phosphate de-hydrogenase(H6PD)disrupted gluconeogenesis.Myocardial hypertrophy was associ-ated with the downregulation of SRC proto-oncogene,non-receptor tyrosine kinase(SRC),mitogen-activated protein kinase 14(MAPK14),emerin(EMD),and integrin subunit beta 1(ITGB1).Conclusions:An 18-month HFD successfully established a translational M.fascicula-ris model replicating key metabolic disorders(MASH,diabetes,cardiac hypertrophy).BAAT,CS/MDH1/H6PD,and SRC/MAPK14/EMD/ITGB1 were identified as mecha-nistic biomarkers for these conditions.展开更多
Tiller number represents a critical agronomic trait determining sugarcane yield.Strigolactones(SLs) are plant hormones regulating plant architecture.D27,an essential enzyme in the SL biosynthetic pathway,catalyzes a r...Tiller number represents a critical agronomic trait determining sugarcane yield.Strigolactones(SLs) are plant hormones regulating plant architecture.D27,an essential enzyme in the SL biosynthetic pathway,catalyzes a reversible isomerization reaction.ScD27.2,the D27 homolog in sugarcane,contains abiotic stress-responsive elements in its promoter,suggesting its potential importance in SL biosynthesis and stress tolerance.ScD27.2 potentially optimizes sugarcane agronomic traits,particularly tiller number and yield.Understanding its mechanisms will advance the development of high-yielding,stresstolerant sugarcane varieties.To investigate the role of D27 in sugarcane tillering,the key carotene isomerase gene ScD 27.2 was silenced(via RNAi) and overexpressed(OE) in sugarcane cultivar ‘XTT22' plantlets.ScD27-RNAi-2 sugarcane exhibited decreased ScD27.2 expression and increased tiller numbers compared to the wild type ‘XTT22'.Conversely,overexpression lines(ScD27-OE-1,ScD27-OE-5,and ScD27-OE-9) showed increased ScD27.2 expression and decreased tiller numbers.ScD27-OE-9 demonstrated notable lateral bud germination,while ScD27-RNAi-2 exhibited reduced drought tolerance.Under normal light and water management conditions,transgenic sugarcane plants showed significant differences in tiller number and plant height.During extended drought conditions,ScD27-RNAi-2 height was significantly reduced compared to wild type ‘XTT22' and ScD27-OE-9,manifesting a dwarf,multi-tiller phenotype.Additionally,ScD27-RNAi-2 showed significantly reduced SLs content.These findings demonstrate that ScD27.2 regulates tillering under drought stress,likely through SL biosynthesis,and that its drought response may be mediated by the transcription factor ScMYB44.展开更多
Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we develop...Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we developed a bacterial type-II toxin-antitoxin-mediated method to manipulate genomic integration of tandem gene repeats in Saccharomyces cerevisiae and further visualised the evolutionary trajectories of gene repeats.We designed a tri-vector system to introduce toxin-antitoxin-driven gene amplification modules.Results:This system delivered multi-copy gene integration in the form of tandem gene repeats spontaneously and independently from toxin-antitoxin-mediated selection.Inducing the toxin(RelE)expressing via a copper(II)-inducible CUP1 promoter successfully drove the in-situ gene amplification of the antitoxin(RelB)module,resulting in~40 copies of a green fluorescence reporter gene per copy of genome.Copy-number changes,copy-number increase and copy-number decrease,and stable maintenance were visualised using the green fluorescence protein and blue chromoprotein AeBlue as reporters.Copy-number increases happened spontaneously and independent on a selection pressure.Increased copy number was quickly enriched through toxin-antitoxin-mediated selection.Conclusion:In summary,the bacterial toxin-antitoxin systems provide a flexible mechanism to manipulate gene copy number in eukaryotic cells and can be exploited for synthetic biology and metabolic engineering applications.展开更多
Utility-scale PV plants increasingly operate under partial shading,soiling,temperature swings,and rapid irradiance ramps that depress yield and challenge stability on weak grids.This critical review addresses those co...Utility-scale PV plants increasingly operate under partial shading,soiling,temperature swings,and rapid irradiance ramps that depress yield and challenge stability on weak grids.This critical review addresses those conditions by(i)unifying a stressor-to-method taxonomy that links field stressors to global intelligent MPPT(metaheuristics and learning-based trackers)and to advanced inverter controls(adaptive/MPC and grid-forming),(ii)standardizing metrics and reporting aligned with IEC 61724-1 and IEEE 1547/1547.1 to enable fair,reproducible comparisons,and(iii)framing MPPT and grid support as a co-design problem with a DT→HIL→Field validation pathway and seedable scenarios.We identify persistent gaps—fragmented partial-shading benchmarks,limited low-SCR testing,and scarce field-grade validation—and compile a quantitative synthesis:global soiling typically reduces annual production by≈3%–5%,and hybrid/learning MPPT frequently report≈99%tracking efficiency under PSC in simulation/HIL studies.To demonstrate practical relevance,we validate the framework on a seeded scenario library:DRL trackers achieve medianηMPPT≈0.996 with t95≈0.19 s and Hybrid trackers≈0.992/0.26 s,outperforming Metaheuristics(≈0.984/0.42 s);at SCR=2.5,grid-forming control raises VRI from~0.78(tuned GFL)to~0.95 while keeping THD within 2.5%–3.2%,with all stacks meeting IEEE-1547.1 Category-II ride-through.The resulting taxonomy,standards-aligned reporting,and open seeds provide a replicable basis for comparable,grid-relevant benchmarking and clear guidance for real-world design and operations.展开更多
The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cereb...The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.展开更多
基金supported by the Ministry of Health National Medical Research Council (to JL)the National University of Singapore (to JJEC)
文摘Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone of treatment,they often fail to fully address certain symptoms.Additionally,treatment-resistant schizophrenia,affecting 30%-40%of patients,remains a substantial clinical challenge.Positive,negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic,serotonin,GABAergic,and muscarinic pathways in the brain.Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new,and reinforced prior,concepts on the genetic and neurological underpinnings of schizophrenia,including abnormalities in synaptic function,immune processes,and lipid metabolism.Concurrently,new therapeutics targeting different modalities,which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients,are currently being evaluated.Collectively,these efforts provide new momentum for the next phase of schizophrenia research and treatment.
基金supported by the National Natural Science Foundation of China(32460767)Jiangxi Provincial Key Research and Development Program(20232BBF60007)Jiangxi Provincial Natural Science Foundation(20224BAB205024).
文摘The yam Dioscorea alata L.is widely cultivated globally.Purple-fleshed varieties of this important crop have enhanced market value due to their high anthocyanin contents,but how anthocyanin biosynthesis in D.alata tubers is regulated remains poorly understood.In this study,we identified and functionally validated key transcription factors that regulate anthocyanin biosynthesis based on a comparative transcriptome and metabolome analysis of three D.alata cultivars with different colored tubers(dark purple,light purple,and white).The anthocyanin glycoside cyanidin-3-O-(2′′-O-glucosyl)glucoside was abundant during early tuber development,and we determined that its accumulation is regulated in opposite manners by two R2R3-MYB transcription factors:DaMYB75 and DaMYB56.Yeast two-hybrid and bimolecular fluorescence complementation assays in Nicotiana benthamiana and co-expression assays in D.alata demonstrated that DaMYB75 promotes anthocyanin biosynthesis by specifically activating the promoter of the late anthocyanin biosynthesis gene DaANS and enhancing its expression through an interaction with DabHLH72.By contrast,DaMYB56 is a negative regulator of anthocyanin biosynthesis that binds to the DaANS promoter together with DabHLH72.Furthermore,the methylation levels of the DaMYB75 promoter were significantly lower in purple tubers than in white tubers.These findings shed light on the regulation of anthocyanin biosynthesis by MYBs and provide the basis for genetically improving anthocyanin content in D.alata.
基金supported by Chulabhorn Graduate Institute(Fundamental Fund by National Science Research and Innovation Fund(NSRF):fiscal year 2025)(FRB680079/0518 Project code 209041)Chulabhorn Graduate Institute(651-AB01).
文摘Ischemic stroke is one of the major causes of long-term disability and mortality worldwide.It results from an interruption in the cerebral blood flow,triggering a cascade of detrimental events like oxidative stress,mitochondrial dysfunction,neuroinflammation,excitotoxicity,and apoptosis,causing neuronal injury and cellular death.Melatonin,a pleiotropic indoleamine produced by the pineal gland,has multifaceted neuroprotective effects on stroke pathophysiology.Interestingly,the serum melatonin levels are associated with peroxidation and antioxidant status,along with mortality score in patients with severe middle cerebral artery infarction.Melatonin exhibits strong antioxidant,anti-inflammatory,and anti-apoptotic properties and preserves mitochondrial function and homeostasis.Several preclinical studies have shown that melatonin administration conserves blood-brain barrier integrity,reduces infarct size,and edema.These mechanisms contribute to minimizing tissue damage and improving the neurological outcomes following ischemic events.Therefore,the present review evaluates evidence from experimental studies furthered with limited clinical investigations and explores the mechanistic pathways ofmelatonin functions to establish its therapeutic potential in stroke management.
基金supported by NIH grants,Nos.R01NS125074,R01AG083164,R01NS107365,and R21NS127177(to YL),1F31NS129204-01A1(to KW)and Albert Ryan Fellowship(to KW).
文摘Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postnatal neurogenesis remains unclear.In this study,to define the precise role of transforming growth factor-βsignaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo,we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-βsignaling in neural stem cells in(mGFAPcre-ALK5fl/fl-Ai9)or immature neuroblasts in(DCXcreERT2-ALK5fl/fl-Ai9).Our data showed that exogenous transforming growth factor-βtreatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration.These effects were abolished in activin-like kinase 5(ALK5)knockout primary neural stem cells.Consistent with this,inhibition of transforming growth factor-βsignaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells.Interestingly,deletion of transforming growth factor-βreceptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice,while abolishment of transforming growth factor-βsignaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus.In summary,our data supports a dual role of transforming growth factor-βsignaling in the proliferation and migration of neural stem cells in vitro.Moreover,our data provides novel insights on cell type-specific-dependent requirements of transforming growth factor-βsignaling on neural stem cell proliferation and migration in vivo.
基金supported by the Liaoning Science and Technology Innovation Team Project,China(JYTTD2024007)。
文摘Flower and fruit abscission reduce crop yield,so decreasing abscission is a significant agricultural issue.HAESA(HAE)and HAESA-like2(HSL2)kinases and their ligand,INFLORESCENCE DEFICIENT IN ABSCISSION(IDA)peptide,have been confirmed to be the core elements regulating floral organ abscission in Arabidopsis thaliana.Our earlier research revealed that Sl IDL6,a homolog of IDA in tomato,functions similarly to At IDA,regulating the abscission of tomato flower organs.Here,we further isolated three HAESA-like homologs,Sl HSL1/2/3,which are involved in tomato flower abscission.Sl HSL1/2/3 are highly expressed in the abscission zone(AZ).The knockout mutant lines of Slhsl1,Slhsl2,and Slhsl3 showed lower flower pedicel abscission than wild type(WT).The double mutant of Slhsl1Slhsl2,Slhsl1Slhsl3,and Slhsl2Slhsl3 further depressed abscission than each of the single mutant lines,while triple mutants Slhsl1Slhsl2Slhsl3 exhibited the lowest abscission,indicating that Sl HSL1/2/3 mediated abscission is non-redundancy,at least partially.Treating tomato pedicel explants with Sl IDL6 peptide significantly accelerated pedicel abscission in WT.However,it had little effect on the abscission rate of Sl HSL1/2/3 knockout lines,indicating that Sl HSL1/2/3 are the receptors of Sl IDL6 in pedicel abscission.Ethylene action inhibitor 1-methylcyclopropene(1-MCP)can significantly depress the expression of Sl HSL1/2/3.Ethylene can significantly accelerate the abscission of WT,while less abscission was found in Sl HSL1/2/3 knockout lines.Our findings indicate that Sl HSL1/2/3 can act as receptors for Sl IDL6 to positively regulate tomato pedicel abscission,and the abscission regulated by Sl HSL1/2/3 was partially dependent on ethylene.
基金supported by grants from the Guangxi Science and Technology Major Project(GKAA24206023)the Biological Breeding-National Science and Technology Major Project(2024ZD04077)+2 种基金the National Natural Science Foundation of China(32272120)the National Key Research and Development Program of China(2024YFF1000800)the Guangdong Basic Research Center of Excellence for Precise Breeding of Future Crops Major Project(FCBRCE-202502,FCBRCE-202504).
文摘A growing global population and the increasing prevalence of diet-related health issues such as“hidden hunger”,obesity,hypertension,and diabetes necessitate a fundamental rethinking of crop design and breeding.Synthetic metabolic engineering offers a method to modify and redesign metabolic pathways to increase the nutritional value of crops.We summarize recent advances in the biofortification of key nutrients including provitamin A,vitamin C,vitamin B9,iron,zinc,anthocyanins,flavonoids,and unsaturated fatty acids.We discuss the potential of multi-gene stacking,gene editing,enzyme engineering,and artificial intelligence in synthetic metabolic engineering.We propose future research directions and potential solutions centered on leveraging AI-driven systems biology,precision gene editing,enzyme engineering,agrobacterium-mediated genotype-independent transformation,and modular metabolic engineering strategies to develop next-generation nutritionally enhanced super crops and transform global food systems.
文摘Dear Editor,Systemic sclerosis(SSc)is an autoimmune connective tissue disease in which there are vascular abnormalities,inflammation,and fibrosis[1].These three characteristics primarily affect the skin and lungs.Of all the autoimmune rheumatic diseases,SSc has the highest all-cause mortality rate,and the underlying pathogenic processes that mediate disease are still obscure,with wide diff erences in presentation and progression[2,3].
基金supported by the Wellcome Trust(grant No.103852).
文摘The nervous system function requires a precise but plastic neural architecture.The neuronal shape dictates how neurons interact with each other and with other cells,being the morphology of dendrites and axons the central determinant of the functional properties of neurons and neural circuits.The topological and structural morphology of axons and dendrites defines and determines how synapses are conformed.The morphological diversity of axon and dendrite arborization governs the neuron’s inputs,synaptic integration,neuronal computation,signal transmission,and network circuitry,hence defining the particular connectivity and function of the different brain areas.
基金funded by JSPS KAKENHI to Y.K.(22K19629,22H03288,and 21KK0162)JSPS Program for Forming Japan's Peak Research Universities:J-PEAKS(JPJS00420240022)to Y.K.JST SPRING,Grant Number JPMJSP2113 to C.W.and C.S.
文摘Oral squamous cell carcinoma(OSCC)is a prevalent malignancy with high morbidity and mortality.Globally,about 400000 people are affected,often with a poor quality of life.Its high mortality is mainly due to its aggressive growth and tendency to spread.Epithelial-mesenchymal transition(EMT)is a central regulatory hub driving tumor cell migration and invasion by enabling changes in cell characteristics.During EMT,epithelial cells gradually take on mesenchymal traits,gaining mobility and spreading mo re easily.Recent multi-omics studies show that many cancer cells exist in a hybrid or partial-EMT state,which lies between the full epithelial and mesenchymal forms.Cells in this state are especially invasive and metastatic,with high plasticity that promotes tumor progression.This review summarizes the role of partial-EMT in OSCC,with a focus on how it alters the tumor microenvironment(TME),promotes invasion and metastasis,and influences cancer stem cells(CSCs).We also highlight the link between partial-EMT and treatment resistance in OSCC.Based on these insights,we discuss therapeutic strategies targeting partial-EMT to improve outcomes.Targeting partial-EMT may offer promising strategies to enhance treatment effectiveness and improve patient survival and quality of life.
基金supported by research projects:PID2019-111641RB-I00 and PID2023-149027OB-I00 funded by MCIN/AEI/10.13039/501100011033/to DR and PRE2020-094452 to RM。
文摘Backgroud Efficient communication between the embryo and the endometrium is essential for the successful establishment and maintenance of pregnancy.Uterine-derived extracellular vesicles(EVs)contribute to embryomaternal communication,supporting early embryonic development.This study aimed to:(i)compare the protein cargo of uterine fluid EVs(UF-EVs)from CYCLIC and PREGNANT heifers;(ii)characterize the protein profile of conditioned medium(CM)-EVs from endometrial explants cultured alone(EXPL)or co-cultured with five d 7 blastocysts(EXPL+EMB)in vitro;and(iii)compare the EV protein cargo between the in vivo and in vitro models(i.e.,EXPL vs.CYCLIC and EXPL+EMB vs.PREGNANT).Results We identified 1,459 and 1,752 proteins in the UF-EVs of CYCLIC and PREGNANT heifers,respectively.Among these,12 were exclusive to CYCLIC,and 18 were exclusive to PREGNANT.Among the 1,329 proteins identified in both groups,16 were differently abundant;ten were more abundant,and six were less abundant in UF-EVs from PREGNANT heifers.In vivo,the changes in UF-EV protein cargo induced by the presence of a blastocyst were related to inflammatory and immune responses,endometrial receptivity,and support of early embryonic development by promoting cell polarity,cell–cell adhesion,and stem cell differentiation.In vitro,we identified 1,501 proteins in the CM-EVs from EXPL,1,975 in the CM-EVs from EXPL+EMB,and 82 in the CM-EVs from EMB.Additionally,50 proteins were unique to EXPL+EMB,and another 33 were differentially abundant due to the synergistic interaction between the embryo and the endometrium.These proteins are involved in embryonic development,regulation of stem cell differentiation,establishment and maintenance of cell polarity,interferon tau(IFNT)-mediated cell signaling,endometrial receptivity,and immune modulation.Although there are qualitative and quantitative differences between in vivo and in vitro-derived EVs,UF-EVs from CYCLIC heifers compared to CM-EVs from EXPL,as well as UFEVs from PREGNANT heifers compared to CM-EVs from EXPL+EMB shared common proteins.Conclusions These findings highlight the pivotal role of EVs in embryo-maternal communication,suggesting that their protein cargo may actively contribute to the modulation of the uterine environment to support early embryonic development.Understanding these molecular interactions could provide valuable insights into the mechanisms of implantation and pregnancy establishment.
基金funded by VLAIO(Flemish Innovation&Entrepreneurship),grant number HBC.2020.3165。
文摘Background Fast-growing broilers are poorly adapted to heat.Adjusting feed composition may mitigate heat stress(HS)effects in temperate climates,while maintaining performance and health during cooler days.Methods One thousand nine hundred and twenty Ross 308 male broilers were housed in 64 pens in 4 climate-controlled rooms,2 under cyclical HS(d 28–43;32±2℃;60%–70%RH;09:30–15:30)and 2 under thermoneutral(TN)conditions.In the finisher phase,broilers were allocated to 4 dietary treatments,analyzed values are given except for metabolizable energy(ME):low crude protein(CP)and control fat(LowCP-ConF;17.0%CP,5.9%crude fat(CF),2,925 kcal/kg ME),low CP and high fat(LowCP-HighF;17.2%CP,7.9%CF,3,019 kcal/kg ME),control CP and high fat(ConCP-HighF;18.1%CP,8.0%CF,2,992 kcal/kg ME)and a basal control(ConCP-ConF;18.7%CP,6.3%CF,2,913 kcal/kg ME).LowCP diets contained control levels of digestible amino acids.Results During the finisher phase,compared to control CP levels,LowCP increased average daily feed intake(ADFI)(+2.15%;P=0.020)and affected average daily gain(ADG)and feed conversion ratio(FCR)negatively under TN(-3.77%and+6.49%;P=0.003 and P<0.001,respectively),but not during HS.Compared to control CF,HighF decreased ADFI during TN and HS(-3.16%and-3.17%;P<0.001 and P=0.022)and reduced ADG in TN groups(-3.17%;P=0.010),but not during HS.Mortality was higher in broilers receiving HighF during HS(P=0.040).Slaughter weights were unaffected.LowCP decreased plasma uric acid and lactate dehydrogenase levels during TN,but increased plasma glucose during HS.LowCP increased breast meat redness(a*)during TN and HS(P<0.05).HighF decreased fat(-1.68%;P=0.017),but increased protein levels(+1.53%;P<0.001)in breast meat of HS-broilers.Conclusion LowCP and HighF impaired performance under TN but not under HS.HighF increased mortality under HS,yet improved breast meat composition.These findings highlight the challenge of designing an optimal diet for both conditions and underscore the need to better understand amino acid needs and energy-to-protein ratios during HS.
文摘Psoriasis is a hereditary,autoimmune,chronic illness that influences the immune system and can have both cutaneous and systemic symptoms.It can seriously impair a patient’s quality of life.Psoriasis affects 2.3 percent of people globally and has a significant financial cost for those who suffer from it.Genes and environmental factors are the primary etiological factors.Dendritic cells,T cells,human neutrophilic peptides,lipoprotein-2,galactosin-3,fractalkine,vaspin,and familial predispositions,among other factors,are characteristics of the pathophysiology of psoriasis.Conventional psoriasis treatments for patients include corticosteroids,biological agents,vitamin D3 analogs,acitretin,calcineurin inhibitors,cyclosporine,methotrexate,and phototherapy.Growing in popularity as a multidisciplinary field of study,nano dermatology is being used to treat psoriasis.Over the years,major advancements have been made in understanding its complex pathogenesis and developing more effective,targeted treatments.Medication delivery methods utilizing nanocarriers demonstrate promise in treating psoriasis because they improve medication penetration,reduce side effects,and provide targeted action at the afflicted areas.Because of their biological compatibility,adaptability,and capacity for carrying a variety of therapeutic substances,lipid-based and polymer-based nanocarriers have demonstrated exceptional promise among them.This article summarizes the pathogenesis,epidemiology,clinical diagnosis,and conventional psoriasis treatments.Furthermore,the review includes an overview of various nanotechnology-based psoriasis treatments.
基金supported by the European Union Horizon 2020 Research and Innovation Programme(Marie Skłodowska-Curie grant agreement No 847419)supported by the Biotechnology and Biological Sciences Research Council via a Discovery Fellowship(BB/W00934X/1)+6 种基金the Aston University RKE Pump Priming Programmefunded by UKRI’s Research England as part of their Expanding Excellence in England(E3)fundsupported by a UKRI Frontier Research Grant EP/Y023684/1(following assessment as an ERC Advanced grant,FORTIFY,ERC-2022-ADG-101096882 under the UK Government Guarantee scheme)acknowledged a Biotechnology and Biological Sciences Research Council Pioneer Award(BB/Y512874/1)MMS was supported by a Medical Research Council Career Development Award(MR/W027119/1)acknowledged support from the BHF Centre of Research Excellence,University of Oxford(grant code:RE/24/130024)a Biotechnology and Biological Sciences Research Council Pioneer Award(BB/Y512874/1).
文摘Glymphatic flow has been proposed to clear brain waste while we sleep.Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma,with subsequent cerebrospinal fluid drainage to dural lymphatics.Glymphatic disruption is associated with neurological conditions such as Alzheimer’s disease and traumatic brain injury.Therefore,investigating its structure and function may improve understanding of pathophysiology.The recent controversy on whether glymphatic flow increases or decreases during sleep demonstrates that the glymphatic hypothesis remains contentious.However,discrepancies between different studies could be due to limitations of the specific techniques used and confounding factors.Here,we review the methods used to study glymphatic function and provide a toolkit from which researchers can choose.We conclude that tracer analysis has been useful,ex vivo techniques are unreliable,and in vivo imaging is still limited.Finally,we explore the potential for future methods and highlight the need for in vitro models,such as microfluidic devices,which may address technique limitations and enable progression of the field.
基金supported by the Hellenic Foundation for Research and Innovation,HFRI,“2nd Call for HFRI Research Projects to support Faculty Members&Researchers”Project 02667 to GL.
文摘Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).
基金supported by the Center for Cognition and Sociality,Institute for Basic Science(IBS)(IBS-R001-D2)(to WK).
文摘The early developmental period is a critical window during which brain cells mature and contribute to both brain development and later life functions.Gamma-aminobutyric acid(GABA),recognized as a major neurotransmitter,plays a crucial role in coordinating synapse formation,neuronal proliferation,and migration during this time.
基金National Key Research and Development Program of China,Grant/Award Number:2021YFF0702200Science and Technology Projects in Guangzhou,Grant/Award Number:202206010084,202206010197 and 202206060002+1 种基金Guangdong S&T programme,Grant/Award Number:2009A081000002 and 2023B0303040004Technology Planning Project of Linzhi,Grant/Award Number:2023-YZ-01。
文摘Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male macaques aged 10-15 years underwent an 18-month HFD intervention.Physiological parameters(BMI,BP,hematology),liver fat fraction(evaluated by ultrasound/MRI),cardiac function(assessed by echocardiography),and histopathology(using liver biopsy)were measured before and after the intervention.Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.Results:Within 6 months,HFD induced dyslipidemia(elevated TG,TCHO,HDL-C,LDL-C).After 18 months,metabolic dysfunction-associated steatohepatitis(MASH)was confirmed by histopathology in 57.14%(16/28)of macaques,diabetes(elevated FPG/HbA1c)in 17.86%(5/28),and myocardial hypertrophy(elevated LVMass/LAD)in 46.43%(13/28).Proteomics identified Bile acid-CoA:amino acid N-acyltransferase(BAAT)as a MASH hallmark protein,the level of which was inversely correlated with the degree of fibrosis.For diabetes,citrate synthase(CS)and malate dehydrogenase 1(MDH1)impaired glucose oxidation via the TCA cycle,while hexose-6-phosphate de-hydrogenase(H6PD)disrupted gluconeogenesis.Myocardial hypertrophy was associ-ated with the downregulation of SRC proto-oncogene,non-receptor tyrosine kinase(SRC),mitogen-activated protein kinase 14(MAPK14),emerin(EMD),and integrin subunit beta 1(ITGB1).Conclusions:An 18-month HFD successfully established a translational M.fascicula-ris model replicating key metabolic disorders(MASH,diabetes,cardiac hypertrophy).BAAT,CS/MDH1/H6PD,and SRC/MAPK14/EMD/ITGB1 were identified as mecha-nistic biomarkers for these conditions.
基金funded by the National Natural Science Foundation of China (31860405)the National Key Laboratory for Tropical Crop Breeding,China (NKLTCB-YAAS-2024-S05)+4 种基金the Yunnan Provincial Modern Agricultural Technology System,Chinathe Yunnan Provincial Science and Technology Innovation TalentProgram,China (202305AD160041)the Yunnan Provincial “Xingdian Talent Support Program”,Chinathe Yunnan Haizhi Station for Sugarcane Research Institute of Yunnan Academy of Agricultural Sciences,China (HHZ202201)the Yunnan Provincial Key Research and Development Program,China (202403AM140025)。
文摘Tiller number represents a critical agronomic trait determining sugarcane yield.Strigolactones(SLs) are plant hormones regulating plant architecture.D27,an essential enzyme in the SL biosynthetic pathway,catalyzes a reversible isomerization reaction.ScD27.2,the D27 homolog in sugarcane,contains abiotic stress-responsive elements in its promoter,suggesting its potential importance in SL biosynthesis and stress tolerance.ScD27.2 potentially optimizes sugarcane agronomic traits,particularly tiller number and yield.Understanding its mechanisms will advance the development of high-yielding,stresstolerant sugarcane varieties.To investigate the role of D27 in sugarcane tillering,the key carotene isomerase gene ScD 27.2 was silenced(via RNAi) and overexpressed(OE) in sugarcane cultivar ‘XTT22' plantlets.ScD27-RNAi-2 sugarcane exhibited decreased ScD27.2 expression and increased tiller numbers compared to the wild type ‘XTT22'.Conversely,overexpression lines(ScD27-OE-1,ScD27-OE-5,and ScD27-OE-9) showed increased ScD27.2 expression and decreased tiller numbers.ScD27-OE-9 demonstrated notable lateral bud germination,while ScD27-RNAi-2 exhibited reduced drought tolerance.Under normal light and water management conditions,transgenic sugarcane plants showed significant differences in tiller number and plant height.During extended drought conditions,ScD27-RNAi-2 height was significantly reduced compared to wild type ‘XTT22' and ScD27-OE-9,manifesting a dwarf,multi-tiller phenotype.Additionally,ScD27-RNAi-2 showed significantly reduced SLs content.These findings demonstrate that ScD27.2 regulates tillering under drought stress,likely through SL biosynthesis,and that its drought response may be mediated by the transcription factor ScMYB44.
基金supported partially by the Australian Government through the Australian Research Council Centres of Excellence funding scheme(project CE200100029)。
文摘Background:Tandem gene repeats naturally occur as important genomic features and determine many traits in living organisms,like human diseases and microbial productivities of target bioproducts.Methods:Here,we developed a bacterial type-II toxin-antitoxin-mediated method to manipulate genomic integration of tandem gene repeats in Saccharomyces cerevisiae and further visualised the evolutionary trajectories of gene repeats.We designed a tri-vector system to introduce toxin-antitoxin-driven gene amplification modules.Results:This system delivered multi-copy gene integration in the form of tandem gene repeats spontaneously and independently from toxin-antitoxin-mediated selection.Inducing the toxin(RelE)expressing via a copper(II)-inducible CUP1 promoter successfully drove the in-situ gene amplification of the antitoxin(RelB)module,resulting in~40 copies of a green fluorescence reporter gene per copy of genome.Copy-number changes,copy-number increase and copy-number decrease,and stable maintenance were visualised using the green fluorescence protein and blue chromoprotein AeBlue as reporters.Copy-number increases happened spontaneously and independent on a selection pressure.Increased copy number was quickly enriched through toxin-antitoxin-mediated selection.Conclusion:In summary,the bacterial toxin-antitoxin systems provide a flexible mechanism to manipulate gene copy number in eukaryotic cells and can be exploited for synthetic biology and metabolic engineering applications.
文摘Utility-scale PV plants increasingly operate under partial shading,soiling,temperature swings,and rapid irradiance ramps that depress yield and challenge stability on weak grids.This critical review addresses those conditions by(i)unifying a stressor-to-method taxonomy that links field stressors to global intelligent MPPT(metaheuristics and learning-based trackers)and to advanced inverter controls(adaptive/MPC and grid-forming),(ii)standardizing metrics and reporting aligned with IEC 61724-1 and IEEE 1547/1547.1 to enable fair,reproducible comparisons,and(iii)framing MPPT and grid support as a co-design problem with a DT→HIL→Field validation pathway and seedable scenarios.We identify persistent gaps—fragmented partial-shading benchmarks,limited low-SCR testing,and scarce field-grade validation—and compile a quantitative synthesis:global soiling typically reduces annual production by≈3%–5%,and hybrid/learning MPPT frequently report≈99%tracking efficiency under PSC in simulation/HIL studies.To demonstrate practical relevance,we validate the framework on a seeded scenario library:DRL trackers achieve medianηMPPT≈0.996 with t95≈0.19 s and Hybrid trackers≈0.992/0.26 s,outperforming Metaheuristics(≈0.984/0.42 s);at SCR=2.5,grid-forming control raises VRI from~0.78(tuned GFL)to~0.95 while keeping THD within 2.5%–3.2%,with all stacks meeting IEEE-1547.1 Category-II ride-through.The resulting taxonomy,standards-aligned reporting,and open seeds provide a replicable basis for comparable,grid-relevant benchmarking and clear guidance for real-world design and operations.
基金supported by the Grant PID2021-126715OB-IOO financed by MCIN/AEI/10.13039/501100011033 and"ERDFA way of making Europe"by the Grant PI22CⅢ/00055 funded by Instituto de Salud CarlosⅢ(ISCⅢ)+6 种基金the UFIECPY 398/19(PEJ2018-004965) grant to RGS funded by AEI(Spain)the UFIECPY-396/19(PEJ2018-004961)grant financed by MCIN (Spain)FI23CⅢ/00003 grant funded by ISCⅢ-PFIS Spain) to PMMthe UFIECPY 328/22 (PEJ-2021-TL/BMD-21001) grant to LM financed by CAM (Spain)the grant by CAPES (Coordination for the Improvement of Higher Education Personnel)through the PDSE program (Programa de Doutorado Sanduiche no Exterior)to VSCG financed by MEC (Brazil)
文摘The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.
