bluuebunny/crossref_metadata_2025 huggingface dataset:
Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients
Authors: Mazzetti Samanta , Giampietro Federica , Isilgan Huseyin Berkcan , Calogero Alessandra Maria , Gagliardi Gloria , Rolando Chiara , Cantele Francesca , Ascagni Miriam , Bramerio Manuela , Giaccone Giorgio , Isaias Ioannis Ugo , Pezzoli Gianni , Cappelletti Graziella
Published: December 2022

Highly specialized microtubules in neurons are crucial to the health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including α-Tubulin acetylation. An imbalance in the levels of acetylated α-Tubulin has been reported in experimental models of Parkinson’s disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated α-Tubulin successfully rescues axonal transport defects and inhibits α-Synuclein aggregation. However, the role of acetylation of α-Tubulin in the human nervous system is largely unknown as most studies are based onin vitroevidence.

To capture the complexity of the pathological processesin vivo, we analysedpost-mortemhuman brain of PD patients and control subjects. In the brain of PD patients at Braak stage 6, we found a redistribution of acetylated α-Tubulin, which accumulates in the neuronal cell bodies in subcortical structures but not in the cerebral cortex, and decreases in the axonal compartment, both in the central and peripheral nervous system. High-resolution and 3D reconstruction analysis linked acetylated α-Tubulin redistribution to α-Synuclein oligomerization, leading us to propose a model for Lewy body (LB) morphogenesis. Finally, for the first time inpost-mortemhuman brain, we observed threadlike structures, resembling tunnelling nanotubes that contain α-Synuclein oligomers and are associated with acetylated α-Tubulin enriched neurons.

In conclusion, we disclose a novel aspect of LB morphogenesis, indicating the role of acetylated α-Tubulin in PD, that may provide clues to design novel therapeutic interventions.
Predicting regulators of epithelial cell state through regularized regression analysis of single cell multiomic sequencing
Authors: Ledru Nicolas , Wilson Parker C. , Muto Yoshiharu , Yoshimura Yasuhiro , Wu Haojia , Asthana Amish , Tullius Stefan G. , Waikar Sushrut S. , Orlando Giuseppe , Humphreys Benjamin D.
Published: December 2022

Chronic disease processes are marked by cell-specific transcriptomic and epigenomic changes. Single nucleus joint RNA- and ATAC-seq offers an opportunity to study the gene regulatory networks underpinning these changes in order to identify key regulatory drivers. We developed a regularized regression approach, RENIN, (RegulatoryNetworkInference) to construct genome-wide parametric gene regulatory networks using multiomic datasets. We generated a single nucleus multiomic dataset from seven adult human kidney biopsies and applied RENIN to study drivers of a failed injury response associated with kidney disease. We demonstrate that RENIN is highly effective tool at predicting keycis-andtrans-regulatory elements.
MicroRNA-205 promotes hair regeneration by modulating mechanical properties of hair follicle stem cells
Authors: Wang Jingjing , Fu Yuheng , Huang Wenmao , Biswas Ritusree , Banerjee Avinanda , Broussard Joshua A. , Zhao Zhihai , Wang Dongmei , Bjerke Glen , Raghavan Srikala , Yan Jie , Green Kathleen J. , Yi Rui
Published: December 2022

Stiffness and actomyosin contractility are intrinsic mechanical properties of animal cells required for the shaping of tissues. However, whether tissue stem cells (SCs) and progenitors located within SC niche have different mechanical properties that govern their size and functions remains unclear. We show that hair follicle SCs in the bulge are stiff with high actomyosin contractility and resistant to size change, whereas hair germ (HG) progenitors are soft and periodically enlarge and contract during quiescence. During activation, HGs reduce contraction and more frequently enlarge, a process that is associated with weakening of the actomyosin network, nuclear YAP accumulation and cell cycle re-entry. Induction of miR-205, a novel regulator of the actomyosin cytoskeleton, reduces actin contractility, decreases the stiffness of the bulge and HG, and activates hair regeneration in young and old mice. This study reveals the control of tissue SC size and activities by spatiotemporally compartmentalized mechanical properties and demonstrates the possibility to stimulate tissue regeneration by fine-tuning cell mechanics.
dcSBM: A federated constrained source-based morphometry approach for multivariate brain structure mapping
Authors: Saha Debbrata K. , Silva Rogers F. , Baker Bradley T. , Saha Rekha , Calhoun Vince D.
Published: December 2022

The examination of multivariate brain morphometry patterns has gained attention in recent years, especially for their powerful exploratory capabilities in the study of differences between patients and controls. Among many existing methods and tools for analysis of brain anatomy based on structural magnetic resonance imaging (sMRI) data, data-driven source based morphometry (SBM) focuses on the exploratory detection of such patterns. Constrained source-based morphometry (constrained SBM) is a widely used semi-blind extension of SBM that enables extracting maximally independent reference-alike sources using the constrained independent component analysis (ICA) approach. In order to operate, constrained SBM needs the data to be locally accessible. However, there exist many reasons (e.g., the concerns of revealing identifiable rare disease information, or violating strict IRB policies) that may preclude access to data from different sites. In this scenario, constrained SBM fails to leverage the benefits of decentralized data. To mitigate this problem, we present a novel approach: decentralized constrained source-based morphometry (dcSBM). In dcSBM, the original data never leaves the local site. Each site operates constrained ICA on their private local data while using a common distributed computation platform. Then, an aggregator/master node aggregates the results estimated from each local site and applies statistical analysis to find out the significant sources. In our approach, we first use UK Biobank sMRI data to investigate the reliability of our dcSBM algorithm. Finally, we utilize two additional multi-site patient datasets to validate our model by comparing the resulting group difference estimates from both centralized and decentralized constrained SBM.
Polygenic prediction across populations is influenced by ancestry, genetic architecture, and methodology
Authors: Wang Ying , Kanai Masahiro , Tan Taotao , Kamariza Mireille , Tsuo Kristin , Yuan Kai , Zhou Wei , Okada Yukinori ,   the BioBank Japan Project, Huang Hailiang , Turley Patrick , Atkinson Elizabeth G. , Martin Alicia R.
Published: December 2022

Polygenic risk scores (PRS) developed from multi-ancestry genome-wide association studies (GWAS), PRSmulti, hold promise for improving PRS accuracy and generalizability across populations. To establish best practices for leveraging the increasing diversity of genomic studies, we investigated how various factors affect the performance of PRSmulticompared to PRS constructed from single-ancestry GWAS (PRSsingle). Through extensive simulations and empirical analyses, we showed that PRSmultioverall outperformed PRSsinglein understudied populations, except when the understudied population represented a small proportion of the multi-ancestry GWAS. Notably, for traits with large-effect ancestry-enriched variants, such as mean corpuscular volume, using substantially fewer samples from Biobank Japan achieved comparable accuracies to a much larger European cohort. Furthermore, integrating PRS based on local ancestry-informed GWAS and large-scale European-based PRS improved predictive performance in understudied African populations, especially for less polygenic traits with large ancestry-enriched variants. Our work highlights the importance of diversifying genomic studies to achieve equitable PRS performance across ancestral populations and provides guidance for developing PRS from multiple studies.
Association between obesity, brain atrophy and accelerated brain aging and their genetic mechanisms
Authors: Kang Jujiao , Jia Tianye , Linli Zeqiang , Li Yuzhu , Cheng Wei , Guo Shuixia , Feng Jianfeng
Published: December 2022

Objective

To investigate the causal relationship and the underlying biological mechanisms between body mass index (BMI) and grey matter volume (GMV).

Methods

We applied Mendelian randomization analyses utilizing 33,6514 individuals from the UK Biobank cohort to establish the causal relationship between BMI and GMV. We also quantified obesity-related accelerated brain aging using an XGBoost prediction paradigm. Then, mediation analyses were performed to test the association between BMI, brain atrophy, brain aging and cognitive function. Finally, the gene expression data from the Allen Human Brain Atlas were used to identify genes contributing to the BMI-GMV association.

Results

A causal effect of increased BMI on decreased GMV was established using multiple Mendelian randomization methods. The brain age prediction paradigm achieved appreciable performance in both training (R = 0.725, mean-absolute-error (MAE) = 4.130) and test data (R= 0.71, MAE = 4.239). On average, overweight and obese individuals exhibited significantly accelerated brain aging by +0.59 years and +1.7 years, respectively. Further, the accelerated brain age and total GMV mediated 18% of the association of higher BMI with poorer cognitive function. BMI-associated lower GMVs were related to the over-expression of gene TRIM27 and other genes involved in the autophagy biological process.

Conclusion

Obesity led to GMV decline and accelerated brain aging. Genes including TRIM27 and biological process pathways involved in autophagy may contribute to the BMI-GMV association.
Mood symptoms and chronic fatigue syndrome due to relapsing remitting multiple sclerosis are associated with immune activation and aberrations in the erythron
Authors: Almulla Abbas F. , Abdul Jaleel Al-Karrar Kais , Abo Algon Ali Abbas , Tunvirachaisakul Chavit , Hassoun Hayder K. , Al-Hakeim Hussein K. , Maes Michael
Published: December 2022

Background

Multiple sclerosis (MS) is a chronic autoimmune and neuroinflammatory disease of the central nervous system characterized by peripheral activation of immune-inflammatory pathways which culminate in neurotoxicity causing demyelination of central neurons. Nonetheless, the pathophysiology of relapsing-remitting MS (RRMS)-related chronic fatigue, depression, anxiety, cognitive impairments, and autonomic disturbances is not well understood.

Objectives

The current study aims to delineate whether the remitted phase of RRMS is accompanied by activated immune-inflammatory pathways and if the latter, coupled with erythron variables, explain the chronic fatigue and mood symptoms due to RRMS.

Material and Methods

We recruited 63 MS patients, 55 in the remitted phase of RRMS and 8 with secondary progressive MS, and 30 healthy controls and assessed erythron variables and used a bio-plex assay to measure 27 serum cytokines.

Results

A significant part of the MS patients (46%) displayed activation of the immune-inflammatory response (IRS) and compensatory immune response (CIRS) systems, T helper (Th)1 and Th-17 cytokine profiles. Remitted RRMS patients showed increased chronic fatigue, depression, anxiety, physiosomatic, autonomic, and insomnia scores, which could partly be explained by M1 macrophage, Th1, Th-17, growth factor, and CIRS activation, as well as aberrations in the erythron including lowered hematocrit and hemoglobin levels.

Conclusions

Around 50% of remitted RRMS patients show activation of immune-inflammatory pathways in association with mood and chronic-fatigue-like symptoms. IRS and CIRS activation as well as the aberrations in the erythron are new drug targets to treat chronic fatigue and affective symptoms due to MS.
Epigenetics ofPNLIPRP1in human pancreas reveals a molecular path between type 2 diabetes and pancreatic cancer
Authors: Maurin Lucas , Marselli Lorella , Ning Lijiao , Boissel Mathilde , Boutry Raphael , Suleiman Mara , Leloire Audrey , Pascat Vincent , Maina Jared , Toussaint Bénédicte , Amanzougarene Souhila , Badreddine Alaa , Derhourhi Mehdi , Prokopenko Inga , Jörns Anne , Lenzen Sigurd , Pattou François , Kerr-Conte Julie , Canouil Mickaël , Bonnefond Amélie , Marchetti Piero , Froguel Philippe , Khamis Amna
Published: December 2022

Background

Type 2 diabetes (T2D) increases the risk of pancreatic ductal adenocarcinoma (PDAC), which could be due to an epigenetic mechanism.

Methods

We explored the association between T2D and whole pancreas methylation in 141 individuals, of which 28 had T2D, using Illumina MethylationEPIC 850K BeadChip arrays. We performed downstream functional assessment in the rat acinar pancreas cell line AR42J. To further understand the role of our candidate gene in humans, we tested whether null variants were associated with T2D and related traits using the UK biobank.

Results

Methylation analysis identified one significant CpG associated with T2D: hypermethylation in an enhancer inPNLIPRP1, an acinar-specific gene.PNLIPRP1expression was decreased in T2D individuals. Using a rat acinar cell line, we 1/ confirmed decreasedPnliprp1in response to a diabetogenic treatment, and 2/ inPnliprp1knockdown, an up-regulation of cholesterol biosynthesis, cell cycle down-regulation, decreased expression of acinar markers and increased expression of ductal markers pointing towards acinar-to-ductal metaplasia (ADM), a hallmark of PDAC initiation. Using exome data from UK Biobank, we show that rarePNLIPRP1null variants associated with increased glucose, BMI and LDL-cholesterol.

Conclusions/interpretation

We present evidence that an epigenetically-regulated gene associates with T2D risk, and might promote ADM and PDAC progression, opening new insights into early prevention of PDAC.
Effectiveness of Sotrovimab in Preventing COVID-19-related Hospitalizations or Deaths Among U.S. Veterans
Authors: Young-Xu Yinong , Korves Caroline , Zwain Gabrielle , Satram Sacha , Drysdale Myriam , Reyes Carolina , Cheng Mindy M. , Epstein Lauren , Marconi Vincent C. , Ginde Adit
Published: December 2022

Background

Data on effectiveness of sotrovimab preventing COVID-19-related hospitalization or mortality, particularly after the emergence of the Omicron variant, are limited.

Method

Determine the real-world clinical effectiveness of sotrovimab for prevention of 30-day COVID-19 related hospitalization or mortality using a retrospective cohort within the U.S. Department of Veterans Affairs (VA) healthcare system.

Veterans aged ≥18 years, diagnosed with COVID-19 between December 1, 2021, and April 4, 2022, were included. Sotrovimab recipients (n=2,816) were exactly matched to untreated controls (n=11,250) on date of diagnosis, vaccination status, and region.

The primary outcome was COVID-19-related hospitalization or all-cause mortality within 30 days from diagnosis. Cox proportional hazards modeling estimated the hazard ratios (HR) and 95% Confidence Interval (CI) for the association between receipt of sotrovimab and outcomes.

Results

During BA.1 dominance, compared to matched controls, sotrovimab-treated patients had a 70% lower risk hospitalization within 30 days or mortality (HR 0.30; 95%CI, 0.23-0.40), a 66% lower risk of 30-day hospitalization (HR 0.34; 95%CI, 0.25-0.46), and a 77% lower risk of 30-day all-cause mortality (HR 0.23; 95%CI, 0.14-0.38). During BA.2 dominance sotrovimab-treated patients had a 71% (HR .29; 95%CI, 0.08-0.98) lower risk of 30-day COVID-19-related-hospitalization, emergency, or urgent care. Limitations include confounding by indication.

Conclusions

Using national real-world data from high risk and predominantly vaccinated Veterans, administration of sotrovimab, compared with no treatment, was associated with reduced risk of 30-day COVID-19-related hospitalization or all-cause mortality during the Omicron BA.1 period and reduced risk of progression to severe COVID-19 during the BA.2 dominant period.

Examination of national real-world evidence demonstrates sotrovimab is effective in preventing at risk positive COVID-19 cases from progressing to severe SARS-CoV-2 infections compared to matched untreated cases during Delta and early Omicron variant waves in the U.S. Veteran population.
A Randomized, Double-Blind Trial of the Analgesic and Anti-Inflammatory Effects of Naproxen Sodium and Acetaminophen Following Implant Placement Surgery
Authors: Theken Katherine N. , Chen Mengxiang , Wall D. Lucas , Pham Truongan , Secreto Stacey A. , Yoo Thomas H. , Rascon Allison N. , Chang Yu-Cheng , Korostoff Jonathan M. , Mitchell Claire H. , Hersh Elliot V.
Published: December 2022

Objectives

The objectives of this study were to compare the analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen after implant placement surgery.

Materials and Methods

Adult patients who received one or two dental implants were treated with naproxen sodium (440 mg loading dose + 220 mg q8h, n=15) or acetaminophen (1000 mg q6h - max daily dose 3000 mg, n=15) for three days after implant placement in a randomized, double-blind design. Pain was assessed on a 0-10 scale every 20 minutes for 6 h. Tramadol (50 mg) was available as a rescue medication. Plasma and gingival crevicular fluid (GCF) were collected prior to the surgery and 0, 1, 2, 4, 6, 24, and 72h after surgery for quantification of interleukin (IL)-6, IL-8, and IL-1β levels.

Results

Pain scores were significantly lower in patients treated with naproxen sodium compared to those treated with acetaminophen. Inflammatory mediator levels in plasma and GCF increased after surgery and returned to near baseline levels by 72h. Plasma IL-6 levels were significantly lower 6h after surgery in patients treated with naproxen sodium compared to acetaminophen. No differences in inflammatory mediator concentrations in GCF were observed between the treatment groups.

Conclusions

Naproxen sodium was more effective than acetaminophen in reducing post-operative pain and systemic inflammation following surgical placement of one or two dental implants. Further studies are needed to determine whether these findings are applicable to more complex implant cases and how they affect clinical outcomes following implant placement.
Effects of counteracting measures on muscle contraction determinants in CKD: what muscle biopsy studies tell us?
Authors: Mitrou Georgia I.
Published: December 2022

Chronic kidney disease (CKD) is characterized by muscle atrophy, fatigue intolerance and other indicators of muscle dysfunction, collectively termed uremic myopathy, with devastating consequences in overall health status and mortality rates. Although many factors such as metabolic acidosis, substrate availability and neuropathy have been implicated, the mechanisms underlying uremic myopathy have not yet been fully understood. However, there is clear evidence that muscle specific factors such as fiber atrophy, fiber type alterations and mitochondrial abnormalities are presented in muscle biopsies of CKD patients and can negatively affect muscle contraction. Counteracting measures such as exercise and nutritional interventions have been shown to improve muscle performance, health indices and overall quality of life of CKD patients. However, little is known about their effects on factors affecting muscle contraction at the muscle biopsy level and therefore on the mechanisms underlying uremic myopathy. The current systematic review aims to summarize the effects of recent interventional studies on muscle contraction determinants based on muscle biopsies of human patients.
Exploring the Efficacy and Feasibility of using Biomarkers for Early Screening of Lung Cancer and their Potential Reverberation on Mortality Rate: A Review
Authors: Safari Vejin T , OLeary J , Singh L , Sullivan T , Aziague S , Akbariansaravi A
Published: December 2022

Introduction

Lung cancer patients often have a poor prognosis, due to various factors that play into the diagnosis, such as timeframe, early detection, and progression. The rate of patients with advanced-stage lung cancer is often high due to the inability to be diagnosed early. The lack of screening, therefore, increases the mortality rate of lung cancer. High mortality rate is also attributed to advanced lung cancer cases that are undiagnosed due to the lack of symptoms in patients early in disease acquisition.

Methods

This review explores lung cancer screening methods adopted around the world and those with the most promising standardizations. Criteria used to filter articles included lung cancer methods using biomarkers, research conducted in the United States within the past 10 years, screening methods observed in a clinical setting, and patients with primary lung cancer. Some practices that can be utilized to improve screening for lung cancer may involve using genetic markers to identify patients possessing genetic makeup associated with lung cancer.

Results

Our study included 32 articles in our review calculating the sensitivity and specificity for a variety of potential biomarkers including: 1) Volatile organic compounds has a specificity of 80% and sensitivity of 80% 2) Circulating tumor DNA has a sensitivity of 80% and specificity of 96% 3) miRNA molecules (miR-146-5p, miR-324-5p, miR-223-3p, and miR-223-5p) displayed sensitivities of 93%, 94%, 96%, and 95% respectively, with specificities of 33%, 23%, 27%, and 26% respectively 4) methylation beads specific genomic sequences (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42) with sensitivities of 84%, 86%, 63%, 78%, 93%, and 87% respectively when found in sputum and 73%, 76%, 34%, 65%, 86%, and 84% respectively when found in serum. Specificities were calculated at 88%, 75%, 92%, 67%, 8%, and 63% respectively when found in sputum, and 84%, 78%, 92%, 74%, 46%, and 54% respectively in serum 5) Ga-Alfatide II scans were found to have a sensitivity of 86% and a specificity of 85% 6) Combined score had a sensitivity of 78% and specificity of 50% 7) WT-IDH had a sensitivity of 63% and specificity of 93%.

Discussion

In such a high-risk patient population, cautious preventative measures can be used such as lifestyle choices and environmental exposures that are known risk factors. Informed physicians will be able to provide care directed toward minimizing patient’s modifiable risk factors to lower incidence rate and routine imaging offered when there is an index of suspicion to minimize mortality rate in high-risk populations. This review highlighted practices such as circulating tumor DNA and a Ga-Alfatide II CT/PET scan that can be utilized to improve screening in the future and further dissected errors made in lung cancer diagnosis.
Interplay of EXO70 and MLO proteins modulates trichome cell wall composition and powdery mildew susceptibility
Authors: Huebbers Jan W. , Caldarescu George A. , Kubátová Zdeňka , Sabol Peter , Levecque Sophie C. J. , Kuhn Hannah , Kulich Ivan , Reinstädler Anja , Büttgen Kim , Manga-Robles Alba , Mélida Hugo , Pauly Markus , Panstruga Ralph , Žárský Viktor
Published: December 2022

EXO70 proteins are essential constituents of the octameric exocyst complex implicated in vesicle tethering during exocytosis, while MLO proteins are plant-specific calcium channels of which some isoforms play a key role during fungal powdery mildew pathogenesis. We here detected by a variety of histochemical staining procedures an unexpected phenotypic overlap ofA. thaliana exo70H4andmlo2 mlo6 mlo12triple mutant plants regarding the biogenesis of leaf trichome secondary cell walls. Biochemical and Fourier transform infrared spectroscopic analyses of isolated trichomes corroborated deficiencies in the composition of trichome cell walls inexo70H4andmlo2 mlo6 mlo12mutants. Transgenic lines expressing fluorophore- tagged EXO70H4 and MLO variants exhibited extensive co-localization of these proteins at the trichome plasma membrane and cell wall. Furthermore, mCherry- EXO70H4 mislocalized in trichomes of themlotriple mutant and,vice versa, MLO6- GFP exhibited aberrant subcellular localization in trichomes of theexo70H4mutant. Transgenic expression of GFP-marked PMR4 callose synthase, a previously identified cargo of EXO70H4 dependent exocytosis, revealed reduced cell wall delivery of GFP- PMR4 inmlotriple mutant plants.In vivoprotein-protein interaction assays uncovered isoform-preferential physical interaction between EXO70 and MLO proteins. Finally,exo70H4andmlomutants, when combined, showed synergistically enhanced resistance to powdery mildew attack. Taken together, our data point to an isoform- specific interplay of EXO70 and MLO proteins in the modulation of trichome cell wall biogenesis and powdery mildew susceptibility, possibly by (co-)regulating focal secretion of cell wall-related cargo.
A multi-omicNicotiana benthamianaresource for fundamental research and biotechnology
Authors: Ranawaka Buddhini , An Jiyuan , Lorenc Michał T. , Jung Hyungtaek , Sulli Maria , Aprea Giuseppe , Roden Sally , Hayashi Satomi , Cooper Tal , LeBlanc Zacharie , Llaca Victor , Orzaez Diego , Bombarely Aureliano , Bally Julia , Winefield Christopher , Giuliano Giovanni , Waterhouse Peter M.
Published: December 2022

Nicotiana benthamianais an invaluable model plant and biotechnology platform. To further improve its usefulness and versatility, we have produced high quality chromosome level genome assemblies and multi-omic datasets for both the ubiquitously used LAB strain and a distantly related wild accession, QLD, as well as mapping their single nucleotide polymorphisms with two additional laboratory and four additional wild accessions. LAB and QLD have many genetic, functional, and metabolic differences. These coupled with their high inter-fertility and equally efficient transient and stable transformation and genome editing provide a powerful resource partnership. Their ∼3Gb allotetraploid genomes show advanced diploidisation with major chromosome loss and rearrangement, extensive homoeologous gene loss, and widespread segmental allopolyploidy. Recent bursts of Copia mobility, not seen in otherNicotianagenomes, have probably aidedN. benthamiana’s adaptation to a spectrum of Australian ecologies.
Obtaining Increased Functional Proteomics Insights from Thermal Proteome Profiling through Optimized Melt Shift Calculation and Statistical Analysis
Authors: McCracken Neil A. , Liu Hao , Runnebohm Avery M. , Wijeratne H.R. Sagara , Wijeratne Aruna B. , Staschke Kirk A. , Mosley Amber L.
Published: December 2022

Thermal Proteome Profiling (TPP) is an invaluable tool for functional proteomics studies that has been shown to discover changes associated with protein-ligand, protein- protein, and protein-RNA interaction dynamics along with changes in protein stability resulting from cellular signaling. The increasing number of reports employing this assay has not been met concomitantly with advancements and improvements in the quality and sensitivity of the corresponding data analysis. The gap between data acquisition and data analysis tools is even more apparent as TPP findings have reported more subtle melt shift changes related to protein post-translational modifications. In this study, we have improved the Inflect data analysis pipeline (now referred to as InflectSSP, available athttps://CRAN.R-project.org/package=InflectSSP) to increase the sensitivity of detection for both large and subtle changes in the proteome as measured by TPP. Specifically, InflectSSP now has integrated statistical and bioinformatic functions to improve objective functional proteomics findings from the quantitative results obtained from TPP studies through increasing both the sensitivity and specificity of the data analysis pipeline. To benchmark InflectSSP, we have reanalyzed two publicly available datasets to demonstrate the performance of this publicly available R based program for TPP data analysis. Additionally, we report new findings following temporal treatment of human cells with the small molecule Thapsigargin which induces the unfolded protein response (UPR). InflectSSP analysis of our UPR study revealed highly reproducible target engagement over time while simultaneously providing new insights into the dynamics of UPR induction.
Enzyme encapsulation peptides bind to the groove between tessellating subunits of the bacterial microcompartment shell
Authors: Bradley-Clarke Jack , Gu Shuang , Rose Ruth-Sarah , Warren Martin J. , Pickersgill Richard W.
Published: December 2022

Bacterial microcompartments are prokaryotic organelles consisting of encapsulated enzymes within a thin protein shell. They are involved in metabolic processing including propanediol, choline, glycerol and ethanolamine utilization, and carbon fixation. Enzymes targeted to the inside of the microcompartment frequently possess a cargo-encapsulation peptide, but the binding-site has not been revealed. We provide evidence that the encapsulation peptides bind to the hydrophobic groove formed between tessellating tiles of major shell proteins.In silicodocking studies provide a compelling model of peptide binding to this hydrophobic groove. This result is consistent with the now widely accepted view that the convex side of the shell proteins faces the lumen of the microcompartment. Binding between shell protein tiles explains why the encapsulation peptide binding site has been elusive, how encapsulation-peptide bearing enzymes can promote shell assembly, and how the presence of cargo affects the size and shape of the bacterial microcompartment.
Neural populations in the language network differ in the size of their temporal receptive windows
Authors: Regev Tamar I. , Casto Colton , Hosseini Eghbal A. , Adamek Markus , Ritaccio Anthony L. , Willie Jon T. , Brunner Peter , Fedorenko Evelina
Published: December 2022

Despite long knowing what brain areas support language comprehension, our knowledge of the neural computations that these frontal and temporal regions implement remains limited. One important unresolved question concerns functional differences among the neural populations that comprise the language network. Leveraging the high spatiotemporal resolution of intracranial recordings, we examined responses to sentences and linguistically degraded conditions and discovered three response profiles that differ in their temporal dynamics. These profiles appear to reflect different temporal receptive windows (TRWs), with average TRWs of about 1, 4, and 6 words, as estimated with a simple one-parameter model. Neural populations exhibiting these profiles are interleaved across the language network, which suggests that all language regions have direct access to distinct, multi-scale representations of linguistic input—a property that may be critical for the efficiency and robustness of language processing.
Transcriptional control of visual neural circuit development by GS homeobox 1
Authors: Schmidt Alexandra Rose , Shephard Rebekah , Patrick Regina L , Bergeron Sadie A
Published: December 2022

As essential components of gene expression networks, transcription factors regulate neural circuit assembly.GS homeobox 1 (gsx1) is expressed in the developing visual system; however, no studies have examined its role in visual system formation. In zebrafish, retinal ganglion cell (RGC) axons terminate in ten arborization fields (AFs) in the optic tectum (TeO) and pretectum (Pr). Pretectal AFs (AF1-AF9) mediate distinct and essential visual behaviors, yet we understand less about their development compared to AF10 in the TeO. Usinggsx1zebrafish mutants, immunohistochemistry, and transgenic lines, we observed thatgsx1is required for vesicular glutamate transporter,slc17a6b, expression in the Pr, but not overall neuron number.gsx1mutants have normal eye morphology, yet exhibit impaired vision and a significantly reduced volume of RGC axons innervating the Pr and TeO, including loss of AF7. Consistent with this, prey capture is reduced ingsx1mutants. Timed laser ablation ofslc17a6b-positiveneurons reveals that they aide directly in AF7 formation. This work is the first to implicategsx1in establishing cell identity and functional neural circuits in the visual system.

SUMMARY STATEMENT

This is the first study in any vertebrate model to establish a requirement for the homeobox transcription factor encoding gene,gsx1, in visual neural circuit formation and function.
CLIP-Seq Analysis Enables the Design of Ribosomal RNA Bait Oligonucleotides That Protect AgainstC9ORF72ALS/FTD-Associated Poly-GR Pathophysiology
Authors: Ortega Juan A. , Sasselli Ivan R. , Boccitto Marco , Fleming Andrew C. , Fortuna Tyler R. , Li Yichen , Sato Kohei , Clemons Tristan D. , Daley Elizabeth L. , Nguyen Thao P. , Anderson Eric N. , Ichida Justin K. , Pandey Udai B. , Wolin Sandra , Stupp Samuel I. , Kiskinis Evangelos
Published: December 2022

Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion inC9ORF72(C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind to low complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remains unclear. We used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA “bait” oligonucleotides restore poly-GR-associated ribosomal deficits in cells and ameliorate poly-GR toxicity in patient neurons andDrosophilamodels. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal disfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms.
European Beech Spring Phenological Phase Prediction with UAV-derived Multispectral Indices and Machine Learning Regression
Authors: Krause Stuart , Sanders Tanja G.M.
Published: December 2022

The acquisition of phenological events play an integral part in investigating the effects of climate change on forest dynamics and assessing the potential risk involved with the early onset of young leaves. Large scale mapping of forest phenological timing using earth observation data, could facilitate a better understanding of phenological processes due to an added spatial component. The translation of traditional phenological ground observation data into reliable ground truthing for the purpose of the training and validation of Earth Observation (EO) mapping applications is a challenge. In this study, we explored the possibility of predicting high resolution phenological phase data for European beech (Fagus sylvatica) with the use of Unmanned Aerial Vehicle (UAV)-based multispectral indices and machine learning. Using a comprehensive feature selection process, we were able to identify the most effective sensors, vegetations indices, training data partitions, and machine learning models for phenological phase prediction. The best performing model that generalised well over various sites was the model utilising the Green Chromatic Coordinate (GCC) and Generalized Addictive Model (GAM) boosting. The GCC training data was derived from the radiometrically calibrated visual bands from a multispectral sensor and predicted using uncalibrated RGB sensor data. The final GCC/GAM boosting model was capable in predicting phenological phases on unseen datasets within a RMSE threshold of 0.5. This research shows the potential of the interoperability among common UAV-mounted sensors in particular the utility of readily available low cost RGB sensors. Considerable limitations were however discovered with indices implementing the near-infrared (NIR) band due to oversaturation. Future work involves adapting models to facilitate the ICP Forests phenological flushing stages.
Biphasic curvature-dependence of cell migration inside microcylinders: persistent randomness versus directionality
Authors: Yu Xiaoyu , Wang Haiqin , Ye Fangfu , Wang Xiaochen , Fan Qihui , Xinpeng Xu
Published: December 2022

Cell-scale curvature plays important roles in controlling cell and tissue behaviors. However, these roles have not been well quantified, and the underlying mechanisms remain elusive. We combine experiments with theory to study systematically the curvature-dependence of cell migration inside PDMS microcylinders. We find that persistence is positively correlated with speed, following the universal speed-persistence coupling relation,i.e., faster cells turn less. Cell migration inside microcylinders is anisotropic and depends on curvature in a biphasic manner. At small curvatures, as curvature increases, the average speed and anisotropy both increase, but surprisingly, the average persistence decreases. Whereas as the curvature increases over some threshold, cells detach from the surface, the average speed and anisotropy both decrease sharply but the average persistence increases. Moreover, interestingly, cells are found to leave paxillins along their trajectories (on curved but not planar surfaces), facilitating the assembly of focal adhesions of following cells. We propose a minimal model for the biphasic curvotaxis based on three mechanisms: the persistent random “noise”, the bending penalty of stress fibers, and the cell-surface adhesion. The findings provide a novel and general perspective on directed cell migration in the widely existing curved microenvironment of cellsin vivo.
Neuroendocrine control of catch-up growth in Drosophila
Authors: Vallejo Diana M , Saez Ernesto , García-López Lucia , Santoro Roberto , Dominguez Maria
Published: December 2022

Children and other vertebrate animals stunted due to malnutrition can compensate for this deficit by resuming growth at a higher-than-normal rate via a still ill-defined mechanism. High mortality and adverse effects later in life may offset the positive effects of catch-up growth. Here we report that the invertebrateDrosophila melanogasteralso experiences catch-up growth following a period of starvation, and the relaxin receptor Lgr4 instigates this catch-up growth. Starved larvae compensate for weight loss by growing two or more times faster and starting maturation within the same time as the non-starved sibling by preventing a rise in insulin-like growth (IGF)-induced ecdysone under Lgr4 control. Our data reveal that catch-up growth is associated with a surge of insulin, not IGF, which may clarify how catch-up growth often leads to metabolic problems and obesity.
Diversity and evolution of cerebellar folding in mammals
Authors: Heuer Katja , Traut Nicolas , de Sousa Alexandra A. , Valk Sofie , Toro Roberto
Published: December 2022

The process of brain folding is thought to play an important role in the development and organisation of the cerebrum and the cerebellum. The study of cerebellar folding is challenging due to the small size and abundance of its folia. In consequence, little is known about its anatomical diversity and evolution. We constituted an open collection of histological data from 56 mammalian species and manually segmented the cerebrum and the cerebellum. We developed methods to measure the geometry of cerebellar folia and to estimate the thickness of the molecular layer. We used phylogenetic comparative methods to study the diversity and evolution of cerebellar folding and its relationship with the anatomy of the cerebrum. Our results show that the evolution of cerebellar and cerebral anatomy follows a stabilising selection process. Ancestral estimations indicate that size and folding of the cerebrum and cerebellum increase and decrease concertedly through evolution. Our analyses confirm the strong correlation between cerebral and cerebellar volumes across species, and show that large cerebella are disproportionately more folded than smaller ones. Compared with the extreme variations in cerebellar surface area, folial wavelength and molecular layer thickness varied only slightly, showing a much smaller increase in the larger cerebella. These findings provide new insights into the diversity and evolution of cerebellar folding and its potential influence on brain organisation across species.
SAP30BP interacts with RBM17/SPF45 to promote splicing in a subset of human short introns
Authors: Fukumura Kazuhiro , Sperotto Luca , Seuß Stefanie , Kang Hyun-Seo , Yoshimoto Rei , Sattler Michael , Mayeda Akila
Published: December 2022

Human pre-mRNA splicing requires the removal of introns with highly variable lengths, from tens to over a million nucleotides. Therefore, mechanisms of intron recognition and splicing are likely not universal. Recently, we reported that splicing in a subset of human short introns with truncated polypyrimidine tracts depends on RBM17 (SPF45), instead of the canonical splicing factor U2AF heterodimer. Here, we demonstrate that SAP30BP, a factor previously implicated in transcriptional control, is an essential splicing cofactor for RBM17.In vitrobinding and NMR analyses demonstrate that a U2AF-homology motif (UHM) in RBM17 binds directly to a newly identified UHM-ligand motif (ULM) in SAP30BP. We show that this RBM17–SAP30BP interaction is required to specifically recruit RBM17 to phosphorylated SF3B1 (SF3b155), a U2 snRNP component in active spliceosomes. We propose a unique mechanism for splicing in a subset of short introns, in which SAP30BP guides RBM17 in the assembly of active spliceosomes.

Graphical abstract

In brief

Fukumura et al. discover a general splicing mechanism in a subset of human short introns with truncated polypyrimidine tracts. This splicing reaction is mediated by intermediary RBM17–SAP30BP complex, instead of the known U2AF heterodimer. SAP30BP binding to RBM17 may support RBM17 association with active phosphorylated SF3B1 in U2 snRNP.

Highlights

RBM17 (SPF45) is a splicing factor required for a subset of human short introns

SAP30BP is an essential cofactor, which interacts with RBM17viaUHM–ULM binding

RBM17 forms a weak complex with SAP30BP before its binding with SF3B1 in U2 snRNP

RBM17–SAP30BP complex supports RBM17 to be recruited to active phosphorylated SF3B1
The development of object recognition requires experience with the surface features of objects
Authors: Wood Justin N. , Wood Samantha M. W.
Published: December 2022

What role does visual experience play in the development of object recognition? Prior controlled-rearing studies suggest that newborn animals require slow and smooth visual experiences to develop object recognition. Here we examined whether the development of object recognition also requires experience with the surface features of objects. We raised newborn chicks in automated controlled-rearing chambers that contained a single virtual object, then tested their ability to recognize that object from familiar and novel viewpoints. When chicks were reared with an object that had surface features, the chicks developed view-invariant object recognition. In contrast, when chicks were reared with a line drawing of an object, the chicks failed to develop object recognition. The chicks reared with line drawings performed at chance level, despite acquiring over 100 hours of visual experience with the object. These results indicate that the development of object recognition requires experience with the surface features of objects.
The ketone body acetoacetate activates human neutrophils through FFA2R
Authors: Mårtensson Jonas , Björkman Lena , Lind Simon , Viklund Moa Bjerhem , Zhang Linjie , Gutierrez Saray , Dahlgren Claes , Sundqvist Martina , Xie Xin , Forsman Huamei
Published: December 2022

Neutrophils express many surface receptors that sense environmental changes. One such sensor is FFA2R (free fatty acid receptor 2), a receptor that detects gut microbiota-derived short chain fatty acids. As such, FFA2R has been regarded as a molecular link between metabolism and inflammation. Our recent studies on FFA2R, using its endogenous agonist propionate in combination with allosteric modulators, have identified several novel aspects of FFA2R regulation. A recent study has also identified the ketone body acetoacetate as an endogenous ligand for mouse FFA2R. Whether human FFA2R also recognizes acetoacetate and how this recognition modulates human neutrophil functions has not been earlier investigated. In this study, we found that acetoacetate can induce a decrease of cAMP and translocation of β-arrestin in cells overexpressing FFAR2. In addition, we show that similar to propionate, FFA2R specific allosteric modulators enhance acetoacetate-induced transient rise in cytosolic calcium, production of reactive oxygen species and cell migration in human neutrophils. In summary, we demonstrate that human neutrophils recognize the ketone body acetoacetate through FFA2R. Thus, our data further highlight the key role of FFA2R in inflammation and metabolism.
Surveillance for SARS-CoV-2 in Ohio’s wildlife, companion, and agricultural animals
Authors: Ehrlich Margot , Madden Christopher , McBride Dillon S. , Nolting Jaqueline M. , Huey Devra , Kenney Scott , Wang Qiuhong , Saif Linda , Vlasova Anastasia , Dennis Patricia , Lombardi Dusty , Gibson Stormy , McLaine Alexis , Lauterbach Sarah , Yaxley Page , Winston Jenessa , Diaz-Campos Dubraska , Pesapane Risa , Flint Mark , Flint Jaylene , Junge Randy , Faith Seth A. , Bowman Andrew S. , Hale Vanessa L.
Published: December 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in humans in late 2019 and spread rapidly to become a global pandemic. A zoonotic spillover event from animal to human was identified as the presumed origin. Subsequently, reports began emerging regarding spillback events resulting in SARS-CoV-2 infections in multiple animal species. These events highlighted critical links between animal and human health while also raising concerns about the development of new reservoir hosts and potential viral mutations that could alter virulence and transmission or evade immune responses. Characterizing susceptibility, prevalence, and transmission between animal species became a priority to help protect animal and human health. In this study, we coalesced a large team of investigators and community partners to surveil for SARS-CoV-2 in domestic and free-ranging animals around Ohio between May 2020 and August 2021. We focused on species with known or predicted susceptibility to SARS-CoV-2 infection, highly congregated or medically compromised animals (e.g. shelters, barns, veterinary hospitals), and animals that had frequent contact with humans (e.g. pets, agricultural animals, zoo animals, or animals in wildlife hospitals). This included free-ranging deer (n=76), mink (n=57), multiple species of bats (n=65), and other wildlife in addition to domestic cats (n=275) and pigs (n= 184). In total, we tested 800 animals (34 species) via rRT-PCR for SARS-CoV-2 RNA. SARS-CoV-2 viral RNA was not detected in any of the tested animals despite a major peak in human SARS-CoV-2 cases that occurred in Ohio subsequent to the peak of animal samplings. Importantly, due to lack of validated tests for animals, we did not test for SARS-CoV-2 antibodies in this study, which limited our ability to assess exposure. While the results of this study were negative, the surveillance effort was critical and remains key to understanding, predicting, and preventing re-emergence of SARS-CoV-2 in humans or animals.