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Background: The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored., Methods: We generated an oligodendrocyte-specific Bace1 knockout model (Bace1 fl/fl ;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1 fl/fl ;Olig2-Cre model with heterozygous App NL-G-F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1 fl/fl ;Olig2-Cre; App NL-G-F/wt ) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background., Results: Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1 fl/fl ;Olig2-Cre and age-matched Bace1 fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1 fl/fl ;Olig2-Cre; App NL-G-F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1 fl/fl ;App NL-G-F/wt ). Insoluble Aβ 1-40 and Aβ 1-42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APP NL-G-F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1., Conclusion: Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies., Competing Interests: Declarations Ethical Approval and Consent to participate All experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Connecticut School of Medicine in compliance with the guidelines established by the Public Health Service Guide for the Care and Use of Laboratory Animals. Consent for publication All authors have read and approved the final manuscript. Competing interests All authors declare no conflict of interests., (© 2024. The Author(s).)

Purpose: Understanding the technical efficiency of health facilities is essential for an optimal allocation of scarce resources to primary health sectors. The COVID-19 pandemic may have further undermined levels of efficiency in low-resource settings. This study takes advantage of 2019 and 2020 data on characteristics of health facilities, health services inputs and output to examine the levels and changes in efficiency of Ghanaian health facilities. The current study by using a panel dataset contributes to existing evidence, which is mostly based on pre-COVID-19 and single-period data., Methods: The analysis is based on a panel dataset including 151 Ghanaian health facilities. Data Envelopement Analysis (DEA) technique was used to estimate the level and changes in efficiency of health facilities across two years.., Results: The results show a net increase of 26% in inputs, influenced mostly by increases in temporary non-clinical staff (131%) and attrition of temporary clinical staff and permanent non-clinical staff, 40% and 54% respectively. There was also a net reduction in output of 34%, driven by a reduction in in-patient days (37%), immunization (11%), outpatients visits and laboratory test of 9%. Nowithstanding the COVID-19 pandemic, the results indicate that 59 (39%) of sampled health facilities in 2020 were efficient, compared to 48 (32%) in 2019. The results also indicate that smaller-sized health facilities were less likely to be efficient compared to relatively bigger health facilities., Conclusion: Based on the findings, it will be essential to examine factors that accounted for efficiency improvements in some health facilities, to enable health facilities lagging behind to learn from those on the efficiency frontier. In addition, the findings emphasise the need for CHAG to work with health facility managers to optimise inputs allocation through a redistribution of staff. Most importantly, the findings are suggestive of the resilience of CHAG health facilities in responding to a health shock such as the COVID-19 pandemic., (© 2024. The Author(s).)

Aims: Scavenger receptor class B type I (SRBI) promotes cell cholesterol efflux and the clearance of plasma cholesterol. Thus, SRBI deficiency causes abnormal cholesterol metabolism and hyperlipidemia. Studies have suggested that ferroptosis is involved in lipotoxicity; however, whether SRBI deficiency could induce ferroptosis remains to be investigated. Results: We knocked down or knocked out SRBI in renal HK-2 cells and C57BL/6 mice to determine the expression levels of ferroptosis-related regulators. Our results demonstrated that SRBI deficiency upregulates transferrin receptor 1 (TFR1) expression and downregulates ferroportin expression, which induces iron overload and subsequent ferroptosis in renal tubular epithelial cells. TFR1 is known to be regulated by hypoxia-inducible factor-1α (HIF-1α). Next, we investigated whether SRBI deletion affected HIF-1α. SRBI deletion upregulated the mRNA and protein expression of HIF-1α, and promoted its translocation to the nucleus. To determine whether HIF-1α plays a key role in SRBI -deficiency-induced ferroptosis, we used HIF-1α inhibitor and siHIF-1α in HK-2 cells, and found that downregulation of HIF-1α prevented SRBI-silencing-induced TFR1 upregulation and iron overload, and eventually reduced ferroptosis. The underlying mechanism of HIF-1α activation was explored next, and the results showed that SRBI knockout or knockdown may upregulate the expression of HIF-1α, and promote HIF-1α translocation from the cytoplasm into the nucleus via the PKC-β/NF-κB signaling pathway. Innovation and Conclusion: Our study showed, for the first time, that SRBI deficiency induces iron overload and subsequent ferroptosis via the HIF-1α/TFR1 pathway.

Alzheimer's Disease (AD) pathogenesis is thought to begin up to 20 years before cognitive symptoms appear, suggesting the need for more sensitive diagnostic biomarkers of AD. In this report, we demonstrated pathological changes in retinal Müller glia significantly earlier than amyloid pathology in AD mouse models. By utilizing the knock-in NLGF mouse model, we surprisingly discovered an increase in reticulon 3 (RTN3) protein levels in the NLGF retina as early as postnatal day 30 (P30). Despite RTN3 being a canonically neuronal protein, this increase was noted in the retinal Müller glia, confirmed by immunohistochemical characterization. Further unbiased transcriptomic assays of the P30 NLGF retina revealed that retinal Müller glia were the most sensitive responding cells in this mouse retina, compared with other cell types including photoreceptor cells and ganglion neurons. Pathway analyses of differentially expressed genes in glia cells showed activation of ER stress response via the upregulation of unfolded protein response (UPR) proteins such as ATF4 and CHOP. Early elevation of RTN3 in response to challenges by toxic Aβ likely facilitated UPR. Altogether, these findings suggest that Müller glia act as a sentinel for AD pathology in the retina and should aid for both intervention and diagnosis., (© 2024 Wiley Periodicals LLC.)

Anecdotal evidence and available literature indicated that contaminated water played a major role in spreading the prolonged cholera epidemic in Malawi from 2022 to 2023. This study assessed drinking water quality in 17 cholera-affected Malawi districts from February to April 2023. Six hundred and thirty-three records were analysed. The median counts/100 ml for thermotolerant coliform was 98 (interquartile range (IQR): 4-100) and that for Escherichia coli was 0 (IQR: 0-9). The drinking water in all (except one) districts was contaminated by thermotolerant coliform, while six districts had their drinking water sources contaminated by E. coli. The percentage of contaminated drinking water sources was significantly higher in shallow unprotected wells (80.0% for E. coli and 95.0% for thermotolerant coliform) and in households (55.8% for E. coli and 86.0% for thermotolerant coliform). Logistic regression showed that household water has three times more risk of being contaminated by E. coli and two and a half times more risk of being contaminated by thermotolerant coliform compared to other water sources. This study demonstrated widespread contamination of drinking water sources during a cholera epidemic in Malawi, which may be the plausible reason for the protracted nature of the epidemic., Competing Interests: The authors declare there is no conflict., (© 2024 The Authors This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY 4.0), which permits copying, adaptation and redistribution, provided the original work is properly cited (http://creativecommons.org/licenses/by/4.0/).)

This study examined the factors influencing vaccine uptake using the Fogg Behavioral Model (FBM) and validated a multi-dimensional index for measuring a key construct in the FBM, motivation, using Confirmatory Factor Analysis (CFA) and Cronbach's alpha. The research was conducted in Yopougon Est, Côte d'Ivoire, and Kinshasa, Democratic Republic of Congo. We aimed to develop a motivation index for COVID-19 vaccination uptake informed by the FBM. The motivation index was developed and refined using interviews and cognitive testing, and then used in baseline and endline surveys to measure the motivation to uptake COVID-19 vaccination among 2173 respondents. The index was simplified to six items validated using Confirmatory Factor Analysis (CFA) and demonstrated strong internal reliability with Cronbach's alphas of 0.89 for the baseline and 0.77 for the endline. The study's findings indicate that this motivation index is a valid tool for measuring motivation to receive COVID-19 vaccination, with potential applications in other vaccination campaigns. However, further testing in diverse settings is needed to enhance generalizability, including in rural areas. This research provides valuable insights for designing effective behavior change interventions to increase COVID-19 vaccination rates.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26 Tdtomato and Tff1-CreERT2; Apc fl/fl ; p53 fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Alzheimer's disease (AD) increases the risk for seizures and sleep disorders. We show here that germline deletion of β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) in neurons, but not in astrocytes, increased epileptiform activity. However, Bace1 deletion at adult ages did not alter the normal EEG waveform, indicating less concern for BACE1 inhibition in patients. Moreover, we showed that deletion of Bace1 in the adult was able to reverse epileptiform activity in 5xFAD mice. Intriguingly, treating 5xFAD and APP NL-G-F/NL-G-F (APP KI) mice of either sex with one BACE1 inhibitor Lanabecestat (AZD3293) dramatically increased epileptiform spiking, likely resulting from an off-target effect. We also monitored sleep-wake pathologies in these mice and showed increased wakefulness, decreased non-rapid eye movement sleep, and rapid eye movement sleep in both 5xFAD and APP KI mice; BACE1 inhibition in the adult 5xFAD mice reversed plaque load and sleep disturbances, but this was not seen in APP KI mice. Further studies with and without BACE1 inhibitor treatment showed different levels of plaque-associated microgliosis and activated microglial proteins in 5xFAD mice compared with APP KI mice. Together, BACE1 inhibition should be developed to avoid off-target effect for achieving benefits in reducing epileptic activity and sleep disturbance in Alzheimer's patients. SIGNIFICANCE STATEMENT BACE1 is widely recognized as a therapeutic target for treating Alzheimer's disease patients. However, BACE1 inhibitors failed in clinical trials because of inability to show cognitive improvement in patients. Here we show that BACE1 inhibition actually reduces sleep disturbances and epileptic seizures; both are seen in AD patients. We further showed that one of clinically tested BACE1 inhibitors does have off-target effects, and development of safer BACE1 inhibitors will be beneficial to AD patients. Results from this study will provide useful guidance for additional drug development., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Yao et al.)

Boosting trophic support to striatal neurons by increasing levels of brain-derived neurotrophic factor (BDNF) has been considered as a target for therapeutic intervention for several neurodegenerative diseases, including Huntington's disease (HD). To aid in the implementation of such a strategy, a thorough understanding of BDNF cortical-striatal transport is critical to help guide its strategic delivery. In this manuscript, we investigate the dynamic behavior of BDNF transport along the cortical-striatal axis in Q140 primary neurons, a mouse model for HD. We examine this by using single-molecule labeling of BDNF conjugated with quantum dots (QD-BDNF) to follow the transport along the cortical-striatal axis in a microfluidic chamber system specifically designed for the co-culture of cortical and striatal primary neurons. Using this approach, we observe a defect of QD-BDNF transport in Q140 neurons. Our study demonstrates that QD-BDNF transport along the cortical-striatal axis involves the impairment of anterograde transport within axons of cortical neurons, and of retrograde transport within dendrites of striatal neurons. One prominent feature we observe is the extended pause time of QD-BDNF retrograde transport within Q140 striatal dendrites. Taken together, these finding support the hypothesis that delinquent spatiotemporal trophic support of BDNF to striatal neurons, driven by impaired transport, may contribute to the pathogenesis of HD, providing us with insight into how a BDNF supplementation therapeutic strategy may best be applied for HD.

Poor sleep is a long-term public health issue that has become increasingly prevalent among socially isolated older adults. However, research on the mechanisms explaining the link between social isolation and impaired sleep (IS) remains limited, particularly in low- and middle-income countries. This study explored the serial mediating effects of loneliness and mental distress on the association of social isolation with IS among Ghanaian older adults. We analyzed data from 1201 adults aged ≥ 50 from Ghana's AgeHeaPsyWel-HeaSeeB study (mean age = 66.14, SD = 11.85, age range = 50-111; women = 63.28%). Measures included the UCLA 3-item Loneliness Scale, modified Berkman-Syme Social Network Index, Sleep Quality Scale, and Mental Distress Questionnaire. We used bootstrapping techniques from Hayes' PROCESS macro program to estimate the hypothesized serial mediation. Social isolation was significantly associated with IS (β = 0.242, p < 0.001). Crucially, social isolation indirectly predicted IS via three significant mediating pathways. Loneliness accounted for 17.6% (β = 0.054, CI = 0.096, 0.016), mental distress accounted for 6.5% (β = 0.020, 95% CI = 0.004, 0.040), and loneliness and mental distress accounted for 32.2% (β = 0.099, 95% CI = 0.065, 0.138) of the overall effect. The total mediating effect was 56.4%. These findings suggest that the social isolation-sleep link is respectively and serially explained by loneliness and mental distress. Social integrative interventions for sleep quality in old age should target mental and emotional well-being., (© 2022. The Author(s).)

This study applied the Fogg Behavioral Model (FBM) to identify and prioritize factors influencing COVID-19 vaccination among residents of Yopougon Est, Abidjan, Côte d'Ivoire. A total of 568 respondents were recruited from among individuals entering eleven participant recruitment and data collection sites located near high pedestrian trafficked areas. Among all respondents, 52% reported being vaccinated versus 48% who reported not being vaccinated. Of those who reported being vaccinated, 42% reported received a single dose, 54% a double dose, and 4% three or more doses. A categorical regression analysis suggested that potential predictors of COVID-19 vaccination included acceptance and rejection factors, which are both aligned with motivation in the FBM and socio-demographic characteristics, proximity to services, and religion. Our findings suggest that demand creation activities should target individuals with less formal education, those who are not formally employed, non-Catholic Christians, and individuals who do not identify as Akan. Results also suggest the need to design programmatic messages and activities that focus on generating family and community support for COVID-19 vaccination.

Introduction: Inadequate, inefficient and slow processing of claims are major contributors to the cost of health insurance schemes, and therefore undermining their sustainability. This study uses the Technology, Organisation and Environment (TOE) framework to examine the preparedness of health facilities of the Christian Health Association of Ghana (CHAG) to implement a digital mobile health insurance claims processing software (CLAIM-it), which aims to increase efficiency., Methods: The study used a cross-sectional mixed method design to collect data (technology and human capital capacity and baseline operational performance of claims management) from a sample of 20 CHAG health facilities across Ghana. While quantitative data was analysed using simple descriptive statistics statistics (frequencies, mean, minimum and maximum values), qualitative interviews were recorded, transcribed and abstracted into two major themes that were reported to re-enforce the quantitative findings., Results: The quantitative results revealed challenges including inadequate computers and accessories, adequate numbers and skills for claims processing, poor intranets and internet access, absence of a robust post-implementation support system and inadequate standard operating procedures (SOPs) for seamless automation of claims processing. In addition to the above, the qualitative results emphasised the need to make CLAIM-it more flexible and capable of being integrated into third-party softwares. Notwithstanding the challenges, decision-makers in CHAG health facilities see the CLAIM-it software as having better functionality and superior capabilities compared to existing claims processing systems in Ghana., Conclusion: Notwithstanding the challenges, the CLAIM-it software is more likely to be adopted by decision-makers, given the positive perception in terms of superior functionality. It is important that key actors in claims management at the National Health Insurance collaborate with relevant stakeholders to adopt the CLAIM-it software for claims processing and management in Ghana., Competing Interests: The authors have declared that no competing interests exist.

Rollout of meningococcal serogroup A conjugate vaccine in Africa started in 2010, aiming to eliminate meningitis outbreaks, in meningitis belt countries. Since then, studies have been conducted, primarily using isolates, to assess the vaccine impact on the distribution of meningococcal strains in the region. Here, we implemented an innovative, culture-free whole-genome sequencing approach on almost 400 clinical specimens collected between 2017 and 2019 from meningococcal meningitis cases in 6 African countries. About 50% of specimens provided high-quality whole-genome sequence data for comprehensive molecular profiling of the meningococcal pathogen. Three major clonal complexes were identified: CC11 associated with serogroup W, CC181 associated with serogroup X, and CC10217 associated with serogroup C, which continues to rise as a predominant clonal complex in the region. Genomic surveillance for meningococcal meningitis can be significantly improved using culture-free methods to increase data representativeness and monitor changes in epidemiological landscape, especially for countries with low culture rate., (Published by Oxford University Press for the Infectious Diseases Society of America 2022.)

Togo has reported seasonal meningitis outbreaks caused by non-Neisseria meningitidis serogroup A (NmA) pathogens since the introduction of meningococcal serogroup A conjugate vaccine (MACV, MenAfriVac) in 2014. From 2016 to 2017, NmW caused several outbreaks. In early 2019, a NmC outbreak was detected in the Savanes region of Togo and its investigation is described here. Under case-based surveillance, epidemiological and clinical data, and cerebrospinal fluid specimens were collected for every suspected case of meningitis. Specimens were tested for meningitis pathogens using confirmatory microbiological and molecular methods. During epidemic weeks 9 to 15, 199 cases were reported, with 179 specimens being available for testing and 174 specimens (97.2%) were tested by at least one confirmatory method. The NmC was the predominant pathogen confirmed (93.9%), belonging to sequence type (ST)-9367 of clonal complex (CC) 10217. All NmC cases were localized to the West Kpendjal district of the Savanes region with attack rates ranging from 4.1 to 18.8 per 100,000 population and case fatality rates ranging up to 2.2% during weeks 9 to 15. Of the 93 NmC confirmed cases, 63.4% were males and 88.2% were in the 5 to 29 age group. This is the first report of a NmC meningitis outbreak in Togo. The changing epidemiology of bacterial meningitis in the meningitis belt post-MACV highlights the importance of monitoring of emerging strain and country preparedness for outbreaks in the region. IMPORTANCE The recent emergence of an invasive NmC strain in Togo is an example of the changing bacterial meningitis epidemiology in the meningitis belt post-MACV. The current epidemiology includes the regional circulation of various non-NmA serogroups, which emphasizes the need for effective molecular surveillance, laboratory diagnosis, and a multivalent vaccine that is effective against all serogroups in circulation.

BACE1 initiates production of β-amyloid peptides (Aβ), which is associated with cognitive dysfunction in Alzheimer's disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in Aβ deposition, they fail to improve cognitive function in patients, largely due to its role in synaptic function. We show that BACE1 is required for optimal release of synaptic vesicles. BACE1 deficiency or inhibition decreases synaptic vesicle docking in the synaptic active zones. Consistently, BACE1-null mice or mice treated with clinically tested BACE1 inhibitors Verubecestat and Lanabecestat exhibit severe reduction in hippocampal LTP and learning behaviors. To counterbalance this synaptic deficit, we discovered that BACE1-null mice treated with positive allosteric modulators (PAMs) of metabotropic glutamate receptor 1 (mGluR1), whose levels were reduced in BACE1-null mice and significantly improved long-term potentiation and cognitive behaviors. Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients., (© 2021. The Author(s).)

Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis worldwide and an occasional cause of meningococcal urethritis. When isolates are unavailable for surveillance or outbreak investigations, molecular characterization of pathogens needs to be performed directly from clinical specimens, such as cerebrospinal fluid (CSF), blood, or urine. However, genome sequencing of specimens is challenging because of low bacterial and high human DNA abundances. We developed selective whole-genome amplification (SWGA), an isothermal multiple-displacement amplification-based method, to efficiently enrich, sequence, and de novo assemble N. meningitidis DNA from clinical specimens with low bacterial loads. SWGA was validated with 12 CSF specimens from invasive meningococcal disease cases and 12 urine specimens from meningococcal urethritis cases. SWGA increased the mean proportion of N. meningitidis reads by 2 to 3 orders of magnitude, enabling identification of at least 90% of the 1,605 N. meningitidis core genome loci for 50% of the specimens. The validated method was used to investigate two meningitis outbreaks recently reported in Togo and Burkina Faso. Twenty-seven specimens with low bacterial loads were processed by SWGA before sequencing, and 12 of 27 were successfully assembled to obtain the full molecular typing and vaccine antigen profile of the N. meningitidis pathogen, thus enabling thorough characterization of outbreaks. This method is particularly important for enhancing molecular surveillance in regions with low culture rates. SWGA produces enough reads for phylogenetic and allelic analysis at a low cost. More importantly, the procedure can be extended to enrich other important human bacterial pathogens.

The activity of γ-secretase is critical to the pathogenesis of Alzheimer's disease (AD). How its activity is regulated is intriguing and highly important for any AD therapy that focuses on reduction of toxic amyloid peptides and amyloid deposition in patients. Recently, interferon-induced transmembrane protein 3 (IFITM3) has been identified as a novel regulator of γ-secretase through a specific interaction. This commentary highlights this exciting study and provides an updated link of γ-secretase activity to innate immunity through IFITM3.

Background: The quality discrimination of dairy products is an important basis on which to achieve quality assurance., Objective: Taking the discriminant analysis of brand yogurt products as an example, a new rapid discriminant method can be constructed., Method: The first three principal components were selected as the pattern vectors of the samples. Then, at random, 75% of the samples were collected as a training set, and their mean values and covariance matrices were calculated to construct a Gauss Bayesian discriminant model. The remaining 25% of samples were employed as a test set, and the pattern vectors of each sample were input into the above model. Next, the posterior probability of each sample in relation to each category could be obtained. Results: The category corresponding to the maximum posterior probability as the brand classification of each sample was defined., Conclusions: We constructed a Gauss Bayesian discriminant model to discriminate these different yogurt products after the principal component feature extraction of Raman properties. The results indicate the rationality and wide application prospects of this approach., Highlights: A fast dairy product discriminant method based on Gauss Bayesian model and Raman spectroscopy was established., (© AOAC INTERNATIONAL 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Worldwide, hepatocellular carcinoma (HCC) remains a crucial medical problem. Precise and concise prognostic models are urgently needed because of the intricate gene variations among liver cancer cells. We conducted this study to identify a prognostic gene signature with biological significance. We applied two algorithms to generate differentially expressed genes (DEGs) between HCC and normal specimens in The Cancer Genome Atlas cohort (training set included) and performed enrichment analyses to expound on their biological significance. A protein-protein interactions network was established based on the STRING online tool. We then used Cytoscape to screen hub genes in crucial modules. A multigene signature was constructed by Cox regression analysis of hub genes to stratify the prognoses of HCC patients in the training set. The prognostic value of the multigene signature was externally validated in two other sets from Gene Expression Omnibus (GSE14520 and GSE76427), and its role in recurrence prediction was also investigated. A total of 2000 DEGs were obtained, including 1542 upregulated genes and 458 downregulated genes. Subsequently, we constructed a 14-gene signature on the basis of 56 hub genes, which was a good predictor of overall survival. The prognostic signature could be replicated in GSE14520 and GSE76427. Moreover, the 14-gene signature could be applied for recurrence prediction in the training set and GSE14520. In summary, the 14-gene signature extracted from hub genes was involved in some of the HCC-related signalling pathways; it not only served as a predictive signature for HCC outcome but could also be used to predict HCC recurrence., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition 1-5 . TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders 6-9 . However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN-thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles. The impaired synaptic plasticity and dendritic loss at the synaptic level is an early event associated with the AD pathogenesis. The abnormal accumulation of soluble oligomeric amyloid-β (Aβ), the major toxic component in amyloid plaques, is viewed to trigger synaptic dysfunctions through binding to several presynaptic and postsynaptic partners and thus to disrupt synaptic transmission. Over time, the abnormalities in neural transmission will result in cognitive deficits, which are commonly manifested as memory loss in AD patients. Synaptic plasticity is regulated through glutamate transmission, which is mediated by various glutamate receptors. Here we review recent progresses in the study of metabotropic glutamate receptors (mGluRs) in AD cognition. We will discuss the role of mGluRs in synaptic plasticity and their modulation as a possible strategy for AD cognitive improvement.

Background: Botulinum toxin has been widely accepted as safe and effective for the treatment of glabellar lines, and previous studies have classified glabellar contraction patterns into 5 categories., Objective: To classify the glabellar contraction patterns among a large-scale Chinese population and provide a reference for injections in Chinese patients., Methods: Four hundred eighty-nine Chinese subjects who received botulinum toxin for the treatment of glabellar lines were selected for a retrospective photographic analysis of their glabellar contraction patterns. Using 2 separate previously established classification systems, the patterns were analyzed and classified by a panel of certified Chinese dermatologists., Results: Two separate classification systems showed different distributions of glabellar contraction patterns among Chinese compared with Caucasians and Koreans. The classifications allowed for identification of the most frequent patterns in Chinese, which were "converging arrows" and "11" pattern, and provided references for identifying the most important muscles., Conclusion: Both classification systems are applicable to the Chinese population with varying distributions. Because the classification system of de Almeida and colleagues focuses more on the muscles involved in the formation of glabellar lines, the authors' subjects classified according to this system displayed a more balanced distribution among the 5 patterns. This provides an easier reference for dermatologists in daily clinical practice and guiding treatment strategies.

Background: The MenAfriNet consortium was established in 2014 to support implementation of case-based meningitis surveillance in 5 countries in the meningitis belt of sub-Saharan Africa: Burkina Faso, Chad, Mali, Niger, and Togo. Assessing surveillance performance is critical for interpretation of the collected data and implementation of future surveillance-strengthening initiatives., Methods: Detailed epidemiologic and laboratory data were collected on suspected meningitis cases through case-based meningitis surveillance in participating districts in 5 countries. Performance of case-based surveillance was evaluated through sensitivity of case ascertainment in case-based versus aggregate meningitis surveillance and an analysis of surveillance indicators., Results: From 2015 to 2017, 18 262 suspected meningitis cases were identified through case-based surveillance and 16 262 were identified through aggregate surveillance, for a case ascertainment sensitivity of 112.3%. Among suspected cases, 16 885 (92.5%) had a cerebrospinal fluid (CSF) specimen collected, 13 625 (80.7%) of which were received at a national reference laboratory. Among these, 13 439 (98.6%) underwent confirmatory testing, and, of those tested, 4371 (32.5%) were confirmed for a bacterial pathogen., Conclusions: Overall strong performance for case ascertainment, CSF collection, and laboratory confirmation provide evidence for the quality of MenAfriNet case-based surveillance in evaluating epidemiologic trends and informing future vaccination strategies., (Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The MenAfriNet Consortium supports strategic implementation of case-based meningitis surveillance in key high-risk countries of the African meningitis belt: Burkina Faso, Chad, Mali, Niger, and Togo. We describe bacterial meningitis epidemiology in these 5 countries in 2015-2017., Methods: Case-based meningitis surveillance collects case-level demographic and clinical information and cerebrospinal fluid (CSF) laboratory results. Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae cases were confirmed and N. meningitidis/H. influenzae were serogrouped/serotyped by real-time polymerase chain reaction, culture, or latex agglutination. We calculated annual incidence in participating districts in each country in cases/100 000 population., Results: From 2015-2017, 18 262 suspected meningitis cases were reported; 92% had a CSF specimen available, of which 26% were confirmed as N. meningitidis (n = 2433; 56%), S. pneumoniae (n = 1758; 40%), or H. influenzae (n = 180; 4%). Average annual incidences for N. meningitidis, S. pneumoniae, and H. influenzae, respectively, were 7.5, 2.5, and 0.3. N. meningitidis incidence was 1.5 in Burkina Faso, 2.7 in Chad, 0.4 in Mali, 14.7 in Niger, and 12.5 in Togo. Several outbreaks occurred: NmC in Niger in 2015-2017, NmC in Mali in 2016, and NmW in Togo in 2016-2017. Of N. meningitidis cases, 53% were NmC, 30% NmW, and 13% NmX. Five NmA cases were reported (Burkina Faso, 2015). NmX increased from 0.6% of N. meningitidis cases in 2015 to 27% in 2017., Conclusions: Although bacterial meningitis epidemiology varied widely by country, NmC and NmW caused several outbreaks, NmX increased although was not associated with outbreaks, and overall NmA incidence remained low. An effective low-cost multivalent meningococcal conjugate vaccine could help further control meningococcal meningitis in the region., (Published by Oxford University Press for the Infectious Diseases Society of America 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: During 2014, 4 regions in Togo within the African meningitis belt implemented vaccination campaigns with meningococcal serogroup A conjugate vaccine (MACV). From January to July 2016, Togo experienced its first major Neisseria meningitidis serogroup W (NmW) outbreak. We describe the epidemiology, response, and management of the outbreak., Methods: Suspected, probable, and confirmed cases were identified using World Health Organization case definitions. Through case-based surveillance, epidemiologic and laboratory data were collected for each case. Cerebrospinal fluid specimens were analyzed by polymerase chain reaction, culture, or latex agglutination. Vaccination campaigns were conducted in affected districts., Results: From January 11 to July 5, 2016, 1995 suspected meningitis cases were reported, with 128 deaths. Among them, 479 (24.0%) were confirmed by laboratory testing, and 94 (4.7%) and 1422 (71.3%) remained as probable and suspected cases, respectively. Seven epidemic districts had cumulative attack rates greater than 100 per 100 000 population. Of the confirmed cases, 91.5% were NmW; 39 of 40 available NmW isolates were sequence type-11/clonal complex-11., Conclusions: This outbreak demonstrates that, although high coverage with MACV has reduced serogroup A outbreaks, large meningococcal meningitis outbreaks due to other serogroups may continue to occur; effective multivalent meningococcal conjugate vaccines could improve meningococcal disease prevention within meningitis belt populations., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Qnr genes are known to confer a low-level resistance to fluoroquinolone in Enterobacteriaceae . They are often found on the same resistance plasmids as extended spectrum β-lactamase (ESBL) and constitute the most common antibiotic resistance mechanism. This study aimed to detect the presence of qn r genes in ESBL -producing E. coli and Klebsiella spp ., Methods: From May 2013 to July 2015, 91 E. coli and 64 Klebsiella spp. strains with phenotypic resistance to quinolone were collected from several specimens and analyzed for the detection of qnrA, qnrB, qnrS genes and the β-lactamase resistance genes ( blaCTX-M , blaTEM , blaSHV ) using simplex and multiplex PCR., Results: In the present study, 107 (69%; 61 E. coli and 46 Klebsiella spp. ) of 155 bacterial strains tested were found harboring at least one qnr gene consisting of 74 (47.74%) qnrB , 73 (47.10%) qnrS and 4 (2.58%) qnrA . Of the 107 strains encoding qnr genes, 102, 96 and 52 carried CTX-M1 , TEM and SHV type ESBL respectively., Conclusion: This study identified quinolone resistance ( qnr ) gene in ESBL -producing E. coli and Klebsiella spp. in Togo. These finding which suggest a possible resistance to quinolone are of high interest for better management of patients and control of antimicrobial resistance in Togo., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: The countries of West Africa are largely portrayed as cholera endemic, although the dynamics of outbreaks in this region of Africa remain largely unclear., Methodology/principal Findings: To understand the dynamics of cholera in a major portion of West Africa, we analyzed cholera epidemics from 2009 to 2015 from Benin to Mauritania. We conducted a series of field visits as well as multilocus variable tandem repeat analysis and whole-genome sequencing analysis of V. cholerae isolates throughout the study region. During this period, Ghana accounted for 52% of the reported cases in the entire study region (coastal countries from Benin to Mauritania). From 2009 to 2015, we found that one major wave of cholera outbreaks spread from Accra in 2011 northwestward to Sierra Leone and Guinea in 2012. Molecular epidemiology analysis confirmed that the 2011 Ghanaian isolates were related to those that seeded the 2012 epidemics in Guinea and Sierra Leone. Interestingly, we found that many countries deemed "cholera endemic" actually suffered very few outbreaks, with multi-year lulls., Conclusions/significance: This study provides the first cohesive vision of the dynamics of cholera epidemics in a major portion of West Africa. This epidemiological overview shows that from 2009 to 2015, at least 54% of reported cases concerned populations living in the three urban areas of Accra, Freetown, and Conakry. These findings may serve as a guide to better target cholera prevention and control efforts in the identified cholera hotspots in West Africa.

The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and Shank3 mutant mice show repetitive grooming and social interaction deficits. Although basal ganglia dysfunction has been proposed to underlie repetitive behaviors, few studies have provided direct evidence to support this notion and the exact cellular mechanisms remain largely unknown. Here, we utilized the Shank3B mutant mouse model of autism to investigate how Shank3 mutation may differentially affect striatonigral (direct pathway) and striatopallidal (indirect pathway) medium spiny neurons (MSNs) and its relevance to repetitive grooming behavior in Shank3B mutant mice. We found that Shank3 deletion preferentially affects synapses onto striatopallidal MSNs. Striatopallidal MSNs showed profound defects, including alterations in synaptic transmission, synaptic plasticity, and spine density. Importantly, the repetitive grooming behavior was rescued by selectively enhancing the striatopallidal MSN activity via a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD). Our findings directly demonstrate the existence of distinct changes between 2 striatal pathways in a mouse model of autism and indicate that the indirect striatal pathway disruption might play a causative role in repetitive behavior of Shank3B mutant mice.

Background: There is some evidence to suggest that within the household, family and community settings, women in sub-Saharan Africa often have limited autonomy and control over their reproductive health decisions. However, there are few studies that examine how intra-familial decision-making power may affect women's ability to access and use maternal health services. The purpose of this paper is to examine how intra-familial decision-making affects women's ability to access and use maternal health services., Methods: We conducted 12 focus group discussions and 81 individual interviews with a total of 185 expectant and lactating mothers in six communities in Ghana. In addition, 20 key informant interviews were completed with healthcare providers. Attride-Stirling's thematic network analysis framework was used to analyse the data., Results: Findings suggest that decision-making regarding access to and use of skilled maternal healthcare services is strongly influenced by the values and opinions of husbands, mothers-in-law, traditional birth attendants and other family and community members, more than those of individual childbearing women. In 49.2%, 16.2%, and 12.4% of cases in which women said they were unable to access maternal health services during their last pregnancy, husbands, mothers-in-law, and husband plus mothers-in-law, respectively, made the decision. Women themselves were the final decision-makers in only 2.7% of the cases. The findings highlight how the goal of improving access to maternal healthcare services can be undermined by women's lack of decision-making autonomy through complex processes of gender inequality, economic marginalisation, communal decision-making and social power., Conclusion: Interventions to improve women's use of maternity services should move beyond individual women to target different stakeholders at multiple levels, including husbands and mothers-in-law.

Background: Since cholera appeared in Africa during the 1970s, cases have been reported on the continent every year. In Sub-Saharan Africa, cholera outbreaks primarily cluster at certain hotspots including the African Great Lakes Region and West Africa., Methodology/principal Findings: In this study, we applied MLVA (Multi-Locus Variable Number Tandem Repeat Analysis) typing of 337 Vibrio cholerae isolates from recent cholera epidemics in the Democratic Republic of the Congo (DRC), Zambia, Guinea and Togo. We aimed to assess the relationship between outbreaks. Applying this method, we identified 89 unique MLVA haplotypes across our isolate collection. MLVA typing revealed the short-term divergence and microevolution of these Vibrio cholerae populations to provide insight into the dynamics of cholera outbreaks in each country. Our analyses also revealed strong geographical clustering. Isolates from the African Great Lakes Region (DRC and Zambia) formed a closely related group, while West African isolates (Togo and Guinea) constituted a separate cluster. At a country-level scale our analyses revealed several distinct MLVA groups, most notably DRC 2011/2012, DRC 2009, Zambia 2012 and Guinea 2012. We also found that certain MLVA types collected in the DRC persisted in the country for several years, occasionally giving rise to expansive epidemics. Finally, we found that the six environmental isolates in our panel were unrelated to the epidemic isolates., Conclusions/significance: To effectively combat the disease, it is critical to understand the mechanisms of cholera emergence and diffusion in a region-specific manner. Overall, these findings demonstrate the relationship between distinct epidemics in West Africa and the African Great Lakes Region. This study also highlights the importance of monitoring and analyzing Vibrio cholerae isolates.

Despite the recognition for rising consumption rate of traditional medicine (TRM) in health and spatio-medical literature in the global scale, the impact of location in traditional therapy use has been explored least in Ghana. This paper analysed the role of spatial variation in TRM use in Kumasi Metropolis and Sekyere South District of Ashanti Region, Ghana. A retrospective cross-sectional and place-based survey was conducted in a representative sample (N=324) selected through systematic random sampling technique. Structured interviewer-administered questionnaires were espoused as the main research instruments. Data were analysed with Pearson's Chi-square and Fisher's exact tests from the Predictive Analytics Software (PASW) version 17.0. The study found that over 86% reported TRM use. Whilst majority (59.1%) of the respondents had used TRM two or more times within the last 12 months, biologically-based therapies and energy healing were common forms of TRM accessed. Although, the use of TRM did not vary (p>0.05), knowledge about TRM, modalities of TRM and the sources of TRM differed significantly across geographically demarcated rural and urban splits (p<0.005). The study advances our understanding of the spatial dimensions as regards TRM utilisation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 μg ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50) < 0.05 μg ml(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 μg ml(-1) of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.

Unlabelled: The widely used immunosuppressant cyclosporin A, a potent calcineurin inhibitor, significantly increases the incidence of cancer in organ transplant patients. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis, in contrast to the effect observed after long-term cyclosporin A treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of cyclosporin A on tumor angiogenesis have not been investigated. Using an in vivo model of skin carcinogenesis, prolonged treatment with cyclosporin A promoted tumor growth and angiogenesis. The addition of cyclosporin A to endothelial cells in vitro increased proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species (ROS). Co-treatment with antioxidants significantly abrogated cyclosporin A-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against cyclosporin A-mediated tumor progression. Taken together, these findings suggest that cyclosporin A affects endothelial cells in a calcineurin-independent manner to potentiate tumor growth by promoting tumor angiogenesis through increasing mitochondrial ROS production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of cyclosporin A and suggests that co-treatment with antioxidants would inhibit the tumor-promoting effects of cyclosporin A., Implications: Targeting the proangiogenic effects of cyclosporin A may be useful in the management of transplant-associated cancers., (©2014 American Association for Cancer Research.)

Recent advances in cancer immunotherapy suggest that manipulation of the immune system to enhance the antitumor response may be a highly effective treatment modality. One understudied aspect of immunosurveillance is antiangiogenic surveillance, the regulation of tumor angiogenesis by the immune system, independent of tumor cell lysis. CD4(+) T cells can negatively regulate angiogenesis by secreting antiangiogenic factors such as thrombospondin-1 (TSP-1). In tumor-bearing mice, we show that a Th1-directed viral infection that triggers upregulation of TSP-1 in CD4(+) and CD8(+) T cells can inhibit tumor angiogenesis and suppress tumor growth. Using bone marrow chimeras and adoptive T-cell transfers, we demonstrated that TSP-1 expression in the T-cell compartment was necessary and sufficient to inhibit tumor growth by suppressing tumor angiogenesis after the viral infection. Our results establish that tumorigenesis can be stanched by antiangiogenic surveillance triggered by an acute viral infection, suggesting novel immunologic approaches to achieve antiangiogenic therapy., (©2014 AACR.)

Objective: To study the expressions of gastric mucosal proteins in chronic gastritis (CG) rats of Pi-Wei damp-heat syndrome (PWDHS), to investigate the pathogenesis correlated to CG rats of PWDHS, to observe the differential expressions of gastric mucosal proteins in CG rats of PWDHS, and to investigate the mechanisms of Sanren Decoction (SD) for treating CG rats of PWDHS., Methods: Totally 36 male SD rats were adaptable fed for 3 days and randomly divided into 3 groups, i.e., the normal control group, the CG of PWDHS rat model group (abbreviated as the model group), and the SD treatment group, 12 in each group. The CG of PWDHS rat model was prepared by composite factors. The gastric mucosal protein was separated using two-dimensional gel electrophoresis technique, and stained by Coomassie brilliant blue. The protein spots expressed differently were analyzed by PDquest 8.0 software. The protein spots expressed differently was identified by MALDI-TOF/TOF-MS., Results: The protein spots were 1 025 +/- 3 9, 994 +/- 51, 1 087 +/- 33 in the normal control group, the model group, and the SD treatment group respectively detected from two-dimensional gel electrophoresis profiles. Compared with the normal control group, there were 74 protein spots differentially expressed in the model group, 30 spots up-regulated and 44 spots down-regulated. Compared with the model group, there were 75 protein spots differentially expressed in the SD treatment group, 49 spots up-regulated and 26 spots down-regulated. Five protein spots differentially expressed were successfully identified, i.e., heat shock protein 72 (HSP72), heat shock protein 60 (HSP60), protein disulfide-isomerase (PDI), malate dehydrogenase (MDH), and unnamed protein., Conclusions: The pathogenesis of CG of PWDHS may be correlated to energy metabolism disturbance and stress. The mechanisms of SD for treating it may possibly adjust differential expressions of gastric mucosal proteins.

Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes., Competing Interests: The authors have declared that no competing interests exist.

Lactic acid bacteria strains Lactobacillus plantarum CWBI-B534 and Leuconostoc ssp. mesenteroïdes (L. mesenteroïdes) Kenya MRog2 were produced in bioreactor, concentrated, with or without cryoprotectants. In general, viable population did not change significantly after freeze-drying (p > 0.05). In most cases, viable population for cells added with cryoprotectants was significantly lower than those without (p < 0.05). Cellular fatty acids (CFAs) from the two strains in this study were analyzed before and after freeze-drying. Six CFAs were identified, namely, palmitic (C(16:0)), palmitoleic (C(16:1)), stearic (C(18:0)), oleic (C(18:1)), linoleic (C(18:2)), and linolenic (C(18:3)) acids were identified. Four of them, C(16:0), C(16:1), C(18:0), and C(18:1), make up more than 94% or 93% of the fatty acids in L. mesenteroides and L. plantarum, respectively, with another one, namely, C18:3, making a smaller (on average 5-6%, respectively) contribution. The C(18:2) contributed very small percentages (on average

Color has an unresolved role in natural scene recognition. Whereas rapid serial visual presentation paradigms typically find no advantage for colored over grayscale scenes, color seems to play a decisive role for recognition memory. The distinction between detection and memorization has not been addressed directly in one paradigm. Here we asked ten observers to detect animals in 2-s 20 Hz sequences. Each sequence consisted of two 1-s segments, one of grayscale images and one of colored; each segment contained one or no target, totaling zero, one, or two targets per sequence. In one-target sequences, hit rates were virtually the same for targets appearing in the first or second segment, as well as for grayscale and colored targets, though observers were more confident about detecting colored targets. In two-target sequences, observers preferentially reported the second of two identical targets, in comparison to categorically related (same-species animals) or unrelated (different-species animals) targets. Observers also showed a strong preference for reporting colored targets, though only when targets were of different species. Our findings suggest that color has little effect on detection, but is used in later stages of processing. We may speculate that color ensures preferential access to or retrieval from memory when distinct items must be rapidly remembered.

We report on a high-power (cw) red laser at 671 nm by intracavity frequency doubling of a double-end-pumped 1342 nm Nd:YVO4 laser based on the nonlinear crystal LiB3O5. A red output power of 3.38 W is obtained for a pump power of 27 W, with corresponding optical-to-optical efficiency of 12.5%. The 671 nm beam is nearly diffraction limited.

The soluble HLA-G1 (sHLA-G1) isoform was found to be secreted by trophoblast cells at the materno-fetal interface, which suggests that it may act as an immunomodulator during pregnancy. In this paper, we reported that GST-sHLA-G1a chain could bind to its receptor ILT-2 on NK92 cells and then the latter recruited Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1), which consequently dephosphorylated some important protein tyrosine kinases and blocked the activation of downstream molecules such as MEK and ERK so that the cytotoxicity of natural killer (NK) cells was inhibited. These results indicated that GST-sHLA-G1a chain might be exploited in new immunotherapy strategies aiming at inducing immunotolerance during allograft, xenograft and autoimmune situations. In addition, we found that modification of O-linked b-N-acetylglucosamine (O-GlcNAc) was involved in NK cells' activating and inhibitory signals. This may provide a novel molecular target for inducing immunotolerance but needs further study.