Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of compounds that bind the centriolar protein SAS-6 and inhibit its oligomerization

Centrioles are key eukaryotic organelles that are responsible for the formation of cilia and flagella, and for organizing the microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerization of the essential protein spindle assembly abnormal 6 (SAS-6), which forms a structural scaffold templating the organization of further organelle components. A dimerization interaction between SAS-6 N-terminal “head” domains was previously shown to be essential for protein oligomerization in vitro and for function in centriole assembly. Here, we developed a pharmacophore model allowing us to assemble a library of low-molecular-weight ligands predicted to bind the SAS-6 head domain and inhibit protein oligomerization. We demonstrate using NMR spectroscopy that a ligand from this family binds at the head domain dimerization site of algae, nematode, and human SAS-6 variants, but also that another ligand specifically recognizes human SAS-6. Atomistic molecular dynamics simulations starting from SAS-6 head domain crystallographic structures, including that of the human head domain which we now resolve, suggest that ligand specificity derives from favorable Van der Waals interactions with a hydrophobic cavity at the dimerization site.
Specificity of Alcohol Dehydrogenase from Clostridium acetobutylicum ATCC 4259

Alcohol dehydrogenase activity of Clostridium acetobutylicum ATCC 4259 was studied for its specificity against substrates in acidogenic and solventogenic cultures. The bacterium reduces propionate, valerate and caproate added to the medium to the corresponding alcohols. Acetaldehyde, propionaldehyde, butyraldhyde, pentanal, and hexanal were used as the substrates by alcohol dehydrogenase, and all were reduced to the corresponding alcohols with varying affinities and reaction velocities. Acetaldehyde showed the lowest affinity and lowest velocity while the other aldehydes showed similar values. NADPH was used as the electron donor for the reduction of aldehydes. Alcohol dehydrogenase activity was low in acidogenic culture, and high in solventogenic culture.
Dynamics and Functions of Stress Granules and Processing Bodies in Plants

RNA granules, such as stress granules and processing bodies, can balance the storage, degradation, and translation of mRNAs in diverse eukaryotic organisms. The sessile nature of plants demands highly versatile strategies to respond to environmental fluctuations. In this review, we discuss recent findings of the dynamics and functions of these RNA granules in plants undergoing developmental reprogramming or responding to environmental stresses. Special foci include the dynamic assembly, disassembly, and regulatory roles of these RNA granules in determining the fate of mRNAs.
The Role of Active-Site Plasticity in Damaged-Nucleotide Recognition by Human Apurinic/Apyrimidinic Endonuclease APE1

Human apurinic/apyrimidinic (AP) endonuclease APE1 hydrolyzes phosphodiester bonds on the 5′ side of an AP-site, and some damaged nucleotides such as 1,N6-ethenoadenosine (εA), α-adenosine (αA), and 5,6-dihydrouridine (DHU). To investigate the mechanism behind the broad substrate specificity of APE1, we analyzed pre-steady-state kinetics of conformational changes in DNA and the enzyme during DNA binding and damage recognition. Molecular dynamics simulations of APE1 complexes with one of damaged DNA duplexes containing εA, αA, DHU, or an F-site (a stable analog of an AP-site) revealed the involvement of residues Asn229, Thr233, and Glu236 in the mechanism of DNA lesion recognition. The results suggested that processing of an AP-site proceeds faster in comparison with nucleotide incision repair substrates because eversion of a small abasic site and its insertion into the active site do not include any unfavorable interactions, whereas the insertion of any target nucleotide containing a damaged base into the APE1 active site is sterically hindered. Destabilization of the α-helix containing Thr233 and Glu236 via a loss of the interaction between these residues increased the plasticity of the damaged-nucleotide binding pocket and the ability to accommodate structurally different damaged nucleotides. Nonetheless, the optimal location of εA or αA in the binding pocket does not correspond to the optimal conformation of catalytic amino acid residues, thereby significantly decreasing the cleavage efficacy for these substrates.
Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Renal cancer ranks twelfth in incidence among cancers worldwide. Despite improving outcomes due to better therapeutic options and strategies, prognosis for those with metastatic disease remains poor. Current systemic therapeutic approaches include inhibiting pathways of angiogenesis, immune checkpoint blockade, and mTOR inhibition, but inevitably resistance develops for those with metastatic disease, and novel treatment strategies are urgently needed. Emerging molecular and epidemiological evidence suggests that quinazoline-based α1-adrenoceptor-antagonists may have both chemopreventive and direct therapeutic actions in the treatment of urological cancers, including renal cancer. In human renal cancer cell models, quinazoline-based α1-adrenoceptor antagonists were shown to significantly reduce the invasion and metastatic potential of renal tumors by targeting focal adhesion survival signaling to induce anoikis. Mechanistically these drugs overcome anoikis resistance in tumor cells by targeting cell survival regulators AKT and FAK, disrupting integrin adhesion (α5β1 and α2β1) and engaging extracellular matrix (ECM)-associated tumor suppressors. In this review, we discuss the current evidence for the use of quinazoline-based α1-adrenoceptor antagonists as novel therapies for renal cell carcinoma (RCC) and highlight their potential therapeutic action through overcoming anoikis resistance of tumor epithelial and endothelial cells in metastatic RCC. These findings provide a platform for future studies that will retrospectively and prospectively test repurposing of quinazoline-based α1-adrenoceptor-antagonists for the treatment of advanced RCC and the prevention of metastasis in neoadjuvant, adjuvant, salvage and metastatic settings.
Copper sulphate enhanced synthesis of azurin from Pseudomonas aeruginosa MTCC 2453

The secondary metabolites from microorganisms play a vital role in developing new chemotherapeutics. Azurin a blue copper protein have redox properties plays a role in electron transfer as donors. Azurin reported as a potential anticancer protein against breast cancer cell lines which evoked biomedical researchers to develop an alternate method for enhanced production of azurin. Early researchers revealed the synthesis of blue copper protein azurin from different microbial sources, especially from pseudomonas aeruginosa ( P. aeruginosa ) this study is concerned about the azurin synthesis from P. aeruginosa MTCC 2453 with evident homogeneity by modified methods. The growth of P. aeruginosa strains 2453 for the synthesis of azurin were monitored for enhanced azurin production. The purity of the enhanced azurin synthesis was evaluated by MALDI and SDS- PAGE. The synthesis of azurin was enhanced by adding copper sulphate (5µg/ml) and KNO 3 (0.02 µg/ml) in to the media under facultative anaerobic condition. A 250 g dry cell paste of ps. aeruginosa yields 3.95 mg/g of azurin. High yield was reported in P. aeruginosa 2453 strain than other strains.
Tofacitinib, the First Oral Janus Kinase Inhibitor Approved for Adult Ulcerative Colitis

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterized by chronic gastrointestinal inflammation. In most patients, the disease cycles through periods of remission and exacerbations. The complex etiology involves multiple factors including environmental, genetic, and immune causal elements. Janus Kinase (JAK) family is an essential component of a cytokine-signaling cascade partially responsible for the pathogenesis of UC. Treating UC presents difficulties despite various therapeutic options. Medications that block the JAK-signaling pathway can interfere with the inflammatory pathway of UC and possibly reduce symptoms and frequency of exacerbations. Tofacitinib is an oral pan-JAK inhibitor, primarily of JAK1 and JAK3, that was recently approved by the Food and Drug Administration (FDA) for the chronic treatment of UC in 2018. The following review describes the newly approved Janus kinase inhibitor, tofacitinib, including its pharmacokinetic properties, efficacy and safety data, and potential place in therapy.
Neurodegeneration, Myelin Loss and Glial Response in the Three-Vessel Global Ischemia Model in Rat

(1) Background: Although myelin disruption is an integral part of ischemic brain injury, it is rarely the subject of research, particularly in animal models. This study assessed for the first time, myelin and oligodendrocyte loss in a three-vessel model of global cerebral ischemia (GCI), which causes hippocampal damage. In addition, we investigated the relationships between demyelination and changes in microglia and astrocytes, as well as oligodendrogenesis in the hippocampus; (2) Methods: Adult male Wistar rats (n = 15) underwent complete interruption of cerebral blood flow for 7 min by ligation of the major arteries supplying the brain or sham-operation. At 10 and 30 days after the surgery, brain slices were stained for neurodegeneration with Fluoro-Jade C and immunohistochemically to assess myelin content (MBP+ percentage of total area), oligodendrocyte (CNP+ cells) and neuronal (NeuN+ cells) loss, neuroinflammation (Iba1+ cells), astrogliosis (GFAP+ cells) and oligodendrogenesis (NG2+ cells); (3) Results: 10 days after GCI significant myelin and oligodendrocyte loss was found only in the stratum oriens and stratum pyramidale. By the 30th day, demyelination in these hippocampal layers intensified and affected the substratum radiatum. In addition to myelin damage, activation and an increase in the number of microglia and astrocytes in the corresponding layers, a loss of the CA1 pyramidal neurons, and neurodegeneration in the neocortex and thalamus was observed. At a 10-day time point, we observed rod-shaped microglia in the substratum radiatum. Parallel with ongoing myelin loss on the 30th day after ischemia, we found significant oligodendrogenesis in demyelinated hippocampal layers; (4) Conclusions: Our study showed that GCI-simulating cardiac arrest in humans—causes not only the loss of pyramidal neurons in the CA1 field, but also the myelin loss of adjacent layers of the hippocampus.
The ownership of digital infrastructure: Exploring the deployment of software libraries in a digital innovation cluster

Boundary resources have been shown to enable the arm’s-length relationships between platform owners and third-party developers that underlie digital innovation in platform ecosystems. While boundary resources that are owned by open-source communities and small-scale software vendors are also critical components in the digital infrastructure, their role in digital innovation has yet to be systematically explored. In particular, software libraries are popular boundary resources that provide functionality without the need for continued interaction with their owners. They are used extensively by commercial vendors to enable customization of their software products, by communities to disseminate open-source software, and by big-tech platform owners to provide functionality that does not involve control. This article reports on the deployment of such software libraries in the web and mobile (Android) contexts by 107 start-up companies in London. Our findings show that libraries owned by big-tech companies, product vendors, and communities coexist; that the deployment of big-tech libraries is unaffected by the scale of the deploying start-up; and that context evolution paths are consequential for library deployment. These findings portray a balanced picture of digital infrastructure as neither the community-based utopia of early open-source research nor the dystopia of the recent digital dominance literature.
Preliminary study on the adhesive properties and mechanisms of three probiotic strains

Objective To study the adhesive properies of three probiotic strains and elucidate the phenomena of bacterial adhesion to intestinal cells.Methods Employing the well-investigated L.rhamnosus GG as a positive control,microscopic examination and plate counting were used to study the adhesive ability of three Lactobacilli to human enterocyte-like Caco-2 cells;hydrophobicity,surface charge,and autoaggregation were used to describe the bacterial cell surface properties;the carbohydrate-binding specificities were also studied by adhesion-inhibition assay and yeast agglutination.Results It was shown that L.plantarum ST-Ⅲ was the most adhesive strain among the four tested strains as determined by both microscopical examination and plate counting.When the ratio of bacterial cells to Caco-2 cells reached 60∶[KG-*3/5]1,the average cells of L.plantarum ST-Ⅲ adhered on Caco-2 was(7.43 ± 0.65) CFU/cell,which was higher than those of L.rhamnosus GG[(3.99 ± 0.57)CFU/cell]. There was a good correlation between the adhesive abilty and hydrophobicity of the tested strains,and the enhancement of the adhesive abilty by autoaggregation was also observed.Except for L.rhamnosus GG,the adhesion of the other three Lactobacillus strains to Caco-2 cells were inhibited by D-mannose and methyl-α-D-mannopyranoside,which could also agglutinate cells of Saccharomyces cerevisiae to different levels.Conclusions Together,these findings suggested that the nonspecific-hydrophobic and mannose-specific interactions were both involved in the adhesion of the three Lactobacillus strains,among which L.plantarum STⅢ was a probiotic strain with high adhesive ability,which could be further investigated.
Secondary Students’ Preferences for Various Learning Conditions and Music Courses: A Comparison of School Music, Out-of-School Music, and Nonmusic Participants

This study was an investigation of middle and high school students’ preferences for various music learning conditions and secondary music course offerings. The stratified random sample included students who were and were not enrolled in school music classes (N = 827). Participants represented secondary school music students (n = 369), students who only participate in music outside of school (n = 254), and nonparticipants in music (n = 204). The research questions for this study concerned students’ preferences for teacher role, group size, and repertoire in the music classroom as well as interest in six different secondary music courses. Findings showed out-of-school music participants and nonparticipants had a stronger preference for small group learning environments and repertoire choice when compared to school music participants. In-school and out-of-school music participants expressed similar levels of interest in four music course offerings and ranked them as follows: (1) piano/guitar class, (2) music composition with technology class, (3) popular music groups, and (4) music history/theory class. In-school and out-of-school music participants differed on only two course offerings: large ensembles and world music groups. In-school music participants expressed high interest in large ensembles, whereas out-of-school music participants conveyed a lower interest in large ensembles.
Presynaptic L-Type Ca2+ Channels Increase Glutamate Release Probability and Excitatory Strength in the Hippocampus during Chronic Neuroinflammation

Neuroinflammation is involved in the pathogenesis of several neurologic disorders, including epilepsy. Both changes in the input/output functions of synaptic circuits and cell Ca2+ dysregulation participate in neuroinflammation, but their impact on neuron function in epilepsy is still poorly understood. Lipopolysaccharide (LPS), a toxic byproduct of bacterial lysis, has been extensively used to stimulate inflammatory responses both in vivo and in vitro. LPS stimulates Toll-like receptor 4, an important mediator of the brain innate immune response that contributes to neuroinflammation processes. Although we report that Toll-like receptor 4 is expressed in both excitatory and inhibitory mouse hippocampal neurons (both sexes), its chronic stimulation by LPS induces a selective increase in the excitatory synaptic strength, characterized by enhanced synchronous and asynchronous glutamate release mechanisms. This effect is accompanied by a change in short-term plasticity with decreased facilitation, decreased post-tetanic potentiation, and increased depression. Quantal analysis demonstrated that the effects of LPS on excitatory transmission are attributable to an increase in the probability of release associated with an overall increased expression of L-type voltage-gated Ca2+ channels that, at presynaptic terminals, abnormally contributes to evoked glutamate release. Overall, these changes contribute to the excitatory/inhibitory imbalance that scales up neuronal network activity under inflammatory conditions. These results provide new molecular clues for treating hyperexcitability of hippocampal circuits associated with neuroinflammation in epilepsy and other neurologic disorders. SIGNIFICANCE STATEMENT Neuroinflammation is thought to have a pathogenetic role in epilepsy, a disorder characterized by an imbalance between excitation/inhibition. Fine adjustment of network excitability and regulation of synaptic strength are both implicated in the homeostatic maintenance of physiological levels of neuronal activity. Here, we focused on the effects of chronic neuroinflammation induced by lipopolysaccharides on hippocampal glutamatergic and GABAergic synaptic transmission. Our results show that, on chronic stimulation with lipopolysaccharides, glutamatergic, but not GABAergic, neurons exhibit an enhanced synaptic strength and changes in short-term plasticity because of an increased glutamate release that results from an anomalous contribution of L-type Ca2+ channels to neurotransmitter release.
Is the deinstitutionalisation of alternative care a ‘wicked problem’? A qualitative study exploring the perceptions of child welfare practitioners and policy actors in Thailand

This study examined deinstitutionalisation in Thailand. Qualitative interviews were conducted with a total of 27 child welfare practitioners and policy actors to explore their perceptions of Thai alternative care provision. Findings show that participants perceive deinstitutionalisation as a complex policy challenge. Some felt that the institutions were necessary in order to meet demand, while others felt that cultural barriers prevent a shift to family-based approaches, such as foster care. However, data suggest that it would be difficult to characterise deinstitutionalisation as a ‘wicked policy problem’ as participants were hopeful for change, citing increased family- strengthening policies alongside efforts to implement foster care.
Genetic and epigenetic modifications of HPDL and SOX17 associated with breast cancer prognosis: a study based on The Cancer Genome Atlas

Background：The high heterogeneity of breast cancer (BRCA) makes it more challenging to interpret the genetic variation mechanisms involved in BRCA pathogenesis and prognosis. Areas with high DNA methylation (such as CpG islands) were accompanied by copy number variation (CNV), and these genomic variations affected the level of DNA methylation. Methods: In this study, we characterized inter-tumor heterogeneity and analyzed the effects of CNV on DNA methylation and gene expression. In addition, we performed a Genetic Set Enrichment Analysis (GSEA) to identify key pathways for changes between patients with low and high expression of genes. Results: Our analysis found that the CNV of HPDL and SOX17 is not only related to the patient's prognosis, but also related to gene methylation and expression levels affecting the patient's survival time. Conclusion: This study provided an effective bioinformatics basis for further exploration of molecular mechanisms related to BRCA and assessment of patient prognosis, but the development of biomarkers for diagnosis and treatment still requires further clinical data validation.
Inhaled corticosteroid use in COVID-19

Background Recent evidence has established a beneficial effect of systemic corticosteroids for treatment of moderate-to-severe COVID-19. However, it is unknown if inhaled corticosteroid use is associated with reduced morbidity of the disease. Methods In a nationwide cohort of hospitalized SARS-CoV-2 test-positive individuals in Denmark, we estimated the 30-day hazard ratio of intensive care unit (ICU) admission or death among users of inhaled corticosteroids (ICS) compared with users of non-ICS inhalers ({beta}2-agonist/muscarinic-antagonists), or non-users of ICS, with Cox regression adjusted for age, sex, and other confounders. We repeated these analyses among influenza test-positive patients during 2010-2018. Results Among 2,180 hospitalized SARS-CoV-2 patients, 282 were admitted to ICU and 421 died within 30 days. ICS use was associated with a hazard ratio of 1.25 (95% CI [CI], 0.60 to 2.61) for ICU admission and 0.84 (95% CI, 0.54 to 1.31) for death compared with non-ICS inhaler use. Compared with no ICS use, the hazard ratio of ICU admission or death was 1.22 (95% CI, 0.77 to 1.94) and 1.05 (95% CI, 0.75 to 1.47), respectively. Among 10,279 hospitalized influenza patients, the hazard ratios were 1.43 (95% CI, 0.89 to 2.30) and 1.11 (95% CI, 0.85 to 1.46) for ICU admission, and 0.80 (95% CI, 0.63 to 1.01) and 1.03 (95% CI, 0.87 to 1.22) for death compared with non-ICS inhaler use and no ICS use, respectively. Conclusions Our results do not support an effect of inhaled corticosteroid use on COVID-19 morbidity, however we can only rule out moderate-to-large reduced or increased risks.
COVID-19: Impact on the health and wellbeing of ex-serving personnel (Veterans-CHECK) protocol paper

Introduction We will use a sub-sample of a current longitudinal study to investigate the impact of COVID-19 on the health and wellbeing of ex-service personnel in the UK. The study will provide evidence for the UK Office of Veterans' Affairs (OVA), UK stakeholders supporting the ex-service community, and evidence to inform our international counterparts working with ex-service communities in allied countries regarding the impact of COVID-19 on the health and wellbeing of ex-service personnel. Methods and analysis Participants were eligible to participate if they lived in the UK, had Regular service history from the UK Armed Forces and had previously completed the King's Centre for Military Health Research (KCMHR) Health and Wellbeing survey between 2014-2016. Participants who met these criteria were recruited through email to take part in an online questionnaire. The study provides additional quantitative longitudinal data on this sub-sample. Data are being collected June 2020-September 2020. Specific measures are used to capture participants' COVID-19 experiences, health and wellbeing status and lifestyle behaviours. Other key topics will include questions regarding the impact of COVID-19 pandemic on employment, finances, volunteering, charitable giving, accommodation and living arrangements, help-seeking behaviours, as well as any potential positive changes during this period. Ethics and dissemination Ethical approval has been gained from King's College London Research Ethics Committee (Ref: HR-19/20-18626). Participants were provided with information and agreed to a series of consent statements before enrolment. Data are kept on secure servers with access to personally identifiable information limited. Findings will be disseminated to the OVA, UK ex-service stakeholders and international research institutions through stakeholder meetings, project reports and scientific publications.