bluuebunny/crossref_metadata_2025 huggingface dataset:
Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice
Authors: Borreguero Cédric Francis , Wueest Stephan , Hantel Constanze , Schneider Holger , Konrad Daniel , Beuschlein Felix , Spyroglou Ariadni
Published: January 2023

Background

Deoxyguanosine kinase (DGUOK) deficiency is one of the genetic causes of mitochondrial DNA depletion syndrome (MDDS) in humans, leading to the hepatocerebral or the isolated hepatic form of MDDS. Mouse models are helpful tools for the improvement of understanding of the pathophysiology of diseases and offer the opportunity to examine new therapeutic options.

Methods

Herein, we describe the generation and metabolic characterization of a mouse line carrying a homozygous DguokF180S/F180S mutation derived from an N-ethyl-N-nitrosourea-mutagenesis screen. Energy expenditure (EE), oxygen consumption (VO2) and carbon dioxide production (VCO2) were assessed in metabolic cages. LC-MS/MS was used to quantify plasma adrenal steroids. Plasma insulin and leptin levels were quantified with commercially available assay kits.

Results

Mutant animals displayed significantly lower body weights and reduced inguinal fat pad mass, in comparison to unaffected littermates. Biochemically, they were characterized by significantly lower blood glucose levels, accompanied by significantly lower insulin, total cholesterol, high density lipoprotein and triglyceride levels. They also displayed an almost 2-fold increase in transaminases. Moreover, absolute EE was comparable in mutant and control mice, but EE in mutants was uncoupled from their body weights. Histological examination of inguinal white adipose tissue (WAT) revealed adipocytes with multilocular fat droplets reminiscent of WAT browning. In addition, mRNA and protein expression of Ucp1 was increased. Mutant mice also presented differing mitochondrial DNA content in various tissues and altered metabolic activity in mitochondria, but no further phenotypical or behavioral abnormalities. Preliminary data imply normal survival of DguokF180S/F180S mutant animals.

Conclusion

Taken together, DGUOK mutation F180S leads to a lean phenotype, with lower glucose, insulin, and lipid levels rendering this mouse model not only useful for the study of MDDS forms but also for deciphering mechanisms resulting in a lean phenotype.
The histone demethylase JMJD2C constitutes a novel NFE2 target gene that is required for the survival of JAK2V617F mutated cells
Authors: Staehle Anne Marie , Peeken Jan Caspar , Vladimirov Georg , Hoeness Mirjam Elisabeth , Bojtine Kovacs Sarolta , Karantzelis Nikolaos , Gruender Albert , Koellerer Christoph , Jutzi Jonas Samuel , Pahl Heike Luise , Staehle Hans Felix
Published: January 2023

The transcription factor NFE2 is overexpressed in most patients with myeloproliferative neoplasms (MPN). Moreover, mutations in NFE2, found in a subset of MPN patients, strongly predispose for transformation to acute leukemia. Transgenic mice overexpressing NFE2 as well as mice harboring NFE2 mutations display an MPN phenotype and spontaneously develop leukemia. However, the molecular mechanisms effecting NFE2-driven leukemic transformation remain incompletely understood. Here we show that the pro-leukemic histone demethylase JMJD2C constitutes a novel NFE2 target gene. JMJD2C expression is elevated in MPN patients as well as in NFE2 transgenic mice. Moreover, we show that loss of JMJD2C selectively impairs proliferation of JAK2V617F mutated cells. Our data suggest that JMJD2C represents a promising drug target in MPN and provide a rationale for further investigation in preclinical and clinical settings.
Interleukin-18-primed human umbilical cord-mesenchymal stem cells achieve superior therapeutic efficacy for severe viral pneumonia via enhancing T-cell immunosuppression
Authors: Liao Yan , Fu Zeqin , Huang Yinfu , Wu Shiduo , Wang Zhen , Ye Shaotang , Zeng Weijie , Zeng Guifang , Li Duanduan , Yang Yulin , Pei Ke , Yang Jian , Hu Zhiwei , Liang Xiao , Hu Junyuan , Liu Muyun , Jin Juan , Cai Cheguo
Published: January 2023

Coronavirus disease 2019 (COVID-19) treatments are still urgently needed for critically and severely ill patients. Human umbilical cord-mesenchymal stem cells (hUC-MSCs) infusion has therapeutic benefits in COVID-19 patients; however, uncertain therapeutic efficacy has been reported in severe patients. In this study, we selected an appropriate cytokine, IL-18, based on the special cytokine expression profile in severe pneumonia of mice induced by H1N1virus to prime hUC-MSCs in vitro and improve the therapeutic effect of hUC-MSCs in vivo. In vitro, we demonstrated that IL-18-primed hUC-MSCs (IL18-hUCMSC) have higher proliferative ability than non-primed hUC-MSCs (hUCMSCcon). In addition, VCAM-1, MMP-1, TGF-β1, and some chemokines (CCL2 and CXCL12 cytokines) are more highly expressed in IL18-hUCMSCs. We found that IL18-hUCMSC significantly enhanced the immunosuppressive effect on CD3+ T-cells. In vivo, we demonstrated that IL18-hUCMSC infusion could reduce the body weight loss caused by a viral infection and significantly improve the survival rate. Of note, IL18-hUCMSC can also significantly attenuate certain clinical symptoms, including reduced activity, ruffled fur, hunched backs, and lung injuries. Pathologically, IL18-hUCMSC transplantation significantly enhanced the inhibition of inflammation, viral load, fibrosis, and cell apoptosis in acute lung injuries. Notably, IL18-hUCMSC treatment has a superior inhibitory effect on T-cell exudation and proinflammatory cytokine secretion in bronchoalveolar lavage fluid (BALF). Altogether, IL-18 is a promising cytokine that can prime hUC-MSCs to improve the efficacy of precision therapy against viral-induced pneumonia, such as COVID-19.
A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo
Authors: Mi Yuan-yuan , Ji Yu , Zhang Lifeng , Sun Chuan-yu , Wei Bing-bing , Yang Dong-jie , Wan Hong-yuan , Qi Xiao-wei , Wu Sheng , Zhu Li-jie
Published: January 2023

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.
Metamorphism in TDP-43 prion-like domain determines chaperone recognition
Authors: Carrasco Jaime , Antón Rosa , Valbuena Alejandro , Pantoja-Uceda David , Mukhi Mayur , Hervás Rubén , Laurents Douglas V. , Gasset María , Oroz Javier
Published: January 2023

The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43´s prion-like domain. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1δ. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease.
Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions
Authors: de Arce Karen Perez , Ribic Adema , Chowdhury Dhrubajyoti , Watters Katherine , Thompson Garth J. , Sanganahalli Basavaraju G. , Lippard Elizabeth T. C. , Rohlmann Astrid , Strittmatter Stephen M. , Missler Markus , Hyder Fahmeed , Biederer Thomas
Published: January 2023

Multiple trans-synaptic complexes organize synapse development, yet their roles in the mature brain and cooperation remain unclear. We analyzed the postsynaptic adhesion protein LRRTM1 in the prefrontal cortex (PFC), a region relevant to cognition and disorders. LRRTM1 knockout (KO) mice had fewer synapses, and we asked whether other synapse organizers counteract further loss. This determined that the immunoglobulin family member SynCAM 1 controls synapse number in PFC and was upregulated upon LRRTM1 loss. Combined LRRTM1 and SynCAM 1 deletion substantially lowered dendritic spine number in PFC, but not hippocampus, more than the sum of single KO impairments. Their cooperation extended presynaptically, and puncta of Neurexins, LRRTM1 partners, were less abundant in double KO (DKO) PFC. Electrophysiology and fMRI demonstrated aberrant neuronal activity in DKO mice. Further, DKO mice were impaired in social interactions and cognitive tasks. Our results reveal concerted roles of LRRTM1 and SynCAM 1 across synaptic, network, and behavioral domains.
Sub-10 fJ/bit radiation-hard nanoelectromechanical non-volatile memory
Authors: Lee Yong-Bok , Kang Min-Ho , Choi Pan-Kyu , Kim Su-Hyun , Kim Tae-Soo , Lee So-Young , Yoon Jun-Bo
Published: January 2023

With the exponential growth of the semiconductor industry, radiation-hardness has become an indispensable property of memory devices. However, implementation of radiation-hardened semiconductor memory devices inevitably requires various radiation-hardening technologies from the layout level to the system level, and such technologies incur a significant energy overhead. Thus, there is a growing demand for emerging memory devices that are energy-efficient and intrinsically radiation-hard. Here, we report a nanoelectromechanical non-volatile memory (NEM-NVM) with an ultra-low energy consumption and radiation-hardness. To achieve an ultra-low operating energy of less than 10$${{{{{{\rm{fJ\; bit}}}}}}}^{-1}$$fJ bit−1, we introduce an out-of-plane electrode configuration and electrothermal erase operation. These approaches enable the NEM-NVM to be programmed with an ultra-low energy of 2.83$${{{{{{\rm{fJ\; bit}}}}}}}^{-1}$$fJ bit−1. Furthermore, due to its mechanically operating mechanisms and radiation-robust structural material, the NEM-NVM retains its superb characteristics without radiation-induced degradation such as increased leakage current, threshold voltage shift, and unintended bit-flip even after 1 Mrad irradiation.
Synaptic vesicle proteins and ATG9A self-organize in distinct vesicle phases within synapsin condensates
Authors: Park Daehun , Wu Yumei , Wang Xinbo , Gowrishankar Swetha , Baublis Aaron , De Camilli Pietro
Published: January 2023

Ectopic expression in fibroblasts of synapsin 1 and synaptophysin is sufficient to generate condensates of vesicles highly reminiscent of synaptic vesicle (SV) clusters and with liquid-like properties. Here we show that unlike synaptophysin, other major integral SV membrane proteins fail to form condensates with synapsin, but co-assemble into the clusters formed by synaptophysin and synapsin in this ectopic expression system. Another vesicle membrane protein, ATG9A, undergoes activity-dependent exo-endocytosis at synapses, raising questions about the relation of ATG9A traffic to the traffic of SVs. We find that both in fibroblasts and in nerve terminals ATG9A does not co-assemble into synaptophysin-positive vesicle condensates but localizes on a distinct class of vesicles that also assembles with synapsin but into a distinct phase. Our findings suggest that ATG9A undergoes differential sorting relative to SV proteins and also point to a dual role of synapsin in controlling clustering at synapses of SVs and ATG9A vesicles.
Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids
Authors: Liu Junchen , van der Hoeven Ransome , Kattan Walaa E. , Chang Jeffrey T. , Montufar-Solis Dina , Chen Wei , Wong Maurice , Zhou Yong , Lebrilla Carlito B. , Hancock John F.
Published: January 2023

Oncogenic KRAS expression generates a metabolic dependency on aerobic glycolysis, known as the Warburg effect. We report an effect of increased glycolytic flux that feeds into glycosphingolipid biosynthesis and is directly linked to KRAS oncogenic function. High resolution imaging and genetic approaches show that a defined subset of outer leaflet glycosphingolipids, including GM3 and SM4, is required to maintain KRAS plasma membrane localization, with GM3 engaging in cross-bilayer coupling to maintain inner leaflet phosphatidylserine content. Thus, glycolysis is critical for KRAS plasma membrane localization and nanoscale spatial organization. Reciprocally oncogenic KRAS selectively upregulates cellular content of these same glycosphingolipids, whose depletion in turn abrogates KRAS oncogenesis in pancreatic cancer models. Our findings expand the role of the Warburg effect beyond ATP generation and biomass building to high-level regulation of KRAS function. The positive feedforward loop between oncogenic KRAS signaling and glycosphingolipid synthesis represents a vulnerability with therapeutic potential.
Hydrogel oxygen reservoirs increase functional integration of neural stem cell grafts by meeting metabolic demands
Authors: Wang Y. , Zoneff E. R. , Thomas J. W. , Hong N. , Tan L. L. , McGillivray D. J. , Perriman A. W. , Law K. C. L. , Thompson L. H. , Moriarty N. , Parish C. L. , Williams R. J. , Jackson C. J. , Nisbet D. R.
Published: January 2023

Injectable biomimetic hydrogels have great potential for use in regenerative medicine as cellular delivery vectors. However, they can suffer from issues relating to hypoxia, including poor cell survival, differentiation, and functional integration owing to the lack of an established vascular network. Here we engineer a hybrid myoglobin:peptide hydrogel that can concomitantly deliver stem cells and oxygen to the brain to support engraftment until vascularisation can occur naturally. We show that this hybrid hydrogel can modulate cell fate specification within progenitor cell grafts, resulting in a significant increase in neuronal differentiation. We find that the addition of myoglobin to the hydrogel results in more extensive innervation within the host tissue from the grafted cells, which is essential for neuronal replacement strategies to ensure functional synaptic connectivity. This approach could result in greater functional integration of stem cell-derived grafts for the treatment of neural injuries and diseases affecting the central and peripheral nervous systems.
The function and evolution of a genetic switch controlling sexually dimorphic eye differentiation in honeybees
Authors: Netschitailo Oksana , Wang Yidong , Wagner Anna , Sommer Vivien , Verhulst Eveline C. , Beye Martin
Published: January 2023

Animals develop sex-specific morphological structures that are diverse between organisms. However, understanding the developmental and evolutionary mechanisms governing these traits is still limited and largely restricted to DM domain genes, which are conserved, sex-specific developmental regulators identified in genetic models. Here, we report a sex-specific developmental regulator gene, glubschauge (glu) that selectively regulates sexually dimorphic eye differentiation in honeybees. We found that the sex determination gene feminizer (fem) controls sex-specific splicing of glu transcripts, establishing a genetic switch in which Glu proteins with a zinc finger (ZnF) domain are only expressed in females. We showed that female coding sequence was essential and sufficient for partial feminization. Comparative sequence and functional studies revealed that the evolutionary origination of the genetic switch was followed by the mutational origin of the essential ZnF domain. Our results demonstrate that glu is a newly evolved sex-specific genetic switch for region-specific regulation of a dimorphic character.
Iron-sulfur clusters are involved in post-translational arginylation
Authors: Van Verna , Brown Janae B. , O’Shea Corin R. , Rosenbach Hannah , Mohamed Ijaz , Ejimogu Nna-Emeka , Bui Toan S. , Szalai Veronika A. , Chacón Kelly N. , Span Ingrid , Zhang Fangliang , Smith Aaron T.
Published: January 2023

Eukaryotic arginylation is an essential post-translational modification that modulates protein stability and regulates protein half-life. Arginylation is catalyzed by a family of enzymes known as the arginyl-tRNA transferases (ATE1s), which are conserved across the eukaryotic domain. Despite their conservation and importance, little is known regarding the structure, mechanism, and regulation of ATE1s. In this work, we show that ATE1s bind a previously undiscovered [Fe-S] cluster that is conserved across evolution. We characterize the nature of this [Fe-S] cluster and find that the presence of the [Fe-S] cluster in ATE1 is linked to its arginylation activity, both in vitro and in vivo, and the initiation of the yeast stress response. Importantly, the ATE1 [Fe-S] cluster is oxygen-sensitive, which could be a molecular mechanism of the N-degron pathway to sense oxidative stress. Taken together, our data provide the framework of a cluster-based paradigm of ATE1 regulatory control.
Quantitative dose-response analysis untangles host bottlenecks to enteric infection
Authors: Campbell Ian W. , Hullahalli Karthik , Turner Jerrold R. , Waldor Matthew K.
Published: January 2023

Host bottlenecks prevent many infections before the onset of disease by eliminating invading pathogens. By monitoring the diversity of a barcoded population of the diarrhea causing bacterium Citrobacter rodentium during colonization of its natural host, mice, we determine the number of cells that found the infection by establishing a replicative niche. In female mice the size of the pathogen’s founding population scales with dose and is controlled by a severe yet slow-acting bottleneck. Reducing stomach acid or changing host genotype modestly relaxes the bottleneck without breaking the fractional relationship between dose and founders. In contrast, disrupting the microbiota causes the founding population to no longer scale with the size of the inoculum and allows the pathogen to infect at almost any dose, indicating that the microbiota creates the dominant bottleneck. Further, in the absence of competition with the microbiota, the diversity of the pathogen population slowly contracts as the population is overtaken by bacteria having lost the critical virulence island, the locus of enterocyte effacement (LEE). Collectively, our findings reveal that the mechanisms of protection by colonization bottlenecks are reflected in and can be generally defined by the impact of dose on the pathogen’s founding population.
Next-Generation Morphometry for pathomics-data mining in histopathology
Authors: Hölscher David L. , Bouteldja Nassim , Joodaki Mehdi , Russo Maria L. , Lan Yu-Chia , Sadr Alireza Vafaei , Cheng Mingbo , Tesar Vladimir , Stillfried Saskia V. , Klinkhammer Barbara M. , Barratt Jonathan , Floege Jürgen , Roberts Ian S. D. , Coppo Rosanna , Costa Ivan G. , Bülow Roman D. , Boor Peter
Published: January 2023

Pathology diagnostics relies on the assessment of morphology by trained experts, which remains subjective and qualitative. Here we developed a framework for large-scale histomorphometry (FLASH) performing deep learning-based semantic segmentation and subsequent large-scale extraction of interpretable, quantitative, morphometric features in non-tumour kidney histology. We use two internal and three external, multi-centre cohorts to analyse over 1000 kidney biopsies and nephrectomies. By associating morphometric features with clinical parameters, we confirm previous concepts and reveal unexpected relations. We show that the extracted features are independent predictors of long-term clinical outcomes in IgA-nephropathy. We introduce single-structure morphometric analysis by applying techniques from single-cell transcriptomics, identifying distinct glomerular populations and morphometric phenotypes along a trajectory of disease progression. Our study provides a concept for Next-generation Morphometry (NGM), enabling comprehensive quantitative pathology data mining, i.e., pathomics.
Coherence protection of spin qubits in hexagonal boron nitride
Authors: Ramsay Andrew J. , Hekmati Reza , Patrickson Charlie J. , Baber Simon , Arvidsson-Shukur David R. M. , Bennett Anthony J. , Luxmoore Isaac J.
Published: January 2023

Spin defects in foils of hexagonal boron nitride are an attractive platform for magnetic field imaging, since the probe can be placed in close proximity to the target. However, as a III-V material the electron spin coherence is limited by the nuclear spin environment, with spin echo coherence times of ∽100 ns at room temperature accessible magnetic fields. We use a strong continuous microwave drive with a modulation in order to stabilize a Rabi oscillation, extending the coherence time up to ∽ 4μs, which is close to the 10 μs electron spin lifetime in our sample. We then define a protected qubit basis, and show full control of the protected qubit. The coherence times of a superposition of the protected qubit can be as high as 0.8 μs. This work establishes that boron vacancies in hexagonal boron nitride can have electron spin coherence times that are competitive with typical nitrogen vacancy centres in small nanodiamonds under ambient conditions.
Wearable in-sensor reservoir computing using optoelectronic polymers with through-space charge-transport characteristics for multi-task learning
Authors: Wu Xiaosong , Wang Shaocong , Huang Wei , Dong Yu , Wang Zhongrui , Huang Weiguo
Published: January 2023

In-sensor multi-task learning is not only the key merit of biological visions but also a primary goal of artificial-general-intelligence. However, traditional silicon-vision-chips suffer from large time/energy overheads. Further, training conventional deep-learning models is neither scalable nor affordable on edge-devices. Here, a material-algorithm co-design is proposed to emulate human retina and the affordable learning paradigm. Relying on a bottle-brush-shaped semiconducting p-NDI with efficient exciton-dissociations and through-space charge-transport characteristics, a wearable transistor-based dynamic in-sensor Reservoir-Computing system manifesting excellent separability, fading memory, and echo state property on different tasks is developed. Paired with a ‘readout function’ on memristive organic diodes, the RC recognizes handwritten letters and numbers, and classifies diverse costumes with accuracies of 98.04%, 88.18%, and 91.76%, respectively (higher than all reported organic semiconductors). In addition to 2D images, the spatiotemporal dynamics of RC naturally extract features of event-based videos, classifying 3 types of hand gestures at an accuracy of 98.62%. Further, the computing cost is significantly lower than that of the conventional artificial-neural-networks. This work provides a promising material-algorithm co-design for affordable and highly efficient photonic neuromorphic systems.
Rapid emergence of extensively drug-resistant Shigella sonnei in France
Authors: Lefèvre Sophie , Njamkepo Elisabeth , Feldman Sarah , Ruckly Corinne , Carle Isabelle , Lejay-Collin Monique , Fabre Laëtitia , Yassine Iman , Frézal Lise , Pardos de la Gandara Maria , Fontanet Arnaud , Weill François-Xavier
Published: January 2023

Shigella sonnei, the main cause of bacillary dysentery in high-income countries, has become increasingly resistant to antibiotics. We monitored the antimicrobial susceptibility of 7121 S. sonnei isolates collected in France between 2005 and 2021. We detected a dramatic increase in the proportion of isolates simultaneously resistant to ciprofloxacin (CIP), third-generation cephalosporins (3GCs) and azithromycin (AZM) from 2015. Our genomic analysis of 164 such extensively drug-resistant (XDR) isolates identified 13 different clusters within CIP-resistant sublineage 3.6.1, which was selected in South Asia ∼15 years ago. AZM resistance was subsequently acquired, principally through IncFII (pKSR100-like) plasmids. The last step in the development of the XDR phenotype involved various extended-spectrum beta-lactamase genes (blaCTX-M-3, blaCTX-M-15, blaCTX-M-27, blaCTX-M-55, and blaCTX-M-134) carried by different plasmids (IncFII, IncI1, IncB/O/K/Z) or even integrated into the chromosome, and encoding resistance to 3GCs. This rapid emergence of XDR S. sonnei, including an international epidemic strain, is alarming, and good laboratory-based surveillance of shigellosis will be crucial for informed decision-making and appropriate public health action.
Stringent response ensures the timely adaptation of bacterial growth to nutrient downshift
Authors: Zhu Manlu , Dai Xiongfeng
Published: January 2023

Timely adaptation to nutrient downshift is crucial for bacteria to maintain fitness during feast and famine cycle in the natural niche. However, the molecular mechanism that ensures the timely adaption of bacterial growth to nutrient downshift remains poorly understood. Here, we quantitatively investigated the adaptation of Escherichia coli to various kinds of nutrient downshift. We found that relA deficient strain, which is devoid of stringent response, exhibits a significantly longer growth lag than wild type strain during adapting to both amino acid downshift and carbon downshift. Quantitative proteomics show that increased (p)ppGpp level promotes the growth adaption of bacteria to amino acid downshift via triggering the proteome resource re-allocation from ribosome synthesis to amino acid biosynthesis. Such type of proteome re-allocation is significantly delayed in the relA-deficient strain, which underlies its longer lag than wild type strain during amino acid downshift. During carbon downshift, a lack of stringent response in relA deficient strain leads to disruption of the transcription-translation coordination, thus compromising the transcription processivity and further the timely expression of related catabolic operons for utilizing secondary carbon sources. Our studies shed light on the fundamental strategy of bacteria to maintain fitness under nutrient-fluctuating environments.
Musculoskeletal research in human space flight – unmet needs for the success of crewed deep space exploration
Authors: Liphardt Anna-Maria , Fernandez-Gonzalo Rodrigo , Albracht Kirsten , Rittweger Jörn , Vico Laurence
Published: January 2023

Based on the European Space Agency (ESA) Science in Space Environment (SciSpacE) community White Paper “Human Physiology – Musculoskeletal system”, this perspective highlights unmet needs and suggests new avenues for future studies in musculoskeletal research to enable crewed exploration missions. The musculoskeletal system is essential for sustaining physical function and energy metabolism, and the maintenance of health during exploration missions, and consequently mission success, will be tightly linked to musculoskeletal function. Data collection from current space missions from pre-, during-, and post-flight periods would provide important information to understand and ultimately offset musculoskeletal alterations during long-term spaceflight. In addition, understanding the kinetics of the different components of the musculoskeletal system in parallel with a detailed description of the molecular mechanisms driving these alterations appears to be the best approach to address potential musculoskeletal problems that future exploratory-mission crew will face. These research efforts should be accompanied by technical advances in molecular and phenotypic monitoring tools to provide in-flight real-time feedback.
Metabolic changes in bile acids with pregnancy progression and their correlation with perinatal complications in intrahepatic cholestasis of pregnant patients
Authors: Ma Zhixin , Liu Yifeng , Chai Lin , Jin Guochen , Sun Yanni , Zhou Shaomin , Yin Peiyuan , Wang Siwen , Zhu Yuning , Zhang Dan , Lu Shiming , Zhu Bo
Published: January 2023

Intrahepatic cholestasis of pregnancy (ICP) is a rare liver disease occurring during pregnancy that is characterized by disordered bile acid (BA) metabolism. It is related to adverse clinical outcomes in both the mother and fetus. Our aim was to evaluate the BA metabolism profiles in different types of ICP and investigate the association between specific BAs and perinatal complications in ICP patients. We consecutively evaluated 95 patients with ICP, in which 53 patients were diagnosed with early-onset ICP (EICP) and 42 patients were diagnosed with late-onset ICP (LICP). Concentrations of 15 BA components were detected using high-performance liquid chromatography tandem mass spectrometry. Clinical information was abstracted from the medical records. The percentage of conjugated bile acids increased in ICP patients. Specifically, taurocholic acid (TCA) accumulated in LICP patients, and glycocholic acid (GCA) predominated in EICP patients. A higher preterm birth incidence was observed among ICP patients. Albumin, total bile acids, total bilirubin and GCA percentage values at ICP diagnosis predicts 83.5% of preterm birth in EICP, and the percentage of TCA in total bile acids at ICP diagnosis predicts 93.2% of preterm birth in LICP. This analysis showed that the BA metabolism profiles of EICP and LICP were distinct. Increased hepatic load was positively correlated with preterm birth in EICP. An elevated TCA percentage in total bile acids provides a biomarker to predict preterm birth in LICP.
Temperature prediction of solar greenhouse based on NARX regression neural network
Authors: Gao Maosheng , Wu Qingli , Li Jianke , Wang Bailing , Zhou Zhongyu , Liu Chunming , Wang Dong
Published: January 2023

Temperature has an important influence on plant growth and development. In protected agriculture production, accurate prediction of temperature environment is of great significance. However, due to the time series, nonlinear and multi coupling characteristics of temperature, it is difficult to achieve accurate prediction. We proposed a method for building a solar greenhouse temperature prediction model based on a timeseries analysis, that considers the time series characteristics and dynamic temperature changes in the greenhouse system. The method would predict the temperature of greenhouse, and provide reference for the temperature change law in protected agriculture. A parameter analysis was performed on the nonlinear autoregressive exogenous (NARX) neural network, and a solar greenhouse temperature time series prediction model was established using the NARX regression neural network. The results showed that the proposed model depicted a maximum absolute error of 0.67 °C, and model correlation coefficient of 0.9996. Compared with the wavelet and BP neural networks, the NARX regression neural network accurately predicted and significantly outperformed in the solar greenhouse temperature prediction model. Moreover, the prediction model can accurately predict temperature trends within the solar greenhouse and is pivotal to obtaining precise control of solar greenhouse temperature.
Quantifying the impact of positive stress on companies from online employee reviews
Authors: Šćepanović Sanja , Constantinides Marios , Quercia Daniele , Kim Seunghyun
Published: January 2023

Workplace stress is often considered to be negative, yet lab studies on individuals suggest that not all stress is bad. There are two types of stress: distress refers to harmful stimuli, while eustress refers to healthy, euphoric stimuli that create a sense of fulfillment and achievement. Telling the two types of stress apart is challenging, let alone quantifying their impact across corporations. By leveraging a dataset of 440 K reviews about S &P 500 companies published during twelve successive years, we developed a deep learning framework to extract stress mentions from these reviews. We proposed a new methodology that places each company on a stress-by-rating quadrant (based on its overall stress score and overall rating on the site), and accordingly scores the company to be, on average, either a low stress, passive, negative stress, or positive stress company. We found that (former) employees of positive stress companies tended to describe high-growth and collaborative workplaces in their reviews, and that such companies’ stock evaluations grew, on average, 5.1 times in 10 years (2009–2019) as opposed to the companies of the other three stress types that grew, on average, 3.7 times in the same time period. We also found that the four stress scores aggregated every year—from 2008 to 2020 —closely followed the unemployment rate in the U.S.: a year of positive stress (2008) was rapidly followed by several years of negative stress (2009–2015), which peaked during the Great Recession (2009–2011). These results suggest that automated analyses of the language used by employees on corporate social-networking tools offer yet another way of tracking workplace stress, allowing quantification of its impact on corporations.
Malaria parasite density and detailed qualitative microscopy enhances large-scale profiling of infection endemicity in Nigeria
Authors: Oyibo Wellington , Latham Victoria , Oladipo Oladosu , Ntadom Godwin , Uhomoibhi Perpetua , Ogbulafor Nnenna , Okoronkwo Chukwu , Okoh Festus , Mahmoud Aminu , Shekarau Emmanuel , Oresanya Olusola , Cherima Yakubu Joel , Jalingo Innua , Abba Bintu , Audu Mohammed , Conway David J.
Published: January 2023

With global progress towards malaria reduction stalling, further analysis of epidemiology is required, particularly in countries with the highest burden. National surveys have mostly analysed infection prevalence, while large-scale data on parasite density and different developmental forms rarely available. In Nigeria, the country with the largest burden globally, blood slide microscopy of children up to 5 years of age was conducted in the 2018 National Demographic and Health Survey, and parasite prevalence previously reported. In the current study, malaria parasite density measurements are reported and analysed for 7783 of the children sampled across the 36 states within the six geopolitical zones of the country. Asexual and sexual stages, and infections with different malaria parasite species are analysed. Across all states of Nigeria, there was a positive correlation between mean asexual parasite density within infected individuals and prevalence of infection in the community (Spearman’s rho = 0.39, P = 0.02). Asexual parasite densities were highest in the northern geopolitical zones (geometric means > 2000 μL−1), extending the evidence of exceptionally high infection burden in many areas. Sexual parasite prevalence in each state was highly correlated with asexual parasite prevalence (Spearman’s rho = 0.70, P < 0.001), although sexual parasite densities were low (geometric means < 100 μL−1 in all zones). Infants had lower parasite densities than children above 1 year of age, but there were no differences between male and female children. Most infections were of P. falciparum, which had higher asexual densities but lower sexual parasite densities than P. malariae or P. ovale mono-infections. However, mixed species infections had the highest asexual parasite densities. It is recommended that future large surveys in high burden countries measure parasite densities as well as developmental stages and species, to improve the quality of malaria epidemiology and tracking of future changes.
Influence of mixed ventilation on particulate-gas diffusion and distribution of diesel engine exhaust in fully mechanized excavation face
Authors: Zhou Gang , Yang Yang , Duan Jinjie , Jing Bin , Song Shuzheng , Sun Biao
Published: January 2023

Tail gas emitted by underground trackless rubber wheel cars poses a serious threat to the health and safety of underground workers. To effectively reduce the tail gas concentration of a comprehensive excavation face, this study adopted a numerical simulation method to investigate the influence of air suction volume Q and distance L between trackless rubber wheel cars and headfaces on the diffusion law of diesel particulate matter, CO, and NOx under long suction and short pressure ventilation. The results showed that under the condition of L = 20 m, the trackless rubber wheel car is closer to the suction air duct. At this point, when Q = 600 m3/min, the tail gas control effect in the roadway is optimum. In addition, under the condition of L = 40 m, the trackless rubber wheel car is in the middle of the roadway. At this point, when Q = 300 m3/min, the tail gas control effect in the roadway is optimum. When L = 60 m and Q = 200 m3/min, the ventilation mode in the roadway is mainly pressure-in ventilation. The high-volume-fraction NOx region and the medium-volume-fraction NOx region under this air volume are small.
Relationship between gut microbiota and nutritional status in patients on peritoneal dialysis
Authors: Tian Na , Yan Yinyin , Chen Na , Xu Siyao , Chu Rui , Wang Mengting , Duan Surong , Ren Hongyan , Song Shuhua , Wang Li , Ma Xiaoqin , Xu Mei , Na Li , Chen Menghua , Li Philip Kam-Tao
Published: January 2023

Malnutrition is a common complication in the dialysis population, both hemodialysis and peritoneal dialysis (PD). We report our exploratory study on the characteristics of intestinal microbiota and nutritional status in PD patients. The nutritional status of our PD patients were evaluated, and their feces were collected for 16S rRNA gene V3-V4 regions amplification and high-throughput sequencing. The characteristics and differences of microbiota between the well-nourished (W) and malnourished (M) groups were compared. We studied the genera and the operational taxonomic units (OTUs) within the genus of our patients, initially comparing the malnourished and the well- nourished groups and later on reanalyzing the whole group using these OTUs. At the OTU level, 6 bacteria were significantly correlated with the serum albumin level. The abundances of 2 OTUs (OTU208 Lachnospiraceae_incertae_sedi and OTU4 Bacteroides) were more in W group. Meanwhile, 4 OTUs (OTU225 Akkermansia, OTU87 Megasphaera, OTU31 Peptostreptococcaceae_incertae_sedi and OTU168 Clostridium_sensu_strictu) displayed higher abundance among individuals in M group. Notably, the OTU168 Clostridium_sensu_stricto was the only bacteria that significantly correlated with serum albumin (r = − 0.356, P = 0.05), pre-albumin (r = − 0.399, P = 0.02), and SGA (r = 0.458, P = 0.01). The higher the OTU168 Clostridium_sensu_strictu, the lower serum albumin and pre-albumin and a higher score of SGA signifying a worse nutritional status. Our preliminary findings suggested a relationship between the nutrition status and microbiota in PD patients. Our results provide a basis for further exploration of the interactions between malnutrition and intestinal flora in PD patients with potential interventions using probiotics and prebiotics.
Synthesis, properties, and application of the new nanocatalyst of double layer hydroxides in the one-pot multicomponent synthesis of 2-amino-3-cyanopyridine derivatives
Authors: Momeni Sarieh , Ghorbani-Vaghei Ramin
Published: January 2023

A new heterogeneous nanocatalyst LDH@3-chloropyltrimethoxysilane@1,3-benzenedisulfonyl amine@Cu (LDH@TRMS@BDSA@Cu) was synthesized and confirmed by analyzes such as Fourier transform infrared spectroscopy, Field Emission Scanning Electron Microscopy, energy scattered X-ray spectroscopy (EDX), elemental mapping, X-ray diffraction analysis, heat gravity/heat derivatization (TGA) and differential scanning calorimetry. The newly synthesized nanocatalyst effectively catalyzed the reaction between different aryl aldehydes, malononitrile, different acetophenones and ammonium acetate in solvent-free conditions and they were converted into 2-amino-3-cyanopyridine derivatives with high efficiency. The reaction showed advantages such as simplicity, high stability, environmental friendliness, excellent efficiency and short time. Also, this catalyst is recyclable and was recycled 4 times without losing significant catalytic power.
Antiviral activities of plant-derived indole and β-carboline alkaloids against human and avian influenza viruses
Authors: Hegazy Akram , Mahmoud Sara H. , Elshaier Yaseen A. M. M. , Shama Noura M. Abo , Nasr Nasr Fawzy , Ali M. A. , El-Shazly Assem Mohamed , Mostafa Islam , Mostafa Ahmed
Published: January 2023

The persistent evolution of drug-resistant influenza strains represents a global concern. The innovation of new treatment approaches through drug screening strategies and investigating the antiviral potential of bioactive natural-based chemicals may address the issue. Herein, we screened the anti-influenza efficacy of some biologically active indole and β-carboline (βC) indole alkaloids against two different influenza A viruses (IAV) with varied host range ranges; seasonal influenza A/Egypt/NRC098/2019(H1N1) and avian influenza A/chicken/Egypt/N12640A/2016(H5N1). All compounds were first assessed for their half-maximal cytotoxic concentration (CC50) in MDCK cells and half-maximal inhibitory concentrations (IC50) against influenza A/H5N1. Intriguingly, Strychnine sulfate, Harmalol, Harmane, and Harmaline showed robust anti-H5N1 activities with IC50 values of 11.85, 0.02, 0.023, and 3.42 µg/ml, respectively, as compared to zanamivir and amantadine as control drugs (IC50 = 0.079 µg/ml and 17.59 µg/ml, respectively). The efficacy of the predefined phytochemicals was further confirmed against influenza A/H1N1 and they displayed potent anti-H1N1 activities compared to reference drugs. Based on SI values, the highly promising compounds were then evaluated for antiviral efficacy through plaque reduction assay and consistently they revealed high viral inhibition percentages at non-toxic concentrations. By studying the modes of antiviral action, Harmane and Harmalol could suppress viral infection via interfering mainly with the viral replication of the influenza A/H5N1 virus, whilst Harmaline exhibited a viricidal effect against the influenza A/H5N1 virus. Whereas, Strychnine sulfate elucidated its anti-influenza potency by interfering with viral adsorption into MDCK cells. Consistently, chemoinformatic studies showed that all studied phytochemicals illustrated HB formations with essential peptide cleft through the NH of indole moiety. Among active alkaloids, harmalol displayed the best lipophilicity metrics including ligand efficiency (LE) and ligand lipophilic efficiency (LLE) for both viruses. Compounds geometry and their ability to participate in HB formation are very crucial.
Half-Heusler phase TmNiSb under pressure: intrinsic phase separation, thermoelectric performance and structural transition
Authors: Ciesielski Kamil , Synoradzki Karol , Szymański Damian , Tobita Kazuki , Berent Katarzyna , Obstarczyk Patryk , Kimura Kaoru , Kaczorowski Dariusz
Published: January 2023

Half-Heusler (HH) phase TmNiSb was obtained by arc-melting combined with high-pressure high-temperature sintering in conditions: p = 5.5 GPa, $$T_{HPHT}$$

T

HPHT

= 20, 250, 500, 750, and 1000 $$^{\circ }$$

∘

C. Within pressing temperatures 20–750 $$^{\circ }$$

∘

C the samples maintained HH structure, however, we observed intrinsic phase separation. The material divided into three phases: stoichiometric TmNiSb, nickel-deficient phase TmNi$$_{1-x}$$

1
-
x

Sb, and thulium-rich phase Tm(NiSb)$$_{1-y}$$

1
-
y

. For TmNiSb sample sintered at 1000 $$^{\circ }$$

∘

C, we report structural transition to LiGaGe-type structure (P$$6_3$$

6
3

mc, a = 4.367(3) Å, c = 7.138(7) Å). Interpretation of the transition is supported by X-ray powder diffraction, electron back-scattered diffraction, ab-initio calculations of Gibbs energy and phonon dispersion relations. Electrical resistivity measured for HH samples with phase separation shown non-degenerate behavior. Obtained energy gaps for HH samples were narrow ($$\le$$
≤
260 meV), while the average hole effective masses in range 0.8–2.5$$m_e$$

m
e

. TmNiSb sample pressed at 750 $$^{\circ }$$

∘

C achieved the biggest power factor among the series, 13 $$\upmu$$
μ
WK$$^{-2}$$

-
2

cm$$^{-1}$$

-
1

, which proves that the intrinsic phase separation is not detrimental for the electronic transport.
A comparison of manual and automated neural architecture search for white matter tract segmentation
Authors: Tchetchenian Ari , Zhu Yanming , Zhang Fan , O’Donnell Lauren J. , Song Yang , Meijering Erik
Published: January 2023

Segmentation of white matter tracts in diffusion magnetic resonance images is an important first step in many imaging studies of the brain in health and disease. Similar to medical image segmentation in general, a popular approach to white matter tract segmentation is to use U-Net based artificial neural network architectures. Despite many suggested improvements to the U-Net architecture in recent years, there is a lack of systematic comparison of architectural variants for white matter tract segmentation. In this paper, we evaluate multiple U-Net based architectures specifically for this purpose. We compare the results of these networks to those achieved by our own various architecture changes, as well as to new U-Net architectures designed automatically via neural architecture search (NAS). To the best of our knowledge, this is the first study to systematically compare multiple U-Net based architectures for white matter tract segmentation, and the first to use NAS. We find that the recently proposed medical imaging segmentation network UNet3+ slightly outperforms the current state of the art for white matter tract segmentation, and achieves a notably better mean Dice score for segmentation of the fornix (+ 0.01 and + 0.006 mean Dice increase for left and right fornix respectively), a tract that the current state of the art model struggles to segment. UNet3+ also outperforms the current state of the art when little training data is available. Additionally, manual architecture search found that a minor segmentation improvement is observed when an additional, deeper layer is added to the U-shape of UNet3+. However, all networks, including those designed via NAS, achieve similar results, suggesting that there may be benefit in exploring networks that deviate from the general U-Net paradigm.