Miracle-dz/UniFAR-FTUs huggingface dataset:
Good from far, but far from good: The impact of a reference genome on evolutionary inference

Genomic diversity and past population histories are key considerations in the fields of conservation and evolutionary biology. In this issue of Molecular Ecology Resources, Prasad et al. (Mol. Ecol. Resour., 2021) examine how the quality and phylogenetic divergence of reference genomes influences the outcomes of downstream analyses such as diversity and demographic history inference. Using the beluga whale and rowi kiwi as examples (Figure 1), they systematically estimate heterozygosity, runs of homozygosity (ROH), and demographic history (PSMC) using reference genomes of varying quality and phylogenetic divergence from the target species. They show that demographic history analyses are impacted by phylogenetic distance, although this is not pronounced until divergence exceeds 3% from the target species. Similarly, their results imply that heterozygosity estimates are dependent on phylogenetic distance and the method used to perform the estimates, and ROHs are potentially undetectable when a nonconspecific reference is used. This investigation into the role of divergence and quality of reference genomes highlights the impact and potential biases generated by genome selection on downstream analyses, and provides a possible alternative in cross‐species scaffolding in instances where a conspecific reference genome is not available.
KIF13B-mediated VEGFR2 trafficking is essential for vascular leakage and metastasis in vivo

The cancer cells secrete VEGF, which induces vascular leakage and metastasis. Inhibition of VEGFR2 trafficking to the cell surface prevents receiving VEGF, vascular leakage, and cancer metastasis. VEGF-A induces vascular leakage and angiogenesis via activating the cell surface localized receptor VEGF receptor 2 (VEGFR2). The amount of available VEGFR2 at the cell surface is however tightly regulated by trafficking of VEGFR2 by kinesin family 13 B (KIF13B), a plus-end kinesin motor, to the plasma membrane of endothelial cells (ECs). Competitive inhibition of interaction between VEGFR2 and KIF13B by a peptide kinesin-derived angiogenesis inhibitor (KAI) prevented pathological angiogenesis in models of cancer and eye disease associated with defective angiogenesis. Here, we show the protective effects of KAI in VEGF-A-induced vascular leakage and cancer metastasis. Using an EC-specific KIF13B knockout (Kif13biECKO) mouse model, we demonstrated the function of EC expressed KIF13B in mediating VEGF-A-induced vascular leakage, angiogenesis, tumor growth, and cancer metastasis. Thus, KIF13B-mediated trafficking of VEGFR2 to the endothelial surface has an essential role in pathological angiogenesis induced by VEGF-A, and is therefore a potential therapeutic target.
Intrapersonal and Social Factors for Problematic Internet Use among Students during the COVID-19 Pandemic.

BACKGROUND During the lockdown due to COVID-19, Internet use may become more frequent in students, with possible negative consequences on mental health. In this emergency situation, variables such as depression, anxiety and external locus of control could be related to a Problematic Internet Use; on the other hand, self-esteem, internal locus of control, self-efficacy, and social support can play the role of protective factors for Problematic Internet Use. The present survey aims to verify the impact of these intrapersonal and social factors on Problematic Internet Use in college and High School students during the COVID-19 pandemic through a web-based cross-sectional study. SUBJECTS AND METHODS 191 students from Lombardy, one of the Italian Regions among the most affected by the COVID-19 pandemic, were included in the study. An online questionnaire has been administered during the first Italian period of forced lockdown. A logistic regression analysis was performed to assess intrapersonal and social factors as predictors of Problematic Internet Use. RESULTS Analysis highlighted a higher risk of Problematic Internet Use (5.77 times more) in males compared to females. Individuals with high external locus of control and severe depression have respectively 6.56 and 2.84 times more the risk of presenting Problematic Internet Use. In contrast, social support, self-efficacy, and self-esteem were negatively related to Problematic Internet Use. In total sample, the percentage of Problematic Internet Use was high (55.5%). CONCLUSIONS An increasing use of the Internet has been observed during lockdown, leading to a progressive increase in the diffusion of Problematic Internet Use. Gender, depression and external locus of control emerge as risk factors for Problematic Internet Use, while social support, self-efficacy and self-esteem represent protective factors. The current research identifies some intrapersonal and social factors in an epidemic context for which the development of effective behavioural, supportive and/or educational interventions would be appropriate.
Reliability and validity of a Spanish-language measure assessing clinical capacity to sustain Paediatric Early Warning Systems (PEWS) in resource-limited hospitals

Background Paediatric Early Warning Systems (PEWSs) improve identification of deterioration, however, their sustainability has not been studied. Sustainability is critical to maximise impact of interventions like PEWS, particularly in low-resource settings. This study establishes the reliability and validity of a Spanish-language Clinical Sustainability Assessment Tool (CSAT) to assess clinical capacity to sustain interventions in resource-limited hospitals. Methods Participants included PEWS implementation leadership teams of 29 paediatric cancer centres in Latin America involved in a collaborative to implement PEWS. The CSAT, a sustainability assessment tool validated in high-resource settings, was translated into Spanish and distributed to participants as an anonymous electronic survey. Psychometric, confirmatory factor analysis (CFA), and multivariate analyses were preformed to assess reliability, structure and initial validity. Focus groups were conducted after participants reviewed CSAT reports to assess their interpretation and utility. Results The CSAT survey achieved an 80% response rate (n=169) with a mean score of 4.4 (of 5; 3.8–4.8 among centres). The CSAT had good reliability with an average internal consistency of 0.77 (95% CI 0.71 to 0.81); and CFAs supported the seven-domain structure. CSAT results were associated with respondents’ perceptions of the evidence for PEWS, its implementation and use in their centre, and their assessment of the hospital culture and implementation climate. The mean CSAT score was higher among respondents at centres with longer time using PEWS (p<0.001). Focus group participants noted the CSAT report helped assess their centre’s clinical capacity to sustain PEWS and provided constructive feedback for improvement. Conclusions We present information supporting the reliability and validity of the CSAT tool, the first Spanish-language instrument to assess clinical capacity to sustain evidence-based interventions in hospitals of variable resource levels. This assessment demonstrates a high capacity to sustain PEWS in these resource-limited centres with improvement over time from PEWS implementation.
Uncovering a conserved vulnerability site in SARS‐CoV‐2 by a human antibody

An essential step for SARS‐CoV‐2 infection is the attachment to the host cell receptor by its Spike receptor‐binding domain (RBD). Most of the existing RBD‐targeting neutralizing antibodies block the receptor‐binding motif (RBM), a mutable region with the potential to generate neutralization escape mutants. Here, we isolated and structurally characterized a non‐RBM‐targeting monoclonal antibody (FD20) from convalescent patients. FD20 engages the RBD at an epitope distal to the RBM with a KD of 5.6 nM, neutralizes SARS‐CoV‐2 including the current Variants of Concern such as B.1. 1.7, B.1. 351, P.1, and B.1. 617.2 (Delta), displays modest cross‐reactivity against SARS‐CoV, and reduces viral replication in hamsters. The epitope coincides with a predicted “ideal” vulnerability site with high functional and structural constraints. Mutation of the residues of the conserved epitope variably affects FD20‐binding but confers little or no resistance to neutralization. Finally, in vitro mode‐of‐action characterization and negative‐stain electron microscopy suggest a neutralization mechanism by which FD20 destructs the Spike. Our results reveal a conserved vulnerability site in the SARS‐CoV‐2 Spike for the development of potential antiviral drugs.
CV2/CRMP5-antibody-related Paraneoplastic Neurologic Syndrome Associated with Gastrointestinal Stromal Tumor

Paraneoplastic neurological syndrome (PNS) is a heterogeneous group of neurological disorders caused by immune-mediated inflammatory mechanisms. We herein report a 77-year-old man with CV2/CRMP5-antibody-related PNS associated with a gastrointestinal stromal tumor (GIST). He was admitted for forgetfulness and delusional behavior. His neurological symptoms were subacute, and a whole-body examination revealed a gastric GIST. Serology showed CV2/collapsin response mediator protein (CRMP)-5 antibodies. Partial gastrectomy was performed for the GIST, and the neurological symptoms and serum CV2/CRMP5 antibodies disappeared. No relapse has occurred since the surgery. PNS should be considered in patients with subacute neurological disorders.
Coprinopsis cinerea Uses Laccase Lcc9 as a Defense Strategy To Eliminate Oxidative Stress during Fungal‐Fungal Interactions

The overproduction of laccase during interspecific fungal interactions is well known. However, the exact role of the upregulated laccases remains underexplored. ABSTRACT Frequently, laccases are triggered during fungal cocultivation for overexpression. The function of these activated laccases during coculture has not been clarified. Previously, we reported that Gongronella sp. w5 (w5) (Mucoromycota, Mucoromycetes) specifically triggered the laccase Lcc9 overexpression in Coprinopsis cinerea (Basidiomycota, Agaricomycetes). To systematically analyze the function of the overexpressed laccase during fungal interaction, C. cinerea mycelia before and after the initial Lcc9 overexpression were chosen for transcriptome analysis. Results showed that accompanied by specific utilization of fructose as carbohydrate substrate, oxidative stress derived from antagonistic compounds secreted by w5 appears to be a signal critical for laccase production in C. cinerea. A decrease in reactive oxygen species (ROS) in the C. cinerea wild-type strain followed the increase in laccase production, and then lcc9 transcription and laccase activity stopped. By comparison, increased H2O2 content and mycelial ROS levels were observed during the entire cocultivation in lcc9 silenced C. cinerea strains. Moreover, lcc9 silencing slowed down the C. cinerea mycelial growth, affected hyphal morphology, and decreased the asexual sporulation in coculture. Our results showed that intracellular ROS acted as signal molecules to stimulate defense responses by C. cinerea with the expression of oxidative stress response regulator Skn7 and various detoxification proteins. Lcc9 takes part in a defense strategy to eliminate oxidative stress during the interspecific interaction with w5. IMPORTANCE The overproduction of laccase during interspecific fungal interactions is well known. However, the exact role of the upregulated laccases remains underexplored. Based on comparative transcriptomic analysis of C. cinerea and gene silencing of laccase Lcc9, here we show that oxidative stress derived from antagonistic compounds secreted by Gongronella sp. w5 was a signal critical for laccase Lcc9 production in Coprinopsis cinerea. Intracellular ROS acted as signal molecules to stimulate defense responses by C. cinerea with the expression of oxidative stress response regulator Skn7 and various detoxification proteins. Ultimately, Lcc9 takes part in a defense strategy to eliminate oxidative stress and help cell growth and development during the interspecific interaction with Gongronella sp. w5. These findings deepened our understanding of fungal interactions in their natural population and communities.
Differential expression analysis of CCDC107 and RMRP lncRNA as potential biomarkers in colorectal cancer diagnosis

Abstract Long noncoding RNAs (lncRNAs) have been found to be correlated with different cell biological processes and progression of various types of cancers including colorectal cancer (CRC). CRC is one of the most widespread cancers, thus, introducing new methods or biomarkers for its early diagnosis are desirable. The Crucial role of RMRP lncRNA and its nearby gene, CCDC107, has been shown in numerous types of malignancies. The current study aims to compare expression of CCDC107 and RMRP in CRC and its adjacent normal tissues. For this study, RT-qPCR was applied to evaluate the expression level of candidate gene and lncRNA in 72 CRC cases. ROC curve was plotted to examine the diagnostic capacity. Additionally, for more supporting data, The Cancer Gene Atlas (TCGA, Firehose Legacy) dataset hosted by the cBioportal server and GEPIA online database were enrolled to investigate the effect of both genes expression level on clinicopathological parameters. We observed expression of CCDC107 was significantly down-regulated in the patients group (p < 0.05) which was associated with poor disease-free survival, friction genome alteration and surgical margin status. In contrast, RMRP expression was not significantly altered in CRC versus normal tissues. ROC curve analysis revealed that the area under the curve (AUC) for CCDC107 and RMRP were 0.871 and 0.5, respectively. Additionally, expression of these two genes did not change significantly in different stages of the disease. In conclusion, CCDC107 significantly decreased in colorectal tumor samples and can be considered as a biomarker for diagnostic aims in CRC, but not RMRP.
Phase II study of chidamide in combination with cisplatin in patients with metastatic triple-negative breast cancer.

BACKGROUND Platinum-based regimens are the mainstay treatments for advanced triple-negative breast cancer (TNBC). Preclinical studies have shown that the histone deacetylase (HDAC) inhibitor chidamide induced antitumor effects in TNBC, and chidamide plus chemotherapy was shown to be tolerable in several malignancies. This study sought to investigate the efficacy and safety of a combination treatment of chidamide and cisplatin in metastatic TNBC patients. METHODS In this phase II, single-arm study, women with metastatic TNBC were administered chidamide (20 mg twice weekly for 2 weeks on a 21-day cycle) and cisplatin (75 mg/m2 on a 21-day cycle). The primary endpoint was the objective response rate (ORR) by RECIST 1.1. The severity of adverse events was measured by the CTCAE 4.03. RESULTS Sixteen patients were enrolled in this study. Of these, 15 were available for evaluation. In these 15 patients, confirmed objective responses were seen in 4 patients [26.67%, 95% confidence interval (CI): 10.9%, 51.95%]. The ORRs did not meet the predefined criteria (of a response by at least 5 of the 15 patients); thus, the study remained at stage I. The median progression-free survival (PFS) was 9.8 weeks; 4 patients had a PFS of >25 weeks. In relation to the treatment-related AEs ≥ grade 3, >2 patients had neutropenia (33%), thrombocytopenia (20%), leucopenia (20%), and vomiting (20%). CONCLUSIONS The addition of chidamide did not improve the efficacy of cisplatin in the first-line treatment against advanced TNBC; thus, the phase II clinical trial did not progress any further. Our study appears to be the first to investigate the HDAC inhibitor in TNBC patients and showed disappointing results, which should inform future studies. Future research on cisplatin-based combination treatments for TNBC should consider selecting patients based on predictive biomarkers to increase the clinical benefits.
Considering the Relevance of Childhood Religious Experiences Through Centenarian Oral Histories

The current study explored a sub-sample of 57 narrative focused on childhood religious experiences from the Oklahoma Oral History Project. Analyses identified three primary themes connected to childhood religiosity, including transmission, accessibility, and socializing. First, transmission of religiosity during childhood dependent upon a parent or grandparent. A second theme involved accessibility, which highlighted various advantages and disadvantages regarding child and family ability to attend religious services. Such opportunities and barriers were centered upon three subthemes involving rurality, transportation, and infrastructure. Finally, socializing represented a third theme. In particular, church attendance during childhood created unique opportunities for early-life socializing with family, friends, and neighbors. As a whole, key themes indicate that religiosity during childhood may be vital to the early formation of social opportunities and connections that may support positive and adaptive developmental processes in human longevity. Findings have implications relative to advancing conceptual understanding of the impact of childhood religious experience on developmental outcomes among long-lived adults.
Virtual screening of natural compounds as selective inhibitors of polo-like kinase-1 at C-terminal polo box and N-terminal catalytic domain

Abstract The over-expression of Polo-like kinase-1 (PLK1) is associated with cancer prognosis due to its pivotal role in cell proliferation. The N-terminal catalytic domain (NCD) and C-terminal polo box domain (PBD) of PLK1 are critical for the activity of the protein. Drugs that inhibit PLK1 by targeting these domains are on clinical trials, but so far, none has been approved by FDA. Thus, this study targets the two domains of PLK1 to identify compounds with inhibitory potential. Four validated e-pharmacophore models from NCD (PDB ID: 2OU7 and 4J52) and PBD (PDB ID: 5NEI and 5NN2) were used to screen over 26,000 natural compounds from NPASS database. Hits were identified after the well-fitted compounds were subjected to molecular docking study and ADME prediction. The pIC50 and electronic behaviour of the identified hits selectively targeting NCD and PBD of PLK1 were predicted via an externally validated QSAR model and quantum mechanics. The results showed that CAA180504, CAA197326, CAA74619, CAA328856 modulating PLK1 at NCD, and CBB130581, CBB230713, CBB206123, CBB12656 and CBB267117 modulating PLK1 at PBD had better molecular docking scores, pharmacokinetics and drug-like properties than NCD (volasertib) and PBD (purpurogallin) reference inhibitors. The compounds all had satisfactory inhibitory (pIC50) values which range from 6.187 to 7.157. The electronic behaviours of understudied compounds using HOMO/LUMO and global descriptive parameters revealed the atomic portion of the compounds prone to donating and accepting electrons. In conclusion, the hit compounds identified from the library of natural compounds are worthy of further experimental validation. Communicated by Ramaswamy H. Sarma
Multiplex protein analysis for the study of glaucoma

ABSTRACT Introduction Glaucoma, a leading cause of irreversible blindness in the world, is a chronic neurodegenerative disease of multifactorial origin. Extensive research is ongoing to better understand, prevent, and treat progressive degeneration of retinal ganglion cells in glaucoma. While experimental models of glaucoma and postmortem tissues of human donors are analyzed for pathophysiological comprehension and improved treatment of this blinding disease, clinical samples of intraocular biofluids and blood collected from glaucoma patients are analyzed to identify predictive, diagnostic, and prognostic biomarkers. Multiplexing techniques for protein analysis offer a valuable approach for translational glaucoma research. Areas covered This review provides an overview of the increasing applications of multiplex protein analysis for glaucoma research and also highlights current research challenges in the field and expected solutions from emerging technological advances. Expert opinion Analytical techniques for multiplex analysis of proteins can help uncover neurodegenerative processes for enhanced treatment of glaucoma and can help identify molecular biomarkers for improved clinical testing and monitoring of this complex disease. This evolving field and continuously growing availability of new technologies are expected to broaden the comprehension of this complex neurodegenerative disease and speed up the progress toward new therapeutics and personalized patient care to prevent blindness from glaucoma.
A Low-Power DNN Accelerator Enabled by a Novel Staircase RRAM Array

Enhancing the ubiquitous sensors and connected devices with computational abilities to realize visions of the Internet of Things (IoT) requires the development of robust, compact, and low-power deep neural network accelerators. Analog in-memory matrix–matrix multiplications enabled by emerging memories can significantly reduce the accelerator energy budget while resulting in compact accelerators. In this article, we design a hardware-aware deep neural network (DNN) accelerator that combines a planar-staircase resistive random access memory (RRAM) array with a variation-tolerant in-memory compute methodology to enhance the peak power efficiency by <inline-formula> <tex-math notation="LaTeX">$5.64\times $ </tex-math></inline-formula> and area efficiency by <inline-formula> <tex-math notation="LaTeX">$4.7\times $ </tex-math></inline-formula> over state-of-the-art DNN accelerators. Pulse application at the bottom electrodes of the staircase array generates a concurrent input shift, which eliminates the input unfolding, and regeneration required for convolution execution within typical crossbar arrays. Our in-memory compute method operates in charge domain and facilitates high-accuracy floating-point computations with low RRAM states, device requirement. This work provides a path toward fast hardware accelerators that use low power and low area.
The Red Edge: Bilin-Binding Photoreceptors as Optogenetic Tools and Fluorescence Reporters

This review adds the bilin-binding phytochromes to the Chemical Reviews thematic issue “Optogenetics and Photopharmacology”. The work is structured into two parts. We first outline the photochemistry of the covalently bound tetrapyrrole chromophore and summarize relevant spectroscopic, kinetic, biochemical, and physiological properties of the different families of phytochromes. Based on this knowledge, we then describe the engineering of phytochromes to further improve these chromoproteins as photoswitches and review their employment in an ever-growing number of different optogenetic applications. Most applications rely on the light-controlled complex formation between the plant photoreceptor PhyB and phytochrome-interacting factors (PIFs) or C-terminal light-regulated domains with enzymatic functions present in many bacterial and algal phytochromes. Phytochrome-based optogenetic tools are currently implemented in bacteria, yeast, plants, and animals to achieve light control of a wide range of biological activities. These cover the regulation of gene expression, protein transport into cell organelles, and the recruitment of phytochrome- or PIF-tagged proteins to membranes and other cellular compartments. This compilation illustrates the intrinsic advantages of phytochromes compared to other photoreceptor classes, e.g., their bidirectional dual-wavelength control enabling instant ON and OFF regulation. In particular, the long wavelength range of absorption and fluorescence within the “transparent window” makes phytochromes attractive for complex applications requiring deep tissue penetration or dual-wavelength control in combination with blue and UV light-sensing photoreceptors. In addition to the wide variability of applications employing natural and engineered phytochromes, we also discuss recent progress in the development of bilin-based fluorescent proteins.