Miracle-dz/UniFAR-FTUs huggingface dataset:
BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein

Bone morphogenetic protein‐15 (BMP15) is selectively synthesized by oocytes as a pre‐proprotein and is considered an ovarian follicle organizer whose adequate function is critical for female fertility. Missense mutations were reported in primary ovarian insufficiency (POI) but their biological impact remained unexplored. Here, screening of 300 unrelated idiopathic overt POI women with primary or secondary amenorrhea (SA) led to the identification of six heterozygous BMP15 variations in 29 of them. All alterations are nonconservative and include one insertion of three nucleotides (p.L262_L263insL) and five missense substitutions. Except for the p.S5R located in the signal sequence, the other variants (p.R68W, p.R138H, p.L148P, and p.A180T) localize in the proregion, which is essential for the processing and secretion of bioactive dimers. The mutations p.R68W, p.L148P, and the novel p.R138H lead to marked reductions of mature protein production. Their biological effects, evaluated by a novel luciferase‐reporter assay in a human granulosa cell (GC) line, were significantly reduced. Cotransfection experiments of defective mutants with equal amounts of wild‐type BMP15 cDNA, thus reproducing the heterozygous state seen in patients, did not generate a complete recovery of wild‐type activity. No or minor deleterious effects were detected for the variants p.L262_L263insL, p.A180T, or p.S5R. In conclusion, heterozygous BMP15 mutations associated with the early onset of overt POI lead to defective secretion of bioactive dimers. These findings support the concept that an adequate amount of BMP15 secreted in the follicular fluid is critical for female fertility. We propose to consider the screening of BMP15 mutations among the analyses for the prediction of POI risk. Hum Mutat 0, 1–7, 2009. © 2009 Wiley‐Liss, Inc.
A linguistic data acquisition front-end for language recognition evaluation

One of the major challenges of the language identification (LID) system comes from the sparse training data. Manually collecting the linguistic data through the controlled studio is usually expensive and impractical. But multilingual broadcast programs (Voice of America, for instance) can be collected as a reasonable alternative to the linguistic data acquisition issue. However, unlike studio collected linguistic data, broadcast programs usually contain many contents other than pure linguistic data: musical contents in foreground/background, commercials, noise from practical life. In this study, a systematic processing approach is proposed to extract the linguistic data from the broadcast media. The experimental results obtained on NIST LRE 2009 data show that the proposed method can provide 22.2% relative improvement of segmentation accuracy and 20.5% relative improvement of LID accuracy.
Construction of oncogenetic tree models reveals multiple pathways of oral cancer progression

Oral cancer develops and progresses by accumulation of genetic alterations. The interrelationship between these alterations and their sequence of occurrence in oral cancers has not been thoroughly understood. In the present study, we applied oncogenetic tree models to comparative genomic hybridization (CGH) data of 97 primary oral cancers to identify pathways of progression. CGH revealed the most frequent gains on chromosomes 8q (72.4%) and 9q (41.2%) and frequent losses on 3p (49.5%) and 8p (47.5%). Both mixture and distance‐based tree models suggested multiple progression pathways and identified +8q as an early event. The mixture model suggested two independent pathways namely a major pathway with −8p and a less frequent pathway with +9q. The distance‐based tree identified three progression pathways, one characterized by −8p, another by −3p and the third by alterations +11q and +7p. Differences were observed in cytogenetic pathways of node‐positive and node‐negative oral cancers. Node‐positive cancers were characterized by more non‐random aberrations (n = 11) and progressed via −8p or −3p. On the other hand, node‐negative cancers involved fewer non‐random alterations (n = 6) and progressed along −3p. In summary, the tree models for oral cancers provided novel information about the interactions between genetic alterations and predicted their probable order of occurrence. © 2009 UICC
The Longevity of Hippocampus-Dependent Memory Is Orchestrated by the Locus Coeruleus-Noradrenergic System

The locus coeruleus is connected to the dorsal hippocampus via strong fiber projections. It becomes activated after arousal and novelty, whereupon noradrenaline is released in the hippocampus. Noradrenaline from the locus coeruleus is involved in modulating the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. Memory storage can be modified by the activation of the locus coeruleus and subsequent facilitation of hippocampal long-term plasticity in the forms of long-term depression and long-term potentiation. Recent evidence indicates that noradrenaline and dopamine are coreleased in the hippocampus from locus coeruleus terminals, thus fostering neuromodulation of long-term synaptic plasticity and memory. Noradrenaline is an inductor of epigenetic modifications regulating transcriptional control of synaptic long-term plasticity to gate the endurance of memory storage. In conclusion, locus coeruleus activation primes the persistence of hippocampus-based long-term memory.
Glutamate neurons in the substantia nigra compacta and retrorubral field

Dopaminergic neurons of the substantia nigra compacta (SNC), ventral tegmental area (VTA) and retrorubral field (RRF) play a role in reward, motivation, learning, memory, and movement. These neurons are intermingled with GABAergic neurons. Recent evidence shows that the VTA contains glutamatergic neurons expressing vesicular glutamate transporter type 2 (VGluT2); some of them co‐express tyrosine hydroxylase (TH). Here, we used a combination of radioactive in situ hybridisation and immunohistochemistry to explore whether any of the vesicular glutamate transporters [vesicular glutamate transporter type 1 (VGluT1), VGluT2, or vesicular glutamate transporter type 3 (VGluT3)] were encoded by neurons in the SNC or RRF. We found expression of VGluT2 mRNA, but not of VGluT1 or VGluT3, in the SNC and RRF. These VGluT2 neurons rarely showed TH immunoreactivity. Within the SNC, the VGluT2 neurons were infrequently found at the rostral level, but were often seen at the medial and caudal levels intercalated in the mediolateral portion of the dorsal tier, at a ratio of one VGluT2 neuron per 4.4 TH neurons. At this level, VGluT2 neurons were also found in the adjacent substantia nigra reticulata and substantia nigra pars lateralis. Within the RRF, the VGluT2 neurons showed an increasing rostrocaudal gradient of distribution. The RRF proportion of VGluT2 neurons in relation to TH neurons was constant throughout the rostrocaudal levels, showing an average ratio of one VGluT2 neuron per 1.7 TH neurons. In summary, we provide evidence indicating that the SNC and RRF, which are traditionally considered to be dopaminergic areas, have neurons with the ability to participate in glutamate signaling.
Intrinsic Differences in the Initiation of B Cell Receptor Signaling Favor Responses of Human IgG+ Memory B Cells over IgM+ Naive B Cells

The acquisition of long-lived memory B cells (MBCs) is critical for the defense against many infectious diseases. Despite their importance, little is known about how Ags trigger human MBCs, even though our understanding of the molecular basis of Ag activation of B cells in model systems has advanced considerably. In this study, we use quantitative, high-resolution, live-cell imaging at the single-cell and single-molecule levels to describe the earliest Ag-driven events in human isotype-switched, IgG-expressing MBCs and compare them with those in IgM-expressing naive B cells. We show that human MBCs are more robust than naive B cells at each step in the initiation of BCR signaling, including interrogation of Ag-containing membranes, formation of submicroscopic BCR oligomers, and recruitment and activation of signaling-associated kinases. Despite their robust response to Ag, MBCs remain highly sensitive to FcγRIIB-mediated inhibition. We also demonstrate that in the absence of Ag, a portion of MBC receptors spontaneously oligomerized, and phosphorylated kinases accumulated at the membrane and speculate that heightened constitutive signaling may play a role in maintaining MBC longevity. Using high-resolution imaging, we have provided a description of the earliest events in the Ag activation of MBCs and evidence for acquired cell-intrinsic differences in the initiation of BCR signaling in human naive and MBCs.
Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury.

BACKGROUND It is generally believed that the hepatoprotective effect of interleukin-6 (IL-6) is mediated via activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. IL-6-deficient mice are more susceptible to alcohol-induced hepatocyte apoptosis and steatosis and elevation of serum alanine transaminase (ALT); however, whereas hepatocyte-specific STAT3 knockout mice are more susceptible to alcohol-induced hepatic steatosis, they have similar hepatocyte apoptosis and serum ALT after alcohol feeding compared with wild-type mice. This suggests that the hepatoprotective effect of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. We have previously shown that IL-6 also activates STAT3 in sinusoidal endothelial cells (SECs). Thus, the purpose of this study was to investigate whether STAT3 in endothelial cells also plays a protective role in alcoholic liver injury. METHODS Wild-type and endothelial cell-specific STAT3 knockout (STAT3(E-/-)) mice were pair-fed and fed ethanol containing diet for 4 weeks. Liver injury and inflammation were determined. RESULTS Feeding mice with ethanol-containing diet for 4 weeks induced greater hepatic injury (elevation of serum ALT) and liver weight in STAT3(E-/-) mice than wild-type control groups. In addition, ethanol-fed STAT3(E-/-) mice displayed greater hepatic inflammation and substantially elevated serum and hepatic levels of IL-6 and TNF-alpha compared with wild-type mice. Furthermore, ethanol-fed STAT3(E-/-) mice displayed a greater abundance of apoptotic SECs and higher levels of serum hyaluronic acid than wild-type controls. CONCLUSIONS These data suggest that endothelial cell STAT3 plays important dual functions of attenuating hepatic inflammation and SEC death during alcoholic liver injury.
Risk Measurement and Management in a Crisis-Prone World

The current subprime crisis has prompted us to look again into the nature of risk at the tail of the distribution. In particular, we investigate the risk contribution of an asset, which has infrequent but huge losses, to a portfolio using two risk measures, namely Value-at-Risk (VaR) and Expected Shortfall (ES). While ES is found to measure the tail risk contribution effectively, VaR is consistent with intuition only if the underlying return distribution is well behaved. To facilitate the use of ES, we present a power function formula that can calculate accurately the critical values of the ES test statistic. This in turn enables us to derive a size-based multiplication factor for risk capital requirement.
Identification of Vitronectin as an Extrinsic Inducer of Cancer Stem Cell Differentiation and Tumor Formation

There is mounting evidence that tumors are initiated by a rare subset of cells called cancer stem cells (CSCs). CSCs are generally quiescent, self‐renew, form tumors at low numbers, and give rise to the heterogeneous cell types found within a tumor. CSCs isolated from multiple tumor types differentiate both in vivo and in vitro when cultured in serum, yet the factors responsible for their differentiation have not yet been identified. Here we show that vitronectin is the component of human serum driving stem cell differentiation through an integrin αVβ3‐dependent mechanism. CSCs cultured on vitronectin result in downregulation of stem cell genes, modulation of differentiation markers, and loss of β‐catenin nuclear localization. Blocking integrin αVβ3 inhibits differentiation and subsequently tumor formation. Thus, CSCs must be engaged by one or more extracellular signals to differentiate and initiate tumor formation, defining a new axis for future novel therapies aimed at both the extrinsic and intracellular pathways. STEM CELLS 2010;28:390–398
A Video Protocol of Retroviral Infection in Primary Intestinal Organoid Culture

Lgr5-positive stem cells can be supplemented with the essential growth factors Egf, Noggin, and R-Spondin, which allows us to culture ever-expanding primary 3D epithelial structures in vitro. Both the architecture and physiological properties of these 'mini-guts', also called organoids, closely resemble their in vivo counterparts. This makes them an attractive model system for the small intestinal epithelium. Using retroviral transduction, functional genetics can now be performed by conditional gene overexpression or knockdown. This video demonstrates the procedure of organoid culture, the generation of retroviruses, and the retroviral transduction of organoids to assist phenotypic analysis of the small intestinal epithelium in vitro. This novel organotypic model system in combination with retroviral mediated gene expression provides a valuable tool for rapid analysis of gene function in vitro without the need of costly and time-consuming generation for transgenic animals.
Action Video Game Experience Related to Altered Large-Scale White Matter Networks

With action video games (AVGs) becoming increasingly popular worldwide, the cognitive benefits of AVG experience have attracted continuous research attention over the past two decades. Research has repeatedly shown that AVG experience can causally enhance cognitive ability and is related to neural plasticity in gray matter and functional networks in the brain. However, the relation between AVG experience and the plasticity of white matter (WM) network still remains unclear. WM network modulates the distribution of action potentials, coordinating the communication between brain regions and acting as the framework of neural networks. And various types of cognitive deficits are usually accompanied by impairments of WM networks. Thus, understanding this relation is essential in assessing the influence of AVG experience on neural plasticity and using AVG experience as an interventional tool for impairments of WM networks. Using graph theory, this study analyzed WM networks in AVG experts and amateurs. Results showed that AVG experience is related to altered WM networks in prefrontal networks, limbic system, and sensorimotor networks, which are related to cognitive control and sensorimotor functions. These results shed new light on the influence of AVG experience on the plasticity of WM networks and suggested the clinical applicability of AVG experience.
Sex, Parity, and Scars: A Meta‐analytic Review

The ability to identify whether a female has been pregnant or has given birth has significant implications for forensic investigations and bioarcheological research. The meaning of “scars of parturition,” their causes, and their significance are a matter of contention, with a substantial literature of re‐evaluations and tests of the relationship between pelvic scarring and parity. The aim of this study was to use meta‐analytic techniques (the methodological approach) to test whether pelvic scarring, namely dorsal pubic pitting and the preauricular groove, is a predictor of parity and sex. Meta‐analyses indicated that neither dorsal pubic pitting nor the preauricular groove are predictors of parity status, while dorsal pubic pitting is a moderate predictor of sex. A weak relationship between dorsal pubic pitting and parity was identified, but this is believed to be a product of the moderate relationship with sex. This calls into question whether any causal relationship between parity and pelvic scarring exists.
Differential Gender Response to Respiratory Infections and to the Protective Effect of Breast Milk in Preterm Infants

OBJECTIVE. The protective role of breastfeeding against severe acute lung disease in infants is well established, but its mechanism is unclear. Most hypotheses assume that breastfeeding confers similar passive protection to every infant; however, a few observations have suggested that the benefits of breast milk against severe lung disease may differ according to gender. The objective of this study was to determine whether the effect of breastfeeding on susceptibility to severe acute lung disease among infants at high risk is different for girls and boys. METHODS. A cohort was analyzed prospectively by use of 2 different strategies: (1) predictors of first episode of rehospitalization by univariate and multivariate analyses using robust Poisson regression and (2) mean number of rehospitalizations between groups using multiple regression negative binomial models. RESULTS. A total of 119 high-risk, very low birth weight infants were enrolled. Breast milk protected girls but not boys against severe acute lung disease. The interaction between breastfeeding and gender was clinically and statistically significant, even after adjustment for variables that can affect severity of acute lung disease. Disease was most severe in formula-fed girls (versus formula-fed boys). CONCLUSIONS. Breastfeeding decreased the risk for severe acute lung disease in girls but not in boys. These findings suggest that breast milk protection is not universally conferred by passive transfer of humoral immunity (which should be gender indifferent), show that respiratory symptoms may be amenable to nonspecific modulation, and identify nonbreastfed preterm infant girls as an at-risk group for severe acute lung disease.
Pricing, Caching Selection, and Content Delivery in Wireless Networks: A Hierarchical Approach

Caching content at the edge of the network is a promising way to improve content delivery efficiency. In most existed research, content caching strategies are typically designed to maximize local hit rates, improve energy efficiency or reduce network cost. However, this metric cannot guarantee the utility of content providers (CPs). To encounter with this challenge, we construct a hierarchical content distribution problem, within this which, two layers are included called caching selection and content delivery, respectively. The former layer intends to find content caching places, i.e. service providers(SPs) for contents while guaranteeing CP's utility, and the latter layer utilizes multi-seller multi-buyer multi- content trading auction (MMMTA) to characterize the competition between the SPs and users. To solve the proposed problem, a hierarchical content distribution iteration (HCDI) method is designed. Various simulation results show the property of the proposed scheme.
Developmental Benefits of Extracurricular Sports Participation Among Brazilian Youth

Youth sporting activities have been explored as a way to impact positive personal transformation and development, glaringly demonstrated by world-wide investments in public policies, programs, and projects. We studied positive effects of participation in sports on the developmental assets of 614 adolescents (13.1 ± 1.7 years) actively engaged in extracurricular sport programs targeted at socially disadvantaged youths, from five municipalities across five states of the southern, south-eastern and north-eastern regions of Brazil. Participants responded to a developmental assets questionnaire designed to capture sociodemographic and human development data. Multilevel logistic regression was used to explore associations between years of participation in sport and human development indicators, controlling for age and sex. Our results showed that the quality of the young people’s support network and duration of program participation positively influenced sport participation, which, in turn, was associated with willingness to learn. A strong association was also observed between sport participation and developmental assets. Thus, we offer new evidence of a relationship between positive development and environmental factors in which individual and contextual forces can be aligned, and we provide new reference data for developing countries.
Unconscious fearful body expression perception enhances discrimination of conscious anger expressions under continuous flash suppression

The continuous flash suppression (CFS) paradigm has been increasingly used to study unconscious visual perception. To compare to lesion and backward masking studies, we bilaterally presented whole-body postures expressing fear or anger in an emotion discrimination task, and rendered the stimuli invisible in one of the visual fields. We found that the CFS paradigm did not sustain the classical redundant target effect that would facilitate responses when the unconscious emotional bodies had congruent emotions; instead we found a facilitation effect on reaction times induced by the body stimuli of incongruent emotions, especially by the unconscious fearful body on the discrimination of conscious angry body. Our result with healthy participants showed similarities to hemianopia patients without blindsight, but not to blindsight or neglect patients, indicating that unconscious visual processing is not a single phenomenon, but is likely to involve multiple processes and brain regions. Further studies are necessary to validate the facilitation effect of fearful bodies on other tasks, and to study the neural substrates of this effect.
Extrastriatal dopamine D2/3 receptors and cortical grey matter volumes in antipsychotic-naïve schizophrenia patients before and after initial antipsychotic treatment

Abstract Objectives: Long-term dopamine D2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D2/3 receptor binding potentials (BPND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment. Methods: Twenty-two initially antipsychotic-naïve patients underwent magnetic resonance imaging (MRI), [123I]epidepride single-photon emission computerised tomography (SPECT), and psychopathology assessments before and after 3 months of treatment with either risperidone (N = 13) or zuclopenthixol (N = 9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT. Results: Neither extrastriatal D2/3 receptor BPND at baseline, nor blockade at follow-up, was related to regional cortical volume changes. In post-hoc analyses excluding three patients with cannabis use we found that higher D2/3 receptor occupancy was significantly associated with an increase in right frontal grey matter volume. Conclusions: The present data do not support an association between extrastriatal D2/3 receptor blockade and extrastriatal grey matter loss in the early phases of schizophrenia. Although inconclusive, our exclusion of patients tested positive for cannabis use speaks to keeping attention to potential confounding factors in imaging studies.