Miracle-dz/UniFAR-FTUs huggingface dataset:
LS‐106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo

With the wide clinical use of the third‐generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR‐mutated non–small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth‐generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS‐106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell‐free assay, LS‐106 potently inhibited the kinase activities of EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S with IC50 values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS‐106 exhibited comparable kinase inhibitory effect to osimertinib on EGFRL858R/T790M and wild‐type EGFR. Results from cellular experiments demonstrated that LS‐106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR19del/T790M/C797S or EGFRL858R/T790M/C797S, and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR19del/T790M/C797S (named PC‐9‐OR cells) using the CRISPR/Cas9 system and found that LS‐106 markedly suppressed the activation of EGFR19del/T790M/C797S and the proliferation of PC‐9‐OR cells. Moreover, cells harboring EGFR19del/T790M/C797S underwent remarkable apoptosis upon LS‐106 treatment. In vivo experiments further demonstrated that oral administration of LS‐106 caused significant tumor regression in a PC‐9‐OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS‐106 as a novel fourth‐generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S–triple‐mutant tumor models.
Binding of phosphatidylserine‐positive microparticles by PBMCs classifies disease severity in COVID‐19 patients

Abstract Infection with SARS‐CoV‐2 is associated with thromboinflammation, involving thrombotic and inflammatory responses, in many COVID‐19 patients. In addition, immune dysfunction occurs in patients characterised by T cell exhaustion and severe lymphopenia. We investigated the distribution of phosphatidylserine (PS), a marker of dying cells, activated platelets and platelet‐derived microparticles (PMP), during the clinical course of COVID‐19. We found an unexpectedly high amount of blood cells loaded with PS+ PMPs for weeks after the initial COVID‐19 diagnosis. Elevated frequencies of PS+PMP+ PBMCs correlated strongly with increasing disease severity. As a marker, PS outperformed established laboratory markers for inflammation, leucocyte composition and coagulation, currently used for COVID‐19 clinical scoring. PS+ PMPs preferentially bound to CD8+ T cells with gene expression signatures of proliferating effector rather than memory T cells. As PS+ PMPs carried programmed death‐ligand 1 (PD‐L1), they may affect T cell expansion or function. Our data provide a novel marker for disease severity and show that PS, which can trigger the blood coagulation cascade, the complement system, and inflammation, resides on activated immune cells. Therefore, PS may serve as a beacon to attract thromboinflammatory processes towards lymphocytes and cause immune dysfunction in COVID‐19.
Health impacts of a scale-up of supervised injection services in a Canadian setting: an interrupted time series analysis.

BACKGROUND AND AIMS In response to a dramatic rise in overdose deaths due to injection drug use, there was a rapid scale-up of low-threshold supervised injection services (SIS), termed 'overdose prevention sites' (OPS), in Vancouver, Canada in December 2016. We measured the potential impact of this intervention on SIS use and related health outcomes among people who inject drugs (PWID). DESIGN Segmented regression analyses of interrupted time series data from two community-recruited prospective cohorts of PWID from January 2015 to November 2018 were used to measure the impact of the OPS scale-up on changes in SIS use, public injection, syringe sharing and addiction treatment participation, controlling for pre-existing secular trends. SETTING Vancouver, Canada. PARTICIPANTS Of 745 PWID, 292 (39.7%) were women, 441 (59.6%) self-reported white ancestry and the median age was 47 years (interquartile range = 38, 53) at baseline. MEASUREMENTS Immediate (i.e. step level) and gradual (i.e. slope) changes in the monthly proportion of participants who self-reported past 6-month SIS use, public injection, syringe sharing and participation in any form of addiction treatment. FINDINGS Post OPS expansion, the monthly prevalence of SIS use immediately increased by an estimated 6.4% [95% confidence interval (CI) = 1.7, 11.2] and subsequently further increased by an estimated 0.7% (95% CI = 0.3, 1.1) per month. The monthly prevalence of addiction treatment participation immediately increased by an estimated 4.5% (95% CI = 0.5, 8.5) following the OPS expansion, while public injection and syringe sharing were estimated to immediately decrease by 5.5% (95% CI = 0.9, 10.0) and 2.5% (95% CI = 0.5, 4.6), respectively. Findings were inconclusive as to whether or not an association was present between the intervention and subsequent gradual changes in public injection, syringe sharing and addiction treatment participation. CONCLUSIONS Scaling-up overdose prevention sites in Vancouver, Canada in December 2016 was associated with immediate and continued gradual increases in supervised injection service engagement and immediate increases in related health benefits.
Two new ultra‐wideband antennas with 3.4/5.5 GHz dual band‐notched characteristics

This letter presents two ultra‐wideband (UWB) antennas with 3.4/5.5 GHz dual‐notched bands. The U‐ and V‐slots are used to reject the frequency band (3.3–4.2 GHz) limited by C‐band satellite communication and Wimax systems. Another rejection band (5.15–5.825 GHz), limited by IEEE 802.11b or HIPERLAN/2 system, is obtained by using the U/V‐slot defected ground structure. Experimental results indicate that these antennas cover the entire UWB for voltage standing wave radio <2, except two notched bands. Moreover, these antennas have omnidirectional radiation patterns in the H‐plane and good gain flatness. © 2009 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 2942–2945, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24792
How to Lay Bricks: Local-Global Alignment Predicts Preference for Shifted Tile Patterns

We examine the aesthetic characteristics of row tile patterns defined by repeating strips of polygons. In experiment 1 participants rated the perceived beauty of equilateral triangle, square and rectangular tilings presented at vertical and horizontal orientations. The tiles were shifted by one-fourth increments of a complete row cycle. Shifts that preserved global symmetry were liked the most. Local symmetry by itself did not predict ratings but tilings with a greater number of emergent features did. In a second experiment we presented row tiles using all types of three- and four-sided geometric figures: acute, obtuse, isosceles and right triangles, kites, parallelograms, a rhombus, trapezoid, and trapezium. Once again, local polygon symmetry did not predict responding but measures of correspondence between local and global levels did. In particular, number of aligned polygon symmetry axes and number of aligned polygon sides were significantly and positively correlated with beauty ratings. Preference was greater for more integrated tilings, possibly because they encourage the formation of gestalts and exploration within and across levels of spatial scale.
Live imaging of transcription sites using an elongating RNA polymerase II–specific probe

Uchino et al. have developed a genetically encoded probe to specifically detect the Ser2-phosphorylated, elongating form of RNA polymerase II in living cells. Ser2-phosphorylated RNA polymerase foci exhibit more dynamic motion than chromatin replication domains and p300-enriched foci.
Timing considerations for removal of early cumulus cells in short-term insemination strategies.

CONTEXT The timing of early cumulus cell removal (ECCR) can be changed within a range. The change has an effect on the multiple pronuclei (MPN) rate and the exposure time of oocytes to sperm waste products. The timing of ECCR effects the outcomes of assisted reproductive technology, however, it is still unclear what time is best for ECCR. AIMS To find the best time for ECCR based on clinical outcomes in order to increase the success rate of assisted reproductive technology. METHODS A retrospective study was performed. Cycles were categorised into six groups according to the timing of ECCR. The clinical outcomes of these six groups were compared by Kruskal-Wallis test and Pearson X 2 test. KEY RESULTS The timing of ECCR had a significant effect on the MPN rate, 0PN without cleavage rate and grade 1-2 embryo rate at Day3. Among our six time groups of ECCR, the cumulus cell removal ≤4h post-insemination group had the highest MPN rate and grade 1-2 embryo rate at Day3, and the 5.5h<time≤6h group had the highest pronuclear formation failure rate. In addition, 2PN rate was not significantly different among the six time groups. CONCLUSIONS Within the time range of ECCR in our study, selecting an earlier timing to remove the cumulus cells may have a better outcome. IMPLICATIONS ECCR is helpful for optimisation of the short-term insemination strategy.
Predictors of Incident Mild Cognitive Impairment and Its Course in a Diverse Community-Based Population

Background and Objectives To investigate sociodemographic and medical predictors of incident mild cognitive impairment (MCI) and subsequent course of MCI at follow-up, including sustained MCI diagnosis, classification as cognitively normal, and progression to dementia. Methods Within a community-based cohort, diagnoses of MCI were made with a published algorithm. Diagnosis of dementia was based on clinical consensus. Cox regressions estimated hazard ratios of incident MCI associated with several predictors. Modified Poisson regressions estimated relative risks associated with predictors of diagnostic status at follow-up after incidence. Results Among 2,903 cognitively normal participants at baseline, 752 developed MCI over an average of 6.3 (SD 4.5) years (incidence rate 56 per 1,000 person-years). Presence of APOE ε4 and higher medical burden increased risk of incident MCI, while more years of education, more leisure activities, and higher income decreased this risk. Of the incident MCI cases, after an average of 2.4 years of follow-up, 12.9% progressed to dementia, 9.6% declined in functioning and did not meet the algorithmic criteria for MCI but did not meet the clinical criteria for dementia, 29.6% continued to meet MCI criteria, and 47.9% no longer met MCI criteria. Multidomain MCI, presence of APOE ε4, depressive symptoms, and antidepressant use increased the risk of progression to dementia. Discussion This community-based study showed that almost half of the individuals with incident MCI diagnoses were classified as cognitively normal at follow-up. Predictors of incident MCI demonstrably differed from those of subsequent MCI course; these findings can refine expectations for cognitive and functional course of those presenting with MCI.
Characterization of bone homeostasis in individuals affected by cardio‐facio‐cutaneous syndrome

Cardio‐facio‐cutaneous syndrome (CFCS) is a rare disorder characterized by distinctive craniofacial appearance, cardiac, neurologic, cutaneous, and musculoskeletal abnormalities. It is due to heterozygous mutations in BRAF, MAP2K1, MAP2K2, and KRAS genes, belonging to the RAS/MAPK pathway. The role of RAS signaling in bone homeostasis is highly recognized, but data on bone mineral density (BMD) in CFCS are lacking. In the present study we evaluated bone parameters, serum and urinary bone metabolites in 14 individuals with a molecularly confirmed diagnosis of CFCS. Bone assessment was performed through dual X‐ray absorptiometry (DXA); height‐adjusted results were compared to age‐ and sex‐matched controls. Blood and urinary bone metabolites were also analyzed and compared to the reference range. Despite vitamin D supplementation and almost normal bone metabolism biomarkers, CFCS patients showed significantly decreased absolute values of DXA‐assessed subtotal and lumbar BMD (p ≤ 0.05), compared to controls. BMD z‐scores and t‐scores (respectively collected for children and adults) were below the reference range in CFCS, while normal in healthy controls. These findings confirmed a reduction in BMD in CFCS and highlighted the importance of monitoring bone health in these affected individuals.
The Minimal Clinically Important Difference: A Review of Clinical Significance

Background: The minimal clinically important difference (MCID) is a term synonymous with orthopaedic clinical research over the past decade. The term represents the smallest change in a patient-reported outcome measure that is of genuine clinical value to patients. It has been derived in a myriad of ways in existing orthopaedic literature. Purpose: To describe the various modalities for deriving the MCID. Study Design: Narrative review; Level of evidence, 4. Methods: The definitions of common MCID determinations were first identified. These were then evaluated by their clinical and statistical merits and limitations. Results: There are 3 primary ways for determining the MCID: anchor-based analysis, distribution-based analysis, and sensitivity- and specificity-based analysis. Each has unique strengths and weaknesses with respect to its ability to evaluate the patient’s clinical status change from baseline to posttreatment. Anchor-based analyses are inherently tied to clinical status yet lack standardization. Distribution-based analyses are the opposite, with strong foundations in statistics, yet they fail to adequately address the clinical status change. Sensitivity and specificity analyses offer a compromise of the other methodologies but still rely on a somewhat arbitrarily defined global transition question. Conclusion: This current concepts review demonstrates the need for (1) better standardization in the establishment of MCIDs for orthopaedic patient-reported outcome measures and (2) better study design—namely, until a universally accepted MCID derivation exists, studies attempting to derive the MCID should utilize the anchor-based within-cohort design based on Food and Drug Administration recommendations. Ideally, large studies reporting the MCID as an outcome will also derive the value for their populations. It is important to consider that there may be reasonable replacements for current derivations of the MCID. As such, future research should consider an alternative threshold score with a more universal method of derivation.
Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses – termed bias – potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct.
A CaCDPK29-CaWRKY27b module promotes CaWRKY40-mediated thermotolerance and immunity to Ralstonia solanacearum in pepper.

CaWRKY40 in pepper (Capsicum annuum) promotes immune responses to Ralstonia solanacearum infection (RSI) and to high-temperature, high-humidity (HTHH) stress, but how it interacts with upstream signaling components remains poorly understood. Herein, using approaches of reverse genetics, biochemical and molecular biology we functionally characterized the relationships among the WRKYGMK-containing WRKY protein CaWRKY27b, the calcium-dependent protein kinase CaCDPK29, and CaWRKY40 during pepper response to RSI or HTHH. Our data indicate that CaWRKY27b is upregulated and translocated from cytoplasm to the nucleus upon phosphorylation of Ser137 in the NLS by CaCDPK29. Using electrophoretic mobility shift assays and microscale thermophoresis, we observed that, due to the replacement of Q by M in the conserved WRKYGQK, CaWRKY27b in the nucleus failed to bind to W-boxes in the promoters of immunity- and thermotolerance-related marker genes. Instead, CaWRKY27B interacted with CaWRKY40 and promoted its binding and positive regulation of the tested marker genes including CaNPR1, CaDEF1 and CaHSP24. Notably, mutation of the WRKYGMK motif in CaWRKY27b to WRKYGQK restored the W-box binding ability. Our data thus suggest that CaWRKY27b is phosphorylated by CaCDPK29 and acts as transcriptional activator of CaWRKY40 during pepper response to RSI and HTHH.
Age at menopause in women living with HIV: a systematic review

Supplemental Digital Content is available in the text Abstract Importance: With improved HIV care, more women living with HIV (WLWH) are aging and entering menopause. Understanding any increased risk conferred by a potentially earlier menopause transition is important for the care of these women. Objective: There is conflicting literature regarding the association between HIV and an earlier onset of menopause. We conducted a systematic review to summarize the literature on the association between HIV and age at menopause. Evidence Review: A search of Ovid MEDLINE, EMBASE, and Web of Science identified 894 articles. We included cohort studies that assessed age at menopause, primary ovarian insufficiency (POI), or early menopause among WLWH and used the World Health Organization definition of menopause as ≥12 months of amenorrhea. Findings: Nine studies were included and eight reported on age at menopause. Across studies, the age at menopause for WLWH fell between 46 and 50 years. Five of seven studies reported that WLWH had an earlier menopausal transition than HIV negative controls/the general population. Six studies reported on the prevalence of POI or early menopause among WLWH, with all studies demonstrating an increased prevalence of both among WLWH. Conclusions: Our systematic review summarizes the literature around HIV and age at menopause. Many studies reported a high prevalence of POI and early menopause among WLWH; a factor that may partially account for the observed lower age at menopause. As only one study included biochemical confirmation of menopause, it remains unclear whether individuals with early menopause or POI were truly menopausal or had prolonged amenorrhea due to other causes. Overall, our findings highlight the need for further investigation with studies that include an HIV negative control group and biochemical confirmation of menopause to better understand whether menopause truly is occurring earlier among WLWH.
Full Genome Sequence of a Methanomassiliicoccales Representative Enriched from Peat Soil

The full genome of a Methanomassiliicoccales strain, U3.2. 1, was obtained from enrichment cultures of percolation fen peat soil under methanogenic conditions, with methanol and hydrogen as the electron acceptor and donor, respectively. Metagenomic assembly of combined long-read and short-read sequences resulted in a 1.51-Mbp circular genome. ABSTRACT The full genome of a Methanomassiliicoccales strain, U3.2. 1, was obtained from enrichment cultures of percolation fen peat soil under methanogenic conditions, with methanol and hydrogen as the electron acceptor and donor, respectively. Metagenomic assembly of combined long-read and short-read sequences resulted in a 1.51-Mbp circular genome.
Draft Genome Sequence of a Basidiomycetous Yeast, Ustilago shanxiensis CBS 10075, Which Produces Mannosylerythritol Lipids

The basidiomycetous yeast Ustilago shanxiensis CBS 10075, which was isolated from a wilting leaf in China, produces mannosylerythritol lipid (MEL) biosurfactants. Here, we report the draft genome sequence of U. shanxiensis CBS 10075, which was 21.7 Mbp in size, with a GC content of 52.55%, comprising 65 scaffolds. ABSTRACT The basidiomycetous yeast Ustilago shanxiensis CBS 10075, which was isolated from a wilting leaf in China, produces mannosylerythritol lipid (MEL) biosurfactants. Here, we report the draft genome sequence of U. shanxiensis CBS 10075, which was 21.7 Mbp in size, with a GC content of 52.55%, comprising 65 scaffolds.
Draft Genome Sequence of Bacillus sp. Strain IITD106, Isolated from Oil-Contaminated Soil

Here, we report the whole-genome sequence of Bacillus sp. strain IITD106. The bacterium has the unique ability to produce saponins. The complete nucleotide sequence will provide insights into the various genes and regulators involved in the biosynthesis of saponin. ABSTRACT Here, we report the whole-genome sequence of Bacillus sp. strain IITD106. The bacterium has the unique ability to produce saponins. The complete nucleotide sequence will provide insights into the various genes and regulators involved in the biosynthesis of saponin.
5‐Aminolevulinic acid and sodium ferrous citrate ameliorate muscle aging and extend healthspan in Drosophila

Declines in mitochondrial functions are associated with aging. The combination of 5‐aminolevulinic acid (5‐ALA) and sodium ferrous citrate (SFC) improves mitochondrial functions in cultured cells. In this study, we investigated the effects of dietary supplementation with 5‐ALA and SFC (5‐ALA/SFC) on the healthspan and life span of Drosophila melanogaster. Adult Drosophila fruit flies were fed cornmeal food containing various concentrations of 5‐ALA/SFC. Locomotor functions, life span, muscle architecture, and age‐associated changes in mitochondrial function were analyzed. We found that feeding 5‐ALA/SFC mitigated age‐associated declines in locomotor functions and extended organismal life span. Moreover, 5‐ALA/SFC preserved muscle architecture and maintained the mitochondrial membrane potential in aged animals. Since 5‐ALA phosphate/SFC is used as a human dietary supplement, our results suggest that it could be used to slow the age‐related declines in muscle functions, prevent age‐associated clinical conditions such as frailty, and extend healthspan and life span.