bluuebunny/crossref_metadata_2025 huggingface dataset:
Hernia surgical treatment; multi-options and paucity of statistical conformation for the preferred surgical option
Authors: Marzoog Basheer Abdullah , Vladimirovich Kostin Sergey
Published: December 2022

Background

Hernia is a common pathology in the globe and reported more frequently, particularly, inguinal hernia.

Aims

To identify the surgery of choice for the treatment of hernias by evaluating the required postoperative hospitalization time, as no other complications have been reported according to data from Mordovian Republic hospital.

Material and methods

A retrospective cohort study involved 790 patients for the period 2017-2022 treated surgically for various types of hernia; inguinal hernia, umbilical hernia, spontaneously reduced strangulated post-operative ventral hernia, incarcerated post-operative ventral hernia, and hernia of the Lina Alba. For statistical analysis, used T test, one way ANOVA test, and Pearson correlation test by using Statistica program.

Results

The hospitalization period after Lichtenstein surgery is statistically less than Postemsky surgery (mean 6.88 days, 7.43 days, respectively, t value -2.29593, p<0.02) and laparoscopic surgery (mean 6.88 days, 8.19072 days, respectively, t value 4,206817, p<0,000031). Whereas, Postemsky surgery has shorter post-operative hospitalization period in compare to laparoscopic surgery (mean 7.43 days, 8.19072 days, respectively, t value -2.19326, p<0.02). According to the used surgical approach, the patient’s post-operative hospitalization days differs (mean days: min. days; max. days, 7.50192: 0.00; 30.00). According to Postemsky (M ± m; 7.43262, ±0.167012), according to Martynov (M ± m; 8.37500, ±0.113440), according to Lichtenstein (M ± m; 6.88153, ±0.146845), according to Mayo (M ± m; 7.51282, ±0.280156), according to Bassini (M ± m; 8.77778, ± 2.379179), laparoscopically (M ± m; 8.19072, ± 0.268434), according to Sapezhko (M ± m; 8.25000, ± 1.380074), and another type of surgery (M ± m; 11.40000, ± 2.501999). Women (mean 8.525114 days) hospitalized longer than men (mean 7.065371 days), t value 5.871044, p< 0.001. A statistically significant correlation has been found between age and post-operative hospitalization time (Pearson Rank Order Correlations r=0.215561, p <0.05).

Conclusions

The study shows that the Lichtenstein surgery is the surgery of choice in terms of hospitalization time after the surgery. Straight association between sex and age with postoperative hospitalization days.
Altitude, not potential larval habitat availability, explains pronounced variation inPlasmodium falciparuminfection prevalence in the western Kenya highlands
Authors: Oduma Colins O. , Ombok Maurice , Zhao Xingyuan , Huwe Tiffany , Ondigo Bartholomew N. , Kazura James W. , Grieco John , Achee Nicole , Liu Fang , Ochomo Eric , Koepfli Cristian
Published: December 2022

Background

Progress in malaria control has stalled over the recent years. Knowledge on main drivers of transmission explaining small-scale variation in prevalence can inform targeted control measures.

Methods

We collected finger-prick blood samples from 3061 individuals irrespective of clinical symptoms in 20 clusters in Busia in western Kenya and screened forPlasmodium falciparumparasites using qPCR and microscopy. Clusters spanned an altitude range of 207 meters (1077-1284 m). We mapped potential mosquito larval habitats and determined their number within 250 m of a household and distances to households using ArcMap.

Results

Across all clusters,P. falciparumparasites were detected in 49.8% (1524/3061) of individuals by qPCR and 19.5% (596/3061) by microscopy. Across the clusters, prevalence ranged from 26% to 70% by qPCR. Three to 34 larval habitats per cluster and 0-17 habitats within a 250m radius around households were observed. Using a generalized linear mixed effect model (GLMM), a 5% decrease in the odds of getting infected per each 10m increase in altitude was observed, while the number of larval habitats and their proximity to households were not statistically significant predictors for prevalence. Kitchen located indoors, open eaves, a lower level of education of the household head, older age, and being male were significantly associated with higher prevalence.

Conclusion

Pronounced variation in prevalence at small scales was observed and needs to be taken into account for malaria surveillance and control. Potential larval habitat frequency had no direct impact on prevalence.
SARS-CoV-2 seroprevalence and longitudinal antibody response following natural infection in pregnancy: a prospective cohort study
Authors: Drake Alison L. , Escudero Jaclyn N. , Aurelio Morgan C. , Ellington Sascha R. , Zapata Lauren B. , Galang Romeo R. , Snead Margaret C. , Yamamoto Krissy , Salerno Carol , Richardson Barbra A. , Greninger Alexander L. , Kachikis Alisa B. , Englund Janet A. , LaCourse Sylvia M.
Published: December 2022

Importance

Antenatal care provides unique opportunities to assess SARS-CoV-2 seroprevalence and antibody response duration after natural infection detected during pregnancy; transplacental antibody transfer may inform peripartum and neonatal protection.

Objective

Estimate seroprevalence and durability of antibodies from natural infection (anti-nucleocapsid (anti-N) IgG) among pregnant people, and evaluate transplacental transfer efficiency.

Design

Seroprevalence study: cross-sectional SARS-CoV-2 antibody screening among pregnant people December 9, 2020-June 19, 2021. Cohort study: Pregnant people screened anti-N IgG+ by Abbott Architect chemiluminescent immunoassay in seroprevalence study or identified through medical records with RT-PCR+ or antigen positive results enrolled in a prospective cohort December 9, 2020-June 30, 2022 to longitudinally measure anti-N IgG responses. We collected cord blood and assessed transplacental transfer of maternally-derived anti-N antibodies.

Setting

Three hospitals and 14 affiliated clinics providing antenatal and delivery care, Seattle, Washington metropolitan area.

Participants

Seroprevalence study: pregnant people were screened for SAR-CoV-2 anti-N IgG during routine care. Cohort study: Pregnant people with evidence of prior SARS-CoV-2 infection (screened anti-N IgG+ from seroprevalence study or identified with a RT-PCR+ or antigen positive result from medical records) were enrolled in a cohort study to longitudinally measure anti-N IgG responses.

Exposure(s) (for observational studies)

COVID-19 diagnosis, symptoms, and disease severity.

Main Outcome(s) and Measure(s)

Presence and durability of SARS-CoV-2 anti-N IgG, transplacental transfer of maternally-derived anti-N IgG.

Results

Of 1289 pregnant people screened in the seroprevalence study, 5% (65) tested SARS-CoV-2 anti-N IgG+, including 39 (60%) without prior RT-PCR+ or antigen positive results and 53 (82%) without symptoms. Among 89 participants enrolled in the cohort study, 73 (82%) had anti-N IgG+ results during pregnancy. Among 49 participants with delivery samples 33 (67%) were anti-N IgG negative by delivery. Of 24 remaining anti-N IgG+ at delivery with paired cord blood samples, 12 (50%) had efficient transplacental anti-N IgG antibody transfer. Median time from first anti-N IgG to below positive antibody threshold was 17 weeks and did not differ by prior RT-PCR+ or antigen positive status.

Conclusions and Relevance

Maternally-derived SARS-CoV-2 antibodies to natural infection may wane before delivery. Vaccines are recommended for pregnant persons to reduce severe illness and confer protection to infants.
Agricultural paraquat dichloride use and Parkinson’s disease in California Central Valley
Authors: Paul Kimberly C , Cockburn Myles , Gong Yufan , Bronstein Jeff , Ritz Beate
Published: December 2022

Background

Paraquat dichloride is currently among the most widely used commercial herbicides in the United States. Exposure has been broadly linked to Parkinson’s disease (PD) through experimental and epidemiologic research. In the current study, we provide further epidemiologic assessment of ambient paraquat exposure and Parkinson’s risk in a large population-based study of PD in agricultural regions of Central California.

Methods

Based on 829 PD patients and 824 community controls, we assessed associations between ambient paraquat dichloride exposure and PD. We estimated residential and workplace proximity to commercial agricultural applications in three California counties since 1974 using the CA pesticide use reporting (PUR) data and land use maps. We evaluated any, duration, and average intensity (pounds per acre per year) of exposure to paraquat in four time-windows prior to PD diagnosis or interview for controls.

Results

Ambient paraquat exposure assessed at both residence and workplace was associated with PD based on all three exposure measures, indicating that PD patients lived and worked near agricultural facilities that applied greater amounts of the herbicide than community controls. For workplace proximity to commercial applications since 1974, any exposure (yes/no, OR=1.25, 95% CI=1.00, 1.57), duration of exposure (per SD, OR=1.26, 95% CI=1.10, 1.44), and long-term average intensity of exposure (per SD, OR=1.30, 95% CI=1.10, 1.53) increased the odds of PD. Similar associations were observed for residential proximity (duration of exposure: OR=1.23 per SD, 95% CI=1.07,1.40; long-term average exposure: OR=1.22 per SD, 95% CI=1.03, 1.46). Risk estimates were comparable for men and women and the strongest odds were observed for those diagnosed ≤60 years of age.

Conclusion

This study provides further evidence that paraquat dichloride exposure increases the risk of Parkinson’s disease.
Metaproteogenomic Analysis of Saliva Samples from Parkinson’s Disease Patients Across the Spectrum of Cognitive Impairment
Authors: Arıkan Muzaffer , Demir Tuğçe Kahraman , Yıldız Zeynep , Nalbantoğlu Özkan Ufuk , Korkmaz Nur Damla , Yılmaz Nesrin H. , Şen Aysu , Özcan Mutlu , Muth Thilo , Hanoğlu Lütfü , Yıldırım Süleyman
Published: December 2022

Cognitive impairment (CI) is very common in patients with Parkinson’s Disease (PD) and progressively develops on a spectrum from mild cognitive impairment (PD-MCI) to full dementia (PDD). Identification of PD patients at risk of developing cognitive decline, therefore, is unmet need in the clinic to manage the disease. Previous studies reported that oral microbiota of PD patients was altered even at early stages and poor oral hygiene is associated with dementia. However, data from single modalities often unable to explain complex chronic diseases in the brain and cannot reliably predict the risk of disease progression. Here, we performed integrative metaproteogenomic characterization of salivary microbiota and tested the hypothesis that biological molecules of saliva and saliva microbiota dynamically shift in association with the progression of cognitive decline and harbor discriminatory key signatures across the spectrum of CI in PD. We recruited a cohort of 115 participants in a multi-center study and employed multi-omics factor analysis (MOFA) to integrate amplicon sequencing and metaproteomic analysis to identify signature taxa and proteins in saliva. Our baseline analyses revealed contrasting interplay between the genusNeisseriaandLactobacillusandLigilactobacillusgenera across the spectrum of CI. The group specific signature profiles enabled us to identify candidate biomarkers including 7 bacterial genera (Neisseria, Lactobacillus, Rothia, Ligilactobacillus, Alloprevotella, TM7xandCorynebacteirum) and 4 protein groups (40S ribosomal protein SA, 40S ribosomal protein S15, pyruvate, phosphate dikinase and bactericidal permeability-increasing protein) discriminating CI stages in PD (AUC 0.74-0.86). Our study describes compositional dynamics of saliva across the spectrum of CI in PD and paves the way for developing novel, non-invasive biomarker strategies to predict the risk of CI progression in PD.
MULTIMODAL-MULTITASK-SELFSUPERVISED XDEEP-MSI: EXPLAINABLE BIAS-REJECTING MICROSATELLITE INSTABILITY DEEP LEARNING SYSTEM IN COLORECTAL CANCER
Authors: Bustos Aurelia , Payá Artemio , Torrubia Andres , Alenda Cristina
Published: December 2022

Abstract

The prediction of microsatellite instability (MSI) in colorectal cancer (CRC) using deep learning (DL) techniques directly from hematoxylin and eosin stained slides (H&E) has been shown feasible by independent works. Nonetheless, when available, relevant information from clinical, oncological and family history could be used to further inform DL predictions. The present work analyzes the effects from leveraging multimodal inputs and multitask supervision in a previously published DL system for the prediction of MSI in CRC (xDEEP-MSI). xDEEP-MSI was a multiple bias rejecting DL system based on adversarial networks trained and validated in 1788 patients from a total of 25 participating centers from EPICOLON and HGUA projects. In the present work, xDEEP-MSI is further enriched with weakly supervised learning in multiple molecular alterations (MSI status, K-RAS and BRAF mutations and Lynch Syndrome confirmed by germline mutations), adapted to multimodal inputs with variable degree of completeness (image, age, gender, localization of CRC, revised Bethesda criteria, Amsterdam II criteria and additional oncological history) and a self-supervised multiple instance learning that integrates multiple image-tiles, to obtain patient-level predictions. The AUC, including all three selected tissues (tumor epithelium, mucin and lymphocytic regions) and 5 magnifications, increases from 0.9 ± 0.03, to 0.94 ± 0.02. The sensibility and specificity reaches 92.5% 95%CI(79.6-98.4%) and 93.4% 95%CI(90.0-95.8%) respectively. To the best of our knowledge this is the first work that jointly uses multimodal inputs, multiple instance learning and multiple molecular supervision for the prediction of MSI in CRC from H&E, demonstrating their gains in performance. Prospective validation in an external independent dataset is still required.
High Sensitivity Top-down Proteomics Captures Single Muscle Cell Heterogeneity in Large Proteoforms
Authors: Melby Jake A. , Brown Kyle A. , Gregorich Zachery R. , Roberts David S. , Chapman Emily A. , Ehlers Lauren E. , Gao Zhan , Larson Eli J. , Jin Yutong , Lopez Justin , Hartung Jared , Zhu Yanlong , Wang Daojing , Guo Wei , Diffee Gary M. , Ge Ying
Published: December 2022

Single-cell proteomics has emerged as a powerful method to characterize cellular phenotypic heterogeneity and the cell-specific functional networks underlying biological processes. However, significant challenges remain in single-cell proteomics for the analysis of proteoforms arising from genetic mutations, alternative splicing, and post-translational modifications. Herein, we have developed a highly sensitive functionally integrated top-down proteomics method for the comprehensive analysis of proteoforms from single cells. We applied this method to single muscle fibers (SMFs) to resolve their heterogeneous functional and proteomic properties at the single cell level. Notably, we have detected single-cell heterogeneity in large proteoforms (>200 kDa) from the SMFs. Using SMFs obtained from three functionally distinct muscles, we found fiber-to-fiber heterogeneity among the sarcomeric proteoforms which can be related to the functional heterogeneity. Importantly, we reproducibly detected multiple isoforms of myosin heavy chain (~223 kDa), a motor protein that drives muscle contraction, with high mass accuracy to enable the classification of individual fiber types. This study represents the first “single-cell” top-down proteomics analysis that captures single muscle cell heterogeneity in large proteoforms and establishes a direct relationship between sarcomeric proteoforms and muscle fiber types, highlighting the potential of top-down proteomics for uncovering the molecular underpinnings of cell-to-cell variation in complex systems.

Significance Statement

Single-cell technologies are revolutionizing biology and molecular medicine by allowing direct investigation of the biological variability among individual cells. Top-down proteomics is uniquely capable of dissecting biological heterogeneity at the intact protein level. Herein, we develop a highly sensitive single-cell top-down proteomics method to reveal diverse molecular variations in large proteins (>200 kDa) among individual single muscle cells. Our results both reveal and characterize the differences in protein post-translational modifications and isoform expression possible between individual muscle cells. We further integrate functional properties with proteomics and accurately measure myosin isoforms for individual muscle fiber type classification. Our study highlights the potential of top-down proteomics for understanding how single-cell protein heterogeneity contributes to cellular functions.
nucMACC: A MNase-seq pipeline to identify structurally altered nucleosomes in the genome
Authors: Sara Wernig-Zorc , Fabian Kugler , Leo Schmutterer , Patrick Räß , Clemens Hausmann , Simon Holzinger , Gernot Längst , Uwe Schwartz
Published: December 2022

Micrococcal nuclease sequencing (MNase-seq) is the state-of-the-art method for determining chromatin structure and nucleosome positioning. Data analysis is complex due to the AT-dependent sequence bias of the endonuclease, and the requirement for high sequencing depth. Here, we present the newly developed nucleosome-based MNase accessibility (nucMACC) pipeline unveiling the regulatory chromatin landscape by measuring nucleosome accessibility and stability. nucMACC represents the first systematic, and genome-wide approach for detecting unstable (“fragile”) nucleosomes.

We characterized the regulatory nucleosomal landscape inD. melanogasterandS. cerevisiae. Two functionally distinct sets of promoters were identified, one associated with an unstable nucleosome and the other being nucleosome depleted. Chromatin structure analysis shows that unstable nucleosomes present intermediate states of nucleosome remodeling, preparing inducible genes for transcriptional activation in response to stimuli or stress. The presence of unstable nucleosomes correlates with RNA polymerase II proximal pausing. The nucMACC pipeline offers unparalleled precision and depth in nucleosome research and is a valuable tool for future nucleosome studies.

Teaser

The nucMACC pipeline quantifies the local and global functional alterations of chromatin structure.
Starvation sensing by mycobacterial RelA/SpoT homologue through constitutive surveillance of translation
Authors: Li Yunlong , Majumdar Soneya , Treen Ryan , Sharma Manjuli R. , Corro Jamie , Gamper Howard B. , Manjari Swati R. , Prusa Jerome , Banavali Nilesh K. , Stallings Christina L. , Hou Ya-Ming , Agrawal Rajendra K. , Ojha Anil K.
Published: December 2022

The stringent response, which leads to persistence of nutrient-starved mycobacteria, is induced by activation of the RelA/SpoT homologue (Rsh) upon entry of a deacylated-tRNA in a translating ribosome. However, the mechanism by which Rsh identifies such ribosomesin vivoremains unclear. Here, we show that conditions inducing ribosome hibernation result in loss of intracellular Rsh in a Clp protease-dependent manner. This loss is also observed in non-starved cells using mutations in Rsh that block its interaction with the ribosome, indicating that Rsh association with the ribosome is important for Rsh stability. The cryo-EM structure of the Rsh-bound 70S ribosome in a translation initiation complex reveals unknown interactions between the ACT domain of Rsh and components of the ribosomal L7/L12-stalk base, suggesting that the aminoacylation status of A-site tRNA is surveyed during the first cycle of elongation. Altogether, we propose a surveillance model of Rsh activation that originates from its constitutive interaction with the ribosomes entering the translation cycle.

Significance

Bacteria persist under nutrient starvation by activating RelA/SpoT homologue (Rsh), which synthesizes a growth regulating alarmone, ppGpp. Rsh is activated specifically upon recognizing a translation elongation complex with deacylated tRNA at the A-site. It is however unclear how Rsh identifies such a complex in vivo. We show here that conditions inducing ribosome hibernation in mycobacteria cause loss of intracellular Rsh, implying that association with translating ribosomes is necessary for intracellular stability of Rsh. Using structural analysis of Rsh-bound 70S translation initiation complex, we propose here that mycobacterial Rsh identifies a Rsh-activating ribosomal complex by constitutively surveying the ribosome entering the translation cycle at the early elongation stage.
Yttrium-iron garnet film magnetometer for magnetic microparticles in vivo registration studies
Authors: Koshev N. , Kapralov P. , Evstigneeva S. , Lutsenko O. , Shilina P. , Zharkov M. , Pyataev N. , Darwish A. , Timin A. , Ostras M. , Radchenko I. , Sukhorukov G. , Vetoshko P.
Published: December 2022

In the current article, we present a new kind of magnetometer for quantitative determination of magnetic objects in biological fluids and tissues. The sensor is based on yttrium-iron garnet film with optical signal registration system. Inheriting the working principle of a fluxgate magnetometers, the sensor works at a room-temperature, its wide dynamic range allows the measurements in an unshielded environment. A small size of sensitive element combined with a short recovery time after the excitation coils are off provide us with a potentially high spatial and temporal resolution of measurements. We show the feasibility of the sensor by sensing the remanent magnetization of Magnetic Nanoparticles (MNPs) both in vitro (test tubes, dry MNPs) and in vivo (local injection of the MNPs into mice).
Correlation Single Molecule Localization Microscopy (corrSMLM) Detects Fortunate Molecules for High Signal-to-Background Ratio and Better Localization Precision
Authors: Aravinth S , Zanacchi Francesca C. , Mondal Partha P.
Published: December 2022

Single-molecule localization microscopy can decipher fine details that are otherwise not possible using diffraction-limited microscopy. Often the reconstructed super-resolved image contains unwanted noise, random background and is prone to false detections. This cause spurious data that necessitates several trials, multiple experimentations, and repeated preparation of specimens. Moreover, this is not suitable for experiments that require time-lapse imaging and real-time microscopy. To overcome these limitations, we propose a technique(corrSMLM) that can recognize and detect fortunate molecules (molecules with long fluorescence cycles) from the recorded data. The technique uses correlation between two or more consecutive frames to extract fortunate molecules that blink for longer than the standard blinking time. Accordingly, strongly-correlated spots (single molecule signatures) are compared in consecutive frames, followed by data integration (mean centroid position and the total number of photons) and estimation of critical parameters (position and localization precision). The technique addresses two major problems that plague SMLM : (1) random noise due to false detection that contributes to strong background, and (2) poor localization precision offered by standard SMLM techniques. On the brighter side,corrSMLMallows only fortunate molecules contribute to the super-resolved image, thereby suppressing the background and improving localization precision by a factor of 2-4 times as compared to standard SMLM. To substantiate, corrSMLM is used for imaging fixed cell samples (Dendra2-Actin and Dendra2-Tubulin transfected NIH3T3 cells). Results show multi-fold reduction in noise and localization precision with a marked improvement in overall resolution and SBR. We anticipatecorrSMLMto improve overall image quality and offer a better understanding of single molecule dynamics in cell biology.
Ongoing rapid evolution of a post-Y region revealed by chromosome-scale genome assembly of a hexaploid monoecious persimmon (Diospyros kaki)
Authors: Horiuchi Ayano , Masuda Kanae , Shirasawa Kenta , Onoue Noriyuki , Fujita Naoko , Ushijima Koichiro , Akagi Takashi
Published: December 2022

Sex chromosomes have evolved independently in many plant lineages. They have often undergone rapid structural degeneration and extension of non-recombining regions, which is conventionally considered to be strongly associated with the expression of sexually dimorphic traits. In this study, we assembled a monoecious hexaploid persimmon (Diospyros kaki) in which the Y chromosome had lost its function in male determination. Comparative genomic analysis amongD. kakiand its dioecious relatives revealed that the non-functional Y chromosome (Ym) via silencing of the sex-determining gene,OGI, arose approximately two million years ago. Comparative analyses of the whole X and Ymchromosomes suggested that the non-functional male-specific region of the Y-chromosome (MSY), or post-MSY, retained certain conserved characteristics of the original functional MSY. Specifically, comparison of the functional MSY inD. lotusand the non-functional post-MSY inD. kakiindicated that the post-MSY had been rapidly rearranged mainly via ongoing transposable element bursts, as well as in the functional MSY. These results suggest a novel interpretation that the rapid evolution of the post-MSY (and possibly also MSYs in dioeciousDiospyrosspecies) might reflect the ancestral genomic properties of these regions, rather than the evolution of male-determining functions and/or sexually dimorphic traits.
Treatment with Tumor-Treating Fields (TTFields) Suppresses Intercellular Tunneling Nanotube FormationIn Vitroand Upregulates Immuno-Oncologic BiomarkersIn Vivoin Malignant Mesothelioma
Authors: Sarkari Akshat , Korenfeld Sophie , Deniz Karina , Ladner Katherine , Wong Phillip , Padmanabhan Sanyukta , Vogel Rachel I , Sherer Laura , Courtemanche Naomi , Steer Clifford J , Wainer-Katsir Kerem , Lou Emil
Published: December 2022

Intercellular communication is critical for the development of invasive cancers. Multiple forms of intercellular communication have been well characterized, involving diffusible soluble factors or contact-dependent channels for immediately adjacent cells. Over the past 1-2 decades, the emergence of a unique form of F-actin-based cellular protrusion known as tunneling nanotubes (TNTs) has filled the niche of long-range cell-contact dependent intercellular communication that facilitates cell growth, differentiation, and in the case of invasive cancer phenotypes, a more chemoresistant phenotype. The cellular machinery of TNT-mediated transport is an area of active investigation, and microtubules have been implicated in this process as they are in other membranous protrusions. Tumor-Treating Fields (TTFields) therapy is a novel therapeutic strategy in clinical use for patients with advanced cancers, based on the principle of using low-intensity alternating electric fields to disrupt microtubules in cancer cells undergoing mitosis. Other mechanisms of action have also been demonstrated. In this study, we investigated the effects of TTFields on TNTs in malignant pleural mesothelioma (MPM)in vitroand also on the spatial transcriptomic landscapein vivo. We found that applying TTFields at 1.0 V/cm significantly suppressed TNT formation in a biphasic MPM cell line (MSTO-211H), but not in sarcomatoid MPM (VAMT). At these parameters, TTFields significantly reduced cell count in MSTO-211H, but did not significantly alter intercellular transport of mitochondria via intact TNTs. To understand how TTFields may impact expression of genes with known involvement to TNT formation and overall tumor growth, we performed spatial genomic assessment of TTFields-treated tumors from anin vivoanimal model of MPM, and detected upregulation of immuno-oncologic biomarkers with simultaneous downregulation of pathways associated with cell hyperproliferation, invasion, and other critical regulators of oncogenic growth. Several molecular classes and pathways coincide with markers that we and others have found to be differentially expressed in cancer cell TNTs, including MPM specifically. In this study, we report novel cellular and molecular effects of TTFields in relation to tumor communication networks enabled by TNTs and related molecular pathways. These results position TNTs as potential therapeutic targets for TTFields-directed cancer treatment strategies; and also identify the ability of TTFields to potentially remodel the tumor microenvironment, thus enhancing response to immunotherapeutic drugs.
Structural titration reveals Ca2+-dependent conformational landscape of the IP3receptor
Authors: Paknejad Navid , Sapuru Vinay , Hite Richard K.
Published: December 2022

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+-permeable cation channels whose biphasic dependence on cytoplasmic Ca2+gives rise to cytosolic Ca2+oscillations that regulate fertilization, cell division and cell death. Despite the critical roles of IP3R-mediated Ca2+oscillations, the structural underpinnings of the biphasic Ca2+dependence that underlies Ca2+oscillations are incompletely understood. Here, we collected images of an IP3R with Ca2+at concentrations spanning five orders of magnitude. Unbiased image analysis revealed that Ca2+binding does not explicitly induce conformational changes but rather biases a complex conformational landscape consisting of resting, preactivated, activated, and inhibited states. Using particle counts as a proxy for free energy, we demonstrate that Ca2+binding at a high-affinity site allows IP3Rs to activate by escaping a low-energy resting state through an ensemble of preactivated states. At high Ca2+, IP3Rs preferentially enter an inhibited state stabilized by a second, low-affinity Ca2+binding site. Together, these studies provide a mechanistic basis for the biphasic Ca2+-dependence of IP3R channel activity.
A ubiquitin-proteasome pathway degrades the inner nuclear membrane protein Bqt4 to maintain nuclear membrane homeostasis
Authors: Le Toan Khanh , Hirano Yasuhiro , Asakawa Haruhiko , Okamoto Koji , Fukagawa Tatsuo , Haraguchi Tokuko , Hiraoka Yasushi
Published: December 2022

Aberrant accumulation of inner nuclear membrane (INM) proteins is associated with deformed nuclear morphology and mammalian diseases. However, the mechanisms underlying the maintenance of INM homeostasis remain poorly understood. In this study, we explored the degradation mechanisms of the INM protein, Bqt4, in the fission yeastSchizosaccharomyces pombe. We have previously shown that Bqt4 interacts with the transmembrane protein Bqt3 at the INM and is degraded in the absence of Bqt3. Here, we revealed that excess Bqt4, unassociated with Bqt3, was targeted for degradation by the ubiquitin-proteasome system localized in the nucleus and Bqt3 antagonized this process. The degradation process involved the Doa10 E3 ligase complex at the INM. Bqt4 is a tail-anchored protein and extraction from the membrane by the Cdc48 complex is required for its degradation. The C-terminal transmembrane domain of Bqt4 is necessary and sufficient for proteasome-dependent protein degradation. Accumulation of Bqt4 at the INM impaired cell viability with nuclear envelope deformation, suggesting that quantity control of Bqt4 plays an important role in nuclear membrane homeostasis.

Summary statement

Appropriate levels of the inner nuclear membrane protein Bqt4 are maintained by ubiquitin-proteasome-mediated degradation. Aberrant accumulation of Bqt4 disturbs nuclear membrane homeostasis.
A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence
Authors: Pabis Kamil , Barardo Diogo , Sirbu Olga , Selvarajoo Kumar , Gruber Jan , Kennedy Brian K.
Published: December 2022

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons.

To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice.

In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data suggests that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.
Natural Shortwave UV-B Radiation Increases UV absorbing pigments levels in Texas native grassesChasmanthium latifoliumandBouteloua curtipendula
Authors: Nebhut AN , Semro MR , Worley CA , Shinkle JR
Published: December 2022

Plants are routinely exposed to UV-B radiation (280–315 nm) as a natural component of incident solar radiation. UV-B radiation is relevant to plants as both a source of damage and as a photomorphogenic cue, but the relative impacts of different wavelengths within the UV-B waveband are largely unresolved. Previous studies indicate that the full spectrum of solar UV-B radiation elicits unique responses in model plants under laboratory conditions compared to photons within the longwave UV-B band (300–315 nm), but the impacts of shortwave UV-B radiation (SW-UVB; 280–300 nm) remain unknown in a field environment. In this study, we examine the impact of shortwave UV-B radiation on the pigmentation and morphology of C3shade-adapted inland sea oats (Chasmanthium latifolium) and C4sun-adapted side-oats grama (Bouteloua curtipendula) in field conditions. We characterized the responses of these grasses to SW-UVB radiation by placing UV-naive individuals under SW-UVB excluding or transmitting filters at three field sites in Central Texas and measuring their responses through leaf pigment extract absorbance, leaf surface reflectance, and whole leaf chlorophyll and flavonoid content. We found that both species exhibited changes to their UV-B associated traits following exposure to the field environment, which were influenced by field site location, maximum daily temperature, and SW-UVB exposure. In particular,C. latifoliumincreased the ratio of its maximum to minimum absorbance in response to SW-UVB, whileB. curtipendulaexhibited higher flavonoid content in response to SW-UVB exposure. We believe this is the first time that the effects of SW-UVB radiation have been documented in a field environment.
Dorsal pulvinar inactivation leads to spatial selection bias without perceptual deficit
Authors: Kaduk Kristin , Wilke Melanie , Kagan Igor
Published: December 2022

The dorsal pulvinar has been implicated in visuospatial attentional and perceptual confidence processing. Pulvinar lesions in humans and monkeys lead to spatial neglect symptoms, including an overt spatial saccade bias during free choices. But it remains unclear whether disrupting the dorsal pulvinar during target selection that relies on a perceptual decision leads to a perceptual impairment or a more general spatial orienting and choice deficit. To address this question, we reversibly inactivated the unilateral dorsal pulvinar by injecting GABA-A agonist THIP while two macaque monkeys performed a color discrimination saccade task with varying perceptual difficulty. We used Signal Detection Theory and simulations to dissociate perceptual sensitivity (d-prime) and spatial selection bias (response criterion) effects. We expected a decrease in d-prime if dorsal pulvinar affects perceptual discrimination and a shift in response criterion if dorsal pulvinar is mainly involved in spatial orienting. After the inactivation, we observed response criterion shifts away from contralesional stimuli, especially when two competing stimuli in opposite hemifields were present. Notably, the d-prime and overall accuracy remained largely unaffected. Our results underline the critical contribution of the dorsal pulvinar to spatial orienting and action selection while showing it to be less important for visual perceptual discrimination.
Ventral posterolateral and ventral posteromedial thalamus neurons have distinct synaptic and cellular physiology
Authors: Studtmann Carleigh , Ladislav Marek , Safari Mona , Chen Yang , Topolski Mackenzie A. , Khondaker Rabeya , Tomović Eni , Balík Aleš , Swanger Sharon A.
Published: December 2022

Somatosensory information is propagated from the periphery to the cerebral cortex by two parallel pathways through the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus. VPL and VPM neurons receive somatosensory signals from the body and head, respectively. VPL and VPM neurons also receive cell-type-specific GABAergic input from the reticular nucleus of the thalamus (nRT). Although VPL and VPM neurons have distinct connectivity and physiological roles, differences in the functional properties of VPL and VPM neurons remain unclear as they are often studied as one ventrobasal (VB) thalamus neuron population. Here, we directly compared synaptic and intrinsic properties of VPL and VPM neurons in C57Bl/6J mice of both sexes aged P25-P32. Recordings of spontaneous synaptic transmission suggested that VPL neurons receive excitatory synaptic input with higher frequency and strength than VPM neurons, while VPL neurons exhibited weaker inhibitory synapse strength than VPM neurons. Furthermore, VPL neurons showed enhanced depolarization-induced spike firing and greater spike frequency adaptation than VPM neurons. VPL and VPM neurons fired similar numbers of spikes during hyperpolarization rebound bursts, but VPM neurons exhibited shorter burst latency compared to VPL neurons, which correlated with increased sag potential during hyperpolarization. This work indicates that VPL and VPM thalamocortical neurons are functionally distinct populations. The observed functional differences could have important implications for their specific physiological and pathophysiological roles within the somatosensory thalamocortical network.
Rac negative feedback links local PIP3rate-of-change to dynamic control of neutrophil guidance
Authors: Town Jason , Weiner Orion
Published: December 2022

To migrate efficiently, neutrophils must polarize their cytoskeletal regulators along a single axis of motion. This polarization process is thought to be mediated through local positive feedback that amplifies leading edge signals and global negative feedback that enables sites of positive feedback to compete for dominance. Though this two-component model efficiently establishes cell polarity, it has potential limitations, including a tendency to “lock” onto a particular direction, limiting the ability of cells to reorient. We use spatially-defined optogenetic control of a leading edge organizer (PI3K) to probe how cells balance “decisiveness” needed to polarize in a single direction with the flexibility needed to respond to new cues. Underlying this balancing act is a local Rac inhibitor that destabilizes the leading edge to promote exploration. We show that this local inhibitor enables cells to process input signal dynamics, linking front stability and orientation to local temporal increases in input signals.
A thermally stable protein nanoparticle that stimulates long lasting humoral immune response
Authors: Wong Ten-Tsao , Liou Gunn-Guang , Kan Ming-Chung
Published: December 2022

Thermally stable vaccine platform is considered to be the missing piece of vaccine technology. In this article, we are reporting the development of a novel protein nanoparticle and evaluating its ability in withstanding extended high temperature incubation and stimulating long lasting humoral immune response. This protein nanoparticle is assembled from a fusion protein composed of an amphipathic helical peptide derived from M2 protein of H5N1 influenza virus (AH3) and a super folder green fluorescent protein(sfGFP). The proposed structure of this protein nanoparticle is modeled according to transmission electronic microscope (TEM) images of protein nanoparticle. From this proposed protein model, we have generated a mutant with two gain-of-function mutations that function synergistically on particle stability. Protein nanoparticle assembled from this gain-of-function mutant is able to remove a hydrophobic patch from the surface of protein nanoparticle. This gain-of-function mutant also contributes to higher thermostability of protein nanoparticle and stimulates long lasting humoral immune response after single immunization. This protein nanoparticle shows increasing particle stability in higher temperature and higher salt concentration. This novel protein nanoparticle may serve as a thermal-stable platform for vaccine development.
A thalamo-parietal cortex circuit is critical for place-action coordination
Authors: Simmons Christine M. , Moseley Shawn C. , Ogg Jordan D. , Johnson Madeline , Clark Benjamin J. , Wilber Aaron A.
Published: December 2022

The anterior and lateral thalamus (ALT) contains head direction cells that signal the directional orientation of an animal within an environment. ALT has direct and indirect connections with the parietal cortex (PC), an area hypothesized to play a role in coordinating viewer-dependent and viewer-independent spatial reference frames. This coordination between reference frames would allow an individual to translate movements toward a desired location from memory. Thus ALT-PC functional connectivity would be critical for moving toward remembered locations. This hypothesis was tested with a place-action task that requires associating an appropriate action (left or right turn) with a spatial location. There are four arms, each offset by 90 degrees, positioned around a central starting point. A trial begins in the central starting point. After exiting a pseudorandomly selected arm, the rat had to displace the correct object covering one of two (left versus right) feeding stations to receive a reward. For a pair of arms facing opposite directions, the reward was located on the left, and for the other pair, the reward was located on the right. Thus, each reward location had a different combination of allocentric location and egocentric action. Removal of an object was scored as correct or incorrect. Trials in which the rat did not displace any objects were scored as ‘no response’ trials. After an object was removed, the rat returned to the center starting position and the maze was reset for the next trial. To investigate the role of the ALT-PC network, muscimol inactivation infusions targeted bilateral PC, bilateral ALT, or the ALT-PC network. Muscimol sessions were counterbalanced and compared to saline sessions within the same animal. All inactivations resulted in decreased accuracy. Only bilateral PC inactivations resulted in increased no response trials, increased errors, and longer latency responses on the remaining trials. Thus, the ALT-PC network is critical for linking an action with a spatial location for successful navigation.
An integrated systems-biology platform for power-to-gas technology
Authors: Casini Isabella , McCubbin Tim , Esquivel-Elizondo Sofia , Luque Guillermo G. , Evseeva Daria , Fink Christian , Beblawy Sebastian , Youngblut Nicholas D. , Aristilde Ludmilla , Huson Daniel H. , Dräger Andreas , Ley Ruth E. , Marcellin Esteban , Angenent Largus T. , Molitor Bastian
Published: December 2022

Methanogenesis allows methanogenic archaea (methanogens) to generate cellular energy for their growth while producing methane. Hydrogenotrophic methanogens thrive on carbon dioxide and molecular hydrogen as sole carbon and energy sources. Thermophilic and hydrogenotrophicMethanothermobacterspp. have been recognized as robust biocatalysts for a circular carbon economy and are now applied in power-to-gas technology. Here, we generated the first manually curated genome-scale metabolic reconstruction for threeMethanothermobacterspp‥ We investigated differences in the growth performance of three wild-type strains and one genetically engineered strain in two independent chemostat bioreactor experiments. In the first experiment, with molecular hydrogen and carbon dioxide, we found the highest methane production rate forMethanothermobacter thermautotrophicusΔH, whileMethanothermobacter marburgensisMarburg reached the highest biomass growth rate. Systems biology investigations, including implementing a pan-model that contains combined reactions from all three microbes, allowed us to perform an interspecies comparison. This comparison enabled us to identify crucial differences in formate anabolism. In the second experiment, with sodium formate, we found stable growth with anM. thermautotrophicusΔH plasmid-carrying strain with similar performance parameters compared to wild-typeMethanothermobacter thermautotrophicusZ-245. Our findings reveal that formate anabolism influences the diversion of carbon to biomass and methane with implications for biotechnological applications ofMethanothermobacterspp. in power-to-gas technology and for chemical production.

Graphical Abstract

Broader context

Renewable energy sources (e.g., wind and solar) provide carbon-free electric power. However, their intermittency and offset between peak production and demand generate the need to store this electric power. Furthermore, these technologies alone do not satisfy the demand for carbon-based commodities. Power-to-gas technology provides a means to store intermittent renewable electric power with concomitant carbon dioxide recycling into a chemical energy carrier, such as methane, on a centralized and decentralized scale. This is particularly important to establish equitable energy strategies forallcountries, as is highlighted by the United Nations Sustainable Development Goals. With this work, we provide an integrated systems-biology platform forMethanothermobacterspp. to optimize biological power-to-gas technology and formulate strategies to produce other value-added products besides methane.