Notes

Bioclimatic and also anthropogenic factors shape the occurrence of Batrachochytrium dendrobatidis over a large latitudinal slope.
Our study provides the first genetic, biochemical and structural evidence of high-affinity binding for the likely evolutionary precursor of extant TpG-containing GBS.SARS-CoV-2 initiates entry into airway epithelia by binding its receptor, ACE2. To explore whether inter-individual variation in ACE2 abundance contributes to variability in COVID-19 outcomes, we measured ACE2 protein abundance in primary airway epithelial cultures derived from 58 human donor lungs. We found no evidence for sex- or age-dependent differences in ACE2 protein expression. Further, we found that variations in ACE2 abundance had minimal effects on viral replication and induction of the interferon response in airway epithelia infected with SARS-CoV-2. Our results highlight the relative importance of additional host factors, beyond viral receptor expression, in determining COVID-19 lung disease outcomes.DNMT3A/3L heterotetramers contain two active centers binding CpG sites at 12 bp distance, however their interaction with DNA not containing this feature is unclear. Using randomized substrates, we observed preferential co-methylation of CpG sites with 6, 9 and 12 bp spacing by DNMT3A and DNMT3A/3L. Co-methylation was favored by AT bases between the 12 bp spaced CpG sites consistent with their increased bending flexibility. SFM analyses of DNMT3A/3L complexes bound to CpG sites with 12 bp spacing revealed either single heterotetramers inducing 40° DNA bending as observed in the X-ray structure, or two heterotetramers bound side-by-side to the DNA yielding 80° bending. SFM data of DNMT3A/3L bound to CpG sites spaced by 6 and 9 bp revealed binding of two heterotetramers and 100° DNA bending. Modeling showed that for 6 bp distance between CpG sites, two DNMT3A/3L heterotetramers could bind side-by-side on the DNA similarly as for 12 bp distance, but with each CpG bound by a different heterotetramer. For 9 bp spacing our model invokes a tetramer swap of the bound DNA. These additional DNA interaction modes explain how DNMT3A and DNMT3A/3L overcome their structural preference for CpG sites with 12 bp spacing during the methylation of natural DNA.Coexistence and cooperation between dogs and humans over thousands of years have supported convergent evolutionary processes in the two species. Previous studies found that Eurasian dogs evolved into a distinct geographic cluster. In this study, we used the genomes of 242 European dogs, 38 Southeast Asian indigenous dogs (SEAI) and 41 grey wolves to identify adaptation of European dogs. We report 86 unique positively selected genes (PSGs) in European dogs, among which is LCT (lactase). LCT encodes lactase which is fundamental for the digestion of lactose. We found that an A-to-G mutation (chr1938,609,592) is almost fixed in Middle Eastern and European dogs. The results of 2 D SFS support that the mutation is under soft sweep. We inferred that the onset of positive selection of the mutation is shorter than 6,535 years and behind the well-developed dairy economy in central Europe. It increases the expression of LCT by reducing its binding with ZEB1, which would enhance dog's ability to digest milk-based diets. Our study uncovers the genetic basis of convergent evolution between humans and dogs with respect to diet, emphasizing the import of the dog as a bio-medical model for studying mechanisms of the digestive system.
The detection of SARS-CoV-2 in patient samples is of critical importance in the management of patients and monitoring transmission in the population. However, data on the analytical performance characteristics for detection of SARS-CoV-2 in clinical specimens between individual targets within the same platform, and among different analytical platforms are limited.

Here we evaluated the performance of six different sample-to-answer SARS-CoV-2 detection methods -Roche cobas 6800, Cepheid GeneXpert, Diasorin Simplexa, Luminex Aries EUA, Luminex Aries RUO, and bioMérieux BioFire in clinical specimens with a range of viral loads.

The positive percent agreement (PPA) between the Roche cobas 6800 and GeneXpert was 100%, Diasorin 95%, Aries EUA 74%, Aries RUO 83%, and BioFire 97%. Notably, in samples with cycle threshold (Ct) values below 30 for the E gene on the Roche cobas 6800 platform, we found 100% positive percent agreement among all platforms. Given these results, we examined the distribution of over 10,000 Ct values of all positive specimens from individuals at our institution on the Roche cobas platform. Nearly 60% of specimens from asymptomatic individuals had a PCR Ct value >30 as measured using the cobas 6800 assay E gene.

Our results demonstrate performance characteristics between different platforms by Ct value, and provide data regarding the distribution of viral RNA present in positive specimens.
Our results demonstrate performance characteristics between different platforms by Ct value, and provide data regarding the distribution of viral RNA present in positive specimens.The coronavirus diseases 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 has caused more than 140 million infections worldwide by the end of April 2021. As an enveloped single-stranded positive-sense RNA virus, SARS-CoV-2 underwent constant evolution that produced novel variants carrying mutation conferring fitness advantages. The current prevalent D614G variant, with glycine substituted for aspartic acid at position 614 in the spike glycoprotein (S protein), is one of such variants that became the main circulating strain worldwide in a short period of time. Over the past year, intensive studies from all over the world had defined the epidemiological characteristics of this highly contagious variant and revealed the underlying mechanisms. This review aims at presenting an overall picture of the impacts of D614G mutation on virus transmission, elucidating the underlying mechanisms of D614G in virus pathogenicity, and providing insights into the development of effective therapeutics.Efficient biomarker-driven randomized clinical trials are a key tool for implementing precision oncology. A commonly used biomarker phase III design is focused on testing the treatment effect in biomarker-positive and overall study populations. This approach may result in recommending new treatments to biomarker-negative patients when these treatments have no benefit for these patients.Burns are routinely assessed at the scene of the incident by prehospital or emergency medical services providers. The initial management of burns is based on the calculation of the extent of the injury, reported as percent total body surface area. This study evaluates discrepancies in estimation of total body surface area (TBSA) between prehospital providers and burn team physicians over a 3-year period at an academic, university medical center serving as the regional burn center. A total of 120 adult and 27 pediatric patients (less than age 16 years) were included, with 95 (65%) male, 67 (45.6%) Caucasian, 62, median age 35 years (Interquartile Range 27). The most common etiology of burns was hot liquid, 39 (26.5%). Median [IQR] and mean (SD) estimated TBSA (%) were 4[1, 10] and 8.6 (12.8) for prehospital providers, and 2 [1, 6] and 5.9 (9.9) for burn team physicians. Bland-Altman plots evaluating 2nd and 3rd degree burns separately and combined demonstrated that, as burns involved more surface area, agreement decreased between emergency medical service providers and burn physicians. Agreement between pre-hospital providers and burn physicians decreased as total body surface areas of burns increased. This finding reaffirms the need for more standardized education and training for all medical personnel.Obesity has reached epidemic proportions globally. Although modern adoption of a sedentary lifestyle coupled with energy-dense nutrition is considered to be the main cause of obesity epidemic, genetic preposition contributes significantly to the imbalanced energy metabolism in obesity. However, the variants of genetic loci identified from large-scale genetic studies do not appear to fully explain the rapid increase in obesity epidemic in the last 4‒5 decades. Recent advancements of next-generation sequencing technologies and studies of tissue-specific effects of epigenetic factors in metabolic organs have significantly advanced our understanding of epigenetic regulation of energy metabolism in obesity. The epigenome, including DNA methylation, histone modifications, and RNA-mediated processes, is characterized as mitotically or meiotically heritable changes in gene function without alteration of DNA sequence. Importantly, epigenetic modifications are reversible. Therefore, comprehensively understanding the landscape of epigenetic regulation of energy metabolism could unravel novel molecular targets for obesity treatment. In this review, we summarize the current knowledge on the roles of DNA methylation, histone modifications such as methylation and acetylation, and RNA-mediated processes in regulating energy metabolism. We also discuss the effects of lifestyle modifications and therapeutic agents on epigenetic regulation of energy metabolism in obesity.The link between long-term host-parasite coevolution and genetic diversity is key to understanding genetic epidemiology and the evolution of resistance. The model of Red Queen host-parasite coevolution posits that high genetic diversity is maintained when rare host resistance variants have a selective advantage, which is believed to be the mechanistic basis for the extraordinarily high levels of diversity at disease-related genes such as the Major Histocompatibility Complex in jawed vertebrates and R-genes in plants. The parasites that drive long-term coevolution are, however, often elusive. Here we present evidence for long-term balancing selection at the phenotypic (variation in resistance) and genomic (resistance locus) level in a particular host-parasite system the planktonic crustacean Daphnia magna and the bacterium Pasteuria ramosa. The host shows widespread polymorphisms for pathogen resistance regardless of geographic distance, even though there is a clear genome-wide pattern of isolation by distance at other sites. In the genomic region of a previously identified resistance super-gene, we observed consistent molecular signals of balancing selection, including higher genetic diversity, older coalescence times, and lower differentiation between populations, which set this region apart from the rest of the genome. We propose that specific long-term coevolution by negative-frequency-dependent selection drives this elevated diversity at the host's resistance loci on an intercontinental scale and provide an example of a direct link between the host's resistance to a virulent pathogen and the large-scale diversity of its underlying genes.Pneumocystis spp. interaction with myeloid cells is well known, especially in macrophages. Contrary, how the organism binds to lung epithelial cells is incompletely understood. Ephrin type-A receptor (EphA2), has been previously identified as a lung epithelial pattern recognition receptor (PRR) that binds to fungal β-glucans. Herein, we also report that EphA2 can also bind Pneumocystis β-glucans, both in isolated forms and also on exposed surfaces of the organism. Furthermore, binding of Pneumocystis β-glucans resulted in phosphorylation of the EphA2 receptor, which has been shown to be important for downstream proinflammatory response. Indeed, we also show that IL-6 cytokine is significantly increased when lung epithelial cells are exposed to Pneumocystis β-glucans, and that this response could be blocked with preincubation with a specific antibody to EphA2. Our study presents yet another Pneumocystis lung epithelial cell receptor with implications for initial colonization and possible therapeutic intervention.
Leishmaniasis is a zoonotic disease and several drugs have been used in the treatment, including meglumine antimoniate (AME). The chemotherapy reaches clinical cure but does not eliminate parasites, contributing to drug resistance. To improve AME efficacy we incorporated it in anionic liposomes. The antiparasitic activity and intracellular localization were investigated in canine macrophages infected with Leishmania infantum.

Liposomes (L-AME) is composed of egg phosphatidylcholine, cholesterol, palmitoyl oleoyl phosphatidyl serine and α-tocopherol (4 3 0.4 0.07 mol%) plus AME. L-AME size, polydispersity, zeta potential and morphology were analysed as well as antileishmanial activity and intracellular localization in DH82 macrophages.

Liposomes (360 nm) zeta potential range from -40 to -65 mV, had 23% encapsulation efficiency and were stable for 180 days at 4°C. Free AME was cytotoxic towards L. infantum infected macrophages (ID50 = 0.012 M) while L-AME did not reduce cell viability. L-AME colocalized with parasites inside macrophages in a time-dependent manner, and reduced the percentage of infected cells and the number of intracellular parasites, decreasing the infection index (75-80%) twice as compared with AME treatment.

Liposomal AME is a promising delivery system for treating visceral leishmaniasis, improving meglumine efficacy against L. infantum and minimizing its cytotoxicity towards canine macrophages.
Liposomal AME is a promising delivery system for treating visceral leishmaniasis, improving meglumine efficacy against L. infantum and minimizing its cytotoxicity towards canine macrophages.Whole genome comparisons based on Average Nucleotide Identities (ANI) and the Genome-to-genome distance calculator have risen to prominence in rapidly classifying prokaryotic taxa using whole genome sequences. Some implementations have even been proposed as a new standard in species classification and have become a common technique for papers describing newly sequenced genomes. However, attempts to apply whole genome divergence data to delineation of higher taxonomic units and to phylogenetic inference have had difficulty matching those produced by more complex phylogenetic methods. We present a novel method for generating statistically supported phylogenies of archaeal and bacterial groups using a combined ANI and alignment fraction-based metric. For the test cases to which we applied the developed approach we obtained results comparable with other methodologies up to at least the family-level. The developed method uses non-parametric bootstrapping to gauge support for inferred groups. This method offers the opportunity to make use of whole-genome comparison data, that are already being generated, to quickly produce phylogenies including support for inferred groups. Additionally, the developed ANI methodology can assist classification of higher taxonomic groups.The genome guardian p53 functions as a transcription factor that senses numerous cellular stresses and orchestrates the corresponding transcriptional events involved in determining various cellular outcomes, including cell cycle arrest, apoptosis, senescence, DNA repair, and metabolic regulation. In response to diverse stresses, p53 undergoes multiple posttranslational modifications (PTMs) that coordinate with intimate interdependencies to precisely modulate its diverse properties in given biological contexts. Notably, PTMs can recruit 'reader' proteins that exclusively recognize specific modifications and facilitate the functional readout of p53. Targeting PTM‒reader interplay has been developing into a promising cancer therapeutic strategy. In this review, we summarize the advances in deciphering the 'PTM codes' of p53, focusing particularly on the mechanisms by which the specific reader proteins functionally decipher the information harbored within these PTMs of p53. We also highlight the potential applications of intervention with p53 PTM‒reader interactions in cancer therapy and discuss perspectives on the 'PTMomic' study of p53 and other proteins.The microbial communities associated to the rhizosphere (the rhizomicrobiome) have a substantial impact on plant growth and yield. Understanding the effects of agricultural management on the rhizomicrobiome is very important for selecting efficient practices. By sequencing the V4 region of 16S rRNA for bacteria and the ITS1 regions and fungi, we investigated the influences of agronomic practices, including cucumber grafting on cucurbit hybrid (Cucurbita moschata × C. maxima), cucumber-garlic intercropping, and treatment with fungicide iprodione-carbendazim on cucumber rhizosphere microbial communities during plant growth. Soil dehydrogenase activity (DHA) and plant vegetative parameters were assessed as an indicator of overall soil microbial activity. We found that both treatments and growth stage induced significant shifts in microbial community structure. Grafting had the highest number of differentially abundant OTUs compared to control samples, followed by intercropping and fungicide treatment, while plant development stage affected both alpha and beta diversities indices and composition of the rhizomicrobiome. DHA was more dependent on plant growth stages than on treatments. Among the assessed factors, grafting and plant developmental stage resulted in the greatest changes in the microbial community composition. Grafting also increased the plant growth parameters, suggesting that this method should be further investigated in vegetable production systems.Onion thrips (Thrips tabaci Lindeman) is one of onion's most damaging insect pests and has a history of developing resistance across insecticide classes. The susceptibility of T. tabaci populations to insecticides can be determined using laboratory bioassays. Three types of bioassays have been documented in the literature specifically for use with T. tabaci vial assay (contact only), feeding assay (ingestion only), and leaf-dip assay (contact + ingestion). The objectives of this study were to 1) compare insecticide susceptibility levels of a T. tabaci population using these three assays and 2) determine which bioassay's results were most similar to those generated from exposing thrips to whole plants treated with insecticide. All experiments were conducted using a colony of T. tabaci known to be susceptible to insecticides and all were evaluated for their susceptibility to spinetoram (Radiant SC). Results indicated that 1) each bioassay generated a unique concentration-mortality relationship and LC50 value (0.01, 0.03 and 1.6 ppm for leaf-dip, vial, and feeding assays, respectively), and 2) all bioassays overestimated the susceptibility of the population relative to the whole-plant assay (LC50 = 5.3 ppm). Attributes of these bioassays are discussed relative to their future use in insecticide resistance monitoring programs for T. tabaci.Human granulocytic anaplasmosis (HGA) and human babesiosis are tick-borne diseases spread by the blacklegged tick (Ixodes scapularis Say, Acari Ixodidae) and are the result of infection with Anaplasma phagocytophilum and Babesia microti, respectively. In New York State (NYS), incidence rates of these diseases increased concordantly until around 2013, when rates of HGA began to increase more rapidly than human babesiosis, and the spatial extent of the diseases diverged. Surveillance data of tick-borne pathogens (2007 to 2018) and reported human cases of HGA (n = 4,297) and human babesiosis (n = 2,986) (2013-2018) from the New York State Department of Health (NYSDOH) showed a positive association between the presence/temporal emergence of each pathogen and rates of disease in surrounding areas. Incidence rates of HGA were higher than human babesiosis among White and non-Hispanic/non-Latino individuals, as well as all age and sex groups. Human babesiosis exhibited higher rates among non-White individuals. Climate, weather, and landscape data were used to build a spatially weighted zero-inflated negative binomial (ZINB) model to examine and compare associations between the environment and rates of HGA and human babesiosis. HGA and human babesiosis ZINB models indicated similar associations with forest cover, forest land cover change, and winter minimum temperature; and differing associations with elevation, urban land cover change, and winter precipitation. These results indicate that tick-borne disease ecology varies between pathogens spread by I. scapularis.To determine the functional organization of premotor areas in the cat pericruciate cortex we applied intracortical microstimulation (ICMS) within multiple cytoarchitectonically identified subregions of areas 4 and 6 in the awake cat, both at rest and during treadmill walking. ICMS in most premotor areas evoked clear twitch responses in the limbs and/or head at rest. During locomotion, these same areas produced phase-dependent modifications of muscle activity. ICMS in the primary motor cortex (area 4γ) produced large phase-dependent responses, mostly restricted to the contralateral forelimb or hindlimb. Stimulation in premotor areas also produced phase-dependent responses that, in some cases, were as large as those evoked from area 4γ. However, responses from premotor areas had more widespread effects on multiple limbs, including the ipsilateral limbs, than did stimulation in 4γ. During locomotion, responses in both forelimb and hindlimb muscles were evoked from cytoarchitectonic areas 4γ, 4δ, 6aα, and 6aγ. However, the prevalence of effects in a given limb varied from one area to another. The results suggest that premotor areas may contribute to the production, modification, and coordination of activity in the limbs during locomotion and may be particularly pertinent during modifications of gait.We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10‒5 threshold). Patient-level data were pooled from all four studies, and for patients with TIE NDMM plus patients with RRMM who received ≤2 prior lines of therapy (≤2PL). PFS was evaluated by response and MRD status. Median follow-up (months) was POLLUX, 54.8; CASTOR, 50.2; ALCYONE, 40.1; and MAIA, 36.4. Patients who achieved ≥CR and MRD negativity had improved PFS versus those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P less then .0001; TIE NDMM and RRMM ≤2PL HR 0.20, P less then .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.ClinicalTrials.gov NCT02076009/NCT02136134/NCT02195479/NCT02252172.The prevailing coronavirus disease (COVID-19) caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has presented some neurological manifestations including hyposmia, hypogeusia, headache, stroke, encephalitis, Guillain‒Barre syndrome, and some neuropsychiatric disorders. Although several cell types in the brain express angiotensin converting enzyme-2 (ACE2), the main SARS-CoV-2 receptor, and other related proteins, it remains unclear whether the observed neurological manifestations are attributed to virus invasion into the brain or just comorbidities caused by dysregulation of systemic factors. Here, we briefly review the neurological manifestations of SARS-CoV-2, summarize recent evidence for the potential neurotropism of SARS-CoV-2, and discuss the potential mechanisms of COVID-19-associated neurological diseases.Tests based on the dN/dS statistic are used to identify positive selection of nonsynonymous polymorphisms. Using these tests on alignments of all orthologs from related species can provide insights into which gene categories have been most frequently positively selected. However, longer alignments have more power to detect positive selection, creating a detection bias that could create misleading results from functional enrichment tests. Most studies of positive selection in plant pathogens focus on genes with specific virulence functions, with little emphasis on broader molecular processes. Furthermore, no studies in plant pathogens have accounted for detection bias due to alignment length when performing functional enrichment tests. To address these research gaps, we analyze 12 genomes of the phytopathogenic fungal genus Botrytis, including two sequenced in this study. To establish a temporal context, we estimated fossil-calibrated divergence times for the genus. We find that Botrytis likely originated 16-18 Ma in the Miocene and underwent continuous radiation ending in the Pliocene. An untargeted scan of Botrytis single-copy orthologs for positive selection with three different statistical tests uncovered evidence for positive selection among proteases, signaling proteins, CAZymes, and secreted proteins. There was also a strong overrepresentation of transcription factors among positively selected genes. This overrepresentation was still apparent after two complementary controls for detection bias due to sequence length. Positively selected sites were depleted within DNA-binding domains, suggesting changes in transcriptional responses to internal and external cues or protein-protein interactions have undergone positive selection more frequently than changes in promoter fidelity.Progranulin (PGRN) is a multifunctional growth factor expressed in central nervous system. Although PGRN expression is regulated by various stressors, its precise role(s) and regulatory mechanism(s) remain elusive. In this study, we used HT22 cells to investigate the physiological implications of oxidative stress-induced PGRN expression and the regulation of PGRN expression by oxidative stress. We observed that p38 MAP kinase was activated upon the addition of H2O2, and a selective p38 MAP kinase inhibitor, attenuated PGRN induction by H2O2. To explore the physiological role(s) of the PGRN induction, we first confirmed H2O2-dependent responses of HT22 cells and found that the length and number of neurites were increased by H2O2. Pgrn knockdown experiments suggested these changes were mediated by H2O2-induced PGRN expression, at least in part. Overall, the results suggested that an increase in oxidative stress in HT22 cells induced PGRN expression via p38 MAP kinase pathway, thereby controlling neurite outgrowth.
Cancer subtype identification aims to divide cancer patients into subgroups with distinct clinical phenotypes and facilitate the development for subgroup specific therapies. The massive amount of multi-omics datasets accumulated in the public databases have provided unprecedented opportunities to fulfill this task. As a result, great computational efforts have been made to accurately identify cancer subtypes via integrative analysis of these multi-omics datasets.

In this paper, we propose a Consensus Guided Graph Autoencoder (CGGA) to effectively identify cancer subtypes. First, we learn for each omic a new feature matrix by using graph autoencoders, where both structure information and node features can be effectively incorporated during the learning process. Second, we learn a set of omic-specific similarity matrices together with a consensus matrix based on the features obtained in the first step. The learned omic-specific similarity matrices are then fed back to the graph autoencoders to guide the feature learning. By iterating the two steps above, our method obtains a final consensus similarity matrix for cancer subtyping. To comprehensively evaluate the prediction performance of our method, we compare CGGA with several approaches ranging from general-purpose multi-view clustering algorithms to multi-omics-specific integrative methods. The experimental results on both generic datasets and cancer datasets confirm the superiority of our method. Moreover, we validate the effectiveness of our method in leveraging multi-omics datasets to identify cancer subtypes. In addition, we investigate the clinical implications of the obtained clusters for glioblastoma and provide new insights into the treatment for patients with different subtypes.

The source code of our method is freely available at https//github.com/alcs417/CGGA.

Supplementary data are available at Bioinformatics online.
Supplementary data are available at Bioinformatics online.Like the sword of Damocles, the threat of a post-antibiotic era is hanging over humanity's head. The scientific and medical community is thus reconsidering bacteriophage therapy (BT) as a partial but realistic solution for treatment of difficult to eradicate bacterial infections. Here, we summarize the latest developments in clinical BT applications, with a focus on developments in the following areas i) pharmacology of bacteriophages of major clinical importance and their synergy with antibiotics; ii) production of therapeutic phages; and iii) clinical trials, case studies, and case reports in the field. We address regulatory concerns, which are of paramount importance insofar as they dictate the conduct of clinical trials, which are needed for broader BT application. The increasing amount of new available data confirm the particularities of BT as being innovative and highly personalized. The current circumstances suggest that the immediate future of BT may be advanced within the framework of national BT centers in collaboration with competent authorities, which are urged to adopt incisive initiatives originally launched by some national regulatory authorities.
Sjögren's Syndrome (SS) with childhood onset is a rare autoimmune disease characterised by heterogeneous presentation. The lack of validated classification criteria makes it challenging to diagnose. Evidence-based guidelines for treatment of juvenile SS are not available due to the rarity of disease and the paucity of research in this patient population. This systematic review aims to summarise and appraise the current literature focused on pharmacological strategies for management of SS with childhood onset.

PubMed and MEDLINE/Scopus databases up to December 2020 have been screened for suitable reports highlighting pharmacological treatment of SS with childhood onset using the PRISMA 2009 reporting checklist. Animal studies have been excluded.

43 studies (34 case reports, 8 mini case series and one pilot study) were eligible for analysis. The studies retrieved included girls in 88% (120/137) of cases and had very low confidence level.Hydroxychloroquine (HCQ) was prescribed for parotid swelling, as well as in association with methotrexate (MTX) and non-steroidal anti-inflammatory drugs (NSAIDS) in patients with arthritis and arthralgia. Corticosteroids such as long courses of oral prednisone and IV methylprednisolone were commonly prescribed for children with severe disease presentations. Rituximab was mainly indicated for MALT lymphoma, and renal and nervous system complications. Other conventional DMARDs were prescribed in selected cases with extra-glandular manifestations.

Various therapies are used for the management of juvenile SS and are prescribed based on expert clinician's opinion. There are currently no good quality studies that allow clinical recommendations for treatment in SS with childhood onset.
Various therapies are used for the management of juvenile SS and are prescribed based on expert clinician's opinion. There are currently no good quality studies that allow clinical recommendations for treatment in SS with childhood onset.
Systemic sclerosis (SSc) is a rheumatic autoimmune disease affecting roughly 20 000 people worldwide and characterized by excessive collagen accumulation in the skin and internal organs. Despite the high morbidity and mortality associated with SSc, there are no approved disease-modifying agents. Our objective in this study was to explore transcriptomic and model-based drug discovery approaches for systemic sclerosis.

In this study, we explored the molecular basis for SSc pathogenesis in a well-studied mouse model of scleroderma. We profiled the skin and lung transcriptomes of mice at multiple timepoints, analyzing the differential gene expression that underscores the development and resolution of bleomycin-induced fibrosis.

We observed shared expression signatures of upregulation and downregulation in fibrotic skin and lung tissue, and observed significant upregulation of key pro-fibrotic genes including GDF15, Saa3, Cxcl10, Spp1, and Timp1. To identify changes in gene expression in responses to anti-fibrotic therapy, we assessed the effect of TGF-β pathway inhibition via oral ALK5 (TGF-β receptor I) inhibitor SB525334 and observed a time-lagged response in the lung relative to skin. We also implemented a machine learning algorithm that showed promise at predicting lung function using transcriptome data from both skin and lung biopsies.

This study provides the most comprehensive look at the gene expression dynamics of an animal model of systemic sclerosis to date, provides a rich dataset for future comparative fibrotic disease research, and helps refine our understanding of pathways at work during SSc pathogenesis and intervention.
This study provides the most comprehensive look at the gene expression dynamics of an animal model of systemic sclerosis to date, provides a rich dataset for future comparative fibrotic disease research, and helps refine our understanding of pathways at work during SSc pathogenesis and intervention.
Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration (CNA) and structural variation (SV) events in tumor evolution, which are difficult to profile accurately by prevailing sequencing methods in such a way that subsequent reconstruction by phylogenetic inference algorithms is accurate.

In the present work, we develop computational methods to combine sequencing with multiplex interphase fluorescence in situ hybridization (miFISH) to exploit the complementary advantages of each technology in inferring accurate models of clonal CNA evolution accounting for both focal changes and aneuploidy at whole-genome scales. By integrating such information in an integer linear programming (ILP) framework, we demonstrate on simulated data that incorporation of FISH data substantially improves accurate inference of focal CNA and ploidy changes in clonal evolution from deconvolving bulk sequence data. Analysis of real glioblastoma data for which FISH, bulk sequence, and single cell sequence are all available confirms the power of FISH to enhance accurate reconstruction of clonal copy number evolution in conjunction with bulk and optionally single-cell sequence data.

Source code is available on Github at https//github.com/CMUSchwartzLab/FISH_deconvolution.
Source code is available on Github at https//github.com/CMUSchwartzLab/FISH_deconvolution.The parasubiculum (PaS) is located within the parahippocampal region, where it is thought to be involved in the processing of spatial navigational information. It contains a number of functionally specialized neuron types including grid cells, head direction cells, and border cells; and provides input into layer 2 of the medial entorhinal cortex where grid cells are abundantly located. The local circuitry within the PaS remains so far undefined but may provide clues as to the emergence of spatially tuned firing properties of neurons in this region. We used simultaneous patch-clamp recordings to determine the connectivity rates between the 3 major groups of neurons found in the PaS. We find high rates of interconnectivity between the pyramidal class and interneurons, as well as features of pyramid-to-pyramid interactions indicative of a nonrandom network. The microcircuit that we uncover shares both similarities and divergences to those from other parahippocampal regions also involved in spatial navigation.
Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) compared to conventional venepuncture.

We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire.

Therapeutic drug monitoring requests eutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.Nociceptive processing in the human brain is complex and involves several brain structures and varies across individuals. Determining the structures that contribute to interindividual differences in nociceptive processing is likely to improve our understanding of why some individuals feel more pain than others. Here, we found specific parts of the cerebral response to nociception that are under genetic influence by employing a classic twin-design. We found genetic influences on nociceptive processing in the midcingulate cortex and bilateral posterior insula. In addition to brain activations, we found genetic contributions to large-scale functional connectivity (FC) during nociceptive processing. We conclude that additive genetics influence specific brain regions involved in nociceptive processing. The genetic influence on FC during nociceptive processing is not limited to core nociceptive brain regions, such as the dorsal posterior insula and somatosensory areas, but also involves cognitive and affective brain circuitry. These findings improve our understanding of human pain perception and increases chances to find new treatments for clinical pain.Acute myeloid leukemia (AML) is attractive for the development of CAR T-cell immunotherapy because AML blasts are susceptible to T-cell-mediated elimination. Here, we introduce sialic-acid-binding immunoglobulin-like lectin (Siglec)-6 as a novel target for CAR T-cells in AML. We designed a Siglec-6-specific CAR with a targeting-domain derived from a human monoclonal antibody JML‑1. We found that Siglec-6 is prevalently expressed on AML cell lines and primary AML blasts, including the subpopulation of AML stem cells. Treatment with Siglec-6-CAR T-cells confers specific anti-leukemia reactivity that correlates with Siglec-6-expression in pre-clinical models, including induction of complete remission in a xenograft AML model in immunodeficient mice (NSG/U937). In addition, we confirmed Siglec-6-expression on transformed B-cells in chronic lymphocytic leukemia (CLL) and show specific anti-CLL-reactivity of Siglec-6-CAR T-cells in vitro. Of particular interest, we found that Siglec-6 is not detectable on normal hematopoietic stem and progenitor cells (HSC/P) and that treatment with Siglec-6-CAR T-cells does not affect their viability and lineage differentiation in colony-formation assays. These data suggest that Siglec-6-CAR T-cell therapy may be used to effectively treat AML without a need for subsequent allogeneic hematopoietic stem cell transplantation. In mature normal hematopoietic cells, we detected Siglec-6 in a proportion of memory (and naïve) B-cells and basophilic granulocytes, suggesting the potential for limited on-target/off-tumor reactivity. The lacking expression of Siglec-6 on normal HSC/P is a key differentiator from other Siglec-family members (e.g. Siglec-3=CD33) and other CAR target antigens, e.g. CD123, that are under investigation in AML and warrants the clinical investigation of Siglec-6-CAR T-cell therapy.
In silico identification of linear B-cell epitopes represents an important step in the development of diagnostic tests and vaccine candidates, by providing potential high-probability targets for experimental investigation. Current predictive tools were developed under a generalist approach, training models with heterogeneous data sets to develop predictors that can be deployed for a wide variety of pathogens. However, continuous advances in processing power and the increasing amount of epitope data for a broad range of pathogens indicate that training organism or taxon-specific models may become a feasible alternative, with unexplored potential gains in predictive performance.

This paper shows how organism-specific training of epitope prediction models can yield substantial performance gains across several quality metrics when compared to models trained with heterogeneous and hybrid data, and with a variety of widely-used predictors from the literature. These results suggest a promising alternative for the development of custom-tailored predictive models with high predictive power, which can be easily implemented and deployed for the investigation of specific pathogens.

The data underlying this article, as well as the full reproducibility scripts, are available at https//github.com/fcampelo/OrgSpec-paper. The R package that implements the organism-specific pipeline functions is available at https//github.com/fcampelo/epitopes.

Supplementary materials are available at Bioinformatics online.
Supplementary materials are available at Bioinformatics online.
The increasing number of single cell and bulk RNAseq datasets describing complex gene expression profiles in different organisms, organs or cell types calls for an intuitive tool allowing rapid comparative analysis. Here we present Swift Profiling Of Transcriptomes (SPOT) as a web tool that allows not only differential expression analysis but also fast ranking of genes fitting transcription profiles of interest. Based on a heuristic approach the spot algorithm ranks the genes according to their proximity to the user-defined gene expression profile of interest. The best hits are visualized as a table, bar chart or dot plot and can be exported as an Excel file. While the tool is generally applicable, we tested it on RNAseq data from malaria parasites that undergo multiple stage transformations during their complex life cycle as well as on data from multiple human organs during development and cell lines infected by the SARS-CoV-2 virus. SPOT should enable non-bioinformaticians to easily analyse their own and any available dataset.

SPOT is freely available for (academic) use at https//frischknechtlab.shinyapps.io/SPOT/ and https//github.com/EliasFarr/SPOT.

Supplementary data are available at Bioinformatics online.
Supplementary data are available at Bioinformatics online.To enhance the genomics and genetics of azalea, the whole-genome sequences of two species of Rhododendron were determined and analyzed in this study Rhododendron ripense, the cytoplasmic donor and ancestral species of large-flowered and evergreen azalea cultivars; and Rhododendron kiyosumense, a native of Chiba prefecture (Japan) seldomly bred and cultivated. A chromosome-level genome sequence assembly of R. ripense was constructed by single-molecule real-time (SMRT) sequencing and genetic mapping, while the genome sequence of R. kiyosumense was assembled using the single-tube long fragment read (stLFR) sequencing technology. The R. ripense genome assembly contained 319 contigs (506.7 Mb; N50 length 2.5 Mb) and was assigned to the genetic map to establish 13 pseudomolecule sequences. On the other hand, the genome of R. kiyosumense was assembled into 32,308 contigs (601.9 Mb; N50 length 245.7 kb). A total of 34,606 genes were predicted in the R. ripense genome, while 35,785 flower and 48,041 leaf transcript isoforms were identified in R. kiyosumense through Iso-Seq analysis. Overall, the genome sequence information generated in this study enhances our understanding of genome evolution in the Ericales and reveals the phylogenetic relationship of closely-related species. This information will also facilitate the development of phenotypically attractive azalea cultivars.We aimed to identify symptom-related neuroimaging biomarkers for patients with dysgenesis of the corpus callosum (dCC) by summarizing neurological symptoms reported in clinical evaluations and correlating them with retrospectively collected structural/diffusion brain magnetic resonance imaging (MRI) measures from 39 patients/controls (mean age 8.08 ± 3.98). Most symptoms/disorders studied were associated with CC abnormalities. Total brain (TB) volume was related to language, cognition, muscle tone, and metabolic/endocrine abnormalities. Although white matter (WM) volume was not related to symptoms studied, gray matter (GM) volume was related to cognitive, behavioral, and metabolic/endocrine disorders. Right hemisphere (RH) cortical thickness (CT) was linked to language abnormalities, while left hemisphere (LH) CT was linked to epilepsy. While RH gyrification index (GI) was not related to any symptoms studied, LH GI was uniquely related to cognitive disorders. Between patients and controls, GM volume and LH/RH CT were significantly greater in dCC patients, while WM volume and LH/RH GI were significantly greater in controls. TB volume and diffusion indices for tissue microstructures did not show differences between the groups. In summary, our brain MRI-based measures successfully revealed differential links to many symptoms. Specifically, LH GI abnormality can be a predictor for dCC patients, which is uniquely associated with the patients' symptom. In addition, patients with CC abnormalities had normal TB volume and overall tissue microstructures, with potentially deteriorated mechanisms to expand/fold the brain, indicated by GI.Wilson's disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focussed on specific sequences or regions of interest, often stratifying chronically-treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively-recruited patients with Wilson's disease (age range 16-68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain iute to neurodegeneration in Wilson's disease.Everyday auditory streams are complex, including spectro-temporal content that varies at multiple timescales. Using EEG, we investigated the sensitivity of human auditory cortex to the content of past stimulation in unattended sequences of equiprobable tones. In 3 experiments including 82 participants overall, we found that neural responses measured at different latencies after stimulus onset were sensitive to frequency intervals computed over distinct timescales. Importantly, early responses were sensitive to a longer history of stimulation than later responses. To account for these results, we tested a model consisting of neural populations with frequency-specific but broad tuning that undergo adaptation with exponential recovery. We found that the coexistence of neural populations with distinct recovery rates can explain our results. Furthermore, the adaptation bandwidth of these populations depended on spectral context-it was wider when the stimulation sequence had a wider frequency range. Our results provide electrophysiological evidence as well as a possible mechanistic explanation for dynamic and multiscale context-dependent auditory processing in the human cortex.MYD88 and CXCR4 mutations are common in Waldenström Macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a Phase I trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/day with Cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1-6, with a 3+3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, nine treatment-naive were enrolled. Twelve were evaluable for response. At best response, their median serum IgM declined from 5,574 to 1,114 mg/dL; bone marrow disease decreased from 65% to 10%; and hemoglobin increased from 10.1 to 14.2 g/dL (p less then 0.001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year PFS was 90%. The most frequent recurring Grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib, and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. www.clinicaltrials.gov (NCT03225716).
Healthcare professionals have an important role in ensuring that adverse drug reactions are well documented and reported. The key determinants of adverse drug reactions reporting are the knowledge, attitude and practice of healthcare professionals. A systematic review of the literature was undertaken to identify, critically evaluate and summarise the findings on the knowledge, attitude and practice of Malaysian healthcare professionals towards adverse drug reaction reporting.

Literature search using electronic databases including PubMed, Google Scholar and National Medical Research Register was conducted. Additional articles were identified by reviewing the bibliography of the retrieved articles. The articles were searched with any of the Medical Subject Headings (MeSH) terms in the title adverse drug reaction, attitude, awareness, behaviour, experience, knowledge, Malaysia, perspectives, pharmacovigilance, practice and view. Studies were selected based on fulfilment of inclusion and exclusion criteria. The articles were scrutinised using thematic analysis.
Here's my website: