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Abstract Background and aims As the incidence of heart failure (HF) increases, the need for practical tools to evaluate the long‐term prognosis in these patients remains critical. Our study aimed to develop a 48 month prediction model for all‐cause mortality in decompensated HF patients using available clinical indicators. Methods HF patients (n = 503), 60 years or older, were divided into a training cohort (n = 402) and a validation cohort (n = 101). Data on demographics, comorbidities, laboratory results and medications were gathered. Prediction models were developed using the Prognostic Nutritional Index (PNI), cholinesterase (ChE) and a multifactorial nomogram incorporating clinical variables. These models were constructed using the least absolute shrinkage and selection operator algorithm and multivariate logistic regression analysis. The performance of the model was assessed in terms of calibration, discrimination and clinical utility. Results The mean age was 77.11 ± 8.85 years, and 216 (42.9%) were female. The multifactorial nomogram included variables of ChE, lymphocyte count, albumin, serum creatinine and N‐terminal pro‐brain natriuretic peptide (all P

Summary Background Heart failure (HF) is a prevalent clinical syndrome with diverse etiologies. It is crucial to identify novel therapeutic targets based on underlying causes. Here, we aimed to use proteome-wide Mendelian randomization (MR) analyses to identify the associations between genetically predicted elevated levels of circulating proteins and distinct HF outcomes, along with specific HF etiologies. Methods Protein quantitative trait loci (pQTL) data for circulating proteins were sourced from the Atherosclerosis Risk in Communities (ARIC) study, encompassing 7,213 individuals and profiling 4,657 circulating proteins. Genetic associations for outcomes were obtained from the HERMES Consortium and the FinnGen Consortium. Colocalization analysis was employed to assess the impact of linkage disequilibrium on discovered relationships. For replication, two-sample MR was conducted utilizing independent pQTL data from the deCODE study. Multivariable MR (MVMR) and two-step MR were further conducted to investigate potential mediators. Results Two proteins (PCSK9 and AIDA) exhibited associations with HF in patients with coronary heart disease (CHD), and four proteins (PCSK9, SWAP70, NCF1, and RELT) were related with HF in patients receiving antihypertensive medication. Among these associations, strong evidence from subsequent analyses supported the positive relationship between genetically predicted PCSK9 levels and the risk of HF in the context of CHD. Notably, MVMR analysis revealed that CHD and LDL-C did not exert a complete mediating effect in this relationship. Moreover, two-step MR results yielded valuable insights into the potential mediating proportions of CHD or LDL-C in this relationship. Conclusions Our findings provide robust evidence supporting the association between PCSK9 and concomitant HF and CHD. This association is partly elucidated by the influence of CHD or LDL-C, underscoring the imperative for additional validation of this connection and a thorough exploration of the mechanisms through which PCSK9 directly impacts ischemic HF.

Islet transplantation is a promising therapy for diabetes treatment. However, the molecular underpinnings governing the immune response, particularly T-cell dynamics in syngeneic and allogeneic transplant settings, remain poorly understood. Understanding these T cell dynamics is crucial for enhancing graft acceptance and managing diabetes treatment more effectively. This study aimed to elucidate the molecular mechanisms, gene expression differences, biological pathway alterations, and intercellular communication patterns among T-cell subpopulations after syngeneic and allogeneic islet transplantation. Using single-cell RNA sequencing, we analyzed cellular heterogeneity and gene expression profiles using the Seurat package for quality control and dimensionality reduction through t-SNE. Differentially expressed genes (DEGs) were analyzed among different T cell subtypes. GSEA was conducted utilizing the HALLMARK gene sets from MSigDB, while CellChat was used to infer and visualize cell-cell communication networks. Our findings revealed genetic variations within T-cell subpopulations between syngeneic and allogeneic islet transplants. We identified significant DEGs across these conditions, highlighting molecular discrepancies that may underpin rejection or other immune responses. GSEA indicated activation of the interferon-alpha response in memory T cells and suppression in CD4+ helper and γδ T cells, whereas TNFα signaling via NFκB was particularly active in regulatory T cells, γδ T cells, proliferating T cells, and activated CD8+ T cells. CellChat analysis revealed complex communication patterns within T-cell subsets, notably between proliferating T cells and activated CD8+ T cells. In conclusion, our study provides a comprehensive molecular landscape of T-cell diversity in islet transplantation. The insights into specific gene upregulation in xenotransplants suggest potential targets for improving graft tolerance. The differential pathway activation across T-cell subsets underscores their distinct roles in immune responses posttransplantation.

BackgroundSmall Bowel Adenocarcinoma (SBA) is rare, occult and life-threatening malignancy in digestive system. Given low incidence and nonspecific symptoms, SBA is frequently detected in later stages. Double contrast enhanced ultrasound (DCEUS) is an innovative imaging technique applied to visualize the gastrointestinal tract, merging intravenous contrast-enhanced ultrasound with oral contrast-enhanced ultrasound. In this case, DCEUS was utilized and successfully detected an SBA of the jejunum.Case presentationA Chinese woman, aged 64, sought consultation in the gastroenterology department at our hospital, reporting symptoms of abdominal pain. Three months before entering the hospital, she underwent gastroscopy and colonoscopy which suggested chronic gastritis, and she was treated with oral drugs. However, her symptoms were not relieved, and even worsened. To further investigate, DCEUS was performed. The oral contrast agent dilated the luminal space of the upper gastrointestinal tract, resolving the hindrance caused by gas in the gastrointestinal tract and creating an acoustic window for scanning. Through this acoustic window, oral agent contrast-enhanced ultrasound (OA-CEUS) revealed a localized thickening of jejunal intestinal wall measuring 4x3 cm. Following intravenous injection of ultrasound contrast agent, the jejunal lesion exhibited faster enhancement and heterogeneous hyper-enhancement. Finally, the patient underwent jejunal tumor resection. Pathological examination revealed a jejunal adenocarcinoma.ConclusionThe timely diagnosis of SBA can be challenging. DCEUS may have the potential to contribute to diagnosis and detailed evaluation of SBA, particularly in cases involving jejunum. Further researches are needed to fully explore the benefits of DCEUS in the standard diagnostic approach for small bowel diseases.

Automatic detection and alarm of abnormal electrocardiogram (ECG) events play an important role in an ECG monitor system; however, popular classification models based on supervised learning fail to detect abnormal ECG effectively. Thus, we propose an ECG anomaly detection framework (ECG-AAE) based on an adversarial autoencoder and temporal convolutional network (TCN) which consists of three modules (autoencoder, discriminator, and outlier detector). The ECG-AAE framework is trained only with normal ECG data. Normal ECG signals could be mapped into latent feature space and then reconstructed as the original ECG signal back in our model, while abnormal ECG signals could not. Here, the TCN is employed to extract features of normal ECG data. Then, our model is evaluated on an MIT-BIH arrhythmia dataset and CMUH dataset, with an accuracy, precision, recall, F1-score, and AUC of 0.9673, 0.9854, 0.9486, 0.9666, and 0.9672 and of 0.9358, 0.9816, 0.8882, 0.9325, and 0.9358, respectively. The result indicates that the ECG-AAE can detect abnormal ECG efficiently, with its performance better than other popular outlier detection methods.

Abstract Background This study sought to compare the predictive value of NT-proBNP, sST2 and MMPs in HF with different ejection fractions from a population in southern China. Methods A cross-sectional study was conducted on 113 HF patients admitted to Fujian Provincial Hospital from December 2016 to March 2018.The patients were divided into three subgroups: 60 cases in HFpEF group (LVEF≥50%), 28 cases in HFmrEF group (41% ≤ LVEF≤49%) and 25 cases in HFrEF group (LVEF≤40%). ELISA method was applied to detect the concentrations of sST2, MMP-2 and MMP-9. Electrochemical luminescence immunoassay was applied to detect the concentration of plasma NT-proBNP. Univariate and multivariate Cox and logistic regression models were used to analyze the diagnostic significance of these plasma biomarkers in HF patients. Kaplan–Meier survival curves were used to assess the prognostic value of sST2 in the incidence of long-term adverse events during study. Results This study showed that plasma sST2 levels in HFrEF or HFmrEF patients were significantly higher than in HFpEF patients. Plasma levels of MMP-2 and MMP-9 in HFrEF patients were apparently higher than in HFpEF or HFmrEF patients. For the diagnosis of HFpEF, the AUC of NT-proBNP was higher than that of sST2, MMP-2 and MMP-9, which were 0.881, 0.717, 0.705 and 0.597, respectively. For the diagnosis of HFmrEF, the AUC of plasma sST2 was higher than that of MMP-2, MMP-9 and NT-proBNP, which were 0.799, 0.678, 0.676 and 0.793, respectively. For the diagnosis of HFrEF, the AUC of plasma NT-proBNP, sST2, MMP-2, and MMP-9 were 0.945, 0.820, 0.814, and 0.774 respectively. Spearman correlation analysis showed that plasma sST2 levels were significantly correlated with plasma MMP-2, MMP-9 and NT-proBNP levels. Further logistic regression analysis showed that except MMP-9, the biomarkers sST2 (OR = 1.960), MMP-2 (OR = 0.805) and NT-proBNP (OR = 0.002) were all independent risk factors for patients with heart failure. Survival analysis results suggested that for patients with HFmrEF, a higher level of plasma sST2 (≥ 0.332 ng/ml at admission) may predict a higher risk of endpoint events and a lower survival rate (P

This study aims to investigate mental health among Chinese people living in areas with differing levels of infection severity during the COVID-19 outbreak. It also assesses the association between reciprocal and authoritarian filial piety and mental health in times of crises. A sample of 1,201 Chinese participants was surveyed between April and June 2020. Wuhan city (where 23.4% of participants resided), Hubei province outside Wuhan (13.4% of participants), and elsewhere in China (63.1% of participants) were categorized into high, moderate, and low infection severity areas, respectively. The Depression, Anxiety, and Stress Scale’s severity cut-points were used to categorize participants. In the overall sample, 20.9, 34.2, and 29.0% of the participants showed elevated (mild to extremely severe) levels of stress, anxiety, and depression. Those in the highest infection severity group were significantly more likely to be categorized as having elevated levels of stress, anxiety, and depression. General linear modeling was performed on a composite mental distress variable (taking into account stress, anxiety, and depression scores). This model indicated that, even after adjusting for group differences in age, gender, education, and filial piety, the high infection severity group displayed more mental distress than the low infection severity groups. The model also found reciprocal filial piety to have a negative association with mental distress. Conversely, authoritarian filial piety was found to be unrelated to mental distress when controlling for the other variables in the model. No evidence was found for an interaction between either authoritarian or reciprocal filial piety and infection severity, which suggests that the negative association observed between reciprocal filial piety and mental distress was relatively consistent across the three infection severity groups. The findings suggest that future public health programs may integrate the promotion of filial piety as a strategy to help Chinese people maintain good mental health in the face of pandemic crises.

COVID-19 has created significant concern surrounding the impact of pandemic lockdown on mental health. While the pandemic lockdown can be distressing, times of crisis can also provide people with the opportunity to think divergently and explore different activities. Novelty seeking, where individuals explore novel and unfamiliarly stimuli and environments, may enhance the creativity of individuals to solve problems in a way that allows them to adjust their emotional responses to stressful situations. This study employs a longitudinal design to investigate changes in novelty seeking and mental health outcomes (namely, stress, anxiety, and depression) before, during, and after COVID-19 pandemic lockdown, among a group of students (final N = 173; Mage = 19.81; SDage = 0.98; 135 females and 38 males) from a university in southeast China. Participants were surveyed at three points: November, 2019 (prior to the COVID-19 pandemic); between February and March, 2020 (during the peak of the pandemic and intense lockdown in China); and between May and June, 2020 (after lockdown had been lifted in China). Cross-sectionally, correlation analysis indicated that greater novelty seeking was associated with lower levels of stress, anxiety, and depression at all three time points. Univariate latent curve modeling (LCM) indicated a growth trajectory in which novelty seeking increased over time and then remained high during the post-lockdown period. Stress, anxiety, and depression all showed V-shaped growth trajectories in which these variables decreased during lockdown, before increasing in the post-lockdown period. Multivariate LCM indicated the growth trajectory for novelty seeking was associated with the growth trajectories for stress, anxiety, and depression. This suggests that the observed decreases in stress, anxiety, and depression during the lockdown period may be attributable to the sample’s observed increase in novelty seeking. These findings are valuable in that they challenge the notion that lockdown measures are inherently detrimental to mental health. The findings indicate the important role of novelty seeking in responding to crises. It may be possible for future public health measures to incorporate the promotion of novelty seeking to help individuals’ respond to stressful situations and maintain good mental health in the face of crises.

This work examined quantitatively the key synoptic features influencing the high-impact heavy rainfall event in Beijing, China, on 21 July 2012 using both correlation analysis based on global ensemble forecasts (from TIGGE) and a method previously used for observation targeting. The global models were able to capture the domain-averaged rainfall of >100 mm but underestimated rainfall beyond 200 mm with an apparent time lag. In this particular case, the ensemble forecasts of the National Centres for Environmental Prediction (NCEP) had apparently better performance than those of the European Centre for Medium-Range Weather Forecasts (ECMWF) and the China Meteorological Administration (CMA), likely because of their high accuracies in capturing the key synoptic features influencing the rainfall event. Linear correlation coefficients between the 24-h domain-averaged precipitation in Beijing and various variables during the rainfall were calculated based on the grand ensemble forecasts from ECMWF, NCEP and CMA. The results showed that the distribution of the precipitation was associated with the strength and the location of a mid-level trough in the westerly flow and the associated low-level low. The dominant system was the low-level low, and a stronger low with a location closer to the Beijing area was associated with heavier rainfall, likely caused by stronger low-level lifting. These relationships can be clearly seen by comparing a good member with a bad member of the grand ensemble. The importance of the trough in the westerly flow and the low-level low was further confirmed by the sensitive area identified through sensitivity analyses with conditional nonlinear optimal perturbation method.

Inflammation and reactive oxygen species (ROS) play important roles in the pathogenesis of atherosclerosis. Resveratrol has been shown to possess anti-inflammatory and antioxidative stress activities, but the underlying mechanisms are not fully understood. In the present study, we investigated the molecular basis associated with the protective effects of resveratrol on tumor necrosis factor-alpha (TNF-α)-induced injury in human umbilical endothelial cells (HUVECs) using a variety of approaches including a cell viability assay, reverse transcription and quantitative polymerase chain reaction, western blot, and immunofluorescence staining. We showed that TNF-α induced CD40 expression and ROS production in cultured HUVECs, which were attenuated by resveratrol treatment. Also, resveratrol increased the expression of sirtuin 1 (SIRT1); and repression of SIRT1 by small-interfering RNA (siRNA) and the SIRT1 inhibitor Ex527 reduced the inhibitory effects of resveratrol on CD40 expression and ROS generation. In addition, resveratrol downregulated the levels of p65 and phospho-p38 MAPK, but this inhibitory effect was attenuated by the suppression of SIRT1 activity. Moreover, the p38 MAPK inhibitor SD203580 and the nuclear factor (NF)-κB inhibitor pyrrolidine dithiocarbamate (PDTC) achieved similar repressive effects as resveratrol on TNF-α-induced ROS generation and CD40 expression. Thus, our study provides a mechanistic link between resveratrol and the activation of SIRT1, the latter of which is involved in resveratrol-mediated repression of the p38 MAPK/NF-κB pathway and ROS production in TNF-α-treated HUVECs.

Abstract Background and objectives Congenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making. Methods In this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017–2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses. Results The diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P

Abstract Background Individuals with X chromosomal translocations, variable phenotypes, and a high risk of live birth defects are of interest for scientific study. These characteristics are related to differential breakpoints and various types of chromosomal abnormalities. To investigate the effects of X chromosome translocation on clinical phenotype, a retrospective analysis of clinical data for patients with X chromosome translocation was conducted. Karyotype analysis plus endocrine evaluation was utilized for all the patients. Additional semen analysis and Y chromosome microdeletions were assessed in male patients. Results X chromosome translocations were detected in ten cases, including seven females and three males. Infantile uterus and no ovaries were detected in case 1 (FSH: 114 IU/L, LH: 30.90 mIU/mL, E2:

Background and purpose: Intellectual disability-7 (MRD7) is a subtype disorder of intellectual disability (MRD) involving feeding difficulties, hypoactivity, and febrile seizures at an age of early onset, then progressive intellectual and physical development deterioration. We purposed to identify the underlying causative genetic factors of three individuals in each Chinese family who presented with symptoms of intellectual disability and facial dysmorphic features. We provided prenatal diagnosis for the three families and genetic counseling for the prevention of this disease.Methods: We collected retrospective clinical diagnostic evidence for the three probands in our study, which included magnetic resonance imaging (MRI), computerized tomography (CT), electroencephalogram (EEG), and intelligence tests for the three probands in our study. Genetic investigation of the probands and their next of kin was performed by Trio-whole exome sequencing (WES). Sanger sequencing or quantitative PCR technologies were then used as the next step to verify the variants confirmed with Trio-WES for the three families. Moreover, we performed amniocentesis to explore the state of the three pathogenic variants in the fetuses by prenatal molecular genetic diagnosis at an appropriate gestational period for the three families.Results: The three probands and one fetus were clinically diagnosed with microcephaly and exhibited intellectual developmental disability, postnatal feeding difficulties, and facial dysmorphic features. Combining probands’ clinical manifestations, Trio-WES uncovered the three heterozygous variants in DYRK1A: a novel variant exon3_exon4del p.(Gly4_Asn109del), a novel variant c.1159C>T p.(Gln387*), and a previously presented but rare pathogenic variant c.1309C>T p.(Arg437*) (NM_001396.5) in three families, respectively. In light of the updated American College of Medical Genetic and Genomics (ACMG) criterion, the variant of exon3_exon4del and c.1159C>T were both classified as likely pathogenic (PSV1+PM6), while c1309C>T was identified as pathogenic (PVS1+PS2_Moderate+PM2). Considering clinical features and molecular testimony, the three probands were confirmed diagnosed with MRD7. These three discovered variants were considered as the three causal mutations for MRD7. Prenatal diagnosis detected the heterozygous dominant variant of c.1159C>T p.(Gln387*) in one of the fetuses, indicating a significant probability of MRD7, subsequently the gestation was intervened by the parents’ determination and professional obstetrical operation. On the other side, prenatal molecular genetic testing revealed wild-type alleles in the other two fetuses, and their parents both decided to sustain the gestation.Conclusion: We identified two novel and one rare mutation in DYRK1A which has broadened the spectrum of DYRK1A and provided evidence for the diagnosis of MRD7 at the molecular level. Besides, this study has supported the three families with MRD7 to determine the causative genetic factors efficiently and provide concise genetic counseling for the three families by using Trio-WES technology.

COVID-19 has created significant concern surrounding the impact of pandemic lockdown on mental health. While the pandemic lockdown can be distressing, times of crisis can also provide people with the opportunity to think divergently and explore different activities. Novelty seeking, where individuals explore novel and unfamiliarly stimuli and environments, may enhance the creativity of individuals to solve problems in a way that allows them to adjust their emotional responses to stressful situations. This study employs a longitudinal design to investigate changes in novelty seeking and mental health outcomes (namely, stress, anxiety, and depression) before, during, and after COVID-19 pandemic lockdown, among a group of students (final N = 173; M age = 19.81; SD age = 0.98; 135 females and 38 males) from a university in southeast China. Participants were surveyed at three points: November, 2019 (prior to the COVID-19 pandemic); between February and March, 2020 (during the peak of the pandemic and intense lockdown in China); and between May and June, 2020 (after lockdown had been lifted in China). Cross-sectionally, correlation analysis indicated that greater novelty seeking was associated with lower levels of stress, anxiety, and depression at all three time points. Univariate latent curve modeling (LCM) indicated a growth trajectory in which novelty seeking increased over time and then remained high during the post-lockdown period. Stress, anxiety, and depression all showed V-shaped growth trajectories in which these variables decreased during lockdown, before increasing in the post-lockdown period. Multivariate LCM indicated the growth trajectory for novelty seeking was associated with the growth trajectories for stress, anxiety, and depression. This suggests that the observed decreases in stress, anxiety, and depression during the lockdown period may be attributable to the sample's observed increase in novelty seeking. These findings are valuable in that they challenge the notion that lockdown measures are inherently detrimental to mental health. The findings indicate the important role of novelty seeking in responding to crises. It may be possible for future public health measures to incorporate the promotion of novelty seeking to help individuals' respond to stressful situations and maintain good mental health in the face of crises. [ABSTRACT FROM AUTHOR]

We consider average-cost Markov decision processes (MDPs) with Borel state and action spaces and universally measurable policies. For the nonnegative cost model and an unbounded cost model with a Lyapunov-type stability character, we introduce a set of new conditions under which we prove the average cost optimality inequality (ACOI) via the vanishing discount factor approach. Unlike most existing results on the ACOI, our result does not require any compactness and continuity conditions on the MDPs. Instead, the main idea is to use the almost-uniform-convergence property of a pointwise convergent sequence of measurable functions as asserted in Egoroff's theorem. Our conditions are formulated in order to exploit this property. Among others, we require that for each state, on selected subsets of actions at that state, the state transition stochastic kernel is majorized by finite measures. We combine this majorization property of the transition kernel with Egoroff's theorem to prove the ACOI. [ABSTRACT FROM AUTHOR]

We consider average cost Markov decision processes (MDPs) with Borel state spaces, countable, discrete action spaces, and strictly unbounded one-stage costs. For the minimum pair approach, we introduce a new majorization condition on the state transition stochastic kernel in place of the commonly required continuity conditions on the MDP model. We combine this majorization condition with Lusin's theorem to prove the existence of a stationary minimum pair, i.e., a stationary policy paired with an invariant probability measure induced on the state space, with the property that the pair attains the minimum long-run average cost over all policies and initial distributions. We also establish other optimality properties of a stationary minimum pair, and for the stationary policy in such a pair, under additional recurrence or regularity conditions, we prove its pathwise optimality and strong optimality. Our results can be applied to a class of countable action space MDPs in which the dynamics and one-stage costs are discontinuous with respect to the state variable. [ABSTRACT FROM AUTHOR]

Abstract Background We report a pair of dichorionic diamniotic (DCDA) twin pregnancy affected by Noonan syndrome (NS) with a novel mutation of LZTR1 determined by genetic analysis. Case presentation A pregnant woman with monozygotic twins (DCDA) at 12 + 2 weeks gestation was referred to our center. This was her second pregnancy following a previous delivery of a healthy infant. Nuchal translucency of two fetuses was 11.2 mm (CRL 62.0 mm) and 6.9 mm (CRL 62.1 mm) respectively. Ultrasound examination indicated cystic hygroma and hypoplastic ear. The couple was not consanguineous, and both had normal phenotype. Familial hereditary disease was also excluded. Under ultrasound guidance, 30 mg of chorionic villi was obtained for karyotyping, quantitative fluorescent polymerase chain reaction (QF-PCR), chromosomal microarray analysis(CMA), and Trio-whole-exome sequencing(WES) examination. We used the “target region capture and sequencing” for WES, and the BWA (Burrows Wheeler Aligner) Multi-Vision software package for the data analysis. The results of all these tests were normal except WES detected a c.427 A > G mutation in the exonic region of the LZTR1 gene and a p. Asn143Asp novel heterozygous mutation associated with NS in this pair of twins. In addition, WES suggested that the mutation in the twin fetuses originated from the mother. When the mother got the genetic test report, she came to our fetal medicine department for genetic counseling and she declined the appointment with a clinical geneticist. The couple opted to terminate the pregnancy. Because the patient did not choose to terminate the pregnancy at our hospital, we were unable to take further examination. With the help of colleagues in another hospital, photos of the fetuses were taken. Compared with the prenatal ultrasound results, the appearance of the “cystic hygroma” and “hypoplastic ear” was consistent with the ultrasound. The couple were depressed after knowing this pathogenic result and although we advised the mother to take further investigation, they refused. Conclusion The mutant locus might be incompletely dominant, which led to an abnormal fetal phenotype such as cystic hygroma and hypoplastic ear.

Background and aims: Certain chromosomal structural variations (SVs) in biological parents can lead to recurrent spontaneous abortions (RSAs). Unequal crossing over during meiosis can result in the unbalanced rearrangement of gamete chromosomes such as duplication or deletion. Unfortunately, routine techniques such as karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) cannot detect all types of SVs. In this study, we show that optical genome mapping (OGM) quickly and accurately detects SVs for RSA patients with a high resolution and provides more information about the breakpoint regions at gene level.Methods: Seven couples who had suffered RSA with unbalanced chromosomal rearrangements of aborted embryos were recruited, and ultra-high molecular weight (UHMW) DNA was isolated from their peripheral blood. The consensus genome map was created by de novo assembly on the Bionano Solve data analysis software. SVs and breakpoints were identified via alignments of the reference genome GRCh38/hg38. The exact breakpoint sequences were verified using either Oxford Nanopore sequencing or Sanger sequencing.Results: Various SVs in the recruited couples were successfully detected by OGM. Also, additional complex chromosomal rearrangement (CCRs) and four cryptic balanced reciprocal translocations (BRTs) were revealed, further refining the underlying genetic causes of RSA. Two of the disrupted genes identified in this study, FOXK2 [46,XY,t(7; 17)(q31.3; q25)] and PLXDC2 [46,XX,t(10; 16)(p12.31; q23.1)], had been previously shown to be associated with male fertility and embryo transit.Conclusion: OGM accurately detects chromosomal SVs, especially cryptic BRTs and CCRs. It is a useful complement to routine human genetic diagnostics, such as karyotyping, and detects cryptic BRTs and CCRs more accurately than routine genetic diagnostics.

BackgroundMore than half of the cases of fetal structural anomalies have no known cause with standard investigations like karyotype testing and chromosomal microarray. The differential metabolic profiles of amniotic fluid (AF) and maternal blood may reveal valuable information about the physiological processes of fetal development, which may provide valuable biomarkers for fetal health diagnostics.MethodsThis cohort study of singleton-pregnant women had indications for amniocentesis, including structural anomalies and a positive result from maternal serum screening or non-invasive prenatal testing, but did not have any positive abnormal karyotype or chromosomal microarray analysis results. A total of 1580 participants were enrolled between June 2021 and March 2022. Of the 1580 pregnant women who underwent amniocentesis, 294 were included in the analysis. There were 137 pregnant women in the discovery cohort and 157 in the validation cohort.ResultsHigh-coverage untargeted metabolomic analysis of AF revealed distinct metabolic signatures with 321 of the 602 metabolites measured (53%) (false discovery rate, q < 0.005), among which amino acids predominantly changed in structural anomalies. Targeted metabolomics identified glutamate and glutamine as novel predictive markers for structural anomalies, their vital role was also confirmed in the validation cohort with great predictive ability, and the area under the receiver operating characteristic curves (AUCs) were 0.862 and 0.894 respectively. And AUCs for glutamine/glutamate were 0.913 and 0.903 among the two cohorts.ConclusionsOur results suggested that the aberrant glutamine/glutamate metabolism in AF is associated with nonchromosomal modificantions fetal structural anomalies. Based on our findings, a novel screening method could be established for the nonchromosomal modificantions fetal structural anomalies. And the results also indicate that monitoring fetal metabolic conditions (especially glutamine and glutamine metabolism) may be helpful for antenatal diagnosis and therapy.

To evaluate the performance of expanded non-invasive prenatal testing (expanded noninvasive prenatal testing, NIPT-Plus) in screening for fetal chromosomal abnormalities includes aneuploidies and copy number variations, a total of 23,116 pregnant women with a singleton pregnancy were recruited for NIPT-Plus. Screening positive results were verified by karyotype analysis and chromosomal microarray analysis after amniocentesis. A total of 264 pregnancies (1.14%) were positive results as predicted by NIPT-Plus, including 233 aneuploidies and 31 copy number variations. Following genetic counseling, 233 (88.26%) pregnant women underwent invasive prenatal diagnosis and 136 were verified as true positives, comprising 72 common trisomies (T21, T18, T13), 47 sex chromosomal abnormalities two rare autosomal aneuploidies (RATs) and 15 copy number variations The positive predictive value for common trisomies, SCAs, RATs and CNVs were 68.57%, 68.12%, 6.67% and 51.72%, respectively. Pregnant women with screen-positive results for common trisomies have higher rates of invasive prenatal diagnosis and pregnancy termination than those with positive results for SCAs, RATs, and CNVs. NIPT-Plus showed a good performance in detecting common trisomies, SCAs and also contributed to detecting pathogenic CNVs, but higher accuracy was required in the detection of RATs. In summary, this study provides a reference for the clinical application of NIPT-Plus for screening fetal chromosomal abnormalities in this region. Therefore, we suggest that NIPT-Plus could be widely used in clinical screening for fetal chromosomal abnormalities in combination with prenatal diagnosis and genetic counseling.

Background: Hyperphenylalaninemia (HPA) is the most common inborn error in amino acid metabolism. It can be primarily classified into phenylalanine hydroxylase (PAH) deficiency and tetrahydrobiopterin (BH4) deficiency. BH4 deficiency (BH4D) is caused by genetic defects in enzymes involved in the biosynthesis and regeneration of BH4. 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS), which is encoded by the PTS gene, participates in the biosynthesis of BH4. PTPS deficiency (PTPSD) is the major cause of BH4D. In this study, we investigated that the prevalence of BH4D in Jiangxi province was approximately 12.5 per 1,000,000 live births (69/5,541,627). Furthermore, the frequency of BH4D was estimated to be 28.8% (69/240) in the HPA population of Jiangxi. In this study, we aimed to characterize the mutational spectrum of the PTS gene in patients with PTPSD from Jiangxi province.Method: Newborn screening data of Jiangxi province from 1997 to 2021 were analyzed and 53 families with PTPSD were enrolled for the analysis of the PTS gene variants by Sanger sequencing.Results: 106 variants were identified in 106 alleles of 53 patients with PTPSD, including 13 types of variants reported previously, and two novel variants (c.164-36A>G and c.146_147insTG). The predominant variant was c.259C>T (47.2%), followed by c.84-291A>G (19.8%), c.155A>G (8.5%), c.286G>A (6.6%) and c.379C>T (4.7%).Conclusion: The results of this study can not only provide guidance for the molecular diagnosis and genetic counseling in cases of PTPS deficiency but also enrich the PTS mutation database.

We consider off-policy temporal-difference (TD) learning in discounted Markov decision processes, where the goal is to evaluate a policy in a model-free way by using observations of a state process generated without executing the policy. To curb the high variance issue in off-policy TD learning, we propose a new scheme of setting the Λ-parameters of TD, based on generalized Bellman equations. Our scheme is to set Λ according to the eligibility trace iterates calculated in TD, thereby easily keeping these traces in a desired bounded range. Compared with prior work, this scheme is more direct and flexible, and allows much larger Λ values for off-policy TD learning with bounded traces. As to its soundness, using Markov chain theory, we prove the ergodicity of the joint state-trace process under nonrestrictive conditions, and we show that associated with our scheme is a generalized Bellman equation (for the policy to be evaluated) that depends on both the evolution of Λ and the unique invariant probability measure of the state-trace process. These results not only lead immediately to a characterization of the convergence behavior of least-squares based implementation of our scheme, but also prepare the ground for further analysis of gradient-based implementations. [ABSTRACT FROM AUTHOR]

The poultry red mite Dermanyssus gallinae is an economically important pest in poultry farms worldwide, but an effective treatment option is lacking. The current study determined the effectiveness of six Chinese herbal medicines [Syzygium aromaticum (clove), Hibiscus syriacus (Hibiscus), Illicium verum (star anise), Leonurus artemisia (motherwort), Cinnamomum cassia (cinnamon), and Taraxacum sp. (dandelion)] against D. gallinae. Alcohol extracts were prepared via the solvent extraction method and the phenol, flavonoid, and tannin contents were determined. These active components were highest in S. aromaticum and lowest in H. syriacus, I. verum. No tannin content was detected in L. artemisia. All extracts showed contact toxicity against D. gallinae at a test concentration of 1 g/mL, with S. aromaticum and L. artemisia resulting in 100% mortality. S. aromaticum, L. artemisia, and I. verum showed the best efficacy (LC50 0.159, 0.200, and 0.292 g/mL, respectively). Different combinations of extracts showed an additive effect of I. verum LC90 + L. artemisia LC90. The acaricidal efficacy of this combination was tested against different developmental stages of D. gallinae, being most efficacious against nymphal and larval D. gallinae, with a corrected mortality rate of 100%. However, inhibition of egg hatching was only 53.69%. Taken together, these results highlight I. verum LC90 + L. artemisia LC90 as a promising compound with severe contact toxicity against D. gallinae. Given the wide cultivation of these species and their extensive use in foodstuffs and cosmetics as flavors and fragrances, they could be a cheap, readily available ecofriendly alternative to pesticides currently used in poultry farms.

Background and aims: Hemoglobinopathy associated with the HBB gene, with its two general subtypes as thalassemia and abnormal hemoglobin (Hb) variants, is one of the most prevalent hereditary Hb disorders worldwide. Herein we aimed to elucidate the prevalence of ß-thalassemia and abnormal hemoglobin variants and the prenatal diagnosis of the HBB gene in Jiangxi Province, southern central China.Methods: Hematological indices and capillary Hb electrophoresis were conducted for 136,149 subjects who were admitted to Jiangxi Maternal and Child Health Hospital and requested for hemoglobinopathy investigation. Routine α- and ß-globin genotyping were performed by gap-polymerase chain reaction (Gap-PCR) and reverse dot-blot (RDB) hybridization for the 11,549 individuals suspected to be thalassemia carriers. For participants whose genotypes could not explain their hematological indices, further Sanger sequencing and Gap-PCR were conducted for the detection of rare or novel variants in related globin genes. Prenatal diagnosis was performed for 77 pregnant couples both carrying ß-thalassemia trait at appropriate gestational ages.Results: Among the 11,549 subjects, 2,548 individuals were identified with HBB-associated hemoglobinopathy based on molecular analysis. A total of 2,358 subjects were identified as ß-thalassemia heterozygous carriers and nine cases were diagnosed as compound heterozygous ß-thalassemia. Additionally, 125 cases were detected with composite α- and ß-thalassemia and the remaining 56 individuals with abnormal Hb variants in the HBB. A total of 35 types of variants were identified in the HBB gene, including 26 types of ß-thalassemia and nine types of abnormal Hb variants. Four novel variants were firstly reported, including one variant in HBA2 and three variants in HBB. Overall, 77 prenatal samples underwent ß-thalassemia molecular diagnosis; 20 fetuses were identified with normal ß-thalassemia genotypes, 30 fetuses as ß-thalassemia heterozygotes, 11 as homozygotes, and 16 as compound heterozygotes in HBB.Conclusion: We have demonstrated a relatively high prevalence rate at 1.872% of ß-hemoglobinopathies including common and rare ß-thalassemia as well as abnormal Hb variants among large child-bearing population in the Jiangxi area of southern central China for the first time. Our data presents that prenatal diagnosis is an effective way to prevent and control birth defects of ß-thalassemia.

Plasmonic metal nanostructures have promising applications in biosensing due to their ability to facilitate light–matter interaction. However, the damping of noble metal leads to a wide full width at half maximum (FWHM) spectrum which restricts sensing capabilities. Herein, we present a novel non-full-metal nanostructure sensor, namely indium tin oxide (ITO)–Au nanodisk arrays consisting of periodic arrays of ITO nanodisk arrays and a continuous gold substrate. A narrow-band spectral feature under normal incidence emerges in the visible region, corresponding to the mode-coupling of surface plasmon modes, which are excited by lattice resonance at metal interfaces with magnetic resonance mode. The FWHM of our proposed nanostructure is barely 14 nm, which is one fifth of that of full-metal nanodisk arrays, and effectively improves the sensing performance. Furthermore, the thickness variation of nanodisks hardly affects the sensing performance of this ITO-based nanostructure, ensuring excellent tolerance during preparation. We fabricate the sensor ship using template transfer and vacuum deposition techniques to achieve large-area and low-cost nanostructure preparation. The sensing performance is used to detect immunoglobulin G (IgG) protein molecules, promoting the widespread application of plasmonic nanostructures in label-free biomedical studies and point-of-care diagnostics. The introduction of dielectric materials effectively reduces FWHM, but sacrifices sensitivity. Therefore, utilizing structural configurations or introducing other materials to generate mode-coupling and hybridization is an effective way to provide local field enhancement and effective regulation.

Background and PurposeInfantile neuroaxonal dystrophy (INAD) is a subtype of PLA2G6-Associated Neurodegeneration (PLAN) with an age of early onset and severe clinical phenotypes of neurodegeneration. Individuals affected with INAD are characterized by rapid progressive psychomotor deterioration, neuroregression, and hypotonia followed by generalized spasticity, optic atrophy, and dementia. In this case, we aimed to identify the underlying causative genetic factors of a Chinese family with two siblings who presented with walking difficulty and inability to speak. We provided a prenatal diagnosis for the family and information for the prevention of this genetic disease.MethodsRetrospective clinical information and magnetic resonance imaging (MRI) findings of the proband were collected. Trio-whole exome sequencing (WES) including the proband and his parents was performed to explore the genetic causes, while Sanger sequencing was subsequently used to validate the variants identified by Trio-WES in the pedigree. Furthermore, prenatal molecular genetic diagnosis was carried out through amniocentesis to investigate the status of pathogenic mutations in the fetus by Sanger sequencing at an appropriate gestational age.ResultsThe two siblings were both clinically diagnosed with rapid regression in psychomotor development milestones. Brain MRI showed cerebellar atrophy and typical bilaterally symmetrical T2/FLAIR hyperintense signal changes in periventricular areas, indicating periventricular leukomalacia, and myelin sheath dysplasia. Trio-WES revealed two heterozygous variants in PlA2G6 associated with clinical manifestations in the proband: a novel maternally inherited variant c.217C>T (p.Gln73*) and a previously reported paternally inherited recurrent pathogenic variant c.1894C>T (p.Arg632Trp). These two heterozygous mutations were also detected in the younger brother who had similar clinical features as the proband. The novel variant c.217C>T was classified as “pathogenic (PVS1 + PM2 + PP3),” while the variant c.1894C>T was “pathogenic” (PS1 + PM1 + PM2 + PM3 + PP3) based on the latest American College of Medical Genetics and Genomics (ACMG) guidelines on sequence variants. Combining the molecular evidence and clinical phenotypes, the diagnosis of INAD was established for the two affected siblings. The two variants that were identified were considered the causative mutations for INAD in this family. Prenatal diagnosis suggested compound heterozygous mutations of c.217C>T and c.1894C>T in the fetus, indicating a high risk of INAD, and the parents chose to terminate the pregnancy.ConclusionWe identified a novel pathogenic mutation that broadens the mutation spectrum of PLA2G6 and will provide clues for the molecular diagnosis of INAD. Furthermore, our study has helped to elucidate the causative genetic factors of this Chinese family with INAD effectively and efficiently by using the emerging Trio-WES strategy and providing precise genetic counseling for this family.

Cao Huang Gui Xiang (CHGX) formula, a Chinese herbal medicine, has been empirically used for the treatment of Candida infections. In the present study, we discovered that the CHGX showed potent antifungal activities against the major human fungal pathogen Candida albicans and other clinical Candida species. Besides, we indicated that CHGX had in vivo efficacy on treating C. albicans infection in mice without noticeable toxicity at the clinical therapeutic concentration. We then set out to investigate the antifungal mechanisms of CHGX against C. albicans. We found that CHGX played an important role in inhibiting biofilm formation and filament development, two critical virulence factors of C. albicans. We further demonstrated that CHGX disrupted cell membrane integrity, triggered the accumulation of reactive oxygen species (ROS) and consumption of adenosine triphosphate (ATP), followed by a rapid fungal cell death in C. albicans. Multiple pathways, including the conserved Ras1-cAMP pathway and mitochondrial protein Mcu1 are involved in CHGX-induced cell death. Our finding expands the understanding of antifungal mechanism of CHGX against C. albicans, and provides new insights in treating patients with Candida infections in clinical practice.

A forecast sensitivity to initial perturbation (FSIP) analysis tool for the WRF Model was developed. The tool includes two modules respectively based on the conditional nonlinear optimal perturbation (CNOP) method and the first singular vector (FSV) method. The FSIP tool can be used to identify regions of sensitivity for targeted observation research and important influential weather systems for a given forecast metric. This paper compares the performance of the FSIP tool to its MM5 counterpart, and demonstrates how CNOP, local CNOP (a kind of conditional nonlinear suboptimal perturbation), and FSV were detected using their evolutions of cost function. The column-integrated features of the perturbations were generally similar between the two models. More significant differences were apparent in the details of their vertical distribution. With Typhoon Matsa (2005) in the western North Pacific and a winter storm in the United States (2000) as validation cases, this work examined the tool's capability to identify sensitive regions for targeted observation and to investigate important influential weather systems. The location and pattern of the sensitive areas identified by CNOP, local CNOP, and FSV were quite similar for both the Typhoon Matsa case and the winter storm case. The main differences were mainly in their impact on the growth of forecast difference and the details of their vertical distributions. For both cases, the wind observations might be more important than temperature observations. The results also showed that local CNOP was more capable of capturing the influence of important weather systems on the forecast of total dry energy in the verification area. [ABSTRACT FROM AUTHOR]

Abstract Background TAB2 is an activator of MAP 3 K7/TAK1, which is required for the IL-1 induced signal pathway. Microdeletions encompassing TAB2 have been detected in various patients with congenital heart defects (CHD), indicating that haploinsufficiency of TAB2 causes CHD. To date, seven variants within TAB2 were reported associated with CHD, only two of them are nonsense mutations. Case presentation Here we describe a three-generation Chinese family that included five CHD patients with heart valvular defects, such as mitral or tricuspid valves prolapse or regurgitation, and aortic valve stenosis or regurgitation. Our proband was a pregnant woman presenting with mitral, tricuspid, and aortic defects; her first child experienced sudden cardiac death at the age of 2 years. Whole-exome sequencing of the proband revealed a novel nonsense variant in TAB2 (c.C446G, p.S149X), which results in the elimination of the majority of C-terminal amino acids of TAB2, including the critical TAK1-binding domain. The variant was identified in five affected patients but not in the eight unaffected family members using Sanger sequencing and was classified as “pathogenic” according to the latest recommendation on sequence variants laid out by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Conclusion We described a family with CHD caused by a novel TAB2 nonsense mutation. Our study broadens the mutation spectrum of TAB2; to the best of our knowledge, this is the first report of a pathogenic mutation within TAB2 in a Chinese population.

We consider stochastic optimal control models with Borel spaces and universally measurable policies. For such models the standard policy iteration is known to have difficult measurability issues and cannot be carried out in general. We present a mixed value and policy iteration method that circumvents this difficulty. The method allows the use of stationary policies in computing the optimal cost function in a manner that resembles policy iteration. It can also be used to address similar difficulties of policy iteration in the context of upper and lower semicontinuous models. We analyze the convergence of the method in infinite horizon total cost problems for the discounted case where the one-stage costs are bounded and for the undiscounted case where the one-stage costs are nonpositive or nonnegative. For undiscounted total cost problems with nonnegative one-stage costs, we also give a new convergence theorem for value iteration that shows that value iteration converges whenever it is initialized with a function that is above the optimal cost function and yet bounded by a multiple of the optimal cost function. This condition resembles Whittle's bridging condition and is partly motivated by it. The theorem is also partly motivated by a result of Maitra and Sudderth that showed that value iteration, when initialized with the constant function zero, could require a transfinite number of iterations to converge. We use the new convergence theorem for value iteration to establish the convergence of our mixed value and policy iteration method for the nonnegative cost case. [ABSTRACT FROM AUTHOR]

Tissue kallikrein 1 (TK1) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) are important in inhibiting vascular smooth muscle cell (VSMC) proliferation and improving vascular remodeling, respectively. It was hypothesized that a combination of TK1 and TIMP1 genes, mediated by an adenovirus vector could augment or act in synergy to enhance the inhibitory effects. The promoter, mCMV carrying hTIMP1 cDNA was subcloned into pDC316-hTK1 to construct a recombinant plasmid carrying hTK1 and hTIMP1 genes. Subsequently, the double gene plasmid and adenovirus backbone plasmid were packaged into HEK293A cells. Gene transcription and protein expression were examined, respectively using reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting assays. VSMC proliferation was assessed using cell counting and methyl-thiazolyl-tetrazoliuin methods. The constructed plasmid containing hTK1 and hTIMP1 genes was correctly identified by means of PCR, double digestion and sequencing analysis. The co-expression vector, Ad-hTK1-hTIMP1 was successfully constructed and packaged into HEK293A cells. When VSMCs were transfected with the co-expression vector, the mRNA transcription and protein expression of hTK1 and hTIMP1 exhibited abundant expression in a concentration-dependent and time-dependent manner, independently. In conclusion, the co-expression vector synergistically inhibited the cell growth and proliferation induced by platelet-derived growth factor-BB compared with the single gene vector. [ABSTRACT FROM AUTHOR]

We consider a general class of total cost Markov decision processes (MDP) in which the one-stage costs can have arbitrary signs, but the sum of the negative parts of the one-stage costs is finite for all policies and all initial states. This class, which we refer to as the general convergence (GC) total cost model, contains several important subclasses of problems, e.g., positive costs problems, bounded negative costs problems, and discounted problems with unbounded one-stage costs. We study the convergence of value iteration for the (GC) model, in the Borel MDP framework with universally measurable policies. Our main results include (i) convergence of value iteration when starting from certain functions above the optimal cost function; (ii) convergence of transfinite value iteration starting from zero, as well as convergence of ordinary nontransfinite value iteration for finite control or certain finite state (GC) problems, in the special case where the optimal cost function is nonnegative; and (iii) partial convergence of value iteration starting from zero, for a subset of initial states. These results extend several previously known results about the convergence of value iteration for either positive costs problems or (GC) total cost problems. [ABSTRACT FROM AUTHOR]

Abstract Morphological plasticity has historically been an indicator of increased virulence among fungal pathogens, allowing rapid adaptation to changing environments. Candida auris has been identified as an emerging multidrug-resistant human pathogen of global importance. Since the discovery of this species, it has been thought that C. auris is incapable of filamentous growth. Here, we report the discovery of filamentation and three distinct cell types in C. auris: typical yeast, filamentation-competent (FC) yeast, and filamentous cells. These cell types form a novel phenotypic switching system that contains a heritable (typical yeast-filament) and a nonheritable (FC-filament) switch. Intriguingly, the heritable switch between the typical yeast and the FC/filamentous phenotype is triggered by passage through a mammalian body, whereas the switch between the FC and filamentous phenotype is nonheritable and temperature-dependent. Low temperatures favor the filamentous phenotype, whereas high temperatures promote the FC yeast phenotype. Systemic in vivo and in vitro investigations were used to characterize phenotype-specific variations in global gene expression, secreted aspartyl proteinase (SAP) activity, and changes in virulence, indicating potential for niche-specific adaptations. Taken together, our study not only sheds light on the pathogenesis and biology of C. auris but also provides a novel example of morphological and epigenetic switching in fungi.

We consider the classical finite-state discounted Markovian decision problem, and we introduce a new policy iteration-like algorithm for finding the optimal state costs or Q-factors. The main difference is in the policy evaluation phase: instead of solving a linear system of equations, our algorithm requires solving an optimal stopping problem. The solution of this problem may be inexact, with a finite number of value iterations, in the spirit of modified policy iteration. The stopping problem structure is incorporated into the standard Q-learning algorithm to obtain a new method that is intermediate between policy iteration and Q-learning/value iteration. Thanks to its special contraction properties, our method overcomes some of the traditional convergence difficulties of modified policy iteration and admits asynchronous deterministic and stochastic iterative implementations, with lower overhead and/or more reliable convergence over existing Q-learning schemes. Furthermore, for large-scale problems, where linear basis function approximations and simulation-based temporal difference implementations are used, our algorithm addresses effectively the inherent difficulties of approximate policy iteration due to inadequate exploration of the state and control spaces. [ABSTRACT FROM AUTHOR]

We consider linear fixed point equations and their approximations by projection on a low dimensional subspace. We derive new bounds on the approximation error of the solution, which are expressed in terms of low dimensional matrices and can be computed by simulation. When the fixed point mapping is a contraction, as is typically the case in Markov decision processes (MDP), one of our bounds is always sharper than the standard contraction-based bounds, and another one is often sharper. The former bound is also tight in a worst-case sense. Our bounds also apply to the noncontraction case, including policy evaluation in MDP with nonstandard projections that enhance exploration. There are no error bounds currently available for this case to our knowledge. [ABSTRACT FROM AUTHOR]

We consider the average cost problem for partially observable Markov decision processes (POMDP) with finite state, observation, and control spaces. We prove that there exists an ∈-optimal finite-state controller (FSC) functionally independent of initial distributions for any ∈ > 0, under the assumption that the optimal liminf average cost function of the POMDP is constant. As part of our proof, we establish that if the optimal liminf average cost function is constant, then the optimal limsup average cost function is also constant, and the two are equal. We also discuss the connection between the existence of nearly optimal finite-history controllers and two other important issues for average cost POMDP: the existence of an average cost that is independent of the initial state distribution, and the existence of a bounded solution to the constant average cost optimality equation. [ABSTRACT FROM AUTHOR]

While sexual reproduction is pervasive in eukaryotic cells, the strategies employed by fungal species to achieve and complete sexual cycles is highly diverse and complex. Many fungi, including Saccharomyces cerevisiae and Schizosaccharomyces pombe, are homothallic (able to mate with their own mitotic descendants) because of homothallic switching (HO) endonuclease-mediated mating-type switching. Under laboratory conditions, the human fungal pathogen Candida albicans can undergo both heterothallic and homothallic (opposite- and same-sex) mating. However, both mating modes require the presence of cells with two opposite mating types (MTLa/a and α/α) in close proximity. Given the predominant clonal feature of this yeast in the human host, both opposite- and same-sex mating would be rare in nature. In this study, we report that glucose starvation and oxidative stress, common environmental stresses encountered by the pathogen, induce the development of mating projections and efficiently permit same-sex mating in C. albicans with an "a" mating type (MTLa/a). This induction bypasses the requirement for the presence of cells with an opposite mating type and allows efficient sexual mating between cells derived from a single progenitor. Glucose starvation causes an increase in intracellular oxidative species, overwhelming the Heat Shock transcription Factor 1 (Hsf1)- and Heat shock protein (Hsp)90-mediated stress-response pathway. We further demonstrate that Candida TransActivating protein 4 (Cta4) and Cell Wall Transcription factor 1 (Cwt1), downstream effectors of the Hsf1-Hsp90 pathway, regulate same-sex mating in C. albicans through the transcriptional control of the master regulator of a-type mating, MTLa2, and the pheromone precursor-encoding gene Mating α factor precursor (MFα). Our results suggest that mating could occur much more frequently in nature than was originally appreciated and that same-sex mating could be an important mode of sexual reproduction in C. albicans.