The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates ...The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.展开更多
Streptococcus suis(S.suis)is a major disease impacting pig farming globally.It can also be transferred to humans by eating raw pork.A comprehensive study was recently carried out to determine the indices throughmultip...Streptococcus suis(S.suis)is a major disease impacting pig farming globally.It can also be transferred to humans by eating raw pork.A comprehensive study was recently carried out to determine the indices throughmultiple geographic regions in China.Methods:The well-posed theorems were employed to conduct a thorough analysis of the model’s feasible features,including positivity,boundedness equilibria,reproduction number,and parameter sensitivity.Stochastic Euler,Runge Kutta,and EulerMaruyama are some of the numerical techniques used to replicate the behavior of the streptococcus suis infection in the pig population.However,the dynamic qualities of the suggested model cannot be restored using these techniques.Results:For the stochastic delay differential equations of the model,the non-standard finite difference approach in the sense of stochasticity is developed to avoid several problems such as negativity,unboundedness,inconsistency,and instability of the findings.Results from traditional stochastic methods either converge conditionally or diverge over time.The stochastic non-negative step size convergence nonstandard finite difference(NSFD)method unconditionally converges to the model’s true states.Conclusions:This study improves our understanding of the dynamics of streptococcus suis infection using versions of stochastic with delay approaches and opens up new avenues for the study of cognitive processes and neuronal analysis.Theplotted interaction behaviour and new solution comparison profiles.展开更多
In 2022,Leukemia is the 13th most common diagnosis of cancer globally as per the source of the International Agency for Research on Cancer(IARC).Leukemia is still a threat and challenge for all regions because of 46.6...In 2022,Leukemia is the 13th most common diagnosis of cancer globally as per the source of the International Agency for Research on Cancer(IARC).Leukemia is still a threat and challenge for all regions because of 46.6%infection in Asia,and 22.1%and 14.7%infection rates in Europe and North America,respectively.To study the dynamics of Leukemia,the population of cells has been divided into three subpopulations of cells susceptible cells,infected cells,and immune cells.To investigate the memory effects and uncertainty in disease progression,leukemia modeling is developed using stochastic fractional delay differential equations(SFDDEs).The feasible properties of positivity,boundedness,and equilibria(i.e.,Leukemia Free Equilibrium(LFE)and Leukemia Present Equilibrium(LPE))of the model were studied rigorously.The local and global stabilities and sensitivity of the parameters around the equilibria under the assumption of reproduction numbers were investigated.To support the theoretical analysis of the model,the Grunwald Letnikov Nonstandard Finite Difference(GL-NSFD)method was used to simulate the results of each subpopulation with memory effect.Also,the positivity and boundedness of the proposed method were studied.Our results show how different methods can help control the cell population and give useful advice to decision-makers on ways to lower leukemia rates in communities.展开更多
Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. Th...Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. The excretion of bicarbonate at both the canaliculi and the bile ducts is an important contributor to the generation of the so-called bile-salt independent flow. Bicarbonate is secreted from hepatocytes and cholangiocytes through parallel mechanisms which involve chloride efflux through activation of Cl- channels, and further bicarbonate secretion via AE2/SLC4A2-mediated Cl-/HCO3- exchange. Glucagon and secretin are two relevant hormones which seem to act very similarly in their target cells （hepatocytes for the former and cholangiocytes for the latter）. These hormones interact with their specific G protein-coupled receptors, causing increases in intracellular levels of cAMP and activation of cAMP-dependent Cl- and HCO3- secretory mechanisms. Both hepatocytes and cholangiocytes appear to have cAMP-responsive intracellular vesicles in which AE2/SLC4A2 colocalizes with cell specific Cl- channels （CFTR in cholangiocytes and not yet determined in hepatocytes） and aquaporins （AQP8 in hepatocytes and AQP1 in cholangiocytes）, cAMP-induced coordinated trafficking of these vesicles to either canalicular or cholangiocyte lumenal membranes and further exocytosis results in increased osmotic forces and passive movement of water with net bicarbonate-rich hydrocholeresis.展开更多
AIM: To review the initial presentation and demonstrate the importance of Takotsubo cardiomyopathy. METHODS: A PubMed search using the terms "Takotsubo cardiomyopathy (TC)" and "apical ballooning syndro...AIM: To review the initial presentation and demonstrate the importance of Takotsubo cardiomyopathy. METHODS: A PubMed search using the terms "Takotsubo cardiomyopathy (TC)" and "apical ballooning syndrome" yield 211 publications. Only those that were relevant were fully reviewed. The gender, age, precipitating stressor, main complaint at presentation, electrocardiogram (ECG) at admission and serum cardiac markers of patients diagnosed with TC, were extracted as available. The data were organized in tables and graphics, and the incidence of the disorder was calculated and analyzed. RESULTS: A total of 250 clinical cases were examined. The predominant gender that was affected was female, with a prevalence of 87.5%. The mean age of presentation was 64±14 years. The cases were divided by age into 10-year intervals. The age interval of 60-69 years showed the highest frequency of TC, accounting for 79 cases. The most common precipitating stressor was physical (50% of cases). Chest pain wasthe primary complaint at presentation (58.8% of cases) followed by dyspnea (30% of cases). The ST segment changes category was the most common (60%), followed by T wave changes (39.6%). Of the 60% of cases with ST segment changes, 12% had concomitant T wave changes. This means that for 27.6% of the cases, the primary abnormality in the ECG was T wave changes; 87.6% of cases with TC had a change in the ST segment, in the T wave or in both. The percentage of ECGs presenting with changes in the anterior wall was 54.4% (35.6% of ST segment elevation +1.6% of ST segment depression +17.2% of T wave inversion). The percentage of patients presenting with changes in the lateral segment of the heart was 46.8%, while the percentage of patients with changes in the inferior heart was 21.6% and the percentage of patients with changes in the apical region was only 16%. The prevalence of elevated creatinine kinase and/or troponin on initial presentation was 89.3%. CONCLUSION: It is essential that every physician consider Takotsubo cardiomyopathy as a possible differential diagnosis when a patient is classified with acute coronary syndrome. To do so, it is necessary to know the clinical presentation of this syndrome in its early stages.展开更多
Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in pati...Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement ofgene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or reporter LacZ gene, was constructed. This hybrid vector showed specificity and high level of expression in HCC both in vitro and in vivo. In a rat orthotropic liver tumor model, treatment of established tumors by the hybrid vector with raiL- 12 gene resulted in a strong anti-tumor activity without accompanying toxicity. Subsequently, a helper-dependent adenovirus vectors containing a mifepristone （RU486） inducible system was constructed for controlled and liver-specific expression of human interleukin 12 （hIL- 12） （HD-Ad/RUhIL- 12） and mouse IL-12 （mIL-12） （HD-Ad/RUmIL-12）. Data showed that high and sustained serum levels of hlL-12 could be attained by continuing administration of RU486 every 12 or 24 h. Repetitive induction ofhlL-12 could be obtained over, at least, a period of 48 weeks after a single injection of HD-Ad/RUhlL-12. Treatment of liver metastases with of HD-Ad/RUmIL- 12 plus RU846 resulted in complete tumor regression in all animals. Then, different cytokine genes were inserted into conditional replicative adenoviruses vectors （also called oncolytic adenovirus）. Replication ofadenovirus in tumor cells would kill tumor cells and release viruses, which infect surrounding tumor cells. The combination of cytopathic effect by oncolytic adenovirus and biological effect of transgene would exert strong antitumor activity. These new types of vectors may provide a potent and safe tool for cancer gene therapy.展开更多
Wilson's disease(WD), which results from the defective ATP7 B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic fail...Wilson's disease(WD), which results from the defective ATP7 B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.展开更多
Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that...Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.展开更多
Ceramic supported cerium, manganese and cerium-manganese catalysts were prepared by direct impregnation of aq precursor, and characterized by scanning electron microscopy （SEM）, X-ray diffraction （XRD）, Brunauer-E...Ceramic supported cerium, manganese and cerium-manganese catalysts were prepared by direct impregnation of aq precursor, and characterized by scanning electron microscopy （SEM）, X-ray diffraction （XRD）, Brunauer-Emmett-Teller rn （BET）, temperature programmed reduction （Ha-TPR）, X-ray photoelectron spectroscopy （XPS） acidity measurements and elec conductivity. The catalytic activity was evaluated for volatile organic compounds （VOC） （ethanol, methyl ethyl ketone and tol oxidation. Additionally, catalysts were tested in particulate matter （PM） combustion. The characterization results indicated that Ce was in the form of Ce4＋ and Ce3＋, and Mn existed in the form of Mn4＋ and Mn3＋ on the surface of the Mn/AC sample and in the of Mn4＋ in the Ce/Mn/AC monolith. VOC oxidation results revealed that the Ce/Mn/AC sample showed an excellent perforr compared with ceramic supported CeO2 （Ce/AC） and MnO, （Mn/AC） samples. The PM combustion was also higher on Ce/M monoliths. The enhanced catalytic activity was mainly attributed to the Ce and Mn interaction which enhanced the acidity, cond ity and the reducibility of the oxides.展开更多
Hepatitis delta virus(HDV)seems to strongly suppress hepatitis B virus(HBV)replication,although little is known about the mechanism of this interaction.Both these viruses show a dynamic distribution of mutants,resulti...Hepatitis delta virus(HDV)seems to strongly suppress hepatitis B virus(HBV)replication,although little is known about the mechanism of this interaction.Both these viruses show a dynamic distribution of mutants,resulting in viral quasispecies.Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra.As the regulatory hepatitis B X protein(HBx)is essential for HBV replication,determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5'region between chronic hepatitis delta(CHD)and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included:7/24(29.2%)with HBeAgnegative chronic HBV infection(CI,previously termed inactive carriers),8/24(33.3%)with HBeAg-negative chronic hepatitis B(CHB)and 9/24(37.5%)with CHD.A serum sample from each patient was first tested for HBV DNA levels.The HBX 5'region[nucleotides(nt)1255-1611]was then PCR-amplified for subsequent next-generation sequencing(MiSeq,Illumina,United States).HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations),abundancebased indices(Hill numbers of order 1 and 2),and functional indices(mutation frequency and nucleotide diversity).We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels[5.4 logIU/mL,interquartile range(IQR)3.5-7.9]than CHD(3.4 logIU/mL,IQR 3-7.6)(P=n.s.)or CI(3.2 logIU/mL,IQR 2.3-3.5)(P<0.01)patients.The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB.A similar trend was observed in CHD patients,although only Hill numbers of order 2 showed statistically significant differences(CHB2.81,IQR 1.11-4.57 vs CHD 8.87,6.56-11.18,P=0.038).There were no significant differences in the functional indices,but CI and CHD patients also showed a trend towards greater complexity than CHB.No differences were found for any HBV quasispecies complexity indices between CHD and CI patients.G-to-A and C-to-T nucleotide changes,characteristic of APOBEC3 G,were higher in CHD and CI than in CHB in genotype A haplotypes,but not in genotype D.The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences.In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group.The mechanisms associated with this greater complexity require elucidation.展开更多
The prolonged mei-yu/baiu system with anomalous precipitation in the year 2020 has swollen many rivers and lakes,caused flash flooding,urban flooding and landslides,and consistently wreaked havoc across large swathes ...The prolonged mei-yu/baiu system with anomalous precipitation in the year 2020 has swollen many rivers and lakes,caused flash flooding,urban flooding and landslides,and consistently wreaked havoc across large swathes of China,particularly in the Yangtze River basin.Significant precipitation and flooding anomalies have already been seen in magnitude and extension so far this year,which have been exerting much higher pressure on emergency responses in flood control and mitigation than in other years,even though a rainy season with multiple ongoing serious flood events in different provinces is not that uncommon in China.Instead of delving into the causes of the uniqueness of this year’s extreme precipitation-flooding situation,which certainly warrants in-depth exploration,in this article we provide a short view toward a more general hydrometeorological solution to this annual nationwide problem.A“glocal”(global to local)hydrometeorological solution for floods(GHS-F)is considered to be critical for better preparedness,mitigation,and management of different types of significant precipitation-caused flooding,which happen extensively almost every year in many countries such as China,India and the United States.Such a GHS-F model is necessary from both scientific and operational perspectives,with the strength in providing spatially consistent flood definitions and spatially distributed flood risk classification considering the heterogeneity in vulnerability and resilience across the entire domain.Priorities in the development of such a GHS-F are suggested,emphasizing the user’s requirements and needs according to practical experiences with various flood response agencies.展开更多
The effect of the Al-6Ce-3La（ACL） on the microstructural behavior of the Al7075 was investigated. Materials were synthesized by mechanical alloying with variation in the ACL content and milling time. Products were c...The effect of the Al-6Ce-3La（ACL） on the microstructural behavior of the Al7075 was investigated. Materials were synthesized by mechanical alloying with variation in the ACL content and milling time. Products were characterized and studied in the as-milled condition and mechanically evaluated after sintering. The synergetic effect of milling time and ACL content in the modified materials led to a reduction in the particle size. Results from electron microscopy showed a homogeneous dispersion of Ce/La phases up to 20 wt.% of ACL content after 10 h of milling. Mechanical evaluation under compressive test showed an improved performance for those alloys reinforced with 0.2 wt.% and 0.5 wt.% of ACL.展开更多
Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide....Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds （fluoropyrimidines, irinotecan and oxaliplatin） and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes （fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab） achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefltinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.展开更多
Abundances of the fireworm Hermodice carunculata were counted through a monitoring assessment study of fish cages in Barranco Hondo（NE Tenerife）. Seven campaigns were conducted from November 2007 to June 2010 and te...Abundances of the fireworm Hermodice carunculata were counted through a monitoring assessment study of fish cages in Barranco Hondo（NE Tenerife）. Seven campaigns were conducted from November 2007 to June 2010 and temporal variations were found, as well as differences among sampling stations. The polychaete H. carunculata obtained its highest abundance in sediments beneath fish cages throughout the study period. Thus, the assemblages of this omnivorous species were favoured by the presence of fish cages.展开更多
Humans and animals use the classic five senses-sight,hearing,touch,smell,and taste-to detect and monitor their environment,with the sense of position and movement often referred to as the sixth sense.The perception of...Humans and animals use the classic five senses-sight,hearing,touch,smell,and taste-to detect and monitor their environment,with the sense of position and movement often referred to as the sixth sense.The perception of external signals through the senses is essential to an organism's survival,transmitting signals to the central nervous system(CNS)and prompting physiological changes in other biological systems.In addition to the direct effects of sense-induced mediators in the brain.展开更多
基金supported by grants PID2020-120308RB-I00 and PID2023-147802OB-I00 funded by MICIU/AEI/10.13039/501100011033FEDER,UE,by Aligning Science Across Parkinson’s(ref.ASAP-020505)through the Michael J.Fox Foundation for Parkinson’s Research+1 种基金by CiberNed Intramural Collaborative Projects(ref.PI2020/09)by the Spanish Fundación Mutua Madrile?a de Investigación Médica(to JLL)。
文摘The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.
基金supported by the Deanship of Scientific Research,Vice Presidency for Graduate Studies and Scientific Research,King Faisal University,Saudi Arabia[KFU250259].
文摘Streptococcus suis(S.suis)is a major disease impacting pig farming globally.It can also be transferred to humans by eating raw pork.A comprehensive study was recently carried out to determine the indices throughmultiple geographic regions in China.Methods:The well-posed theorems were employed to conduct a thorough analysis of the model’s feasible features,including positivity,boundedness equilibria,reproduction number,and parameter sensitivity.Stochastic Euler,Runge Kutta,and EulerMaruyama are some of the numerical techniques used to replicate the behavior of the streptococcus suis infection in the pig population.However,the dynamic qualities of the suggested model cannot be restored using these techniques.Results:For the stochastic delay differential equations of the model,the non-standard finite difference approach in the sense of stochasticity is developed to avoid several problems such as negativity,unboundedness,inconsistency,and instability of the findings.Results from traditional stochastic methods either converge conditionally or diverge over time.The stochastic non-negative step size convergence nonstandard finite difference(NSFD)method unconditionally converges to the model’s true states.Conclusions:This study improves our understanding of the dynamics of streptococcus suis infection using versions of stochastic with delay approaches and opens up new avenues for the study of cognitive processes and neuronal analysis.Theplotted interaction behaviour and new solution comparison profiles.
基金supported by the Fundacao para a Ciencia e Tecnologia,FCT,under the project https://doi.org/10.54499/UIDB/04674/2020(accessed on 1 January 2025).
文摘In 2022,Leukemia is the 13th most common diagnosis of cancer globally as per the source of the International Agency for Research on Cancer(IARC).Leukemia is still a threat and challenge for all regions because of 46.6%infection in Asia,and 22.1%and 14.7%infection rates in Europe and North America,respectively.To study the dynamics of Leukemia,the population of cells has been divided into three subpopulations of cells susceptible cells,infected cells,and immune cells.To investigate the memory effects and uncertainty in disease progression,leukemia modeling is developed using stochastic fractional delay differential equations(SFDDEs).The feasible properties of positivity,boundedness,and equilibria(i.e.,Leukemia Free Equilibrium(LFE)and Leukemia Present Equilibrium(LPE))of the model were studied rigorously.The local and global stabilities and sensitivity of the parameters around the equilibria under the assumption of reproduction numbers were investigated.To support the theoretical analysis of the model,the Grunwald Letnikov Nonstandard Finite Difference(GL-NSFD)method was used to simulate the results of each subpopulation with memory effect.Also,the positivity and boundedness of the proposed method were studied.Our results show how different methods can help control the cell population and give useful advice to decision-makers on ways to lower leukemia rates in communities.
基金the "UTE for CIMA project" as well as by a grant from the "Institute de Salud CarlosⅢ" (PI051098). J. M. B. has a grant from the Spanish Ministry of Science and Technology
文摘Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. The excretion of bicarbonate at both the canaliculi and the bile ducts is an important contributor to the generation of the so-called bile-salt independent flow. Bicarbonate is secreted from hepatocytes and cholangiocytes through parallel mechanisms which involve chloride efflux through activation of Cl- channels, and further bicarbonate secretion via AE2/SLC4A2-mediated Cl-/HCO3- exchange. Glucagon and secretin are two relevant hormones which seem to act very similarly in their target cells （hepatocytes for the former and cholangiocytes for the latter）. These hormones interact with their specific G protein-coupled receptors, causing increases in intracellular levels of cAMP and activation of cAMP-dependent Cl- and HCO3- secretory mechanisms. Both hepatocytes and cholangiocytes appear to have cAMP-responsive intracellular vesicles in which AE2/SLC4A2 colocalizes with cell specific Cl- channels （CFTR in cholangiocytes and not yet determined in hepatocytes） and aquaporins （AQP8 in hepatocytes and AQP1 in cholangiocytes）, cAMP-induced coordinated trafficking of these vesicles to either canalicular or cholangiocyte lumenal membranes and further exocytosis results in increased osmotic forces and passive movement of water with net bicarbonate-rich hydrocholeresis.
文摘AIM: To review the initial presentation and demonstrate the importance of Takotsubo cardiomyopathy. METHODS: A PubMed search using the terms "Takotsubo cardiomyopathy (TC)" and "apical ballooning syndrome" yield 211 publications. Only those that were relevant were fully reviewed. The gender, age, precipitating stressor, main complaint at presentation, electrocardiogram (ECG) at admission and serum cardiac markers of patients diagnosed with TC, were extracted as available. The data were organized in tables and graphics, and the incidence of the disorder was calculated and analyzed. RESULTS: A total of 250 clinical cases were examined. The predominant gender that was affected was female, with a prevalence of 87.5%. The mean age of presentation was 64±14 years. The cases were divided by age into 10-year intervals. The age interval of 60-69 years showed the highest frequency of TC, accounting for 79 cases. The most common precipitating stressor was physical (50% of cases). Chest pain wasthe primary complaint at presentation (58.8% of cases) followed by dyspnea (30% of cases). The ST segment changes category was the most common (60%), followed by T wave changes (39.6%). Of the 60% of cases with ST segment changes, 12% had concomitant T wave changes. This means that for 27.6% of the cases, the primary abnormality in the ECG was T wave changes; 87.6% of cases with TC had a change in the ST segment, in the T wave or in both. The percentage of ECGs presenting with changes in the anterior wall was 54.4% (35.6% of ST segment elevation +1.6% of ST segment depression +17.2% of T wave inversion). The percentage of patients presenting with changes in the lateral segment of the heart was 46.8%, while the percentage of patients with changes in the inferior heart was 21.6% and the percentage of patients with changes in the apical region was only 16%. The prevalence of elevated creatinine kinase and/or troponin on initial presentation was 89.3%. CONCLUSION: It is essential that every physician consider Takotsubo cardiomyopathy as a possible differential diagnosis when a patient is classified with acute coronary syndrome. To do so, it is necessary to know the clinical presentation of this syndrome in its early stages.
文摘Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement ofgene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or reporter LacZ gene, was constructed. This hybrid vector showed specificity and high level of expression in HCC both in vitro and in vivo. In a rat orthotropic liver tumor model, treatment of established tumors by the hybrid vector with raiL- 12 gene resulted in a strong anti-tumor activity without accompanying toxicity. Subsequently, a helper-dependent adenovirus vectors containing a mifepristone （RU486） inducible system was constructed for controlled and liver-specific expression of human interleukin 12 （hIL- 12） （HD-Ad/RUhIL- 12） and mouse IL-12 （mIL-12） （HD-Ad/RUmIL-12）. Data showed that high and sustained serum levels of hlL-12 could be attained by continuing administration of RU486 every 12 or 24 h. Repetitive induction ofhlL-12 could be obtained over, at least, a period of 48 weeks after a single injection of HD-Ad/RUhlL-12. Treatment of liver metastases with of HD-Ad/RUmIL- 12 plus RU846 resulted in complete tumor regression in all animals. Then, different cytokine genes were inserted into conditional replicative adenoviruses vectors （also called oncolytic adenovirus）. Replication ofadenovirus in tumor cells would kill tumor cells and release viruses, which infect surrounding tumor cells. The combination of cytopathic effect by oncolytic adenovirus and biological effect of transgene would exert strong antitumor activity. These new types of vectors may provide a potent and safe tool for cancer gene therapy.
文摘Wilson's disease(WD), which results from the defective ATP7 B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.
基金Supported by The Agreement between FIMA and the "UTE project CIMA"Red Temática de Investigación Cooperativa en Cáncer RD06 00200061 (to Berasain C and ávila MA)Ciberehd (to Prieto J) from Instituto de Salud Carlos Ⅲ,Grants FIS PI070392 and PI070402 from Ministerio de Sanidad y Con-sumo
文摘Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.
基金Project supported by National Scientific and Technical Research Council of Argentina(PIP 942)National Science and Technology Promotion Agency of Argentina(PICT 2012-2366)
文摘Ceramic supported cerium, manganese and cerium-manganese catalysts were prepared by direct impregnation of aq precursor, and characterized by scanning electron microscopy （SEM）, X-ray diffraction （XRD）, Brunauer-Emmett-Teller rn （BET）, temperature programmed reduction （Ha-TPR）, X-ray photoelectron spectroscopy （XPS） acidity measurements and elec conductivity. The catalytic activity was evaluated for volatile organic compounds （VOC） （ethanol, methyl ethyl ketone and tol oxidation. Additionally, catalysts were tested in particulate matter （PM） combustion. The characterization results indicated that Ce was in the form of Ce4＋ and Ce3＋, and Mn existed in the form of Mn4＋ and Mn3＋ on the surface of the Mn/AC sample and in the of Mn4＋ in the Ce/Mn/AC monolith. VOC oxidation results revealed that the Ce/Mn/AC sample showed an excellent perforr compared with ceramic supported CeO2 （Ce/AC） and MnO, （Mn/AC） samples. The PM combustion was also higher on Ce/M monoliths. The enhanced catalytic activity was mainly attributed to the Ce and Mn interaction which enhanced the acidity, cond ity and the reducibility of the oxides.
基金Supported by the Instituto de Salud CarlosⅢ,grants PI15/00856 and PI17/02233co-financed by the European Regional Development Fund(ERDF)
文摘Hepatitis delta virus(HDV)seems to strongly suppress hepatitis B virus(HBV)replication,although little is known about the mechanism of this interaction.Both these viruses show a dynamic distribution of mutants,resulting in viral quasispecies.Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra.As the regulatory hepatitis B X protein(HBx)is essential for HBV replication,determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5'region between chronic hepatitis delta(CHD)and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included:7/24(29.2%)with HBeAgnegative chronic HBV infection(CI,previously termed inactive carriers),8/24(33.3%)with HBeAg-negative chronic hepatitis B(CHB)and 9/24(37.5%)with CHD.A serum sample from each patient was first tested for HBV DNA levels.The HBX 5'region[nucleotides(nt)1255-1611]was then PCR-amplified for subsequent next-generation sequencing(MiSeq,Illumina,United States).HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations),abundancebased indices(Hill numbers of order 1 and 2),and functional indices(mutation frequency and nucleotide diversity).We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels[5.4 logIU/mL,interquartile range(IQR)3.5-7.9]than CHD(3.4 logIU/mL,IQR 3-7.6)(P=n.s.)or CI(3.2 logIU/mL,IQR 2.3-3.5)(P<0.01)patients.The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB.A similar trend was observed in CHD patients,although only Hill numbers of order 2 showed statistically significant differences(CHB2.81,IQR 1.11-4.57 vs CHD 8.87,6.56-11.18,P=0.038).There were no significant differences in the functional indices,but CI and CHD patients also showed a trend towards greater complexity than CHB.No differences were found for any HBV quasispecies complexity indices between CHD and CI patients.G-to-A and C-to-T nucleotide changes,characteristic of APOBEC3 G,were higher in CHD and CI than in CHB in genotype A haplotypes,but not in genotype D.The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences.In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group.The mechanisms associated with this greater complexity require elucidation.
基金This study was supported by the National Key R&D Program of China(Grant No.2017YFA0604300)the National Natural Science Foundation of China(Grant Nos.41861144014,41775106 and U1811464)+1 种基金the Program for Guangdong Introducing Innovative and Entrepreneurial Teams(Grant No.2017ZT07X355)the project of the Chinese Ministry of Emergency Management on“Catastrophe Evaluation Modeling Study”.
文摘The prolonged mei-yu/baiu system with anomalous precipitation in the year 2020 has swollen many rivers and lakes,caused flash flooding,urban flooding and landslides,and consistently wreaked havoc across large swathes of China,particularly in the Yangtze River basin.Significant precipitation and flooding anomalies have already been seen in magnitude and extension so far this year,which have been exerting much higher pressure on emergency responses in flood control and mitigation than in other years,even though a rainy season with multiple ongoing serious flood events in different provinces is not that uncommon in China.Instead of delving into the causes of the uniqueness of this year’s extreme precipitation-flooding situation,which certainly warrants in-depth exploration,in this article we provide a short view toward a more general hydrometeorological solution to this annual nationwide problem.A“glocal”(global to local)hydrometeorological solution for floods(GHS-F)is considered to be critical for better preparedness,mitigation,and management of different types of significant precipitation-caused flooding,which happen extensively almost every year in many countries such as China,India and the United States.Such a GHS-F model is necessary from both scientific and operational perspectives,with the strength in providing spatially consistent flood definitions and spatially distributed flood risk classification considering the heterogeneity in vulnerability and resilience across the entire domain.Priorities in the development of such a GHS-F are suggested,emphasizing the user’s requirements and needs according to practical experiences with various flood response agencies.
文摘The effect of the Al-6Ce-3La（ACL） on the microstructural behavior of the Al7075 was investigated. Materials were synthesized by mechanical alloying with variation in the ACL content and milling time. Products were characterized and studied in the as-milled condition and mechanically evaluated after sintering. The synergetic effect of milling time and ACL content in the modified materials led to a reduction in the particle size. Results from electron microscopy showed a homogeneous dispersion of Ce/La phases up to 20 wt.% of ACL content after 10 h of milling. Mechanical evaluation under compressive test showed an improved performance for those alloys reinforced with 0.2 wt.% and 0.5 wt.% of ACL.
文摘Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds （fluoropyrimidines, irinotecan and oxaliplatin） and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes （fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab） achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefltinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.
基金To the company Cultivos Marinos del Atlántico SL for logistic facilities and financial support throughout the present study
文摘Abundances of the fireworm Hermodice carunculata were counted through a monitoring assessment study of fish cages in Barranco Hondo（NE Tenerife）. Seven campaigns were conducted from November 2007 to June 2010 and temporal variations were found, as well as differences among sampling stations. The polychaete H. carunculata obtained its highest abundance in sediments beneath fish cages throughout the study period. Thus, the assemblages of this omnivorous species were favoured by the presence of fish cages.
基金supported by a grant from the Department of Economic and Business Development from the Government of Navarra(INNOLFACT project,Ref.0011-1411-2023-000094)。
文摘Humans and animals use the classic five senses-sight,hearing,touch,smell,and taste-to detect and monitor their environment,with the sense of position and movement often referred to as the sixth sense.The perception of external signals through the senses is essential to an organism's survival,transmitting signals to the central nervous system(CNS)and prompting physiological changes in other biological systems.In addition to the direct effects of sense-induced mediators in the brain.
