bluuebunny/crossref_metadata_2025 huggingface dataset:
Reuse of osimertinib after small cell lung cancer transformation in lung adenocarcinoma with de-novo epidermal growth factor receptor T790M mutation: case report
Authors: Wang Xiuwen , Liang Jizhen , Li Li , Pan Zhaojun , Wang Lin
Published: October 2022

Osimertinib is a third-generation tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-sensitizing mutations and acquired drug-resistant mutation T790M. Despite promising treatment benefits of osimertinib in first- and second-line settings, drug resistance has been an inevitable clinical issue. The resistance to osimertinib is heterogeneous, which may involve EGFR-dependent and independent mechanisms as well as histological transformation from NSCLC to small cell lung cancer (SCLC). Current clinical studies of NSCLC were mainly focused on patients with EGFR-sensitizing mutations or acquired T790M mutation or both. The treatments and drug-resistant mechanisms in patients with de-novo T790M mutation remain undefined. Herein, we reported the presence of the less common de-novo EGFR T790M mutation in a stage IV NSCLC patient. The patient received osimertinib as first-line treatment and achieved durable progression-free survival (PFS) for 24 months. After osimertinib resistance, tumor biopsy indicated histologic transformation from NSCLC to SCLC. Given persistent presence of de-novo T790M mutation, osimertinib was used in combination with etoposide and cisplatin as second-line treatment and the patient achieved partial response with PFS of 7 months. Our study suggested that NSCLC patients with de-novo T790M mutation could also benefit from osimertinib and the SCLC transformation may be a potential resistance mechanism that could be targeted through the combination of targeted therapy and chemotherapy.
Long-Term Maintenance of Cardiorespiratory Fitness Gains After Cardiac Rehabilitation Reduces Mortality Risk in Patients With Multimorbidity
Authors: Ozemek Cemal , Arena Ross , Rouleau Codie R. , Campbell Tavis S. , Hauer Trina , Wilton Stephen B. , Stone James , Laddu Deepika , Williamson Tamara M. , Liu Hongwei , Chirico Daniele , Austford Leslie D. , Aggarwal Sandeep
Published: October 2022

Purpose:

The objective of this study was to characterize the impact of multimorbidity and cardiorespiratory fitness (CRF) on mortality in patients completing cardiac rehabilitation (CR).

Methods:

This cohort study included data from patients with a history of cardiovascular disease (CVD) completing a 12-wk CR program between January 1996 and March 2016, with follow-up through March 2017. Patients were stratified by the presence of multimorbidity, which was defined as having a diagnosis of ≥2 noncommunicable diseases (NCDs). Cox regression analyses were used to evaluate the effects of multimorbidity and CRF on mortality in patients completing CR. Symptom-limited exercise tests were completed at baseline, immediately following CR (12 wk), with a subgroup completing another test at 1-yr follow-up. Peak metabolic equivalents (METs) were determined from treadmill speed and grade.

Results:

Of the 8320 patients (61 ± 10 yr, 82% male) included in the analyses, 5713 (69%) patients only had CVD diagnosis, 2232 (27%) had CVD+1 NCD, and 375 (4%) had CVD+≥2 NCDs. Peak METs at baseline (7.8 ± 2.0, 6.9 ± 2.0, 6.1 ± 1.9 METs), change in peak METs immediately following CR (0.98 ± 0.98, 0.83 ± 0.95, 0.76 ± 0.95 METs), and change in peak METs 1 yr after CR (0.98 ± 1.27, 0.75 ± 1.17, 0.36 ± 1.24 METs) were different (P < .001) among the subgroups. Peak METs at 12 wk and the presence of coexisting conditions were each predictors (P < .001) of mortality. Improvements in CRF by ≥0.5 METS from baseline to 1-yr follow-up among patients with or without multimorbidity were associated with lower mortality rates.

Conclusion:

Increasing CRF by ≥0.5 METs improves survival regardless of multimorbidity status.
Blood pressure reduction cut-points for orthostatic hypotension in stroke survivors using a sit-up test: a multicentre cross-sectional study
Authors: Oyake Kazuaki , Tateishi Takaki , Murayama Jun , Shijima Naoki , Sekizuka Tasuku , Otaka Yohei , Momose Kimito
Published: October 2022

Objective:

The sit-up test is used to assess orthostatic hypotension in stroke survivors who cannot stand independently without using a tilt table. However, no study has identified the optimal cut-points for orthostatic hypotension using the test. Therefore, this study aimed to examine the decrease in SBP and DBP during the sit-up test to detect orthostatic hypotension in individuals with stroke.

Methods:

Thirty-eight individuals with stroke, recruited from three convalescent rehabilitation hospitals, underwent the sit-up and head-up tilt tests. Systolic and diastolic orthostatic hypotension was defined as a decrease of at least 20 and 10 mmHg in the SBP and DBP, respectively, during the head-up tilt test. The receiver operator characteristic curve with the Youden Index was used to identify the optimal cut-points.

Results:

Eight and three participants showed systolic and diastolic orthostatic hypotension, respectively. The optimal cut-points for orthostatic hypotension using the sit-up test were a decrease of 10 mmHg in SBP [sensitivity = 87.5% (95% confidence interval: 47.4–99.7), specificity = 96.7% (82.8–99.9)] and 5 mmHg in DBP [sensitivity = 100.0% (29.2–100.0), specificity = 88.6% (73.3–96.8)].

Conclusion:

Compared with the conventional cut-points, smaller cut-points of a decrease in SBP and DBP may be better to identify orthostatic hypotension in individuals with stroke using the sit-up test. The findings of this study may provide valuable information for the clinical application of the sit-up test.
Serum parabens and its correlations with immunologic and cellular markers in Southern Taiwan industrialized city systemic lupus erythematosus patients
Authors: Huang Kun-Siang , Chen Chun-Yu , Sun Chiao-Yin , Su Yu-Jih
Published: October 2022

Background:

Although the immune systems of patients with systemic lupus erythematosus (SLE) are affected by both personal characteristics and environmental factors, the effects of parabens on patients with SLE have not been well studied. We investigated the indirect effects of four parabens—methylparaben (MP), ethylparaben (EP), propylparaben (n-PrP), and butylparaben (n-BuP)—on several immunological markers.

Methods:

We assessed the serum levels of MP, EP, n-PrP, and n-BuP in 25 SLE patients and correlated the concentration of each paraben with available clinical and laboratory markers, including intracellular markers of antiviral immunity and apoptosis.

Results:

The expression of aryl hydrocarbon receptor (AhR) was significantly negatively correlated with n-PrP levels (p = 0.03, r = −0.434). In monocytes, APO2.7 was significantly positively correlated with n-BuP levels (p = 0.019, r = 0.467). Glutathione levels were significantly negatively correlated with n-BuP levels (p = 0.019, r = −0.518). Anti- β2 glycoprotein I IgM was significantly positively correlated with both MP (p = 0.011, r = 0.585) and EP levels (p = 0.032, r = 0.506). Anti–cardiolipin IgA was significantly positively correlated with both MP (p = 0.038, r = 0.493) and n-PrP levels (p = 0.031, r = 0.508). On CD8 T cells, the early apoptotic marker annexin V was significantly negatively correlated with both MP (p < 0.05, r = −0.541) and n-BuP levels (p = 0.02, r = −0.616), and L-selectin was significantly positively correlated with both MP (p < 0.05, r = 0.47) and n-PrP levels (p = 0.02, r = 0.556).

Conclusion:

Our findings suggest that higher parabens levels were associated with lower AhR expression in leukocytes, increased monocyte apoptosis, lower serum glutathione levels, reduced annexin V expression on CD8 T cells, and higher L-selectin levels on leukocytes.
Investigation of comorbid autoimmune diseases in women with autoimmune bullous diseases: An interplay of autoimmunity and practical implications
Authors: Karakioulaki Meropi , Murrell Dedee F. , Kyriakou Aikaterini , Patsatsi Aikaterini
Published: October 2022

Autoimmune bullous diseases are a group of skin disorders resulting from an autoimmune reaction against intercellular adhesion molecules or components of the basement membrane of skin and mucosa. Autoimmune disorders often occur in patients with a history of another autoimmune disease and most autoimmune diseases have a striking female predominance. In this review, we aim to analyze the different associations of autoimmune bullous diseases with other autoimmune diseases and highlight the distinctiveness of the female gender in these associations.
Recent Apolipoprotein CIII trials
Authors: Tramontano Daniele , Bini Simone , D’Erasmo Laura , Arca Marcello
Published: October 2022

Purpose of review

This review will briefly revise the evidence concerning the pharmacological inhibition of Apolipoprotein CIII (ApoCIII) in patients with hypertriglyceridemia.

Recent findings

ApoCIII is a plasma apolipoprotein playing a major role in the metabolism of triglyceride-rich lipoproteins, namely chylomicrons and very-low-density lipoproteins as well as in the pathological processes involved in atherosclerosis. Therefore, ApoCIII is a potential new target for reducing plasma levels of TRLs and, thereby, cardiovascular risk. In recent years, there have been extensive preclinical and clinical pharmacological studies aimed at testing drugs directed against ApoCIII.

In this review, firstly we will summarize the molecular function of ApoCIII in lipoprotein metabolism. Then, we will examine the lipid-lowering potential of the pharmacological inhibition of ApoCIII based on the results of clinical trial employing Volansesorsen, the first approved antisense therapeutic oligonucleotide against ApoCIII mRNA. The future perspectives for ApoCIII inhibition will be also revised.
New algorithms for treating homozygous familial hypercholesterolemia
Authors: Tromp Tycho R. , Cuchel Marina
Published: October 2022

Purpose of review

We reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable treatment algorithm.

Recent findings

Lowering LDL-C levels to normal in patients with HoFH is challenging, but a combination of multiple lipid-lowering therapies (LLT) is key. Patients with (near) absence of LDL receptor expression are most severely affected and frequently require regular lipoprotein apheresis on top of combined pharmacologic LLT. Therapies acting independently of the LDL receptor pathway, such as lomitapide and evinacumab, are considered game changers for many patients with HoFH, and may reduce the need for lipoprotein apheresis in future. Liver transplantation is to be considered a treatment option of last resort. Headway is being made in gene therapy strategies, either aiming to permanently replace or knock out key lipid-related genes, with first translational steps into humans being made. Cardiovascular disease risk management beyond LDL-C, such as residual Lp(a) or inflammatory risk, should be evaluated and addressed accordingly in HoFH.

Hypercholesterolemia is notoriously difficult to control in most patients with HoFH, but multi-LLT, including newer drugs, allows reduction of LDL-C to levels unimaginable until a few years ago. Cost and availability of these new therapies are important future challenges to be addressed.
Pancreatic Heterotopia in the Small Bowel
Authors: Chin Ning-Hsuan , Wu Jiann-Ming , Chen Kuan-Chih , Lee Tzong-Hsi , Lin Cheng-Kuan , Chung Chen-Shuan
Published: October 2022

Diagnosing pancreatic heterotopia (PH) is challenging, because it is a rare congenital anomaly. We report the case of a 66-year-old man who presented with ileus and jejunal PH diagnosed using single-balloon enteroscopy. Reviewing 178 cases of small intestinal PH in the literature showed that (1) PH mostly occurred at the duodenum (61.8%), followed by the jejunum (22.5%) and ileum (14.6%); (2) patients with ileal PH were younger (mean, 40.7 vs 54.6 years; P < 0.001), while those with jejunal PH were older (mean, 59.5 vs 51.7 years; P = 0.006); (3) most patients with jejunal PH were females, while those with duodenal or ileal PH were predominantly males (M:F = 0.8:1 vs 2.5:1; P = 0.003); (4) asymptomatic cases were rare (15.2% vs 83.4% in small and nonsmall bowel, respectively); (5) most patients with ileal PH presented with bleeding (61.5%), while the remaining had abdominal pain (42.8%); (6) emergent operation was performed in 11 cases (6.2%), mainly at the jejunum (12.5%) and Meckel’s diverticulum (25%); and (7) Heinrich’s classification may be inconclusive. Enteroscopy was performed in only 6 cases (3.4%), and earlier diagnosis and further minimally invasive procedures could have been achieved with enteroscopy.
Type 1 Diabetes in Acute Pancreatitis Consortium
Authors: Serrano Jose , Laughlin Maren R. , Bellin Melena D. , Yadav Dhiraj , Chinchilli Vernon M. , Andersen Dana K. ,   on behalf of the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC)
Published: October 2022

Acute pancreatitis (AP), resulting from inflammation of the pancreas, accounts for more than 300,000 US hospital discharges per year. Although glucose intolerance has been known as a complication of severe AP, this effect was thought to be transient. Recently, cohort studies and meta-analysis of 24 published studies of 1100 patients who survived one or more episodes of AP revealed that 30% to 40% of patients developed diabetes or impaired glucose tolerance within 3 to 4 years of even a single episode of AP. The National Institute of Diabetes and Digestive and Kidney Diseases funded the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC) to undertake a prospective observational study of the occurrence of diabetes during an AP episode or subsequently, with emphasis on type 1 diabetes. Key factors for funding T1DAPC are the increasing incidence and prevalence of AP, its association with the development of type 1 diabetes and other forms of diabetes after AP, its complications, and associated health care cost. The T1DAPC structure, governance, and research objectives are described in this article. The DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) studies to be undertaken by the T1DAPC are described in other articles in this journal's issue.
Rationale and Development of a Data Coordinating Center to Support the Type 1 Diabetes in Acute Pancreatitis Consortium
Authors: Dyer Anne-Marie , Baab Kendall Thomas , Merchlinski Aimee , Valencia-Moulton Paula A. , Holmes Beth R. , Pichardo-Lowden Ariana , Serrano Jose , Laughlin Maren R. , Chinchilli Vernon M. ,   on behalf of the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC)
Published: October 2022

A data coordinating center (DCC) is a critical member of any multicenter research undertaking, and that is especially true for the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC). We describe how the T1DAPC DCC supports the consortium via its experience and expertise in project management, administration, financial management, regulatory compliance, scientific coordination, data management, research computing, and biostatistics and in facilitating scientific publications. The DCC's matrix management system has been extremely effective in managing all of its responsibilities. The first 16 months in the life of the T1DAPC have been dedicated to the development of its first protocol, titled Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM), addressing the institutional review board and regulatory components, developing the T1DAPC data management system, and providing training and certification of clinical center staff. As a result of its efforts, the DCC was a major contributor to the T1DAPC being able to initiate recruitment for the DREAM study in January 2022.
Empirical antibiotic therapy for difficult-to-treat Gram-negative infections: when, how, and how long?
Authors: Bassetti Matteo , Vena Antonio , Labate Laura , Giacobbe Daniele R.
Published: October 2022

Purpose of review

To discuss empirical therapy for severe infections due to Gram-negative bacteria with difficult-to-treat resistance (GNB-DTR) in current clinical practice, focusing in particular on the positioning of novel therapeutic agents and rapid diagnostic tests.

Recent findings

The current era of novel agents active against GNB-DTR and showing differential activity against specific determinants of resistance is an unprecedented scenario, in which the clinical reasoning leading to the choice of the empirical therapy for treating severe GNB-DTR infections is becoming more complex, but it also allows for enhanced treatment precision.

Novel agents should be used in line with antimicrobial stewardship principles, aimed at reducing selective pressure for antimicrobial resistance. However, this does not mean that they should not be used. Indeed, excesses in restrictive uses may be unethical by precluding access to the most effective and less toxic treatments for patients with severe GNB-DTR infections. Given these premises (the ‘how’), empirical treatment with novel agents should be considered in all patients with risk factors for GNB-DTR and severe clinical presentation of acute infection (the ‘when’). Furthermore, empirical novel agents should preferably be continued only for a few hours, until de-escalation, modification, or confirmation (as targeted therapy) is made possible by the results of rapid diagnostic tests (the ‘how long’).
Cross-disorder genetic analysis of immune diseases reveals distinct disease groups and associated genes that converge on common pathogenic pathways
Authors: Demela Pietro , Pirastu Nicola , Soskic Blagoje
Published: October 2022

Genome-wide association studies (GWAS) have mapped thousands of susceptibility loci associated with immune-mediated diseases, many of which are shared across multiple diseases. To assess the extent of the genetic sharing across nine immune-mediated diseases we applied genomic structural equation modelling (genomic SEM) to GWAS data. By modelling the genetic covariance between these diseases, we identified three distinct groups: gastrointestinal tract diseases, rheumatic and systemic diseases, and allergic diseases. We identified 92, 103 and 91 genetic loci that predispose to each of these disease groups, with only 12 of them being shared across groups. Although loci associated with each of these disease groups were highly specific, they converged on perturbing the same pathways, primarily T cell activation and cytokine signalling. Finally, to assess whether variants associated with each disease group modulate gene expression in immune cells, we tested for colocalization between loci and single-cell eQTLs derived from peripheral blood mononuclear cells. We identified the causal route by which 47 loci contribute to predisposition to these three disease groups. In addition, given that the assessed variants are pleiotropic, we found evidence for eight of these genes being strong candidates for drug repurposing. Taken together, our data suggest that different constellations of diseases have distinct patterns of genetic association, but that associated loci converge on perturbing different nodes in a common set of T cell activation and signalling pathways.
Welcome to the big leaves: best practices for improving genome annotation in non-model plant genomes
Authors: Vuruputoor Vidya S , Monyak Daniel , Fetter Karl C. , Webster Cynthia , Bhattarai Akriti , Shrestha Bikash , Zaman Sumaira , Bennett Jeremy , McEvoy Susan L. , Caballero Madison , Wegrzyn Jill L.
Published: October 2022

•

Premise of the study

Robust standards to evaluate quality and completeness are lacking for eukaryotic structural genome annotation. Genome annotation software is developed with model organisms and does not typically include benchmarking to comprehensively evaluate the quality and accuracy of the final predictions. Plant genomes are particularly challenging with their large genome sizes, abundant transposable elements (TEs), and variable ploidies. This study investigates the impact of genome quality, complexity, sequence read input, and approach on protein-coding gene prediction.

•

Methods

The impact of repeat masking, long-read, and short-read inputs,de novo, and genome-guided protein evidence was examined in the context of the popular BRAKER and MAKER workflows for five plant genomes. Annotations were benchmarked for structural traits and sequence similarity.

•

Results

Benchmarks that reflect gene structures, reciprocal similarity search alignments, and mono-exonic/multi-exonic gene counts provide a more complete view of annotation accuracy. Transcripts derived from RNA-read alignments alone are not sufficient for genome annotation. Gene prediction workflows that combine evidence-based andab initioapproaches are recommended, and a combination of short and long-reads can improve genome annotation. Adding protein evidence fromde novo assemblies, genome-guided transcriptome assemblies, or full-length proteins from OrthoDB generates more putative false positives as implemented in the current workflows. Post-processing with functional and structural filters is highly recommended.

•

Discussion

While annotation of non-model plant genomes remains complex, this study provides recommendations for inputs and methodological approaches. We discuss a set of best practices to generate an optimal plant genome annotation, and present a more robust set of metrics to evaluate the resulting predictions.
Macroevolutionary analysis of swallows revived the sight-line hypothesis
Authors: Hasegawa Masaru
Published: October 2022

The evolution of conspicuous ornamentation is often thought to be the consequence of sexual selection, but this might not always be the case. One such candidate is contrasting pale-dark facial color patterns in front of eyes in insectivorous birds and other animals (lore-forehead borderlines, hereafter). A sight-line hypothesis suggested that the contrasting color between lore and forehead assists in tracking and capturing a fast-moving prey. However, this classic hypothesis have been criticized (and thus ignored) for several reasons including lack of formal statistical test controlling for phylogenetic inertia and confounding effect of dark facial color markings that are beneficial by reducing glare. Here, using a phylogenetic comparative approach, we tested the sight-line hypothesis and a widespread alternative explanation, the sexual selection hypothesis, in hirundines (Aves: Hirundinidae). We found no support for the sexual function of lore-forehead borderline in hirundines, because lore-forehead borderline was not positively related to indices of sexual selection (sexual plumage dimorphism and extrapair mating opportunity). In contrast, we found consistent support for the sight-line hypothesis. Species foraging on large prey items (i.e., fast prey) had higher degrees of lore-forehead borderline than others in this clade. Furthermore, an analysis of evolutionary pathways suggested inter-dependent evolution of lore-forehead borderline and prey size; transitions to the state with large prey and no lore-forehead borderline were less likely to occur than transitions from that state. These results remained significant when excluding species that lack dark lore, and thus, not mere presence of dark lores, but contrasting color patterns would be important. To my knowledge, the current study is the first macroevolutionary support for the sight-line hypothesis.
A Homology Guide for Pacific Salmon Genus Oncorhynchus resolves patterns of Duplicate Retention, Rediploidization and Local Adaptation Following the Salmonid Specific Whole Genome Duplication Event
Authors: Dimos Bradford , Phelps Michael
Published: October 2022

Salmonid fishes have emerged as a tractable model to study whole genome duplications (WGD) as this group has undergone four rounds of WGD, with a significant proportion of the genome yet to rediploidize. The fact that much of modern salmonid genomes retain duplicates from the most recent WGD while other regions have rediploidized creates complications for genetic studies by obscuring homology relationships and the necessity of filtering duplicate regions from many analyses. The difficulty this creates is particularly prominent in Pacific salmonids genus Oncorhynchus who are the focus of intense genetics-based conservation and management efforts owing to the important ecological and cultural role these fish play. To address this gap, we generated a homology guide for six species of Oncorhynchus with available genomes and used this guide to describe patterns of duplicate retention and rediploidization. Overall, we find that retained duplicates comprise over half of modern gene repertoires and that retained duplicate genes are enriched for genes involved in nuclear stability, while rediploidized genes which represent a smaller proportion of genes are heavily enriched in dosage sensitive processes such as mitochondria. Additionally, by reanalyzing published expression data from locally adapted strains of O. mykiss we demonstrate that retained duplicates are more likely to be associated with adaptive divergence than rediploidized genes, highlighting the potential of WGDs to promote adaptation. Finally, we demonstrate the utility of our homology guide by investigating the evolutionary relationship among genes highlighted as playing a role in salmonid life history traits or gene editing targets.
A bacterial microbiome is dispensable for the induction of CD8 T cell exhaustion
Authors: Kuhlmann Miriam , Kolland Daphne Del Carmen , Almeida Gustavo Pereira de , Hoffmann Christian , von Hoesslin Madlaina , Berner Jacqueline , Wurmser Christine , Ohnmacht Caspar , Zehn Dietmar
Published: October 2022

Prolonged antigen exposure in chronic viral infections reduces the effector capacity of cytotoxic T cells - a phenomenon known as T cell exhaustion. Development of T cell exhaustion is driven by high viral titers, strong TCR stimulation, and high antigen concentrations associated with strong inflammatory signals. A largely unexplored factor has been the influence of the microbiome in these processes. Here, we report that T cell exhaustion progresses independently of the presence or absence of a microbiome in chronic lymphocytic choriomeningitis virus (LCMV) infections. Virus-specific CD8 T cells in germ-free mice showed high expression of the inhibitory receptor PD-1 and decreased cytokine production. Moreover, their global gene expression patterns, as determined by single-cell sequencing, were similar to those of cells in specific pathogen-free mice. In line with this, we observed similar pathogen loads with and without a microbiome. Thus, our study demonstrates that the microbiome is dispensable for the induction of T cell exhaustion and for the limited virus control seen in chronic LCMV infections.
KMT2D Regulates thymic Egress by Modulating Maturation and integrin Expression
Authors: Potter Sarah J , Zhang Li , Kotliar Michael , Wu Yuehong , Schafer Caitlin , Stefan Kurtis , Boukas Leandros , Qu’d Dima , Bodamer Olaf , Simpson Brittany N , Barski Artem , Lindsley Andrew W , Bjornsson Hans T
Published: October 2022

Objective

There is a clinical need to understand how dysregulated thymocyte development, caused by pathogenic variants in the gene encoding the histone-modifying enzyme, lysine methyltransferase 2D (KMT2D), contributes to immune dysfunction, including immune deficiency, autoimmunity, and lymphoproliferative sequela, and immune-driven mortality in individuals with Kabuki syndrome type 1 (KS1).

Methods

We studied peripheral T cells and thymocytes in both individuals with KS1 and murine constitutive and conditional targeted Kmt2d in T cells and hematopoietic lineages. KMT2D target genes, identified by RNA-sequencing of murine Kmt2d-knockout single-positive thymocytes, were validated with H3K4me3 ChIP-PCR and flow cytometry.

Results

Recent thymic emigrant (RTE) and naïve T cells were reduced, and memory and double-negative (DN)-T cells were expanded in human KS1 and murine models. Kmt2d loss led to Mature 1 CD8+-single positive (SP) thymocyte accumulation and a decrease in SP thymocyte egress licensing expression (normally associated with the Mature 2 phenotype). Splenomegaly is associated with hematopoietic-driven Kmt2d loss and brings to light potential overlapping phenotypes with lymphoproliferative syndromes. Finally, we identified a KMT2D-regulated cluster of integrins which likely mediates aspects of the T cell egression.

Conclusions

Single-positive thymocyte populations deficient in Kmt2d display less integrin, less maturation, and less egress licensing gene expression; thereby, altering the downstream peripheral T cell composition that contribute to the observed KS1-associated immune deficiency. T cell intrinsic Kmt2d loss increases the percentage of peripheral DNT cells potentially through dysregulated apoptotic signaling, while hematopoietic-driven Kmt2d loss predisposes to splenomegaly; therefore, loss of Kmt2d recapitulates several distinct features of lymphoproliferative syndromes.
Prediction of misfolded proteins spreading in Alzheimer’s disease using machine learning
Authors: Gherardini Luca , Pestka Aleksandra , Pini Lorenzo , Crimi Alessandro
Published: October 2022

The pervasive impact of Alzheimer’s disease on aging society represents one of the main challenges at this time. Current investigations highlight two specific misfolded proteins in its development: Amyloid-β and τ. Previous studies focused on spreading for misfolded proteins exploited simulations, which required several parameters to be empirically estimated. Here, we provide an alternative view based on a machine learning approach. The proposed method applies an autoregressive model, constrained by structural connectivity, to predict concentrations of Amyloid-β two years after the provided baseline. In experiments, the autoregressive model generally outperformed the state-of-art models yielding the lowest average prediction error (mean-squared-error 0.0062). Moreover, we assess its effectiveness and suitability for real case scenarios, for which we provide a web service for physicians and researchers. Despite predicting amyloid pathology alone is not sufficient to clinical outcome, its prediction can be helpful to further plan therapies and other cures.
Early development of electrophysiological activity: contribution of periodic and aperiodic components of the EEG signal
Authors: Rico-Picó Josué , Moyano Sebastián , Conejero Ángela , Hoyo Ángela , Ballesteros-Duperón M. Ángeles , Rueda M. Rosario
Published: October 2022

Brain function rapidly changes in the first two years of life. In the last decades, resting-state EEG has been widely used to explore those changes. Previous studies have focused on the relative power of the signal in canonical frequency bands (i.e., theta, alpha, beta, gamma). However, EEG power is a mixture of a 1/f-like background power (aperiodic) in combination with narrow peaks that appear over that curve (periodic activity; e.g., alpha peak). Therefore, the relative power may capture both, aperiodic and periodic brain activity, misleading actual periodic changes in infancy. For this reason, we explored the early developmental trajectory of the relative power in the canonical frequency bands from infancy to toddlerhood and compared it to changes in periodic activity in a longitudinal study with three waves of data collection at ages 6, 9, and 16 to 18 months. Finally, we analyzed whether the periodic activity and/or aperiodic components of the EEG contributed to explaining age changes in relative power. We found that relative power and periodic activity trajectories differed in this period in all the frequency bands but alpha, and we replicated an increment of alpha peak frequency. We found that age changes in aperiodic parameters (exponent and offset) depend on the frequency range. More importantly, only alpha relative power was directly related to periodic activity but other frequency bands were predicted also by aperiodic components. This suggests that relative power is capturing the developmental changes of the aperiodic brain activity and, therefore, more fine-grained measures are needed.
A possible origin of the inverted vertebrate retina revealed by physical modeling
Authors: Oomens Jan M.M.
Published: October 2022

There is no established explanation for the evolution of the inverted retina in the vertebrate camera-type eye. This report shows that the inverted retina may have evolved in the light-sensitive organ of the predecessor of the vertebrates. A patch of light-sensitive epithelium with light-facing photoreceptors developed through evagination into a transparent spherical organ covered in photoreceptors. Photons can activate a photoreceptor either directly or indirectly through the transparent interior of the organ. Models for photoreceptor distribution and spatial resolution show how the inverted retina may have evolved with minimal morphological changes, assuming that natural selection driven optimization of the maximum detectable spatial resolution played a major role.
Distorted neural signal dynamics create hypersensitivity to background noise after hearing loss
Authors: Sabesan Shievanie , Fragner Andreas , Lesica Nicholas A.
Published: October 2022

Listeners with hearing loss often struggle to understand speech in noise, even with a hearing aid. To better understand the auditory processing deficits that underlie this problem, we made large-scale brain recordings from gerbils, a common animal model for human hearing, while presenting a large database of speech and noise sounds. We first used manifold learning to identify the neural subspace in which speech is encoded and found that it is low-dimensional and that the dynamics within it are profoundly distorted by hearing loss. We then trained a deep neural network (DNN) to replicate the neural coding of speech with and without hearing loss and analyzed the underlying network dynamics. We found that hearing loss primarily impacts spectral processing, creating nonlinear distortions in cross-frequency interactions that result in a hypersensitivity to background noise that persists even after amplification with a hearing aid. Our results identify a new focus for efforts to design improved hearing aids and demonstrate the power of DNNs as a tool for the study of central brain structures.
Host transcriptome and microbiome interactions in Holstein cattle under heat stress condition
Authors: Czech Bartosz , Wang Yachun , Wang Kai , Luo Hanpeng , Hu Lirong , Szyda Joanna
Published: October 2022

Climate changes affects animal physiology. In particular, rising ambient temperatures reduce animal vitality due to heat stress and this can be observed at various levels which included genome, transcriptome, and microbiome. In a previous study, microbiota highly associated with changes in cattle physiology were identified under heat stress conditions which included rectal temperature, drooling score, and respiratory score. In the present study, genes differentially expressed between individuals were selected representing different additive genetic effects towards the heat stress response in cattle in their production condition. Moreover, a correlation network analysis was performed to identify interactions between the transcriptome and microbiome for 71 Chinese Holstein cows sequenced for mRNA from blood samples and for 16S rRNA genes from fecal samples. Bioinformatics analysis was performed comprising: i) clustering and classification of 16S rRNA sequence reads, ii) mapping cows’ transcripts to the reference genome and their expression quantification, and iii) statistical analysis of both data types – including differential gene expression analysis and gene set enrichment analysis. A weighted co-expression network analysis was carried out to assess changes in the association between gene expression and microbiota abundance as well as to find hub genes/microbiota responsible for the regulation of gene expression under heat stress. Results showed 1,851 differentially expressed genes were found that were shared by three heat stress phenotypes. These genes were predominantly associated with the cytokine-cytokine receptor interaction pathway. The interaction analysis revealed three modules of genes and microbiota associated with rectal temperature with which two hubs of those modules were bacterial species, demonstrating the importance of the microbiome in the regulation of gene expression during heat stress. Genes and microbiota from the significant modules can be used as biomarkers of heat stress in cattle.
Sexually dimorphic neural encoding of threat discrimination in nucleus accumbens afferents drives suppression of reward behavior
Authors: Muir J , Tse YC , Iyer E , Sorensen J , Eid R , Cvetkovska V , Wassef K , Gostlin S , Spencer NJ , Bagot RC
Published: October 2022

Learning to predict threat is essential but equally important yet often overlooked is learning about the absence of threat. Interrogating neural activity in two nucleus accumbens afferents in male and female mice during aversive and neutral cues reveals sex-specific encoding of cue discrimination and cuemediated suppression of reward behavior. Sexual dimorphisms in neural bases of threat discrimination may reflect sex differences in behavioral strategy relevant to differential psychiatric risk.
Dynamic switching between distinct oscillatory rhythms in prefrontal-amygdala circuits for dimorphic defensive behaviors under natural threats
Authors: Han Hio-Been , Shin Hee-Sup , Jeong Yong , Kim Jisoo , Choi Jee Hyun
Published: October 2022

The medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) are involved in the regulation of defensive behavior under threat, but their engagement in flexible behavior shifts remains unclear. Here, we report the oscillatory activities of mPFC-BLA circuit in reaction to a naturalistic threat, created by a predatory robot in mice. Specifically, we found dynamic frequency tuning among two different theta rhythms (∼5 or ∼10 Hz) was accompanied by agile changes of two different defensive behaviors (freeze or flight). By analyzing flight trajectories, we also found that high beta (∼30 Hz) is engaged in the top-down process for goal-directed flights and accompanied by a reduction in fast gamma (60–120 Hz, peak near 70 Hz). The elevated beta nested the fast gamma activity by its phase more strongly. Our results suggest that the mPFC-BLA circuit has a potential role in oscillatory gear shifting allowing flexible information routing for behavior switches.

Highlights

When threatened, mice take quick defensive behaviors such as freeze or flight.

mPFC-BLA theta tunes its frequency at 5 or 10 Hz for freeze or flight, respectively.

Low and high theta rhythms in mPFC-BLA emerge in a mutually exclusive way.

mPFC-driven beta emerges during goal-directed flights, coordinating fast gamma in BLA.

eTOC Blurb

Han et al. presents neural dynamics of mPFC-BLA network for freeze-or-flight defensive behaviors under naturalistic threats. Tuning the theta frequency in the mPFC-BLA network is for fast and agile actions under a naturalistic threat, and mPFC-driven beta oscillatory burst is for strategic action.
Rapid ex vivo reverse genetics identifies the essential determinants of prion protein toxicity
Authors: Reimann Regina R. , Puzio Martina , Rosati Antonella , Emmenegger Marc , Schneider Bernard L , Valdés Pamela , Huang Danzhi , Caflisch Amedeo , Aguzzi Adriano
Published: October 2022

The cellular prion protein PrPC mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrPC (GDL) can also initiate neurotoxicity by inducing an intramolecular R208-H140 hydrogen bond (“H-latch”) between the α2-α3 and β2-α2 loops of PrPC. Importantly, GDL that suppress the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced nineteen individual PrPC variants to PrPC-deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K27 or R27) within PrPC. Alanine substitution of K27 also prevented the toxicity of PrPC mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrPC. K27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.
Whole brain evaluation of cortical micro-connectomes
Authors: Matsuda Kouki , Shirakami Arata , Nakajima Ryota , Akutsu Tatsuya , Shimono Masanori
Published: October 2022

The brain is an organ that functions as a network of many elements connected in a non-uniform manner. Especially, the cortex is evolutionarily newest, and is thought to be primarily responsible for the high intelligence of mammals. In the mature mammalian brain, all cortical regions are expected to have some degree of homology, but have some variations of local circuits to achieve specific functions enrolled by individual regions. However, few cellular-level studies have examined how the networks within different cortical regions differ. This study aimed to find rules for systematic changes of connectivity (microconnectomes) across 16 different cortical region groups. We also observed unknown trends in basic parameters in vitro such as firing rate and layer thickness across brain regions. The results revealed that the frontal group shows unique characteristics such as dense active neurons, thick cortex and strong connections with deeper layers. This suggests the frontal side of the cortex is inherently capable of driving, even in isolation.

This may suggest that deep layers of frontal node provide the driving force generating a global pattern of spontaneous synchronous activity, such as the Default Mode Network. This finding may explain why disruption in this region causes a large impact on mental health.
Majority of the highly variable NLRs in maize share genomic location and contain additional target-binding domains
Authors: Prigozhin Daniil M , Sutherland Chandler A , Rangavajjhala Sanjay , Krasileva Ksenia V
Published: October 2022

Nucleotide-binding Leucine Rich Repeat proteins (NLRs) are a major class of immune receptors in plants. NLRs include both conserved and rapidly evolving members, however their evolutionary trajectory in crops remains understudied. Availability of crop pan-genomes enables analysis of the recent events in the evolution of this highly complex gene family within domesticated species. Here, we investigated the NLR complement of 26 nested association mapping (NAM) founder lines of maize. We found that maize has just four main subfamilies containing rapidly evolving highly variable NLR (hvNLR) receptors. Curiously, three of these phylogenetically distinct hvNLR lineages are located in adjacent clusters on chromosome 10. By combining sequence diversity analysis and AlphaFold2 computational structure prediction we predicted ligand binding sites in the hvNLRs. We also observed novel insertion domains in the LRR regions of two hvNLR subfamilies that likely contribute to target recogniton. To make this analysis accessible, we created NLRCladeFinder, a Google Colaboratory notebook, that accepts any newly identified NLR sequence, places it in the evolutionary context of maize pan-NLRome, and provides an updated clade alignment, phylogenetic tree, and sequence diversity information for the gene of interest.
Identifying good practices for detecting inter-regional linear functional connectivity from EEG
Authors: Pellegrini Franziska , Delorme Arnaud , Nikulin Vadim , Haufe Stefan
Published: October 2022

Aggregating voxel-level statistical dependencies between multivariate time series is an important intermediate step when characterising functional connectivity (FC) between larger brain regions. However, there are numerous ways in which voxel-level data can be aggregated into inter-regional FC, and the advantages of each of these approaches are currently unclear.

In this study we generate ground-truth data and compare the performances of various pipelines that estimate directed and undirected linear phase-to-phase FC between regions. We test the ability of several existing and novel FC analysis pipelines to identify the true regions within which connectivity was simulated. We test various inverse modelling algorithms, strategies to aggregate time series within regions, and connectivity metrics. Furthermore, we investigate the influence of the number of interactions, the signal-to-noise ratio, the noise mix, the interaction time delay, and the number of active sources per region on the ability of detecting phase-to-phase FC.

Throughout all simulated scenarios, lowest performance is obtained with pipelines involving the absolute value of coherency. Further, the combination of dynamic imaging of coherent sources (DICS) beamforming with directed FC metrics that aggregate information across multiple frequencies leads to unsatisfactory results. Pipeline that show promising results with our simulated pseudo-EEG data involve the following steps: (1) Source projection using the linearly-constrained minimum variance (LCMV) beamformer. (2) Principal component analysis (PCA) using the same fixed number of components within every region. (3) Calculation of the multivariate interaction measure (MIM) for every region pair to assess undirected phase-to-phase FC, or calculation of time-reversed Granger Causality (TRGC) to assess directed phase-to-phase FC. We formulate recommendations based on these results that may increase the validity of future experimental connectivity studies.

We further introduce the free ROIconnect plugin for the EEGLAB toolbox that includes the recommended methods and pipelines that are presented here. We show an exemplary application of the best performing pipeline to the analysis EEG data recorded during motor imagery.