bluuebunny/crossref_metadata_2025 huggingface dataset:
Tobacco usage among general Indian population: A meta-analysis of evidence drawn from regional studies between 2010 - 2022
Authors: Pahari Shubhajit , Barman Diplina , Talukdar Rounik
Published: June 2023

Objectives

The purpose of this review is to generate a national and zonal pooled estimate of Current Tobacco Usage (CTU) in any form, as well as stratified gender and tobacco type (smokeless & smoke) specific estimates among the general Indian population, utilizing evidence from 2010 to 2022.

Method

PubMed, Scopus, Science Direct, CINAHL and Google Scholar databases were searched for articles on tobacco use among Indian adults published between January 2010 and October 2022. The NIH Quality Assessment Tool was used to assess study quality, and a random-effects inverse-variance method was used to attain a pooled estimate of usage. Heterogeneity was estimated through I2statistics and prediction intervals, and further subgroup analysis and meta-regression were conducted. To estimate publication bias egger’s test was performed and a leave-one-out analysis was done to establish the sensitivity of our overall pooled estimate.

Results

CTU of any form amongst the Indian population irrespective of age group was 35.25% (Confidence Interval (CI) 25.27 - 45.92, I2= 99.7, P-value < 0.001) between the years 2010 - 2022, whereas through 2016 – 2022 regionally drawn estimate was 44.38% (CI 30.57 – 58.64, I2= 99.8, P-value < 0.01). The region-wise highest prevalence was found in the East zone (55.43%) followed by North – East with 51.88% consumption. Though residual heterogeneity was present after subgroup analysis, Variability in estimates was statistically significant by administrative zones and gender-wise consumption (test of subgroup difference P value <0.0001). Leave-one-out analysis proved consistency in our overall CTU estimate.

Conclusion

The differences between national-level surveys and regional estimates are highlighted in this review and thereby warrant more regionally representative surveys of tobacco usage for tailor-making prevention efforts alongside, increased regional efforts, improved community-level advocacy, and more coordinated and stringent tobacco prevention policy implementation at national and state levels.
The broad impact of cell death genes on the human disease phenome
Authors: Rich Abigail , Lin Phillip , Gamazon Eric , Zinkel Sandra
Published: June 2023

Apoptotic, necroptotic, and pyroptotic cell death pathways are attractive and druggable targets for many human diseases, however the tissue specificity of these pathways and the relationship between these pathways and human disease is poorly characterized. Understanding the impact of modulating cell death gene expression on the human phenome could inform clinical investigation of cell death pathway-modulating therapeutics in human disorders by identifying novel trait associations and by detecting tissue-specific side effect profiles. We analyzed the expression profiles of an array of 44 cell death genes across somatic tissues in GTEx v8 and investigated the relationship between tissue-specific genetically determined expression of 44 cell death genes and the human phenome using summary statistics-based transcriptome wide association studies (TWAS) on human traits in the UK Biobank V3 (n ∼500,000). We evaluated 513 traits encompassing ICD-10 defined diagnoses and hematologic traits (blood count labs). Our analysis revealed hundreds of significant (FDR<0.05) associations between cell death gene expression and diverse human phenotypes, which were independently validated in another large-scale biobank. Cell death genes were highly enriched for significant associations with blood traits versus non-cell-death genes, with apoptosis-associated genes enriched for leukocyte and platelet traits and necroptosis gene associations enriched for erythroid traits (e.g., Reticulocyte count, FDR=0.004). This suggests that immunogenic cell death pathways play an important role in regulating erythropoiesis and reinforces the paradigm that apoptosis pathway genes are critical for white blood cell and platelet development. Of functionally analogous genes, for instance pro-survival BCL2 family members, trait/direction-of-effect relationships were heterogeneous across blood traits. Overall, these results suggest that even functionally similar and/or orthologous cell death genes playdistinctroles in their contribution to human phenotypes, and that cell death genes influence a diverse array of human traits.
Genetic and immune determinants ofE. coliliver abscess formation
Authors: Hullahalli Karthik , Dailey Katherine G. , Hasegawa Yuko , Suzuki Masataka , Zhang Hailong , Threadgill David W. , Waldor Matthew K.
Published: June 2023

Systemic infections can yield distinct outcomes in different tissues. In mice, intravenous inoculation ofE.colileads to bacterial replication within liver abscesses while other organs such as the spleen largely clear the pathogen. Abscesses are macroscopic necrotic regions that comprise the vast majority of the bacterial burden in the animal, yet little is known about the processes underlying their formation. Here, we characterizeE. coliliver abscesses and identify host determinants of abscess susceptibility. Spatial transcriptomics revealed that liver abscesses are associated with heterogenous immune cell clusters comprised of macrophages, neutrophils, dendritic cells, innate lymphoid cells, and T-cells that surround necrotic regions of the liver. Susceptibility to liver abscesses is heightened in the C57BL/6 lineage, particularly in C57BL/6N females. Backcross analyses demonstrated that abscess susceptibility is a polygenic trait inherited in a sex-dependent manner without direct linkage to sex chromosomes. As early as one day post infection, the magnitude ofE. colireplication in the liver distinguishes abscess-susceptible and abscess-resistant strains of mice, suggesting that the immune pathways that regulate abscess formation are induced within hours. We characterized the early hepatic response with single-cell RNA sequencing and found that mice with reduced activation of early inflammatory responses, such as those lacking the LPS receptor TLR4, are resistant to abscess formation. Experiments with barcodedE. colirevealed that TLR4 mediates a tradeoff between abscess formation and bacterial clearance. Together, our findings define hallmarks ofE. coliliver abscess formation and suggest that hyperactivation of the hepatic innate immune response drives liver abscess susceptibility.

Importance

Animal models of disseminating bacterial infections are critical for developing therapeutic interventions. Following systemic dissemination in mice,E. coliundergo dramatic replication within abscesses in the liver but not in other organs. Although liver abscesses are the largest reservoir of bacteria within the animal, the processes that lead to abscess formation are not known. Here, we characterizeE. coliliver abscess formation and identify several determinants of abscess susceptibility, including sex, mouse genotype, and innate immune factors. By combining spatial and single-cell transcriptomics with genetic and phenotypic analyses, we delineate critical host pathways that underlie abscess formation. Our findings define several avenues for future studies to unravel how abscess susceptibility determinants interact to modulate clearance of systemic infections and govern tissue-specific bacterial replication.
Hypothalamic neuronal activation in primates drives naturalistic goal-directed eating behavior
Authors: Ha Leslie Jaesun , Yeo Hyeon-Gu , Kim Yu Gyeong , Baek Inhyeok , Baeg Eunha , Lee Young Hee , Won Jinyoung , Jung Yunkyo , Park Junghyung , Jeon Chang-Yeop , Kim Keonwoo , Min Jisun , Song Youngkyu , Park Jeong-Heon , Nam Kyung Rok , Son Sangkyu , Michael Yoo Seng Bum , Park Sung-hyun , Choi Won Seok , Lim Kyung Seob , Choi Jae Yong , Cho Jee-Hyun , Lee Youngjeon , Choi Hyung Jin
Published: June 2023

Eating addiction is the primary cause of modern obesity. Although the causal role of the lateral hypothalamic area (LHA) for eating is demonstrated in rodents, there is no evidence in primates regarding naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating by chemogenetics in three macaques. LHAGABAneuron activation significantly increased naturalistic goal-directed behaviors and food motivation, which was specific for palatable food. PET and MRS validated the chemogenetic activation. Rs-fMRI result revealed that functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after the LHAGABAneuron activation. Thus, our study elucidates the role of LHAGABAneurons in eating and obesity therapeutics for primates and humans.
The distress context of social calls evokes a fear response in the batPipistrellusabramus
Authors: Yoshino-Hashizawa Kazuki , Nishiuchi Yuna , Hiragochi Midori , Kihara Motoki , Kobayasi Kohta I , Hiryu Shizuko
Published: June 2023

Bats primarily use sound information, including echolocation, for social communication. Bats under stressful conditions, for example when confronted by a predator, will emit aggressive social calls. The presentation of aggressive social calls, including distress calls (DCs), is known to increase heart rate (HR), but how this change in HR is related to the bat’s sound perception and how this evokes behaviors such as the fear response is unknown. Herein, we show that the perception of a distress context induces freezing behavior as a fear response in bats. We found that bats responded by freezing and displayed increased HRs when they were presented with a conspecific donor bat in a distress situation evoked by gentle poking with a cotton swab. In addition, when we presented two types of auditory oddball paradigms with different probabilities of DCs and echolocation calls (ECs), the bats’ HRs increased when DCs were presented as deviant or control stimuli within standard ECs but did not increase when DCs were presented as standard stimuli. These results suggest that the situational context created by the frequency of sound presentation, rather than simply a single sound feature, induces HR increases and freezing as fear responses in bats.

Summary statement

We investigated the electrocardiograms of captivePipistrellus abramusand found that their heart rate increased as a fear response when the bats heard sounds with a distress context.
Improved Production of Taxol® Precursors inS. cerevisiaeusing Combinatorialin silicoDesign and Metabolic Engineering
Authors: Malcı Koray , Santibáñez Rodrigo , Jonguitud-Borrego Nestor , Santoyo-Garcia Jorge H. , Kherkoven Eduard J. , Rios-Solis Leonardo
Published: June 2023

Integrated metabolic engineering approaches combining system and synthetic biology tools allow the efficient designing of microbial cell factories to synthesize high-value products. In the present study,in silicodesign algorithms were used on the latest yeast genome-scale model 8.5.0 to predict potential genomic modifications that could enhance the production of early-step Taxol® in previously engineeredSaccharomyces cerevisiaecells. The solution set containing genomic modification candidates was narrowed down by employing the COnstraints Based Reconstruction and Analysis (COBRA) methods. 17 genomic modifications consisting of nine gene deletions and eight gene overexpression were screened using wet-lab studies to determine whether these modifications can increase the production yield of taxadiene, the first metabolite in the Taxol® through the mevalonate pathway. Depending on the cultivation condition, most of the single genomic modifications resulted in higher taxadiene production. The best-performing strain, named KM32, contained four overexpressed genes,ILV2, TRR1, ADE13andECM31, from the branched-chain amino acid biosynthesis, thioredoxin system,de novopurine synthesis, and the pantothenate pathway, respectively. Using KM32, taxadiene production was increased by 50%, reaching 215 mg/L of taxadiene. The engineered strain also produced 43.65 mg/L of taxa-4(20),11-dien-5α-ol (T5α-ol), and 26.2 mg/L of taxa-4(20),11-dien-5-α-yl acetate (T5αAc) which are the highest productions of these early-step Taxol® metabolites reported until now inS. cerevisiae. The findings of this study highlight that the use of computational and integrated approaches can ensure determining promising modifications that are difficult to estimate intuitively to develop yeast cell factories.
PP2A-B55SUR-6promotes nuclear envelope breakdown inC. elegansembryos
Authors: Kapoor Sukriti , Adhikary Kuheli , Kotak Sachin
Published: June 2023

Nuclear envelope (NE) disassembly during mitosis is critical to ensure faithful segregation of the genetic material. NE disassembly is a phosphorylation-dependent process wherein mitotic kinases hyper-phosphorylate lamina and nucleoporins to initiate nuclear envelope breakdown (NEBD). In this study, we uncover an unexpected role of the PP2A phosphatase B55SUR-6in NEBD during the first embryonic division ofCaenorhabditis elegansembryo. B55SUR-6depletion delays NE permeabilization and stabilizes lamina and nucleoporins. As a result, the merging of parental genomes and chromosome segregation is impaired. This NEBD defect upon B55SUR-6depletion is not due to delayed mitotic onset or mislocalization of mitotic kinases. Importantly, we demonstrate that microtubule-dependent mechanical forces synergize with B55SUR-6for efficient NE disassembly. Finally, our data suggest that the lamin LMN-1 is likely a bona fide target of PP2A-B55SUR-6. These findings establish a model highlighting biochemical cross-talk between kinases, PP2A-B55SUR-6phosphatase, and microtubule-generated mechanical forces in timely NE dissolution.
Resting-state EEG signatures of Alzheimer’s disease are driven by periodic but not aperiodic changes
Authors: Kopčanová Martina , Tait Luke , Donoghue Thomas , Stothart George , Smith Laura , Flores Sandoval Aimee Arely , Davila-Perez Paula , Buss Stephanie , Shafi Mouhsin M. , Pascual-Leone Alvaro , Fried Peter J. , Benwell Christopher S.Y.
Published: June 2023

Electroencephalography (EEG) has shown potential for identifying early-stage biomarkers of neurocognitive dysfunction associated with dementia due to Alzheimer’s disease (AD). A large body of evidence shows that, compared to healthy controls (HC), AD is associated with power increases in lower EEG frequencies (delta and theta) and decreases in higher frequencies (alpha and beta), together with slowing of the peak alpha frequency. However, the pathophysiological processes underlying these changes remain unclear. For instance, recent studies have shown that apparent shifts in EEG power from high to low frequencies can be driven either by frequency specific periodic power changes or rather by non-oscillatory (aperiodic) changes in the underlying 1/f slope of the power spectrum. Hence, to clarify the mechanism(s) underlying the EEG alterations associated with AD, it is necessary to account for both periodic and aperiodic characteristics of the EEG signal. Across two independent datasets, we examined whether resting-state EEG changes linked to AD reflect true oscillatory (periodic) changes, changes in the aperiodic (non-oscillatory) signal, or a combination of both. We found strong evidence that the alterations are purely periodic in nature, with decreases in oscillatory power at alpha and beta frequencies (AD < HC) leading to lower (alpha + beta) / (delta + theta) power ratios in AD. Aperiodic EEG features did not differ between AD and HC. By replicating the findings in two cohorts, we provide robust evidence for purely oscillatory pathophysiology in AD and against aperiodic EEG changes. We therefore clarify the alterations underlying the neural dynamics in AD and emphasise the robustness of oscillatory AD signatures, which may further be used as potential prognostic or interventional targets in future clinical investigations.
Comparing kinetic proofreading and kinetic segregation for T cell receptor activation
Authors: Moffett Alexander S. , Ganzinger Kristina A. , Eckford Andrew W.
Published: June 2023

The T cell receptor (TCR) is a key component of the adaptive immune system, recognizing foreign antigens and triggering an immune response. Competing models exist to explain the high sensitivity and selectivity of the TCR in discriminating ‘self’ from ‘non-self’ antigens, particularly models using kinetic proofreading (KP), kinetic segregation (KS), and combinations of the two. In this paper, we consider the role and importance of KS in TCR activation, using two models: classic KP (cKP), without KS, where antigen-TCR binding is required for activation, and a combination of KP and KS (KS-KP), where only residence within a close contact is required for activation. Building on previous work, our computational model is the first to permit a head-to-head comparison of these modelsin silico. While we find that both models can be used to explain the probability of TCR activation across much of the parameter space, we find biologically important regions in the parameter space where significant differences in performance can be expected. Furthermore, we show that the available experimental evidence may favour the KS-KP model over cKP. Our results may be used to motivate and guide future experiments to determine highly accurate computational models for the TCR.

Author summary

The T cell receptor (TCR) is a master of reliable sensing: it detects faint ‘signals’ (rare ligands derived from foreign proteins) over high ‘noise’ (abundant ligands derived from the body’s own proteins) to set T cells on a course to exterminate pathogens and tumours, a process that is central to our immune response. Despite decades of studying TCR signalling, we still do not know how the TCR can be so exceptionally sensitive and accurate. It is widely believed that kinetic proofreading (KP), in which the TCR binds to an antigen and triggers a series of phosphorylation steps prior to activation, plays an important role. However, recent results suggest that kinetic segregation (KS), in which binding is not required, is also important. These models are mutually exclusive, and yet both appear to explain various aspects of T cell activation.

Our work directly addresses this puzzle. We develop a computational modeling framework which can simulate TCR activation by both KP-based and KS-based models, making it possible to compare themin silicofor the first time. Using this framework, we find conditions under which the two models provide different responses, and we show that the limited experimental evidence to date is consistent with KS, which should motivate further investigation.
Developmental transcriptional control of mitochondrial homeostasis is required for activity-dependent synaptic connectivity
Authors: Mohylyak Iryna , Bengochea Mercedes , Pascual-Caro Carlos , Asfogo Noemi , Fonseca-Topp Sara , Danda Natasha , Atak Zeynep Kalender , De Waegeneer Maxime , Plaçais Pierre-Yves , Preat Thomas , Aerts Stein , Corti Olga , de Juan-Sanz Jaime , Hassan Bassem A.
Published: June 2023

During neuronal circuit formation, local control of axonal organelles ensures proper synaptic connectivity. Whether this process is genetically encoded is unclear and if so, its developmental regulatory mechanisms remain to be identified. We hypothesized that developmental transcription factors regulate critical parameters of organelle homeostasis that contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Telomeric Zinc finger-Associated Protein (TZAP) as a temporal developmental regulator of neuronal mitochondrial homeostasis genes, includingPink1. InDrosophila, loss ofdTzapfunction during visual circuit development leads to loss of activity-dependent synaptic connectivity, that can be rescued byPink1expression. At the cellular level, loss ofdTzap/TZAPleads to defects in mitochondrial morphology, attenuated calcium uptake and reduced synaptic vesicle release in fly and mammalian neurons. Our findings highlight developmental transcriptional regulation of mitochondrial homeostasis as a key factor in activity-dependent synaptic connectivity.
Evolution of the gene regulatory network of body axis by enhancer hijacking in amphioxus
Authors: Shi Chenggang , Chen Shuang , Liu Huimin , Li Shiqi , Wang Yanhui , Pan Rongrong , Wu Xiaotong , Li Xuewen , Li Jingjing , Xing Chaofan , Liu Xian , Wang Yiquan , Qu Qingming , Li Guang
Published: June 2023

A central goal of evolutionary developmental biology is to decipher the evolutionary pattern of gene regulatory networks (GRNs) that control morphogenesis during embryonic development, and the underlying molecular mechanism of the GRNs evolution. The Nodal signaling that governs the body axes of deuterostomes exhibits a conserved GRN orchestrated principally by Nodal, Gdf1/3 and Lefty. Despite that the GRN retains a conserved function in deuterostomes, the expression patterns ofGdf1/3andNodalare derived in cephalochordate amphioxus, implying a specific rewiring of the GRN in this lineage. Here we examined the regulatory mechanism and evolution of this GRN in amphioxus by functional genetic manipulations. We found that while the amphioxusGdf1/3orthologue shows nearly no expression during embryogenesis, its duplicateGdf1/3-likelinking toLeftyis zygotically expressed in a similar pattern asLefty. Mutant and transgenic analyses revealed thatGdf1/3is no longer crucial for amphioxus axial development. Instead,Gdf1/3-likeassumes this responsibility, likely through hijackingLeftyenhancers. We also showed that amphioxus Nodal has become an indispensable maternal factor to compensate for the loss of maternalGdf1/3expression. We therefore demonstrated a case that the evolution of an ancestral GRN could be triggered by enhancer hijacking events. This pivotal event has allowed the emergence of a new GRN in the extant amphioxus, presumably evolving through a stepwise process. The co-expression ofGdf1/3-likeandLeftyachieved by shared regulatory region may have provided developmental robustness during body axis formation in extant amphioxus, which provides a selection-based hypothesis for the phenomena called developmental system drift.
Using a Riemannian elastic metric for statistical analysis of tumor cell shape heterogeneity
Authors: Li Wanxin , Prasad Ashok , Miolane Nina , Duc Khanh Dao
Published: June 2023

We examine how a specific instance of the elastic metric, the Square Root Velocity (SRV) metric, can be used to study and compare cellular morphologies from the contours they form on planar surfaces. We process a dataset of images from osteocarcoma (bone cancer) cells that includes different treatments known to affect the cell morphology, and perform a comparative statistical analysis between the linear and SRV metrics. Our study indicates superior performance of the SRV at capturing the cell shape heterogeneity, with a better separation between different cell groups when comparing their distance to their mean shape, as well as a better low dimensional representation when comparing stress statistics. Therefore, our study suggests the use of a Riemannian metric, such as the SRV as a potential tool to enhance morphological discrimination for large datasets of cancer cell images.
Pharmacological or genetic inhibition ofScn9aprotects beta-cells while reducing insulin secretion in type 1 diabetes
Authors: Overby Peter , Provenzano Sophia , Nahirney Natalie S. , Dai Xiao-Qing , Sun WenQing Grace , Xia Yi Han , Zhang Jiashuo Aaron , Cen Haoning , Skovsø Søs , Kolic Jelena , MacDonald Patrick E. , Johnson James D.
Published: June 2023

Pancreatic β-cells are critical for systemic glucose homeostasis, and most of them undergo cell death during the pathogenesis of type 1 diabetes. We previously showed that a Na+channel inhibitor, carbamazepine, could protect β-cellsin vitroandin vivo. Here, we confirmed the effects of carbamazepine and other Na+channel inhibitors on human islets and focused on the specific role of the Na+channel gene,Scn9a(Nav1.7), in β-cell function and survival. BecauseScn9acan be found in multiple human and mouse islet cell types, we generated a β-cell specific knockout ofScn9aon the non-obese diabetic (NOD) background. We crossed anScn9aflox/floxallele onto theIns1Creknock-in mouse line resulting in the following genotypes: knockout (NOD.Ins1Cre;Scn9aflox/flox), heterozygous (NOD.Ins1Cre;Scn9aflox/wt), and wildtype littermate controls (NOD.Ins1Cre;Scn9awt/wt). We observed near complete ablation of Na+currents in knockout β-cells, and intermediate Na+currents in the heterozygotes. Insulin secretion in response to 15 mM glucose, but not lower concentrations, was significantly reduced from NOD.Ins1Cre;Scn9aflox/floxand NOD.Ins1Cre;Scn9awt/wtislets from both male and female mice. These effects of carbamazepine on insulin secretionin vitrowere not additive to the effects ofScn9aknockout, suggesting thatScn9ais the main target of carbamazepine in β-cells that is relevant for insulin secretion. CompleteScn9adeletion also protected β-cells from deathin vitro, similarly and non-additively to carbamazepine treatment. Finally, we assessed diabetes incidence in Nod.Scn9aflox/floxmice and NOD.Ins1Cre;Scn9awt/wtmice injected with AAV8-Ins1Crevirus and a found significant reduction in diabetes incidence in β-cell specific knockout mice compared with littermate controls. Collectively, our data show theScn9aplays important roles in β-cell function, but also contributes to β-cell death and type 1 diabetes progression.Scn9ais a novel drug target to preserve β-cells in type 1 diabetes.
Global seasonal activities of respiratory syncytial virus before the COVID-19 pandemic: a systematic review
Authors: Shan Songwei , Zhang Weixin , Gao Huizhi , Huang Pei-Yu , Du Zhanwei , Bai Yuan , Lau Yiu-Chung , Chen Dongxuan , Lau Eric HY , Nealon Joshua , Wu Peng
Published: June 2023

Background

Varied seasonal patterns of respiratory syncytial virus (RSV) have been reported worldwide. We aimed to review the patterns of RSV activity globally before the COVID-19 pandemic and to explore factors potentially associated with RSV seasonality.

Methods

We conducted a systematic review on articles identified in PubMed reporting RSV seasonality based on data collected before 1 January 2020. Information on the timing of the start, peak, and end of an RSV season, study location, study period, and details in study methods were extracted. RSV seasonal patterns were examined by geographic location, calendar month, analytic method and meteorological factors including temperature and absolute humidity. Correlation and regression analyses were conducted to explore the relationship between RSV seasonality and study methods and characteristics of study locations.

Results

RSV seasons were reported in 209 articles published in 1973-2023 for 317 locations in 77 countries. Variations were identified in types of data, data collection and analytical methods across the studies. Regular RSV seasons were similarly reported in countries in temperate regions, with highly variable seasons identified in subtropical and tropical countries. Durations of RSV seasons were relatively longer in subtropical and tropical regions than from temperate regions. Longer durations of RSV seasons were associated with a higher daily average mean temperature and daily average mean absolute humidity.

Conclusions

The global seasonal patterns of RSV provided important information for optimizing interventions against RSV infection. Heterogeneity in study methods highlighted the importance of developing and applying standardized approaches in RSV surveillance and data reporting.
Engineering of human myotubes toward a mature metabolic and contractile phenotype
Authors: Dreher Simon I. , Grubba Paul , von Toerne Christine , Moruzzi Alessia , Maurer Jennifer , Goj Thomas , Birkenfeld Andreas L. , Peter Andreas , Loskill Peter , Hauck Stefanie M. , Weigert Cora
Published: June 2023

1.

Skeletal muscle mediates the beneficial effects of exercise, thereby improving insulin sensitivity and reducing the risk for type 2 diabetes. Current human skeletal muscle modelsin vitroare incapable of fully recapitulating its physiological functions especially muscle contractility. By supplementation of insulin-like growth factor 1 (IGF1), a growth factor secreted by myofibers in vivo, we aimed to overcome these limitations. We monitored the differentiation process starting from primary human CD56-positive myoblasts in the presence/absence of IGF1 in serum-free medium in daily collected samples for 10 days. IGF1-supported differentiation formed thicker multinucleated myotubes showing physiological contraction upon electrical pulse stimulation following day 6. Myotubes without IGF1 were almost incapable of contraction. IGF1-treatment shifted the proteome toward skeletal muscle-specific proteins that contribute to myofibril and sarcomere assembly, striated muscle contraction, and ATP production. ElevatedPPARGC1A, MYH7 and reduced MYH1/2 suggest a more oxidative phenotype further demonstrated by higher abundance of proteins of the respiratory chain and elevated mitochondrial respiration. IGF1-treatment also upregulated GLUT4 and increased insulin-dependent glucose uptake compared to myotubes differentiated without IGF1.

To conclude, utilizing IGF1, we engineered human myotubes that recapitulate the physiological traits of skeletal musclein vivosuperior to established protocols and overcome limitations of previous standards. This novel “easy to use” model enables investigation of exercise on a molecular level.

Abstract Figure
Vestibular mapping of the naturalistic head-centered motion spectrum
Authors: Ertl Matthias , Eulenburg Peter zu , Woller Marie , Mayadali Ümit , Boegle Rainer , Dieterich Marianne
Published: June 2023

BACKGROUND

Naturalistic head accelerations can be used to elicit vestibular evoked potentials (VestEPs). These potentials allow for analysis of cortical vestibular processing and its multi-sensory integration with a high temporal resolution.

METHODS

We report the results of two experiments in which we compared the differential VestEPs elicited by randomized translations, rotations, and tilts in healthy subjects on a motion platform.

RESULTS

An event-related potential (ERP) analysis revealed that established VestEPs were verifiable in all three acceleration domains (translations, rotations, tilts). A further analysis of the VestEPs showed a significant correlation between rotation axes (yaw, pitch, roll) and the amplitude of the evoked potentials. We found increased amplitudes for rotations in the roll compared to the pitch and yaw plane. A distributed source localization analysis showed that the activity in the cingulate sulcus visual (CSv) area best explained direction-dependent amplitude modulations of the VestEPs, but that the same cortical network (posterior insular cortex, CSv) is involved in processing vestibular information, regardless of the motion direction.

CONCLUSION

The results provide evidence for an anisotropic, direction-dependent processing of vestibular input by cortical structures. The data also suggest that area CSv plays an integral role in ego-motion perception and interpretation of spatial features such as acceleration direction and intensity.
Designing function-specific minimal microbiomes from large microbial communities
Authors: Raghu Aswathy K. , Palanikumar Indumathi , Raman Karthik
Published: June 2023

Motivation

Microorganisms thrive in large communities of diverse species, exhibiting various functionalities. The mammalian gut microbiome, for instance, has the functionality of digesting dietary fibre and producing different short-chain fatty acids. Not all microbes present in a community contribute to a given functionality; it is possible to find aminimalmicrobiome, which is a subset of the large microbiome, that is capable of performing the functionality while maintaining other community properties such as growth rate. Such a minimal microbiome will also contain keystone species for SCFA production in that community. In the wake of perturbations of the gut microbiome that result in disease conditions, cultivated minimal microbiomes can be administered to restore lost functionalities.

Results

In this work, we present a systematic algorithm to design a minimal microbiome from a large community for a user-proposed function. We employ a top-down approach with sequential deletion followed by solving a mixed-integer linear programming problem with the objective of minimising theL1-norm of the membership vector. We demonstrate the utility of our algorithm by identifying the minimal microbiomes corresponding to model communities of the gut, and discuss their validity based on the presence of the keystone species in the community. Our approach is generic and finds application in studying a variety of microbial communities.

Availability

The algorithm is available fromhttps://github.com/RamanLab/minMicrobiome

Author Summary

Microorganisms are ubiquitous in nature. They survive in communities by interacting with each other and influence the biosphere by carrying out specific functions. For instance, the mammalian digestive system is heavily dependent on microbial communities in the gut (known as gut microbiome) to digest dietary fibres which are otherwise indigestible. The capability of gut microbes to convert dietary fibres to short-chain fatty acids help the host by regulating the functionality of the gut epithelial barrier. Oftentimes, some members of a community have redundant functions. Hence, it is possible to find a smaller subset of organisms that is capable of a given functionality, while also maintaining the required growth rate. We call them a minimal microbiome. Knowledge of such function-specific minimal microbiomes is useful for constructing communities for laboratory study and for designing treatment strategies for medical conditions caused by microbiome disruption. We present an optimization algorithm for identifying function-specific minimal microbiomes from a large community. We also demonstrate the performance of the algorithm by analysing minimal microbiomes obtained from some known communities. Overall, our research work highlights the significance of function-specific minimal microbiomes and provides an efficient computational tool for their identification.
The oxygen-induced thiosulfate production during Sulfate reduction, Autotrophic denitrification, Nitrification and Anammox (SANIA) integrated process towards next-generation mainstream wastewater treatment
Authors: Jiang Chu-Kuan , Deng Yang-Fan , Chen Guang-Hao , Wu Di
Published: June 2023

This study proposes a novel integrated process: the oxygen-induced thiosulfate production duringSulfate reduction,Autotrophic denitrification,NItrification andAnammox (SANIA) integrated process, targeting to treat mainstream wastewater after organics capture. Three moving-bed biofilm reactors (MBBRs) were applied for oxygen-induced thiosulfate production during sulfate reduction, mixed sulfide- and thiosulfate-driven partial denitrification and anammox (MSPDA), and nitrification (N), respectively. This study firstly established SANIA with supply of mimic nitrifying effluent to investigated the development of MSPDA (Period I) and subsequently verified SANIA in mainstream condition with implementation of nitrification (Period II). In Period I, the MSPDA-MBBR fed with ERATO-MBBR and mimic nitrifying effluent, was operated for over 300 days. Without inoculation of anammox biomass, the high rates of denitratation and anammox being 2.7 gN/(m2·d) and 2.8 gN/(m2·d), respectively were developed in the bioreactor with the enrichment of anammox bacteria and the coexistence of sulfur-oxidizing bacteria. Batch tests were performed to explore the bioconversion of sulfur and nitrogen compounds in MSPDA with main findings as following: 1) kinetics and pathways of sulfide (S2-➔ S0➔ SO42-) and thiosulfate (S2O32-➔ SO42-) oxidation were revealed; 2) fast denitrification was achieved during oxidation of sulfide and thiosulfate to S0and sulfate, respectively with sufficient nitrite accumulation, supporting the high activity of anammox; 3) nitrite utilization rate of anammox (50.8 mgN/(m2·h)) is higher than sulfur-driven denitritation (12.9−42.6 mgN/(m2·h)), demonstrating the dominance of anammox in nitrogen removal. In Period II, the N-MBBR was set behind MSPDA-MBBR to supply nitrate by recirculation, thus the SANIA system was developed. Afterwards the integrated SANIA system with a short HRT of 4.7 h was continuously operated for over 130 days. Results demonstrated that 90% of COD, 93% of ammonium and 61% of TIN were removed with concentration of COD, ammonium, and TIN below 10 mg/L, 3 mgN/L and 13 mgN/L, respectively in effluent. Combining with organic capture and SANIA for sewage treatment, the energy-neutral and space-efficient treatment of mainstream wastewater is promising.

Highlights

A new sulfur-cycle process (SANIA) was developed for sewage treatment.

High rates of both denitratation and anammox were developed in MSPDA.

Oxidation of TdS (to S0) and S2O32-(to SO42-) in MSPDA boosts nitrite buildup.

74−81% of the removed TIN was via anammox in SANIA process.

SANIA with a short HRT of 4.7h achieved good effluent qualities for sewage treatment.
Direct 3D-bioprinting of hiPSC-derived cardiomyocytes to generate functional cardiac tissues
Authors: Esser Tilman U. , Anspach Annalise , Muenzebrock Katrin A. , Kah Delf , Schrüfer Stefan , Schenk Joachim , Heinze Katrin G. , Schubert Dirk W. , Fabry Ben , Engel Felix B.
Published: June 2023

3D-bioprinting is a promising technology to produce human tissues as drug screening tool or for organ repair. However, direct printing of living cells has proven difficult. Here, we present a method to directly 3D-bioprint human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes embedded in a collagen-hyaluronic acid ink generating centimeter-sized functional ring- and ventricle-shaped cardiac tissues in an accurate and reproducible manner. The printed tissues contained hiPSC-derived cardiomyocytes with well-organized sarcomeres and exhibited spontaneous and regular contractions, which persisted for several months and were able to contract against passive resistance. Importantly, beating frequencies of the printed cardiac tissues could be modulated by pharmacological stimulation. This approach opens up new possibilities for generating complex functional cardiac tissues as models for advanced drug screening or as tissue grafts for organ repair or replacement.
The fungal pathogenUstilago maydistargets the maize corepressor TPL2 to modulate host transcription for tumorigenesis
Authors: Huang Luyao , Ökmen Bilal , Stolze Sara Christina , Kastl Melanie , Khan Mamoona , Hilbig Daniel , Nakagami Hirofumi , Djamei Armin , Doehlemann Gunther
Published: June 2023

Ustilago maydisis a biotrophic fungus that causes tumor formation on all aerial parts of maize.U. maydissecretes effector proteins during penetration and colonization to successfully overcome the plant immune response and reprogram host physiology to promote infection. In this study, we functionally characterized theU. maydiseffector protein Topless (TPL) interacting protein 6 (Tip6). We found that Tip6 interacts with the N-terminus of ZmTPL2 through its two EAR (Ethylene-responsive element binding factor-associated amphiphilic repression) motifs. We show that the EAR motifs are essential for the virulence function of Tip6 and critical for altering the nuclear distribution pattern of ZmTPL2. We propose that Tip6 mimics the recruitment of ZmTPL2 by plant repressor proteins, thus disrupting host transcriptional regulation. We show that a large group of AP2/ERF B1 subfamily transcription factors are misregulated in the presence of Tip6. Our study suggests a regulatory mechanism where theU. maydiseffector Tip6 utilizes repressive domains to recruit the corepressor ZmTPL2 to disrupt the transcriptional networks of the host plant.
Characterizing the targets of transcription regulators by aggregating ChIP-seq and perturbation expression data sets
Authors: Morin Alexander , Chu Eric Ching-Pan , Sharma Aman , Adrian-Hamazaki Alex , Pavlidis Paul
Published: June 2023

Mapping the gene targets of chromatin-associated transcription regulators (TRs) is a major goal of genomics research. ChIP-seq of TRs and experiments that perturb a TR and measure the differential abundance of gene transcripts are a primary means by which direct relationships are tested on a genomic scale. It has been reported that there is a poor overlap in the evidence across gene regulation strategies, emphasizing the need for integrating results from multiple experiments. Although research consortia interested in gene regulation have produced a valuable trove of high-quality data, there is an even greater volume of TR-specific data throughout the literature. In this study, we show a workflow for the identification, uniform processing, and aggregation of ChIP-seq and TR perturbation experiments for the ultimate purpose of ranking human and mouse TR–target interactions. Focusing on an initial set of eight regulators (ASCL1, HES1, MECP2, MEF2C, NEUROD1, PAX6, RUNX1, and TCF4), we identified 497 experiments suitable for analysis. We used this corpus to examine data concordance, to identify systematic patterns of the two data types, and to identify putative orthologous interactions between human and mouse. We build upon commonly used strategies to forward a procedure for aggregating and combining these two genomic methodologies, assessing these rankings against independent literature-curated evidence. Beyond a framework extensible to other TRs, our work also provides empirically ranked TR–target listings, as well as transparent experiment-level gene summaries for community use.
Co-construction of performance indicators for a circular city and its relation to a local action net
Authors: Bekier Justyna , Parisi Cristiana
Published: June 2023

Purpose

This study examines how circular economy (CE) performance indicators are constructed in an urban context characterised by a multitude of conflicting interests and visions of urban development. It explores the process of constructing a shared consensus about the performance indicators in conditions of low contractibility, where intervention objectives and outcomes are not easily quantifiable because the object is ambiguous and cannot be fully specified in advance.

Design/methodology/approach

The construction of performance indicators at the urban level is examined through the lens of an action net. Using group interviews, observations and documentary analysis, this study investigates the case of a CE initiative in the city of Milan.

Findings

The study demonstrates that in cases of low contractibility, the development of CE solutions requires actions that span across organisational boundaries, organised in an action net. As the action net unfolds, it is closely knotted with the construction of performance indicators, indicating a co-constitutive relationship between the two processes.

Originality/value

This interdisciplinary study contributes to the public sector accounting literature by exploring the complexity of performance indicator construction at the urban level. It further recognises performance measurement in cities as a dynamic and flexible process, in which the interconnected actions and involvement of multiple actants shape the composition of the indicators.
Impact of entrepreneurial training on career outcomes: mediated by work passion in Pakistani business owners
Authors: Hussain Sajjad , Rafiq Muhammad , Mahmood Kashif , Nasir Sobia , Zahid Ayesha
Published: June 2023

Purpose

Passion plays a vital role in entrepreneurship, and examining the role of training in passion development is a recent call. This study aims to examine the impact of entrepreneurial training on occupational commitment and career satisfaction of business owners based on goal content theory.

Design/methodology/approach

In doing so the role of harmonious passion is tested as a mediating mechanism. A three-wave time-lagged data were collected from 351 business owners operating in Punjab, Pakistan and were analyzed by using SmartPLS.

Findings

The findings suggested that entrepreneurial training had a positive impact on building entrepreneurial passion, and as a result, they were found to be more committed and satisfied with their entrepreneurial career. The research has theoretical and practical implications for the role of training in the development of entrepreneurial career outcomes.

Originality/value

Despite a growing interest in entrepreneurial passion, only few studies have explored the entrepreneurial training on occupational commitment and career satisfaction of business owners in context of Pakistan.
Is there a liability of foreignness or foreign privilege in developing nation compliance monitoring?
Authors: Florkowski Gary W.
Published: June 2023

Purpose

Drawing on the international business and game theory literature, this study assesses foreign firm treatment in the early stages of regulatory enforcement.

Design/methodology/approach

Treating regulation intensity as an exposure variable, negative binomial regression models were applied to firm-level data from 32 emerging markets (n = 15,331) to identify the determinants of inspection interactions. Robustness checks also were performed via variable substitutions for several predictors and an alternative form of statistical testing (i.e. Tobit regression, since it arguably better addresses dependent variables with corner solution responses).

Findings

Controlling for multiple organizational, regulatory and national characteristics, the findings are consistent with a foreign privilege, manifesting in reduced vulnerability to multiple encounters with labor inspection officials. Moreover, inward FDI stock was negatively related to the general probability of repeat interactions regardless of locus of ownership, an effect that was not moderated by stage of development or the regulatory influence of host interest groups. This collectively suggests that foreign firms not only are favored in compliance monitoring but also work post-entry to influence agencies to generally benefit business.

Research limitations/implications

More comprehensive assessments were precluded given the lack of information on reasons for contact, citations and fines, and inspectorate reactions to company responses. Second, enforcement-risk management was measured indirectly since investors' internal dealings and actions toward officials are unavailable in secondary sources.

Practical implications

These findings have important implications for social responsibility, suggesting CSR stakeholders need to track enforcement more closely and exert pressure where needed so rights are not sacrificed for economic development.

Originality/value

This study provides the most rigorous assessment to date of the role that firm, government and economic factors play in national inspection targeting. It also examined whether foreign owners pool and leverage their political influence to impact general inspection activity, a previously untested prospect.