Miracle-dz/UniFAR-FTUs huggingface dataset:
Structures of the essential efflux pump EfpA from Mycobacterium tuberculosis reveal the mechanisms of substrate transport and small-molecule inhibition

As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA are poorly understood. Herein we report cryo-EM structures of EfpA in outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A in both overall structure and lipid binding sites, and may function as a lipid flippase. Combining AlphaFold-predicted EfpA structure, which is inward-open, we propose a complete conformational transition cycle for EfpA. Together, our results provide a structural and mechanistic foundation to comprehend EfpA function and develop EfpA-targeting anti-TB drugs.
HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells

The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis controls IFN-γ induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1α in T cells (HIF1α−/−) and glycolytic inhibition significantly abrogate IFN-γ induction. Conversely, HIF1α stabilization in T cells by hypoxia and VHL deletion (VHL−/−) promotes IFN-γ production. Mechanistically, reduced IFN-γ production in hypoxic HIF1α−/− T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1α−/− T cells are less able to kill tumor cells, and HIF1α−/− tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1α in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-γ production in hypoxic HIF1α−/− T cells and re-sensitizes HIF1α−/− tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1α-anaerobic glycolysis as a principal mediator of IFN-γ induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need.
Horizontal cortical connections shape intrinsic traveling waves into feature-selective motifs that regulate perceptual sensitivity

Intrinsic, ongoing fluctuations of cortical activity form traveling waves that modulate the gain of sensory-evoked responses and perceptual sensitivity. Several lines of evidence suggest that intrinsic traveling waves (iTWs) may arise, in part, from the coordination of synaptic activity through the recurrent horizontal connectivity within cortical areas, which include long range patchy connections that link neurons with shared feature preferences. In a spiking network model with anatomical topology that incorporates feature-selective patchy connections, which we call the Balanced Patchy Network (BPN), we observe repeated iTWs, which we refer to as motifs. In the model, motifs stem from fluctuations in the excitability of like-tuned neurons that result from shifts in E/I balance as action potentials traverse these patchy connections. To test if feature-selective motifs occur in vivo, we examined data previously recorded using multielectrode arrays in Area MT of marmosets trained to perform a threshold visual detection task. Using a newly developed method for comparing the similarity of wave patterns we found that some iTWs can be grouped into motifs. As predicted by the BPN, many of these motifs are feature selective, exhibiting direction-selective modulations in ongoing spiking activity. Further, motifs modulate the gain of the response evoked by a target and perceptual sensitivity to the target if the target matches the preference of the motif. These results provide evidence that iTWs are shaped by the patterns of horizontal fiber projections in the cortex and that patchy connections enable iTWs to regulate neural and perceptual sensitivity in a feature selective manner.
The link between the Victoria mode in the preceding boreal winter and spring precipitation over the southeastern USA and Gulf of Mexico

Abstract The sea surface temperature anomalies (SSTAs) associated with the Victoria mode (VM) can persist into the following season and then influence climate variability in the tropical Pacific. This paper demonstrates the connection between the preceding boreal winter VM and precipitation in the following spring over the southeastern United States (SE USA) and the Gulf of Mexico (GM). The results indicate that a positive (negative) preceding winter VM is usually followed by increased (reduced) precipitation over the SE USA and GM during the following spring. The corresponding mechanism is similar, but slightly different to, the seasonal footprinting mechanism. For positive VM cases, the preceding-winter VM-related SSTAs appear to persist into the following spring via air–sea interactions, which then induce low-level convergence and vigorous ascending motion, leading to an adjustment of the zonal and meridional circulation. This adjustment can then influence the local Hadley cell by weakening the downward branch. These anomalous patterns of vertical airflow enhance spring precipitation over the SE USA and GM under suitable moisture conditions. Hence, this work demonstrates that the preceding-winter VM has the potential to regulate precipitation over the SE USA and GM in the following spring.
Loss of cholinergic input to the entorhinal cortex is an early indicator of cognitive impairment in natural aging of humans and mice

In a series of translational experiments using fully quantitative positron emission tomography (PET) imaging with a new tracer specific for the vesicular acetylcholine transporter ([18F]VAT) in vivo in humans, and genetically targeted cholinergic markers in mice, we evaluated whether changes to the cholinergic system were an early feature of age-related cognitive decline. We found that deficits in cholinergic innervation of the entorhinal cortex (EC) and decline in performance on behavioral tasks engaging the EC are, strikingly, early features of the aging process. In human studies, we recruited older adult volunteers that were physically healthy and without prior clinical diagnosis of cognitive impairment. Using [18F]VAT PET imaging, we demonstrate that there is measurable loss of cholinergic inputs to the EC that can serve as an early signature of decline in EC cognitive performance. These deficits are specific to the cholinergic circuit between the medial septum and vertical limb of the diagonal band (MS/vDB; CH1/2) to the EC. Using diffusion imaging, we further demonstrate impaired structural connectivity in the tracts between the MS/vDB and EC in older adults with mild cognitive impairment. Experiments in mouse, designed to parallel and extend upon the human studies, used high resolution imaging to evaluate cholinergic terminal density and immediate early gene (IEG) activity of EC neurons in healthy aging mice and in mice with genetic susceptibility to accelerated accumulation amyloid beta plaques and hyperphosphorylated mouse tau. Across species and aging conditions, we find that the integrity of cholinergic projections to the EC directly correlates with the extent of EC activation and with performance on EC-related object recognition memory tasks. Silencing EC-projecting cholinergic neurons in young, healthy mice during the object-location memory task impairs object recognition performance, mimicking aging. Taken together we identify a role for acetylcholine in normal EC function and establish loss of cholinergic input to the EC as an early, conserved feature of age-related cognitive decline in both humans and rodents.
Knowledge and awareness of autism spectrum disorder among Libyans

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by the presence of delayed or defective development before the age of three years, as well as behavioral difficulties in social communication and interaction. To evaluate ASD knowledge and awareness, as well as ASD information sources in a sample of the Libyan general population, and to explore factors that could be associated with the knowledge and awareness. A cross-sectional study was carried out between 22 March and 13 August, 2022 using a self-administered questionnaire. The study included 2350 individual aged 18 and up from households living in different regions in Libya (eastern, southern, central, and western). Out of 2195 participants, 48.9% were females and 51.1% were males. Three-quarters of the participants (74.8%) presented a low level of knowledge about autism causes. Of those whose source of knowledge of autism was social media, 78.9% had a low level of knowledge. However, 57.9% of the participants showed a good level of awareness of autism symptoms and signs. The participants had a limited understanding of the causes and characteristics of ASD. Raising community awareness of the causes and characteristics of ASD is a priority.
Information seeking behavior on hepatitis B virus, and its associated factors among pregnant women at teaching and specialized hospitals, Northwest Ethiopia: A cross-sectional study

Introduction Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. Health information-seeking behavior is critical to obtain information about health, diseases such as the Hepatitis B virus, health risks, and health promotion and it has become a major concern of health policymakers. However, there is little evidence of information-seeking behavior on the Hepatitis B virus in Ethiopia. So, this study aimed to assess Hepatitis B virus information-seeking behavior and its associated factors among pregnant women at teaching and Specialized Hospitals, in Northwest Ethiopia. Methods An institution-based cross-sectional study was conducted among pregnant women at teaching and specialized hospitals, in Northwest Ethiopia from May 01 to June 01, 2022. A total of 423 participants were selected using a systematic random sampling method. The data was collected through an interview-administered questionnaire by kobo-collect software. Then export into SPSS version 20 for analysis. Descriptive statistics, bi-variable, and multivariable logistic regression analyses were done to identify factors associated with Hepatitis B virus information-seeking behavior. Results The proportion of information-seeking behavior on the Hepatitis B virus among pregnant women was 40.5% (CI = 35.7, 45.6). Education(diploma and above) [AOR = 3.3, 95% CI (1.31, 8.16)], more than one ANC visit [AOR = 5.99, 95% CI (3.20, 12.31)], smart-phone ownership [AOR = 4.1, 95%CI (1.35, 12.31)], internet access [AOR = 5.1, 95%CI (1.35, 15.60)], perceived susceptibility [AOR = 2.7, 95%CI (1.38, 5.31)], perceived severity [AOR = 3.7, 95%CI (2.06, 6.55)], and self-efficacy [AOR = 1.9, 95%CI (1.03, 3.73)] were factors influencing information seeking on Hepatitis B virus. Conclusion The overall proportion of information-seeking behavior on HBV among pregnant women was low. To improve information-seeking behavior on HBV among pregnant women we should connect the women to the internet and technology. Creating women’s awareness about the Hepatitis B virus severity and their venerability and increasing their antenatal care (ANC) visits, self-efficacy, internet access, and women’s education can improve information seeking about the Hepatitis B virus.
CETP gene polymorphisms and haplotypes are explanatory variables for HDL cholesterol level in sickle cell disease

Variations in lipid profile have been observed in sickle cell disease (SCD) and understanding their relationship with disease severity is crucial. This study aimed to investigate the association of polymorphisms of the CETP gene and laboratory markers of disease severity with lipid profile in a pediatric population with SCD. Biochemical and anthropometric analyses and CETP and alpha-thalassemia genotyping were performed. The study included 133 children and adolescents with sickle cell anemia (SCA) or hemoglobin SC disease (SCC), in steady-state. The SCA and no hydroxyurea (no HU) groups had higher values of ApoB, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) compared to the SCC and HU groups. However, there were no significant differences in ApoA1 and HDL-C levels between the groups based on genotype. Furthermore, the groups with altered levels of ApoA1, HDL-C, and the triglyceride/HDL ratio exhibited lower hemoglobin (Hb) levels and higher white blood cell counts. Hb level was associated to HDL-C levels. Analysis of CETP gene variants showed that the minor alleles of rs3764261 (C>A), rs247616 (C>T), and rs183130 (C>T), as well as the TTA haplotype, are explanatory variables for HDL-C levels. These findings suggested that dyslipidemia in SCD, specifically related to HDL-C levels, may be influenced by individual genetic background. Additionally, further investigation is needed to determine if clinical manifestations are impacted by CETP gene variants.
A protocol for systematic review and meta-analysis

Background:Multiple sclerosis (MS) is an autoimmune disease characterized by white matter inflammatory demyelination in the central nervous system (CNS). Its clinical manifestations include decreased vision, diplopia, and limb weakness. As a green and simple traditional Chinese medicine method, acupuncture is gradually recognized by the public. At present, there is still a lack of systematic evaluation on acupuncture treatment of MS. This study aims to evaluate the safety and effectiveness of acupuncture in the treatment of MS, in order to provide a basis for clinical decision-making. Methods: Randomized controlled trials (RCTs) of acupuncture for MS will be searched in the relevant database, including PubMed, MEDLINE, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure Database (CNKI), WanFang Database, China BiologyMedicine Database (CBM), Chinese Scientific Journals Database (VIP), regardless of publication date, or language. All relevant RCTs of electronic searches will be exported to EndNote X9.1 software. Data analysis will be performed using RevMan 5.4 and STATA 14.2 software. Results:Our study aims to explore the efficacy of acupuncture for MS and to provide up-to-date evidence for clinical of MS. We will publish our research results in peer review journals. Conclusion:This study will perform a comprehensive systematic review andmeta-analysis on the efficacy of acupuncture for MS, making up for the lack of relevant evidence of the clinical use of acupuncture. Abbreviations: 95%CI = 95% confidence interval, CBM = Chinese Biomedicine, CNKI = China National Knowledge Infrastructure, CNS = central nervous system, EDSS = expanded disability status scale, GRADE = Grading of Recommendations Assessment, Development and Evaluation, MDs = mean differences, MS = multiple sclerosis, OR = odds ratio, PRISMA-P = Preferred Reporting Items for Systematic Reviews andMeta-Analysis Protocols, RCTs= randomized controlled trials, RR= relative risk, SMDs = standard mean differences, VIP = Chinese Scientific Journals Database.
Exercise-Intervened Endothelial Progenitor Cell Exosomes Protect N2a Cells by Improving Mitochondrial Function

We have recently demonstrated that exosomal communication between endothelial progenitor cells (EPCs) and brain endothelial cells is compromised in hypertensive conditions, which might contribute to the poor outcomes of stroke subjects with hypertension. The present study investigated whether exercise intervention can regulate EPC–exosome (EPC-EX) functions in hypertensive conditions. Bone marrow EPCs from sedentary and exercised hypertensive transgenic mice were used for generating EPC-EXs, denoted as R-EPC-EXs and R-EPC-EXET. The exosomal microRNA profile was analyzed, and EX functions were determined in a co-culture system with N2a cells challenged by angiotensin II (Ang II) plus hypoxia. EX-uptake efficiency, cellular survival ability, reactive oxygen species (ROS) production, mitochondrial membrane potential, and the expressions of cytochrome c and superoxide-generating enzyme (Nox4) were assessed. We found that (1) exercise intervention improves the uptake efficiency of EPC-EXs by N2a cells. (2) exercise intervention restores miR-27a levels in R-EPC-EXs. (3) R-EPC-EXET improved the survival ability and reduced ROS overproduction in N2a cells challenged with Ang II and hypoxia. (4) R-EPC-EXET improved the mitochondrial membrane potential and decreased cytochrome c and Nox4 levels in Ang II plus hypoxia-injured N2a cells. All these effects were significantly reduced by miR-27a inhibitor. Together, these data have demonstrated that exercise-intervened EPC-EXs improved the mitochondrial function of N2a cells in hypertensive conditions, which might be ascribed to their carried miR-27a.
Regional Agriculture and Food Systems Amid the COVID-19 Pandemic: The Case of the Near East and North Africa Region

The COVID-19 pandemic affected agri-food systems worldwide. However, while the impacts differed from one country/region to another, the scholarly literature seems to focus on developed countries in the Global North. Consequently, this review scrutinizes the literature on the pandemic’s impacts in the Near East and North Africa (NENA) region. A search on the Web of Science in March 2023 generated 334 documents, of which 151 were eligible for inclusion in the systematic review. According to the bibliometric analysis, the most active nations are Saudi Arabia, Egypt, Jordan, the United Arab Emirates, and Lebanon. In general, the coverage of studies is better in the Gulf region than in the less developed countries of North Africa and those suffering from wars (cf. Libya, Syria, and Yemen). Studies generally focus on crop production and the downstream food chain (cf. distribution and consumption). While the pandemic influenced every pillar of food security, this research concentrates on access and utilization. Meanwhile, the lion’s share of the literature deals with the pandemic’s socio-economic effects, especially those linked to food (in)security and health. The pandemic, which laid bare the agri-food system vulnerabilities, should be seized to foster the transition towards more resilient agri-food systems in the NENA region.
Ex Vivo 13C-Metabolic Flux Analysis of Porcine Circulating Immune Cells Reveals Cell Type-Specific Metabolic Patterns and Sex Differences in the Pentose Phosphate Pathway

In general, females present with stronger immune responses than males, but scarce data are available on sex-specific differences in immunometabolism. In this study, we characterized porcine peripheral blood mononuclear cell (PBMC) and granulocyte energy metabolism using a Bayesian 13C-metabolic flux analysis, which allowed precise determination of the glycolytic, pentose phosphate pathway (PPP), and tricarboxylic acid cycle (TCA) fluxes, together with an assessment of the superoxide anion radical (O2•−) production and mitochondrial O2 consumption. A principal component analysis allowed for identifying the cell type-specific patterns of metabolic plasticity. PBMCs displayed higher TCA cycle activity, especially glutamine-derived aspartate biosynthesis, which was directly related to mitochondrial respiratory activity and inversely related to O2•− production. In contrast, the granulocytes mainly utilized glucose via glycolysis, which was coupled to oxidative PPP utilization and O2•− production rates. The granulocytes of the males had higher oxidative PPP fluxes compared to the females, while the PBMCs of the females displayed higher non-oxidative PPP fluxes compared to the males associated with the T helper cell (CD3+CD4+) subpopulation of PBMCs. The observed sex-specific differences were not directly attributable to sex steroid plasma levels, but we detected an inverse correlation between testosterone and aldosterone plasma levels and showed that aldosterone levels were related with non-oxidative PPP fluxes of both cell types.
The Effectiveness of Water- versus Land-Based Exercise on Specific Measures of Physical Fitness in Healthy Older Adults: An Integrative Review

As the population ages, maintaining an active lifestyle becomes increasingly vital to promote overall health and well-being in older individuals. Water- and land-based exercises have emerged as popular options, each offering a distinct set of benefits tailored to the unique needs of this population group. An electronic database search, including PubMed, Scopus, MEDLINE, and Web of Science, was conducted until 15 September 2023, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to investigate the effects of water-based compared to land-based exercise on selected fitness parameters in older healthy individuals. The eligibility criteria included studies with at least two groups of participants aged 60 and older, with physical fitness outcome measures. A total of ten studies met the inclusion criteria and were analyzed. While both exercise modalities may offer significant benefits, this review’s findings emphasized the absence of conclusive evidence and consensus for recommending a single exercise category applicable to aquatic or land environments and providing more definite guidance to improve health-related physical fitness parameters in healthy older individuals. Finally, combining both training approaches may lead to a comprehensive array of health benefits for this age group population by also considering individual’s needs, preferences, and fitness goals.