Miracle-dz/UniFAR-FTUs huggingface dataset:
Human iPSC-derived neuron of 16p11.2 deletion reveals haplotype-specific expression of MAPK3 and its contribution to variable NDD phenotypes

Recurrent proximal 16p11.2 deletion (16p11.2del) is risk factor of diverse neurodevelopmental disorders (NDDs) with variable penetrance. Although previous human induced pluripotent stem cell (hiPSC) models of 16p11.2del confirmed disrupted neuron development, it is not known which gene(s) at this interval are mainly responsible for the abnormal cellular phenotypes and how the NDD penetrance is regulated. After haplotype phasing of 16p11.2 region, we generated hiPSCs for two 16p11.2del families with distinct residual haplotypes and variable NDD phenotypes. We also differentiated the hiPSCs to cortical neural cells and demonstrated MAPK3 as a driver signal of 16p11.2 region contributing to the dysfunctions in multiple pathways related to neuron development, which leads to altered morphological or electrophysiological properties in neuron cells. Furthermore, residual haplotype-specific MAPK3 expression was identified in 16p11.2del neuron cells, associating MAPK3 down-expression with the minor allele of the residual haplotype. Ten SNPs of the residual haplotype are mapped as enhancer SNPs (enSNPs) of MAPK3, eight enSNPs were functionally validated by luciferase assays, implying enSNPs contribute to residual haplotype-specific MAPK3 expression via cis-regulation. Finally, the analyses of three different patient cohorts showed that the residual haplotype of 16p11.2del is associated with variable NDD phenotypes.
Context-dependent differences in the functional responses of Lactobacillaceae strains to fermentable sugars

Lactobacillaceae are Gram-positive rods, facultative anaerobes, and belong to the lactic acid bacteria (LAB) that frequently serve as probiotics. We systematically compared five LAB strains for the effects of different carbohydrates on their free-living and biofilm lifestyles. We found that fermentable sugars triggered a heterogeneous response in LAB strains, frequently manifested specifically in altered carrying capacity during planktonic growth and colony development. The fermentation capacities of the strains were compatible and could not account for heterogeneity in their differential carrying capacity in liquid and on a solid medium. Among tested LAB strains, L. paracasei, and L. rhamanosus GG survived self-imposed acid stress while L. acidophilus was extremely sensitive to its own glucose utilization acidic products. The addition of a buffering system during growth on a solid medium significantly improved the survival of most tested probiotic strains during fermentation. We suggest that the optimal performance of the beneficial microbiota members belonging to lactobacilli is heterogeneous and varies as a function of the growth model and the dependency on a buffering system.
Effects of age and sex on dendritic D2 autoreceptor inhibition in substantia nigra dopamine neurons

Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type autoreceptors located on dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that D2-receptor inhibitory postsynaptic currents (D2-IPSCs) in aged male mice are moderately smaller compared to young males as well as females, regardless of age. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism that could not be explained by impairment of the GIRK channels or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSCs in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) is also conserved in aging, indicating preservation of plasticity mechanisms. These findings have implications for understanding dopamine transmission in aging in both sexes and could explain in part the increased susceptibility of males to SNc degeneration of dopamine neurons in neurodegenerative disorders such as Parkinson’s disease (PD).
A specific role for importin-5 and NASP in the import and nuclear hand-off of monomeric H3

Core histones package chromosomal DNA and regulate genomic transactions, with their nuclear import and deposition involving importin-β proteins and a dedicated repertoire of histone chaperones. Previously, a histone H3-H4 dimer has been isolated bound to Importin-4 (Imp4) and and the chaperone ASF1, suggesting H3 and H4 fold together in the cytoplasm before nuclear import. However, other studies have shown the existence of monomeric H3 in the nucleus, indicating a post import folding pathway. Here we report that the predominant importin associated with cytoplasmic H3 is Importin-5 (Imp5), which hands-off its monomeric cargo to nuclear sNASP. Imp5, in contrast to Imp4, binds to both H3 and H4 containing constitutively monomeric mutations and binds to newly synthesised, monomeric H3 tethered in the cytoplasm. Constitutively monomeric H3 retains its interaction with NASP, whereas monomeric H4 retains interactions specifically with HAT1 and RBBP7. High-resolution separation of NASP interactors shows the ‘s’ isoform but not the ‘t’ isoform associates with monomeric H3, whilst both isoforms associate with H3-H4 dimers in at least three discrete multi-chaperoning complexes. In vitro binding experiments show mutual exclusivity between sNASP and Imp5 in binding H3, suggesting direct competition for interaction sites, with the GTP-bound form of Ran required for histone transfer. Finally, using pulse-chase analysis we show that cytoplasm-tethered histones do not interact with endogenous NASP until they reach the nucleus, whereupon they bind rapidly. We propose an Imp5-specific import pathway for monomeric H3 that hands off to sNASP in the nucleus, with a parallel H4 pathway involving Imp5 and the HAT1-RBBP7 complex, followed by nuclear folding and hand-off to deposition factors.
Sex bias in utero alters ovarian reserve but not uterine capacity in female offspring

Abstract Environmental stressors to which a fetus is exposed affect a range of physiological functions in postnatal offspring. We aimed to determine the in utero effect of steroid hormones on the reproductive potential of female offspring using a porcine model. Reproductive tracts of pigs from female-biased (>65% female, n = 15), non-biased (45–54.9% female, n = 15), and male-biased litters (<35% females, n = 9) were collected at slaughter (95–115 kg). Ovaries and uterine horns were processed for H&E or immunohistochemistry. Variability of data within groups was analyzed with a Levene's test, while data were analyzed using mixed linear models in R. In the ovarian reserve, there was a significant birth weight by sex ratio interaction (P = 0.015), with low birth weight pigs from male-biased litters having higher numbers of primordial follicles with opposite trends seen in pigs from female-biased litters. Sex bias held no effect on endometrial gland development. A lower birth weight decreased the proportion of glands found in the endometrium (P = 0.045) and was more variable in both male-biased and female-biased litters (P = 0.026). The variability of primordial follicles from male-biased litters was greater than non- and female-biased litters (P = 0.014). Similarly, endometrial stromal nuclei had a greater range in male- and female-biased litters than non-biased litters (P = 0.028). A crucial finding was the greater variability in primordial follicles in the ovaries from females derived from male-biased litters and stromal cell count in the endometrium of females from male- and female-biased litters. This could be inflating the variability of reproductive success seen in females from male-biased litters. Summary Sentence Females gestated in utero in extremes of sex ratios have altered ovarian reserve postnatally but not uterine capacity. Graphical Abstract
The selective autophagy receptor p62 and the heat shock protein HSP27 facilitate lysophagy via the formation of phase-separated condensates

Lysosomes are membrane-bound organelles that regulate cellular proteostasis. Loss of lysosomal integrity initiates cell death pathways. Thus, cells must rely on quality control mechanisms for protection, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy receptor SQSTM1/p62 is an essential lysophagy receptor recruited to damaged lysosomes in both HeLa cells and neurons. p62 oligomers form liquid-like condensates that are critical in lysophagy. These condensates are regulated by the small heat shock protein HSP27, which binds p62 to prevent p62 aggregation and facilitate autophagosome formation. Mutations in p62 are implicated in Amyotrophic Lateral Sclerosis (ALS), and expression of ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to the cellular pathogenesis of ALS. Thus, p62 oligomers cooperate with HSP27 to promote lysophagy by forming a platform for autophagosome biogenesis at damaged lysosomes.
Combining AFM, XPS and chemical hydrolysis to understand the complexity and dynamics of C. vulgaris cell wall composition and architecture

The microalgae cell wall represents its interface with its environment and a strong barrier to disrupt in order to extract the cell’s products. Understanding its composition and architecture is a challenge that if overcome, could lead to substantial advancements in optimizing microalgae-production systems. However, the cell wall is a dynamic and complex structure that evolves depending on the growth phase or culture conditions. To apprehend this complexity, an experimental approach combining AFM, XPS, and chemical hydrolysis followed by HPAEC-PAD was developed to understand the cell wall of Chlorella vulgaris, a biotechnologically-relevant green microalgae species. Exponential and stationary growth stages were investigated, as well as saline stress condition inducing lipid production. Results showed that both the cell wall composition and architecture changes in stationary phase, with an increase of the lipidic fraction at the expanse of the proteic fraction, changes in the polysaccharidic composition, and a significant increase of its rigidity. Under saline stress, cell wall architecture seems to be affected as its rigidity decreases importantly. Altogether, this study demonstrates the power of combining these three techniques to give new insights into C. vulgaris cell wall, in terms of composition and architecture, and of its dynamics in different conditions.
Data-Driven Short-Term Voltage Stability Assessment Considering Sample Imbalance and Overlapping

In recent years, data-driven methods have shown great potential for the practical application of short-term voltage stability (STVS) assessment. However, most existing research works overlook the problem of sample imbalance and overlap in STVS assessment. To tackle this issue, a novel self-adaptive data-driven method for real-time STVS is proposed in this study. First, min-redundancy and max-relevance (mRMR) is employed for feature selection to reduce the computational burden. Taking the key features as inputs, a cascaded LightGBM (CasLightGBM) model is constructed to mine STVS informatization. Based on the LightGBM and cascaded structure, CasLightGBM can enhance the assessment accuracy without sacrificing the assessment earliness. Then, focal loss (FL) is embedded into both offline and online phases of the CasLightGBM to mitigate the loss of accuracy caused by sample imbalance and overlapping, thus deriving a highly comprehensive and reliable classification model for real-time STVS assessment. Extensive numerical tests are conducted on the IEEE 118-bus system, and the simulation results demonstrate that the proposed method outperforms traditional algorithms and exhibits favorable robustness to measurement noise.
Changes in inhibitory control, craving and affect after yoga vs. aerobic exercise among smokers with nicotine dependence

Objectives This study investigated the acute effects of yoga and aerobic exercise on response inhibition and the underlying neural mechanisms in individuals with nicotine dependence, along with changes in craving and affect. Materials and methods Study participants included 30 yoga-naïve adult smokers with moderate-to-high nicotine dependence. Based on a within-subjects design, all participants participated in three experimental sessions: baseline, 30-min yoga, and 30-min aerobic exercise; one session was conducted per day. The pre- and post-exercise Questionnaire of Smoking Urges and the Visual Analogue Scale were used to measure cigarette craving, and the Positive and Negative Affect Schedule was used to assess affective change. For cognitive measurement of inhibition, participants performed a Go/Nogo task consisting of Smoking-Go, Smoking-Nogo, Neutral-Go, and Neutral-Nogo stimulus conditions. Neuroelectric data were collected and the event-related potential (ERP) N2 and P3 amplitudes and latencies were analyzed. Results Both yoga and aerobic exercise significantly reduced negative affect, whereas a reduction in craving was only observed after yoga. ERP results indicated that the P3 amplitudes after yoga were lower than those after aerobic exercise, suggesting increased neural efficiency after yoga, with reduced neural activity while maintaining the same level of cognitive performance as aerobic exercise. Conclusion As yoga and aerobic exercise were equally effective in attenuating negative affect, smokers may expect greater benefits from yoga in craving reduction and inhibitory control with less physical and cognitive effort. We also believe that video-based yoga practice may provide additional benefits to these effects, reaching a large number of smokers in a non-face-to-face manner.
Pelvic Lymph Node Lymphangiomyomatosis Found During Surgery for Gynecological Fallopian Tube Cancer: A Case Report and Literature Review

Background Lymphangioleiomyomatosis (LAM) is a rare low-grade metastatic tumor with an unknown origin that spreads through lymphatic vessels. It is characterized by the proliferation of smooth muscle-like or epithelioid tumor cells in the lung and axial lymphatic system. Extrapulmonary LAM is a localized disease with a low incidence rate, and the location of the related lesions is atypical. It is difficult to diagnose. The LAM of pelvic lymph nodes is hidden. It is usually found through gynecological oncology surgery. Case presentation We report a 57-year-old postmenopausal woman with a pelvic mass and vaginal bleeding as the main symptoms. The patient had no history of pulmonary LAM, tuberous sclerosis complex (TSC), or renal angiomyolipoma and had not used exogenous hormones. We performed a total hysterectomy, bilateral adnexectomy, greater omentum resection, and pelvic lymphadenectomy under laparoscopy. The postoperative pathology confirmed high-grade serous carcinoma of the left fallopian tube, and four lymph nodes were found in the pelvic lymph nodes, suggesting lymphangiomyomatosis. Immunohistochemical results also showed that these cells could express markers of smooth muscle cells and melanoma cells. The patient was treated with chemotherapy after the operation. Chest CT did not suggest lung LAM during the postoperative follow-up, and there was no tumor recurrence. Conclusion The diagnosis of this disease is challenging. At the same time, due to insufficient clinical samples, it is still unknown whether there is a potential relationship between pelvic and peritoneal lymph node LAM found in the surgical staging of gynecological tumors and lung LAM and/or TSC. There is no evidence that pelvic and peritoneal lymph node LAM will increase the risk of pulmonary LAM. Therefore, additional clinical data are required to analyze and summarize the relationship between pelvic and peritoneal lymph node LAM, pulmonary LAM, and the source of LAM. We present a case of pelvic lymph node LAM and propose a hypothesis that the pathogenesis of endometriosis can be used for reference in the study of this disease.
European Lobster Larval Development and Fitness Under a Temperature Gradient and Ocean Acidification

Climate change combined with anthropogenic stressors (e.g. overfishing, habitat destruction) may have particularly strong effects on threatened populations of coastal invertebrates. The collapse of the population of European lobster (Homarus gammarus) around Helgoland constitutes a good example and prompted a large-scale restocking program. The question arises if recruitment of remaining natural individuals and program-released specimens could be stunted by ongoing climate change. We examined the joint effect of ocean warming and acidification on survival, development, morphology, energy metabolism and enzymatic antioxidant activity of the larval stages of the European lobster. Larvae from four independent hatches were reared from stage I to III under a gradient of 10 seawater temperatures (13–24°C) combined with moderate (∼470 µatm) and elevated (∼1160 µatm) seawater pCO2 treatments. Those treatments correspond to the shared socio-economic pathways (SSP), SSP1-2.6 and SSP5-8.5 (i.e. the low and the very high greenhouse gas emissions respectively) projected for 2100 by the Intergovernmental Panel on Climate Change. Larvae under the elevated pCO2 treatment had not only lower survival rates, but also significantly smaller rostrum length. However, temperature was the main driver of energy demands with increased oxygen consumption rates and elemental C:N ratio towards warmer temperatures, with a reducing effect on development time. Using this large temperature gradient, we provide a more precise insight on the aerobic thermal window trade-offs of lobster larvae and whether exposure to the worst hypercapnia scenario may narrow it. This may have repercussions on the recruitment of the remaining natural and program-released specimens and thus, in the enhancement success of future lobster stocks.
Cross-Activation of Hemichannels/Gap Junctions and Immunoglobulin-Like Domains in Innate–Adaptive Immune Responses

Hemichannels (HCs)/gap junctions (GJs) and immunoglobulin (Ig)-like domain-containing proteins (IGLDCPs) are involved in the innate–adaptive immune response independently. Despite of available evidence demonstrating the importance of HCs/GJs and IGLDCPs in initiating, implementing, and terminating the entire immune response, our understanding of their mutual interactions in immunological function remains rudimentary. IGLDCPs include immune checkpoint molecules of the immunoglobulin family expressed in T and B lymphocytes, most of which are cluster of differentiation (CD) antigens. They also constitute the principal components of the immunological synapse (IS), which is formed on the cell surface, including the phagocytic synapse, T cell synapse, B cell synapse, and astrocytes–neuronal synapse. During the three stages of the immune response, namely innate immunity, innate–adaptive immunity, and adaptive immunity, HCs/GJs and IGLDCPs are cross-activated during the entire process. The present review summarizes the current understanding of HC-released immune signaling factors that influence IGLDCPs in regulating innate–adaptive immunity. ATP-induced “eat me” signals released by HCs, as well as CD31, CD47, and CD46 “don’t eat me” signaling molecules, trigger initiation of innate immunity, which serves to regulate phagocytosis. Additionally, HC-mediated trogocytosis promotes antigen presentation and amplification. Importantly, HC-mediated CD4+ T lymphocyte activation is critical in the transition of the innate immune response to adaptive immunity. HCs also mediate non-specific transcytosis of antibodies produced by mature B lymphocytes, for instance, IgA transcytosis in ovarian cancer cells, which triggers innate immunity. Further understanding of the interplay between HCs/GJs and IGLDCPs would aid in identifying therapeutic targets that regulate the HC–Ig-like domain immune response, thereby providing a viable treatment strategy for immunological diseases. The present review delineates the clinical immunology-related applications of HC–Ig-like domain cross-activation, which would greatly benefit medical professionals and immunological researchers alike. HCs/GJs and IGLDCPs mediate phagocytosis via ATP; “eat me and don’t eat me” signals trigger innate immunity; HC-mediated trogocytosis promotes antigen presentation and amplification in innate–adaptive immunity; HCs also mediate non-specific transcytosis of antibodies produced by mature B lymphocytes in adaptive immunity.
Metagenome Analysis of the Bacterial Characteristics in Invasive Klebsiella Pneumoniae Liver Abscesses

Background Klebsiella pneumoniae liver abscess (KPLA) combined with extrahepatic migratory infection (EMI) is defined as invasive KPLA (IKPLA) and is associated with a poor prognosis. The mechanism of IKPLA formation is yet to be elucidated. In this study, metagenomic sequencing was used to compare the bacterial characteristics between IKPLA and KPLA to explore the underlying mechanism of invasiveness. Methods Clinical details, imaging, and microbial features were retrospectively evaluated by medical record review. Metagenomic sequencing was performed on the pus samples of liver abscesses whose culture results were indicative of monomicrobial Klebsiella pneumoniae (K. pneumoniae). Bacterial diversity and composition in IKPLA and KPLA were comparatively analyzed, and the key pathways and genes that may affect invasiveness were further explored. Results Sixteen patients were included in this study. Five patients with EMI were included in the IKPLA group, and the other eleven patients without EMI were assigned to the KPLA group. There was no statistical difference in the hypermucoviscous phenotype and serotype of K. pneumoniae between the two groups. The bacterial diversity of IKPLA was lower than that of KPLA. The abundant taxa in the IKPLA group were primarily species of unclassified Enterobacteriaceae and K. pneumoniae. The KPLA group had a high abundance of the genera Tetrasphaera and Leuconostoc. Metabolic pathway genes represented most of the enriched genes in IKPLA. Fourteen pathogenic genes with significant differences in abundance were identified between the two groups, including ybtS, fepC, phoQ, acrB, fimK, magA, entC, arnT, iucA, fepG, oqxB, entA, tonB, and entF (p < 0.001). Conclusion The diversity and bacterial composition of IKPLA were significantly different from those of KPLA. Microbiological changes in the abscess, activation of the related metabolic pathways, and the pathogenic gene expression may constitute a novel mechanism that regulates the invasiveness of KPLA.