Glass fi ber reinforced gypsum(GFRG) wall panels are prefabricated panels with hollow cores, originally developed in Australia and subsequently adopted by India and China for use in buildings. This paper discusses ide...Glass fi ber reinforced gypsum(GFRG) wall panels are prefabricated panels with hollow cores, originally developed in Australia and subsequently adopted by India and China for use in buildings. This paper discusses identifi cation and calibration of a suitable hysteretic model for GFRG wall panels fi lled with reinforced concrete. As considerable pinching was observed in the experimental results, a suitable hysteretic model with pinched hysteretic rule is used to conduct a series of quasi-static as inelastic hysteretic response analyses of GFRG panels with two different widths. The calibration of the pinching model parameters was carried out to approximately match the simulated and experimental responses up to 80% of the peak load in the post peak region. Interestingly, the same values of various parameters(energy dissipation and pinching related parameters) were obtained for all fi ve test specimens.展开更多
Type 1 diabetes mellitus(T1DM) is one of the most prevalent chronic conditions affecting individuals under the age of 18 years, with increasing incidence worldwide, especially among very young age groups, younger than...Type 1 diabetes mellitus(T1DM) is one of the most prevalent chronic conditions affecting individuals under the age of 18 years, with increasing incidence worldwide, especially among very young age groups, younger than 5. There is still no cure for the disease, and therapeutic goals and guidelines are a challenge. Currently, despite T1 DM intensive management and technological interventions in therapy, the majority of pediatric patients do not achieve glycemic control goals. This leads to a potential prognosis of long term diabetic complications, nephrological, cardiac, ophthalmological and neurological. Unfortunately, the neurological manifestations, including neurocognitive and behavioral complications, may present soon after disease onset, during childhood and adolescence. These manifestations may be prominent, but at times subtle, thus they are often not reported by patients or physicians as related to the diabetes. Furthermore, the metabolic mechanism for such manifestations has been inconsistent and difficult to interpret in practical clinical care, as reported in several reviews on the topic of brain and T1 DM. However, new technological methods for brain assessment, as well as the introduction of continuous glucose monitoring, provide new insights and information regarding brain related manifestations and glycemic variability and control parameters, which may impact the clinical care of children and youth with T1 DM. This paper provides a comprehensive review of the most recently reported behavioral, cognitive domains, sleep related, electrophysiological, and structural alterations in children and adolescences from a novel point of view. The review focuses on reported impairments based on duration of T1 DM, its timeline, and modifiable disease related risk parameters. These findings are not without controversy, and limitations of data are presented in addition to recommendations for future research direction.展开更多
Yield losses of bread wheat due to crown rot can be more severe when drought conditions occur during the grain-filling period.Root architecture characteristics are important for soil exploration and belowground resour...Yield losses of bread wheat due to crown rot can be more severe when drought conditions occur during the grain-filling period.Root architecture characteristics are important for soil exploration and belowground resource acquisition and are essential for adaptation to water-limited environments.Traits such as root angle,length and density have been strongly associated with acquisition efficiency and contribute to yield stability of the crop.The impact of crown rot pathogens on wheat root architecture is poorly understood.We examined differences in root angle,length and number,as well as dry root weight of the crown rot-susceptible bread wheat cultivar,Livingston inoculated with one of two crown rot pathogens Fusarium culmorum or Fusarium pseudograminearum in a transparent-sided root observation chamber.Significant adverse impacts on plant health and growth were revealed by visual discolouration of the leaf sheaths;fresh and dry shoot weight;leaf area of the oldest and the youngest fully expanded leaf and leaf number.Values of most recorded root system measurements were reduced when inoculated with either F.culmorum or F.pseudograminearum.In contrast,root angle was increased in the presence of F.culmorum but was not significantly changed by F.pseudograminearum.The development of whiteheads and grain losses in bread wheat caused by crown rot have previously been associated with blockages of the vascular systems.The method employed here was able to identify differences in the pathogen impacts on roots,which were not detected using previous systems.This research indicates that in the presence of F.culmorum and F.pseudograminearum infection,not only reductions in the size and biomass of the shoot system but also changes in the length,biomass and architecture of the root system could play an important role in yield loss.展开更多
Orotidine 5＇-monophosphate decarboxylase （ODCase） is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 5...Orotidine 5＇-monophosphate decarboxylase （ODCase） is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 5＇-monophosphate （OMP） to uridine 5＇-mono- phosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved DxKxxDx motif is present in all the groups, depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodo- uridine, a potential antimalarial agent.展开更多
Extensive studies have focused on the development and regionalization of neurons in the central nervous system(CNS). Many genes, which play crucial roles in the development of CNS neurons, have been identified. By usi...Extensive studies have focused on the development and regionalization of neurons in the central nervous system(CNS). Many genes, which play crucial roles in the development of CNS neurons, have been identified. By using the technique "direct reprogramming", neurons can be produced from multiple cell sources such as fibroblasts. However, understanding the region-specific regulation of neurons in the CNS is still one of the biggest challenges in the research field of neuroscience. Neurons located in the trigeminal subnucleus caudalis(Vc) and in the spinal dorsal horn(SDH) play crucial roles in pain and sensorimotor functions in the orofacial and other somatic body regions, respectively. Anatomically, Vc represents the most caudal component of the trigeminal system, and is contiguous with SDH. This review is focused on recent data dealing with the regional specificity involved in the development of neurons in Vc and SDH.展开更多
The involvement of mitochondrial dysfunction in many pathophysiological conditions and human diseases is well documented.In order to evaluate mitochondrial function in vitro,many experimental systems have been develop...The involvement of mitochondrial dysfunction in many pathophysiological conditions and human diseases is well documented.In order to evaluate mitochondrial function in vitro,many experimental systems have been developed.Nevertheless the number of in vivo monitoring systems for the evaluation of mitochondrial activities in intact animals and patients is relatively limited.The pioneering development of the conceptual and technological aspects ofmitochondrial monitoring,in vitro and in vivo,was done by the late Prof.Britton Chance(July 24,1913November 16,2010)since the early 1950s.It was my privilege to join his laboratory in 1972 and collaborate with him for almost four decades.The main achievements of our collaboration are presented in this paper.Our activities included cycles of technology development,followed by its applications to study various pathophysiological conditions.In the initial stage,thefirstfiber-opticbased NADHfluorometer was developed.This device enabled us to monitor various organs in anesthetized animals aswell as the brain of nonanesthetized small animals.Later on,the addition of various physiological parameters to NADH monitoring enabled us to correlate mitochondrial function with other cellular functions.The application of the developed technology to clinical situations was a major interest of Prof.Chance and indeed this goal was achieved in the last decade.As of today,the basic tool forNADHmonitoring and the large database of results are available for large-scale experimental and clinical applications.展开更多
Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy ...Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy and minimal toxicity is under controversy.However,it can be evaluated by monitoring oxygen delivery,saturation,and consumption.In this study,the monitoring system fixed on the rats’brain cortex included a time-sharing fluorometer-reflectometer for monitoring mitochondrial NADH and hemoglobin oxygenation(HbO_(2))combined with Laser Doppler Flowmetry(LDF)for blood-flow monitoring.Rats were located in a hyperbaric chamber and exposed to different pressures.The HBO pressure caused an increase in HbO_(2)and a decrease in NADH in proportion to the increase in hyperbaric pressure,up to a nearly maximum effect at 2.5ATA.At 6ATA,15 minutes before convulsions started,blood volume and NADH started to increase,while tissue O_(2)supply by hemoglobin remained stable.Oxygen pool includes oxygen dissolved in the plasma and also bounded to hemoglobin.Above 2.5ATA,hemoglobin is fully saturated and the oxygen pool nourishment derives only from the oxygen dissolved in the plasma,exceeding the physiological ability for autoregulation;hence,homeostasis is disturbed and convulsions appear.This information is vital because pressures around 2.5ATA–3ATA are standard clinically applied pressures used to treat most of the pathophysiological problems considering the potential benefit which must be balanced against the potential toxicity.This study enables,for the first time,to evaluate the oxygenation level of hemoglobin in the microcirculation.Furthermore,our study showed that additional oxygen pressure(above 2.5ATA)caused brain oxygen toxicity within a short variable period of time after the pressure elevation.展开更多
The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithe...The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithesin on brain vitality in these models.Traumatic Brain Injury(TBI)was induced using thefluid percussion injury model in four levels:mild,moderate and two levels of severe TBI.Brain real-time evaluation was performed by the multiparametric monitoring assembly(MPA)which enable cerebral bloodflow(CBF)monitoring by laser Dopplerflowmetry,mitochondrial NADH(Nicotinamide adenine dinucleotide)monitoring by thefluorometric technique,ionic homehostasis using special mini-electrodes,intracranial pressure(ICP)by the ICP camino device and needle electrodes for ECoG(Electrocorticogram)recording.Our results showed high correlation between the level of impact and the extent of changes in the physiological properties of the injury as indicated by the changes in all parameters monitored using the MPA device.Moreover,Equithesin improved CBF,ionic extracellular level and mitochondrial redox state following mild and moderate TBI while in severe TBI,Equithesin did not improve the metabolic state of the cerebral cortex,although it decreased the mortality rate from 66%to 20%,and following extra-severe TBI level,Equithesin did not improve survival rate.In conclusion it seems that Equithesin's protective effect exists under mild to moderate levels of injury and not in case of severe injuries.展开更多
Background : Adherence to therapy is integral to successfully managing asthma, which requires comprehension of what, when, and how to use medication and diligence in following management plan. Asthma patients from eth...Background : Adherence to therapy is integral to successfully managing asthma, which requires comprehension of what, when, and how to use medication and diligence in following management plan. Asthma patients from ethnic minority groups have more morbidity and reported filling their prescriptions less often. Limited information is available in Canadian literature on ethnic differences in their perceptions of asthma management. We aimed to document patient perceived adherence to asthma therapy among targeted ethno-cultural groups. Methods : We evaluated perceived barriers to therapy adherence, including: cultural beliefs and practices, patient/care-provider communication, self-management knowledge, and medication costs. We conducted a cross sectional study and interviewed 85 Chinese or Punjabispeaking adult asthma patients. Results : Lack of sufficient instructions from physicians, language/communication barriers, lack of skills on how to use inhalers, and high medication costs and medication side effects were most reported barriers to proper self-management practices. Most participants lived with others in the same household and reported high social support from home caregivers. The influence of family on self-management practices was obvious. Conclusion: Better understanding of patient needs, provision of culturally and linguistically appropriate education, and inclusion of home caregivers into the management practices are necessary to improve asthma outcomes in Chinese and Punjabi communities.展开更多
Background and Aims: Accurate endoscopic detection of premalignant lesions and earlycancers in the colon is essential for cure, since prognosis is closely related to lesion size andstage. Although it has great clinica...Background and Aims: Accurate endoscopic detection of premalignant lesions and earlycancers in the colon is essential for cure, since prognosis is closely related to lesion size andstage. Although it has great clinical potential, autofluorescence endoscopy has limited tumorto-normal tissue image contrast for detecting small preneoplastic lesions. We have developed amolecularly specific, near-infrared fluorescent monoclonal antibody (CC49) bioconjugate whichtargets tumor-associated glycoprotein 72 (TAG72), as a contrast agent to improve fluorescencebased endoscopy of colon cancer. Methods: The fluorescent anti-TAG72 conjugate was evaluated in vitro and in vivo in athymic nude mice bearing human colon adenocarcinoma (LS174T)subcutaneous tumors. Autofluorescence, a fluorescent but irrelevant antibody and the free fluorescent dye served as controls. Fluorescent agents were injected intravenously, and in vivowhole body fluorescence imaging was performed at various time points to determine pharmacokinetics, followed by ex vivo tissue analysis by confocal fluorescence microscopy and histology Results: Fluorescence microscopy and histology confirmed specific LS174T cell membrane targeting of labeled CC49 in vitro and ex vivo. In vivo fluorescence imaging demonstrated significant tumor-to-normal tissue contrast enhancement with labeled-CC49 at three hours postinjection, with maximum contrast after 48 h. Accumulation of tumor fluorescence demonstratedthat modification of CC49 antibodies did not alter their specific tumor-localizing properties, andwas antibody-dependent since controls did not produce detectable tumor fluorescence. Conclusions: These results show proof-of-principle that our near-infrared fluorescent-antibody probetargeting a tumor-associated mucin detects colonic tumors at the molecular level in real time,and offer a basis for future improvement of image contrast during clinical fluorescence endoscopy.展开更多
Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of th...Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.展开更多
Retinoma,also referred to as retinocytoma,is a benign manifestation of biallelic retinoblastoma gene(RB1)inactivation.Genetic or epigenetic loss of retinoblastoma protein in maturing cone precursors induces genomic in...Retinoma,also referred to as retinocytoma,is a benign manifestation of biallelic retinoblastoma gene(RB1)inactivation.Genetic or epigenetic loss of retinoblastoma protein in maturing cone precursors induces genomic instability which leads to upregulation of senescence-associated p16 INK4a and p130,resulting in non-proliferative retinoma.When senescence pathways fail and genetic instability accumulates to a critical level through altered gene copies of oncogenes and tumor suppression genes,transformation into RB1^(-/-)retinoblastoma occurs.Thus,the management of retinoma involves frequent ophthalmic examination and imaging to monitor the size and characteristics of the tumor,ensure stability,and rule out malignant transformation.Key ophthalmoscopic features of retinoma often include a translucent whitish-gray retinal mass,calcification,retinal pigment epithelial alterations with well-defined margins,located typically around the lesion,as well as a zone of chorioretinal atrophy.This review aims to provide a comprehensive overview of this non-malignant tumor drawing from current understanding of its molecular genetics,clinical characteristics,diagnostic modalities,differential diagnosis,management,and prognosis.A deeper understanding of retinoma could offer valuable insights into how retinoblastoma develops and oncogenesis more broadly,paving the way for improved strategies to prevent and treat this malignant tumor.展开更多
Water-insoluble materials containing amorphous solid dispersions(ASD)are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.ASDs bas...Water-insoluble materials containing amorphous solid dispersions(ASD)are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers.For example,solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate)(PHEMA)can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers.The creation of both immediate-and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels.So far,ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability.This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers,and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.展开更多
Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and he...Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.展开更多
Despite substantial progress in the treatment of castration-resistant prostate cancer (CRPC), including radiation therapy and immunotherapy alone or in combination, the response to treatment remains poor due to the hy...Despite substantial progress in the treatment of castration-resistant prostate cancer (CRPC), including radiation therapy and immunotherapy alone or in combination, the response to treatment remains poor due to the hypoxic and immunosuppressive nature of the tumor microenvironment. Herein, we exploited the bioreactivity of novel polymer–lipid manganese dioxide nanoparticles (PLMDs) to remodel the tumor immune microenvironment (TIME) by increasing the local oxygen levels and extracellular pH and enhancing radiation-induced immunogenic cell death. This study demonstrated that PLMD treatment sensitized hypoxic human and murine CRPC cells to radiation, significantly increasing radiation-induced DNA double-strand breaks and ultimately cell death, which enhanced the secretion of damage-associated molecular patterns, attributable to the induction of autophagy and endoplasmic reticulum stress. Reoxygenation via PLMDs also polarized hypoxic murine RAW264.7 macrophages toward the M1 phenotype, enhancing tumor necrosis factor alpha release, and thus reducing the viability of murine CRPC TRAMP-C2 cells. In a syngeneic TRAMP-C2 tumor model, intravenous injection of PLMDs suppressed, while radiation alone enhanced recruitment of regulatory T cells and myeloid-derived suppressor cells. Pretreatment with PLMDs followed by radiation down-regulated programmed death-ligand 1 and promoted the infiltration of antitumor CD8+ T cells and M1 macrophages to tumor sites. Taken together, TIME modulation by PLMDs plus radiation profoundly delayed tumor growth and prolonged median survival compared with radiation alone. These results suggest that PLMDs plus radiation is a promising treatment modality for improving therapeutic efficacy in radioresistant and immunosuppressive solid tumors.展开更多
Dear Editor Roots play a key role in plant growth regulation. It is well described that the below-ground plant architecture has a significant impact on plant performance under abiotic constraints and maintains stabili...Dear Editor Roots play a key role in plant growth regulation. It is well described that the below-ground plant architecture has a significant impact on plant performance under abiotic constraints and maintains stability under increased grain load （Lynch, 2013）.展开更多
The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden.Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thr...The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden.Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thrombosis and thrombocytopenia;however,the underlying mechanisms remain inadequately understood.Both infection and vaccination utilize the spike protein receptor-binding domain(RBD)of SARS-CoV-2.We found that intravenous injection of recombinant RBD caused significant platelet clearance in mice.Further investigation revealed the RBD could bind platelets,cause platelet activation,and potentiate platelet aggregation,which was exacerbated in the Delta and Kappa variants.The RBD–platelet interaction was partially dependent on theβ3 integrin as binding was significantly reduced inβ3−/−mice.Furthermore,RBD binding to human and mouse platelets was significantly reduced with relatedαIIbβ3 antagonists and mutation of the RGD(arginine-glycine-aspartate)integrin binding motif to RGE(arginine-glycine-glutamate).We developed anti-RBD polyclonal and several monoclonal antibodies(mAbs)and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation,aggregation,and clearance in vivo,and SARS-CoV-2 infection and replication in Vero E6 cells.Our data show that the RBD can bind platelets partially thoughαIIbβ3 and induce platelet activation and clearance,which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and VITT.Our newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.展开更多
文摘Glass fi ber reinforced gypsum(GFRG) wall panels are prefabricated panels with hollow cores, originally developed in Australia and subsequently adopted by India and China for use in buildings. This paper discusses identifi cation and calibration of a suitable hysteretic model for GFRG wall panels fi lled with reinforced concrete. As considerable pinching was observed in the experimental results, a suitable hysteretic model with pinched hysteretic rule is used to conduct a series of quasi-static as inelastic hysteretic response analyses of GFRG panels with two different widths. The calibration of the pinching model parameters was carried out to approximately match the simulated and experimental responses up to 80% of the peak load in the post peak region. Interestingly, the same values of various parameters(energy dissipation and pinching related parameters) were obtained for all fi ve test specimens.
文摘Type 1 diabetes mellitus(T1DM) is one of the most prevalent chronic conditions affecting individuals under the age of 18 years, with increasing incidence worldwide, especially among very young age groups, younger than 5. There is still no cure for the disease, and therapeutic goals and guidelines are a challenge. Currently, despite T1 DM intensive management and technological interventions in therapy, the majority of pediatric patients do not achieve glycemic control goals. This leads to a potential prognosis of long term diabetic complications, nephrological, cardiac, ophthalmological and neurological. Unfortunately, the neurological manifestations, including neurocognitive and behavioral complications, may present soon after disease onset, during childhood and adolescence. These manifestations may be prominent, but at times subtle, thus they are often not reported by patients or physicians as related to the diabetes. Furthermore, the metabolic mechanism for such manifestations has been inconsistent and difficult to interpret in practical clinical care, as reported in several reviews on the topic of brain and T1 DM. However, new technological methods for brain assessment, as well as the introduction of continuous glucose monitoring, provide new insights and information regarding brain related manifestations and glycemic variability and control parameters, which may impact the clinical care of children and youth with T1 DM. This paper provides a comprehensive review of the most recently reported behavioral, cognitive domains, sleep related, electrophysiological, and structural alterations in children and adolescences from a novel point of view. The review focuses on reported impairments based on duration of T1 DM, its timeline, and modifiable disease related risk parameters. These findings are not without controversy, and limitations of data are presented in addition to recommendations for future research direction.
基金supported by a USQ Postgraduate Research Scholarship and the Queensland Government。
文摘Yield losses of bread wheat due to crown rot can be more severe when drought conditions occur during the grain-filling period.Root architecture characteristics are important for soil exploration and belowground resource acquisition and are essential for adaptation to water-limited environments.Traits such as root angle,length and density have been strongly associated with acquisition efficiency and contribute to yield stability of the crop.The impact of crown rot pathogens on wheat root architecture is poorly understood.We examined differences in root angle,length and number,as well as dry root weight of the crown rot-susceptible bread wheat cultivar,Livingston inoculated with one of two crown rot pathogens Fusarium culmorum or Fusarium pseudograminearum in a transparent-sided root observation chamber.Significant adverse impacts on plant health and growth were revealed by visual discolouration of the leaf sheaths;fresh and dry shoot weight;leaf area of the oldest and the youngest fully expanded leaf and leaf number.Values of most recorded root system measurements were reduced when inoculated with either F.culmorum or F.pseudograminearum.In contrast,root angle was increased in the presence of F.culmorum but was not significantly changed by F.pseudograminearum.The development of whiteheads and grain losses in bread wheat caused by crown rot have previously been associated with blockages of the vascular systems.The method employed here was able to identify differences in the pathogen impacts on roots,which were not detected using previous systems.This research indicates that in the presence of F.culmorum and F.pseudograminearum infection,not only reductions in the size and biomass of the shoot system but also changes in the length,biomass and architecture of the root system could play an important role in yield loss.
基金partly supported by a Grant-in-Aid for Scientific Research (C) (24570130 to M.F.). E.F.P.support through a Canada Research Chair. L.P.K.+3 种基金the funding support over the years from Canadian Institutes of Health Research (MOP62704 to EFP and LPK DDP-79122 to LPK, KCK and EFP) ISTPCanada (ICRD08-15)Ministry of Research and Innovation (Ontario, Canada) and Bio Discovery Toronto
文摘Orotidine 5＇-monophosphate decarboxylase （ODCase） is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 5＇-monophosphate （OMP） to uridine 5＇-mono- phosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved DxKxxDx motif is present in all the groups, depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodo- uridine, a potential antimalarial agent.
文摘Extensive studies have focused on the development and regionalization of neurons in the central nervous system(CNS). Many genes, which play crucial roles in the development of CNS neurons, have been identified. By using the technique "direct reprogramming", neurons can be produced from multiple cell sources such as fibroblasts. However, understanding the region-specific regulation of neurons in the CNS is still one of the biggest challenges in the research field of neuroscience. Neurons located in the trigeminal subnucleus caudalis(Vc) and in the spinal dorsal horn(SDH) play crucial roles in pain and sensorimotor functions in the orofacial and other somatic body regions, respectively. Anatomically, Vc represents the most caudal component of the trigeminal system, and is contiguous with SDH. This review is focused on recent data dealing with the regional specificity involved in the development of neurons in Vc and SDH.
文摘The involvement of mitochondrial dysfunction in many pathophysiological conditions and human diseases is well documented.In order to evaluate mitochondrial function in vitro,many experimental systems have been developed.Nevertheless the number of in vivo monitoring systems for the evaluation of mitochondrial activities in intact animals and patients is relatively limited.The pioneering development of the conceptual and technological aspects ofmitochondrial monitoring,in vitro and in vivo,was done by the late Prof.Britton Chance(July 24,1913November 16,2010)since the early 1950s.It was my privilege to join his laboratory in 1972 and collaborate with him for almost four decades.The main achievements of our collaboration are presented in this paper.Our activities included cycles of technology development,followed by its applications to study various pathophysiological conditions.In the initial stage,thefirstfiber-opticbased NADHfluorometer was developed.This device enabled us to monitor various organs in anesthetized animals aswell as the brain of nonanesthetized small animals.Later on,the addition of various physiological parameters to NADH monitoring enabled us to correlate mitochondrial function with other cellular functions.The application of the developed technology to clinical situations was a major interest of Prof.Chance and indeed this goal was achieved in the last decade.As of today,the basic tool forNADHmonitoring and the large database of results are available for large-scale experimental and clinical applications.
文摘Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy and minimal toxicity is under controversy.However,it can be evaluated by monitoring oxygen delivery,saturation,and consumption.In this study,the monitoring system fixed on the rats’brain cortex included a time-sharing fluorometer-reflectometer for monitoring mitochondrial NADH and hemoglobin oxygenation(HbO_(2))combined with Laser Doppler Flowmetry(LDF)for blood-flow monitoring.Rats were located in a hyperbaric chamber and exposed to different pressures.The HBO pressure caused an increase in HbO_(2)and a decrease in NADH in proportion to the increase in hyperbaric pressure,up to a nearly maximum effect at 2.5ATA.At 6ATA,15 minutes before convulsions started,blood volume and NADH started to increase,while tissue O_(2)supply by hemoglobin remained stable.Oxygen pool includes oxygen dissolved in the plasma and also bounded to hemoglobin.Above 2.5ATA,hemoglobin is fully saturated and the oxygen pool nourishment derives only from the oxygen dissolved in the plasma,exceeding the physiological ability for autoregulation;hence,homeostasis is disturbed and convulsions appear.This information is vital because pressures around 2.5ATA–3ATA are standard clinically applied pressures used to treat most of the pathophysiological problems considering the potential benefit which must be balanced against the potential toxicity.This study enables,for the first time,to evaluate the oxygenation level of hemoglobin in the microcirculation.Furthermore,our study showed that additional oxygen pressure(above 2.5ATA)caused brain oxygen toxicity within a short variable period of time after the pressure elevation.
基金This work was supported by the Mina and Everard Goodman Faculty of Life Sciences,and the Leslie and Susan Gonda Multidisciplinary Brain Research Center,Bar-Ilan University,Ramat-Gan,Israel.
文摘The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithesin on brain vitality in these models.Traumatic Brain Injury(TBI)was induced using thefluid percussion injury model in four levels:mild,moderate and two levels of severe TBI.Brain real-time evaluation was performed by the multiparametric monitoring assembly(MPA)which enable cerebral bloodflow(CBF)monitoring by laser Dopplerflowmetry,mitochondrial NADH(Nicotinamide adenine dinucleotide)monitoring by thefluorometric technique,ionic homehostasis using special mini-electrodes,intracranial pressure(ICP)by the ICP camino device and needle electrodes for ECoG(Electrocorticogram)recording.Our results showed high correlation between the level of impact and the extent of changes in the physiological properties of the injury as indicated by the changes in all parameters monitored using the MPA device.Moreover,Equithesin improved CBF,ionic extracellular level and mitochondrial redox state following mild and moderate TBI while in severe TBI,Equithesin did not improve the metabolic state of the cerebral cortex,although it decreased the mortality rate from 66%to 20%,and following extra-severe TBI level,Equithesin did not improve survival rate.In conclusion it seems that Equithesin's protective effect exists under mild to moderate levels of injury and not in case of severe injuries.
文摘Background : Adherence to therapy is integral to successfully managing asthma, which requires comprehension of what, when, and how to use medication and diligence in following management plan. Asthma patients from ethnic minority groups have more morbidity and reported filling their prescriptions less often. Limited information is available in Canadian literature on ethnic differences in their perceptions of asthma management. We aimed to document patient perceived adherence to asthma therapy among targeted ethno-cultural groups. Methods : We evaluated perceived barriers to therapy adherence, including: cultural beliefs and practices, patient/care-provider communication, self-management knowledge, and medication costs. We conducted a cross sectional study and interviewed 85 Chinese or Punjabispeaking adult asthma patients. Results : Lack of sufficient instructions from physicians, language/communication barriers, lack of skills on how to use inhalers, and high medication costs and medication side effects were most reported barriers to proper self-management practices. Most participants lived with others in the same household and reported high social support from home caregivers. The influence of family on self-management practices was obvious. Conclusion: Better understanding of patient needs, provision of culturally and linguistically appropriate education, and inclusion of home caregivers into the management practices are necessary to improve asthma outcomes in Chinese and Punjabi communities.
文摘Background and Aims: Accurate endoscopic detection of premalignant lesions and earlycancers in the colon is essential for cure, since prognosis is closely related to lesion size andstage. Although it has great clinical potential, autofluorescence endoscopy has limited tumorto-normal tissue image contrast for detecting small preneoplastic lesions. We have developed amolecularly specific, near-infrared fluorescent monoclonal antibody (CC49) bioconjugate whichtargets tumor-associated glycoprotein 72 (TAG72), as a contrast agent to improve fluorescencebased endoscopy of colon cancer. Methods: The fluorescent anti-TAG72 conjugate was evaluated in vitro and in vivo in athymic nude mice bearing human colon adenocarcinoma (LS174T)subcutaneous tumors. Autofluorescence, a fluorescent but irrelevant antibody and the free fluorescent dye served as controls. Fluorescent agents were injected intravenously, and in vivowhole body fluorescence imaging was performed at various time points to determine pharmacokinetics, followed by ex vivo tissue analysis by confocal fluorescence microscopy and histology Results: Fluorescence microscopy and histology confirmed specific LS174T cell membrane targeting of labeled CC49 in vitro and ex vivo. In vivo fluorescence imaging demonstrated significant tumor-to-normal tissue contrast enhancement with labeled-CC49 at three hours postinjection, with maximum contrast after 48 h. Accumulation of tumor fluorescence demonstratedthat modification of CC49 antibodies did not alter their specific tumor-localizing properties, andwas antibody-dependent since controls did not produce detectable tumor fluorescence. Conclusions: These results show proof-of-principle that our near-infrared fluorescent-antibody probetargeting a tumor-associated mucin detects colonic tumors at the molecular level in real time,and offer a basis for future improvement of image contrast during clinical fluorescence endoscopy.
基金This work was supported by the Canadian Institutes of Health Research(CIHR PJT-153155)ZPF and a Natural Sciences and Engineering Research Council of Canada Discovery Grant(NSERC RGPIN-2016-04574)to HSS.
文摘Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.
文摘Retinoma,also referred to as retinocytoma,is a benign manifestation of biallelic retinoblastoma gene(RB1)inactivation.Genetic or epigenetic loss of retinoblastoma protein in maturing cone precursors induces genomic instability which leads to upregulation of senescence-associated p16 INK4a and p130,resulting in non-proliferative retinoma.When senescence pathways fail and genetic instability accumulates to a critical level through altered gene copies of oncogenes and tumor suppression genes,transformation into RB1^(-/-)retinoblastoma occurs.Thus,the management of retinoma involves frequent ophthalmic examination and imaging to monitor the size and characteristics of the tumor,ensure stability,and rule out malignant transformation.Key ophthalmoscopic features of retinoma often include a translucent whitish-gray retinal mass,calcification,retinal pigment epithelial alterations with well-defined margins,located typically around the lesion,as well as a zone of chorioretinal atrophy.This review aims to provide a comprehensive overview of this non-malignant tumor drawing from current understanding of its molecular genetics,clinical characteristics,diagnostic modalities,differential diagnosis,management,and prognosis.A deeper understanding of retinoma could offer valuable insights into how retinoblastoma develops and oncogenesis more broadly,paving the way for improved strategies to prevent and treat this malignant tumor.
基金This work was supported in part by funding from the Natural Sciences and Engineering Research Council of Canada(NSERC).D.D.S.was also supported by a University of Toronto Fellowship Award.
文摘Water-insoluble materials containing amorphous solid dispersions(ASD)are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs.ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers.For example,solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate)(PHEMA)can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers.The creation of both immediate-and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels.So far,ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability.This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers,and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.
基金supported in part by an Ontario Research Fund-Research Excellence(ORF-RE)grant(Ontario,Canada)in partnership with Patheon by Thermo Fisher Scientific,Natural Sciences and Engineering Research Council(NSERC)of Canada Discovery Grant and Equipment Grants to Xiao Yu Wu,University of Toronto(Canada),Leslie Dan Faculty of Pharmacy Dean's Fund to Jamie Anne Lugtu-Pe,University of Toronto(Canada),Mitacs Accelerate Internship sponsored by Candoo Pharmatech Company Inc.to Xuning Zhang(Canada),NSERC CREATE ContRoL program support to Sako Mirzaie and Hao Han R.Chang(Canada),Ontario Graduate Scholarship(OGS)to Hao Han R.Chang(Canada),and Pharmaceutical Sciences graduate department scholarships to Hao Han R.Chang and Kuan Chen,University of Toronto(Canada).
文摘Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.
基金the financial support:Canadian Institutes of Health Research Project Grant,Natural Sciences and Engineering Research Council(NSERC)Canada Discovery and Equipment Grants,the Ministry of Education of Libya scholarship to A.E.Z.,the King Abdulaziz City for Science and Technology(KACST)for the scholarship to I.A.,and the funding to the STTARR facilities.
文摘Despite substantial progress in the treatment of castration-resistant prostate cancer (CRPC), including radiation therapy and immunotherapy alone or in combination, the response to treatment remains poor due to the hypoxic and immunosuppressive nature of the tumor microenvironment. Herein, we exploited the bioreactivity of novel polymer–lipid manganese dioxide nanoparticles (PLMDs) to remodel the tumor immune microenvironment (TIME) by increasing the local oxygen levels and extracellular pH and enhancing radiation-induced immunogenic cell death. This study demonstrated that PLMD treatment sensitized hypoxic human and murine CRPC cells to radiation, significantly increasing radiation-induced DNA double-strand breaks and ultimately cell death, which enhanced the secretion of damage-associated molecular patterns, attributable to the induction of autophagy and endoplasmic reticulum stress. Reoxygenation via PLMDs also polarized hypoxic murine RAW264.7 macrophages toward the M1 phenotype, enhancing tumor necrosis factor alpha release, and thus reducing the viability of murine CRPC TRAMP-C2 cells. In a syngeneic TRAMP-C2 tumor model, intravenous injection of PLMDs suppressed, while radiation alone enhanced recruitment of regulatory T cells and myeloid-derived suppressor cells. Pretreatment with PLMDs followed by radiation down-regulated programmed death-ligand 1 and promoted the infiltration of antitumor CD8+ T cells and M1 macrophages to tumor sites. Taken together, TIME modulation by PLMDs plus radiation profoundly delayed tumor growth and prolonged median survival compared with radiation alone. These results suggest that PLMDs plus radiation is a promising treatment modality for improving therapeutic efficacy in radioresistant and immunosuppressive solid tumors.
文摘Dear Editor Roots play a key role in plant growth regulation. It is well described that the below-ground plant architecture has a significant impact on plant performance under abiotic constraints and maintains stability under increased grain load （Lynch, 2013）.
基金the Canadian Institutes of Health Research(CIHR)Foundation grant(389035)CCOA Therapeutics Inc.research fund to Dr.H.N.CIHR grant for COVID-19(OV3-170344,SBC-171482,and VS1-175560)to Dr.H.Z.D.T.M.,Z.C.,and DK are recipients of the Queen Elizabeth II(QE-II)Graduate Scholarship,Ontario,Canada.S.S.is a recipient of the Canadian Blood Services postdoctoral award.D.T.M.is a recipient of a Graduate Scholarship,Department of Physiology,University of Toronto.Z.C.is the recipient of the Canadian Blood Services Graduate Scholarship,Ontario,Canada.C.S.is a recipient of a postdoctoral Mitacs award,University of Toronto.Z.L.is a recipient of Mitacs Accelerate Postdoctoral Fellowship.LL is a recipient of a scholarship from the University of Chinese Academy of Sciences.X.W.is a recipient of Killam Research Fellowship from the Canadian Council for the Arts.D.K.is also the recipient of the St.Michael’s Hospital Research Training Centre Scholarship and the 2021-2022 Vanier Canada Graduate Scholarships(Vanier CGS),and V.P.is the recipient of the CGS awarded by the CIHR.
文摘The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden.Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thrombosis and thrombocytopenia;however,the underlying mechanisms remain inadequately understood.Both infection and vaccination utilize the spike protein receptor-binding domain(RBD)of SARS-CoV-2.We found that intravenous injection of recombinant RBD caused significant platelet clearance in mice.Further investigation revealed the RBD could bind platelets,cause platelet activation,and potentiate platelet aggregation,which was exacerbated in the Delta and Kappa variants.The RBD–platelet interaction was partially dependent on theβ3 integrin as binding was significantly reduced inβ3−/−mice.Furthermore,RBD binding to human and mouse platelets was significantly reduced with relatedαIIbβ3 antagonists and mutation of the RGD(arginine-glycine-aspartate)integrin binding motif to RGE(arginine-glycine-glutamate).We developed anti-RBD polyclonal and several monoclonal antibodies(mAbs)and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation,aggregation,and clearance in vivo,and SARS-CoV-2 infection and replication in Vero E6 cells.Our data show that the RBD can bind platelets partially thoughαIIbβ3 and induce platelet activation and clearance,which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and VITT.Our newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.
