Miracle-dz/UniFAR-FTUs huggingface dataset:
Silent Synapse-Based Mechanisms of Critical Period Plasticity

Critical periods are postnatal, restricted time windows of heightened plasticity in cortical neural networks, during which experience refines principal neuron wiring configurations. Here, we propose a model with two distinct types of synapses, innate synapses that establish rudimentary networks with innate function, and gestalt synapses that govern the experience-dependent refinement process. Nascent gestalt synapses are constantly formed as AMPA receptor-silent synapses which are the substrates for critical period plasticity. Experience drives the unsilencing and stabilization of gestalt synapses, as well as synapse pruning. This maturation process changes synapse patterning and consequently the functional architecture of cortical excitatory networks. Ocular dominance plasticity (ODP) in the primary visual cortex (V1) is an established experimental model for cortical plasticity. While converging evidence indicates that the start of the critical period for ODP is marked by the maturation of local inhibitory circuits, recent results support our model that critical periods end through the progressive maturation of gestalt synapses. The cooperative yet opposing function of two postsynaptic signaling scaffolds of excitatory synapses, PSD-93 and PSD-95, governs the maturation of gestalt synapses. Without those proteins, networks do not progress far beyond their innate functionality, resulting in rather impaired perception. While cortical networks remain malleable throughout life, the cellular mechanisms and the scope of critical period and adult plasticity differ. Critical period ODP is initiated with the depression of deprived eye responses in V1, whereas adult ODP is characterized by an initial increase in non-deprived eye responses. Our model proposes the gestalt synapse-based mechanism for critical period ODP, and also predicts a different mechanism for adult ODP based on the sparsity of nascent gestalt synapses at that age. Under our model, early life experience shapes the boundaries (the gestalt) for network function, both for its optimal performance as well as for its pathological state. Thus, reintroducing nascent gestalt synapses as plasticity substrates into adults may improve the network gestalt to facilitate functional recovery.
Development and Validation of a Radiomics Nomogram Based on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography and Clinicopathological Factors to Predict the Survival Outcomes of Patients With Non-Small Cell Lung Cancer

Purpose: In this study, we developed and validated a radiomics nomogram by combining the radiomic features extracted from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images and clinicopathological factors to evaluate the overall survival (OS) of patients with non-small cell lung cancer (NSCLC). Patients and Methods: A total of 315 consecutive patients with NSCLC (221 in the training cohort and 94 in the validation cohort) were enrolled in this study. A total of 840 radiomic features were extracted from the CT and PET images. Three radiomic scores (rad-scores) were calculated using the least absolute shrinkage and selection operator (LASSO) Cox regression based on subsets of CT, PET, and PET/CT radiomic features. A multivariate Cox regression analysis was performed for each rad-score combined with clinicopathological factors to determine the independent risk factors. The OS nomogram was constructed based on the PET/CT rad-score and independent clinicopathological factors. Validation and calibration were conducted to evaluate the performance of the model in the training and validation cohorts, respectively. Results: A total of 144 (45.71%) women and 171 (54.29%) men with NSCLC were enrolled in this study. The PET/CT rad-score combined with the clinical model had the best C-index (0.776 and 0.789 for the training and validation cohorts, respectively). Distant metastasis, stage, carcinoembryonic antigen (CEA), and targeted therapy were independent risk factors for patients with NSCLC. The validation curve showed that the OS nomogram had a strong predictive power in patients' survival. The calibration curve showed that the predicted survival time was significantly close to the observed one. Conclusion: A radiomic nomogram based on 18F-FDG PET/CT rad-score and clinicopathological factors had good predictive performance for the survival outcome, offering feasible, and practical guidance for individualized management of patients with NSCLC.
Local Gazetteers Reveal Contrasting Patterns of Historical Distribution Changes between Apex Predators and Mesopredators in Eastern China

Background Humans have been causing the sixth wave of mass extinction of biodiversity. The situation of predators, especially of carnivores, is a key indicator of biodiversity, and the mesopredator release is a typical phenomenon in ecosystem recess. Local gazetteers 地方志 are a rich resource for historical biodiversity research. But there are obvious biases in previous studies focusing in only presence records and neglecting the absence records. We recollected and analyze the records by fixed methods to research historical change of biodiversity. Methods Innovatively, this research uses both presence and absence records from local gazetteers to reconstruct the distribution of 8 kinds of mammalian predators (i.e. tiger, leopard, bear, wolf, fox, civet, dhole and mustelid) in eastern China from 1573 A.D. to 1949 A.D. (sorted into 4 periods). Then we analyze the distribution changes, the relation between animals and the influence from human. Results With the human population booming, the distribution of large/apex predators retreated overall, but the distribution of mesopredators expanded overall. Besides, the predator distribution relations formed different groups, not match the body size groups totally. Conclusions Based on our reconstructions, we provide direct proof of human disturbance on mammal distribution in China, and extend support for the mesopredator release hypothesis. And we tested the predator guild hypothesis by proving that dhole were successful to coexist with tiger and leopard in history. Prospects We have also collected records for other wild animals from local gazetteers in China. Based on the collection, we have built the Database of Wild Mammal Records in Chinese Local Gazetteers and are building the Database of Wild Bird Records in Chinese Local Gazetteers. We aim to continue relevant studies using these databases in the future.
Healthcare Workers' Perspectives on the Barriers to Providing HIV Services to Children in Sub-Saharan Africa

Background In order to accelerate the HIV response to meet the UNAIDS 90-90-90 indicators for children, healthcare workers need to lead a scale-up of HIV services in primary healthcare settings. Such a scale-up will require investigation into existing barriers that prevent healthcare workers from effectively providing those services to children. Furthermore, if the identified barriers are not well understood, designing context-specific and effective public health response programmes may prove difficult. Objective This study reviews the current literature pertaining to healthcare workers' perspectives on the barriers to providing HIV services to children in the primary care setting in Sub-Saharan Africa. Methods English articles published between 2010 and April 2018 were searched in electronic databases including Sabinet, MEDLINE, PubMed, and Google Scholar. Key search words used during the search were “healthcare workers' perspectives” and “barriers to providing HIV testing to children” OR “barriers to ART adherence AND children” and “barriers to HIV disclosure AND children. ” Results. There are various barriers to provider-initiated counselling and testing (PICT) of children and disclosure of HIV status to children, including the following: lack of child-friendly infrastructure at clinics; lack of consensus on legal age of consent for both HIV testing and disclosure; healthcare worker unfamiliarity with HIV testing and disclosure guidelines; lack of training in child psychology; and confusion around the healthcare worker's role, which most believed was only to provide health education and clinical services and to correct false information, but not to participate in disclosure. Additionally, primary caregivers were reported to be a barrier to care and treatment of children as they continue to refuse HIV testing for their children and delay disclosure. Conclusion Training, mentoring, and providing healthcare workers with guidelines on how to provide child-focused HIV care have the potential to address the majority of the barriers to the provision of child-friendly HIV services to children. However, the need to educate primary caregivers on the importance of testing children and disclosing to them is equally important.
Barriers to Biodiversity Conservation in Forest Certification

In searching for the meek voice of the biologist among proponents of timber certification, Elizabeth Bennett decries the paucity of attention to biodiversity and conservation in current certification guidelines and raises important issues about their inclusion in sustainability criteria for certification (Bennett 2000). In particular, she asserts that biodiversity and conservation are poorly represented among the principles and guidelines that define certification schemes. There are few principles concerned with wildlife, and those that are use criteria that "are so general and undefined that they are meaningless" (Bennett 2000). Bennett concludes that certification standards must be expanded to include the effects of logging on forest biodiversity and ecology. I agree, but why is the biologist's voice not more loudly and widely heard? I propose two reasons: (1) a lack of confidence in certification as a mechanism for achieving ecologically sustainable production in natural forests and (2) the conceptual and practical difficulties of incorporating objective guidelines for assessing biological diversity in a production forest context. The first of these is more easily explained. Certification is certainly a promising and interesting approach to ensuring sustainable production of timber products, but its adoption has been polarized, with the majority of certified companies operating in the developed world where the conservation crisis is perhaps less acute and biodiversity less complex. Demonstrating ecological sustainability is beyond the capacity of many tropical forest managers, who are blessed with high biodiversity in the forests they manage, but constrained in their actions by inadequate technical, financial, and human resources. Some large timber-producing operations in tropical countries have sought, and obtained, certification, but almost all of these are plantation forests where biodiversity values and conservation benefits are low. Furthermore, and it is here where I depart from Bennett's analysis, the recent downturn in Asian economies is more likely to en-
Causal inference in environmental sound recognition

Sound is caused by physical events in the world. Do humans infer these causes when recognizing sound sources? We tested whether the recognition of common environmental sounds depends on the inference of a basic physical variable – the source intensity (i.e. the power that produces a sound). A source’s intensity can be inferred from the intensity it produces at the ear and its distance, which is normally conveyed by reverberation. Listeners could thus use intensity at the ear and reverberation to constrain recognition by inferring the underlying source intensity. Alternatively, listeners might separate these acoustic cues from their representation of a sound’s identity in the interest of invariant recognition. We compared these two hypotheses by measuring recognition accuracy for sounds with typically low or high source intensity (e.g. pepper grinders vs. trucks) that were presented across a range of intensities at the ear or with reverberation cues to distance. The recognition of low-intensity sources (e.g. pepper grinders) was impaired by high presentation intensities or reverberation that conveyed distance, either of which imply high source intensity. Neither effect occurred for high-intensity sources. The results suggest that listeners implicitly use the intensity at the ear along with distance cues to infer a source’s power and constrain its identity. The recognition of real-world sounds thus appears to depend upon the inference of their physical generative parameters, even generative parameters whose cues might otherwise be separated from the representation of a sound’s identity.
PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes

The discovery that PARP1/2 inhibitors selectively kill BRCA mutant cells has led to a paradigm shift in the treatment of women with homologous recombination (HR)-deficient high-grade serous ovarian cancer (HGSOC), driving unprecedented improvements in progression-free and, more recently, overall survival. However, because most HGSOC cases are not HR-defective, and are therefore unlikely to benefit from PARPi-based therapies, additional strategies will be required to improve outcomes for women with HR-proficient disease. To develop novel therapeutic strategies, considerable attention is now being focused on inhibitors targeting PARG, the poly(ADP ribose) glycohydrolase that counterbalances PARP1/2 activity. Here we characterise ten ovarian cancer cell lines in response to the PARG inhibitor PDD00017273, hereafter PARGi. We demonstrate that six lines are resistant while four are sensitive, and that sensitivity correlates with several markers of persistent DNA replication stress, DNA damage and replication catastrophe, namely the accumulation of asymmetric DNA replication fibres, γH2AX and RPA foci, KAP1 and Chk1 phosphorylation, a pre-mitotic cell cycle block and, following prolonged exposure, a pan-nuclear γH2AX phenotype that indicates RPA exhaustion. We demonstrate that PARGi-sensitive cell lines have down-regulated DNA replication genes, including components of the fork protection complex, namely TIMELESS, TIPIN and CLASPIN. These observations suggest that a subset of HGSOC may respond to PARG inhibitors and that “replication stress” gene expression signature could serve as a predictive biomarker to guide the design of clinical trials.
Movements of Ancient Human Endogenous Retroviruses Detected in SOX2-Expressing Cells

Human endogenous retroviruses (HERVs) account for approximately 8% of the human genome; however, the physiological role of HERV-K remains unknown. This study found that HERV-K LTR5Hs and LTR5B were transactivated by SOX2, which is essential for maintaining and reestablishing pluripotency. ABSTRACT Human endogenous retroviruses (HERVs) occupy approximately 8% of the human genome. HERVs, transcribed in early embryos, are epigenetically silenced in somatic cells, except under pathological conditions. HERV-K is thought to protect embryos from exogenous viral infection. However, uncontrolled HERV-K expression in somatic cells has been implicated in several diseases. Here, we show that SOX2, which plays a key role in maintaining the pluripotency of stem cells, is critical for HERV-K LTR5Hs. HERV-K undergoes retrotransposition within producer cells in the absence of Env expression. Furthermore, we identified new HERV-K integration sites in long-term culture of induced pluripotent stem cells that express SOX2. These results suggest that the strict dependence of HERV-K on SOX2 has allowed HERV-K to protect early embryos during evolution while limiting the potentially harmful effects of HERV-K retrotransposition on host genome integrity in these early embryos. IMPORTANCE Human endogenous retroviruses (HERVs) account for approximately 8% of the human genome; however, the physiological role of HERV-K remains unknown. This study found that HERV-K LTR5Hs and LTR5B were transactivated by SOX2, which is essential for maintaining and reestablishing pluripotency. HERV-K can undergo retrotransposition within producer cells without env expression, and new integration sites may affect cell proliferation. In induced pluripotent stem cells (iPSCs), genomic impairment due to HERV-K retrotransposition has been identified, but it is a rare event. Considering the retention of SOX2-responsive elements in the HERV-K long terminal repeat (LTR) for over 20 million years, we conclude that HERV-K may play important physiological roles in SOX2-expressing cells.
The imprinted lncRNA Peg13 regulates sexual preference and the sex-specific brain transcriptome in mice

Significance Mammalian behavior is known to be influenced by genes that are expressed from only one of the parental chromosomes. The present study shows that mice carrying a specific deletion variant of the paternally expressed gene Peg13 prefer to associate with their own sex, along with additional behavioral changes. RNA expression analysis on the brains of these mice suggests that Peg13 is part of a regulatory network that governs the female–male differentiation of the brain, as well as the neurobiology of social interactions Mammalian genomes include many maternally and paternally imprinted genes. Most of these are also expressed in the brain, and several have been implicated in regulating specific behavioral traits. Here, we have used a knockout approach to study the function of Peg13, a gene that codes for a fast-evolving lncRNA (long noncoding RNA) and is part of a complex of imprinted genes on chromosome 15 in mice and chromosome 8 in humans. Mice lacking the 3′ half of the transcript look morphologically wild-type but show distinct behavioral differences. They lose interest in the opposite sex, instead displaying a preference for wild-type animals of the same sex. Further, they show a higher level of anxiety, lowered activity and curiosity, and a deficiency in pup retrieval behavior. Brain RNA expression analysis reveals that genes involved in the serotonergic system, formation of glutamatergic synapses, olfactory processing, and estrogen signaling—as well as more than half of the other known imprinted genes—show significant expression changes in Peg13-deficient mice. Intriguingly, these pathways are differentially affected in the sexes, resulting in male and female brains of Peg13-deficient mice differing more from each other than those of wild-type mice. We conclude that Peg13 is part of a developmental pathway that regulates the neurobiology of social and sexual interactions.
Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids

Significance Cells sense and respond to nutrients liberated by the degradative activity of lysosomes. PQLC2 is a transporter that mediates the efflux of lysosomal cationic amino acids and also recruits a signaling complex containing WDR41, SMCR8, and C9orf72 proteins to the surface of lysosomes by interacting with WDR41. This interaction is regulated by the availability of the amino acids that PQLC2 transports. Here we define sites of contact between PQLC2 and WDR41 and relate them to conformational changes required for transport activity of PQLC2. In addition to directly advancing our understanding of the WDR41–PQLC2 interaction, this study provides a model for how a transporter can also serve as a sensor that recruits signaling proteins to the membrane where it resides. PQLC2, a lysosomal cationic amino acid transporter, also serves as a sensor that responds to scarcity of its substrates by recruiting a protein complex composed of C9orf72, SMCR8, and WDR41 to the surface of lysosomes. This protein complex controls multiple aspects of lysosome function. Although it is known that this response to changes in cationic amino acid availability depends on an interaction between PQLC2 and WDR41, the underlying mechanism for the regulated interaction is not known. In this study, we present evidence that the WDR41–PQLC2 interaction is mediated by a short peptide motif in a flexible loop that extends from the WDR41 β-propeller and inserts into a cavity presented by the inward-facing conformation of PQLC2. The data support a transceptor model wherein conformational changes in PQLC2 related to substrate transport regulate the availability of the WDR41-binding site on PQLC2 and mediate recruitment of the WDR41-SMCR8-C9orf72 complex to the surface of lysosomes.
On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment

Dating back to the last universal common ancestor (LUCA), the P-loop NTPases and Rossmanns now comprise the most ubiquitous and diverse enzyme lineages. Intriguing similarities in their overall architecture and phosphate binding motifs suggest common ancestry; however, due to a lack of sequence identity and some fundamental structural differences, these families are considered independent emergences. To address this longstanding dichotomy, we systematically searched for ‘bridge proteins’ with structure and sequence elements shared by both lineages. We detected homologous segments that span the first βαβ segment of both lineages and include two key functional motifs: (i) a phosphate binding loop – the ‘Walker A’ motif of P-loop NTPases or the Rossmann equivalent, both residing at the N-terminus of α1; and (ii) an Asp at the tip of β2. The latter comprises the ‘Walker B’ aspartate that chelates the catalytic metal in P-loop NTPases, or the canonical Rossmann β2-Asp that binds the cofactor’s ribose moiety. Tubulin, a Rossmann GTPase, demonstrates the potential of the β2-Asp to take either one of these two roles. We conclude that common P-loops/Rossmann ancestry is plausible, although convergence cannot be completely ruled out. Regardless, both lineages most likely emerged from a polypeptide comprising a βαβ segment carrying the above two functional motifs, a segment that comprises the core of both enzyme families to this very day.
Action Imagery and Observation in Neurorehabilitation for Parkinson’s Disease (ACTION-PD): development and pilot randomised controlled trial of a user-informed home training intervention to improve everyday functional actions

Background Parkinson’s disease (PD) causes difficulties with everyday manual activities, but few studies have addressed these therapeutically. Training with action observation (AO) and motor imagery (MI) can significantly improve performance in healthy individuals, particularly when these techniques are applied simultaneously (AO+MI). Both AO and MI have shown promising effects in PD, but previous studies have used these separately. This article describes the development and pilot testing of an intervention combining AO+MI and physical practice to improve functional manual actions in PD. Methods The home-based intervention, delivered using a tablet computer app, was iteratively designed by an interdisciplinary team including people with PD, and further developed through focus groups and initial testing. The intervention was then tested in a six-week randomised controlled trial (ISRCTN 11184024) of 10 participants with mild to moderate PD (6 intervention; 4 treatment as usual). Results and Conclusions Usage and qualitative data provided preliminary evidence of acceptability and usability, indicating that a feasibility RCT is warranted. Exploratory analyses suggested potential improvements in manual actions. The importance of personalisation, choice, and motivation was highlighted, as well as the need to facilitate engagement in motor imagery. The findings also have broader relevance for AO+MI interventions in PD and other populations. IMPLICATIONS FOR REHABILITATION Parkinson’s disease affects everyday manual activities and there is a need to address these therapeutically. A home-based intervention based on combined action observation and motor imagery is acceptable and usable for people with Parkinson’s, and may improve everyday hand movements. Important considerations for interventions using observation and imagery include personalisation, choice, and motivation. Some people with Parkinson’s may need additional support to engage in motor imagery, and this should be addressed within future interventions.