bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Changes in Value-based Learning in Middle Childhood: Distinct Contributions of Hippocampus and Striatum
Authors: Falck Johannes , Zhang Lei , Raffington Laurel , Mohn Johannes J. , Triesch Jochen , Heim Christine , Shing Yee Lee
Published: May 2024

The hippocampal-dependent memory system and striatal-dependent memory system modulate reinforcement learning depending on feedback timing in adults, but their contributions during development remain unclear. In a 2-year longitudinal study, 6-to-7-year-old children performed a reinforcement learning task in which they received feedback immediately or with a short delay following their response. Children’s learning was found to be sensitive to feedback timing modulations in their reaction time and inverse temperature parameter, which quantifies value-guided decision-making. They showed longitudinal improvements towards more optimal value-based learning, and their hippocampal volume showed protracted maturation. Better delayed model-derived learning covaried with larger hippocampal volume longitudinally, in line with the adult literature. In contrast, a larger striatal volume in children was associated with both better immediate and delayed model-derived learning longitudinally. These findings show, for the first time, an early hippocampal contribution to the dynamic development of reinforcement learning in middle childhood, with neurally less differentiated and more cooperative memory systems than in adults.
Mono-methylated histones control PARP-1 in chromatin and transcription
Authors: Bamgbose Gbolahan , Bordet Guillaume , Lodhi Niraj , Tulin Alexei
Published: May 2024

PARP-1 is central to transcriptional regulation under both normal and stress conditions, with the governing mechanisms yet to be fully understood. Our biochemical and ChIP-seq-based analyses showed that PARP-1 binds specifically to active histone marks, particularly H4K20me1. We found that H4K20me1 plays a critical role in facilitating PARP-1 binding and the regulation of PARP-1-dependent loci during both development and heat shock stress. Here, we report that the sole H4K20 mono-methylase, pr-set7, and parp-1 Drosophila mutants undergo developmental arrest. RNA-seq analysis showed an absolute correlation between PR-SET7- and PARP-1-dependent loci expression, confirming co-regulation during developmental phases. PARP-1 and PR-SET7 are both essential for activating hsp70 and other heat shock genes during heat stress, with a notable increase of H4K20me1 at their gene body. Mutating pr-set7 disrupts monomethylation of H4K20 along heat shock loci and abolish PARP-1 binding there. These data strongly suggest that H4 monomethylation is a key triggering point in PARP-1 dependent processes in chromatin.
Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts
Authors: Luo Yongfeng , Cao Ke , Chiu Joanne , Chen Hui , Wang Hong-Jun , Thornton Matthew E. , Grubbs Brendan H. , Kolb Martin , Parmacek Michael S. , Mishina Yuji , Shi Wei
Published: May 2024

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study, we dissected the roles of BMP receptor 1a (Bmpr1a)- mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal
Bmpr1a
disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal
Bmpr1a
knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal
Bmpr1a
knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal
Bmpr1a
knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.
Serotonergic amplification of odor-evoked neural responses maps onto flexible behavioral outcomes
Authors: Bessonova Yelyzaveta , Raman Barani
Published: May 2024

Behavioral responses to many odorants are not fixed but are flexible, varying based on organismal needs. How such variations arise and the role of various neuromodulators in achieving flexible neural-to-behavioral mapping is not fully understood. In this study, we examined how serotonin modulates the neural and behavioral responses to odorants in locusts (
Schistocerca americana
). Our results indicated that serotonin can increase or decrease appetitive behavior in an odor-specific manner. On the other hand, in the antennal lobe, serotonergic modulation enhanced odor-evoked response strength but left the temporal features or the combinatorial response profiles unperturbed. This result suggests that serotonin allows for sensitive and robust recognition of odorants. Nevertheless, the uniform neural response amplification appeared to be at odds with the observed stimulus-specific behavioral modulation. We show that a simple linear model with neural ensembles segregated based on behavioral relevance is sufficient to explain the serotonin-mediated flexible mapping between neural and behavioral responses.
Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration
Authors: Haase Megan , Comlekoglu Tien , Petrucciani Alexa , Peirce Shayn M. , Blemker Silvia S.
Published: May 2024

Muscle regeneration is a complex process due to dynamic and multiscale biochemical and cellular interactions, making it difficult to identify microenvironmental conditions that are beneficial to muscle recovery from injury using experimental approaches alone. To understand the degree to which individual cellular behaviors impact endogenous mechanisms of muscle recovery, we developed an agent-based model (ABM) using the Cellular Potts framework to simulate the dynamic microenvironment of a cross-section of murine skeletal muscle tissue. We referenced more than 100 published studies to define over 100 parameters and rules that dictate the behavior of muscle fibers, satellite stem cells (SSC), fibroblasts, neutrophils, macrophages, microvessels, and lymphatic vessels, as well as their interactions with each other and the microenvironment. We utilized parameter density estimation to calibrate the model to temporal biological datasets describing cross-sectional area (CSA) recovery, SSC, and fibroblast cell counts at multiple time points following injury. The calibrated model was validated by comparison of other model outputs (macrophage, neutrophil, and capillaries counts) to experimental observations. Predictions for eight model perturbations that varied cell or cytokine input conditions were compared to published experimental studies to validate model predictive capabilities. We used Latin hypercube sampling and partial rank correlation coefficient to identify
in silico
perturbations of cytokine diffusion coefficients and decay rates to enhance CSA recovery. This analysis suggests that combined alterations of specific cytokine decay and diffusion parameters result in greater fibroblast and SSC proliferation compared to individual perturbations with a 13% increase in CSA recovery compared to unaltered regeneration at 28 days. These results enable guided development of therapeutic strategies that similarly alter muscle physiology (i.e. converting ECM-bound cytokines into freely diffusible forms as studied in cancer therapeutics or delivery of exogenous cytokines) during regeneration to enhance muscle recovery after injury.
Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling
Authors: Mühlenbeck Henning , Tsutsui Yuko , Lemmon Mark A. , Bender Kyle W. , Zipfel Cyril
Published: May 2024

Transmembrane signaling by plant receptor kinases (RKs) has long been thought to involve reciprocal trans-phosphorylation of their intracellular kinase domains. The fact that many of these are pseudokinase domains, however, suggests that additional mechanisms must govern RK signaling activation. Non-catalytic signaling mechanisms of protein kinase domainshave been described in metazoans, but information is scarce for plants. Recently, a non-catalytic function was reported for the leucine-rich repeat (LRR)-RK subfamily XIIa member EFR (ELONGATION FACTOR TU RECEPTOR) and phosphorylation-dependent conformational changes were proposed to regulate signaling of RKs with non-RD kinase domains. Here, using EFR as a model, we describe a non-catalytic activation mechanism for LRR-RKs with non-RD kinase domains. EFR is an active kinase, but a kinase-dead variant retains the ability to enhance catalytic activity of its co-receptor kinase BAK1/SERK3 (BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3). Applying hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis and designing homology-based intragenic suppressor mutations, we provide evidence that the EFR kinase domain must adopt its active conformation in order to activate BAK1 allosterically, likely by supporting αC-helix positioning in BAK1. Our results suggest a conformational toggle model for signaling, in which BAK1 first phosphorylates EFR in the activation loop to stabilize its active conformation, allowing EFR in turn to allosterically activate BAK1.
Transdifferentiation of fibroblasts into muscle cells to constitute cultured meat with tunable intramuscular fat deposition
Authors: Ma Tongtong , Ren Ruimin , Lv Jianqi , Yang Ruipeng , Xinyi Zheng , Hu Yang , Zhu Guiyu , Wang Heng
Published: May 2024

Current studies on cultured meat mainly focused on the muscle tissue reconstruction in vitro, but lack the formation of intramuscular fat which is a crucial factor in determining taste, texture and nutritional contents. Therefore, incorporating fat into cultured meat is of superior value. In this study, we employed the myogenic/lipogenic transdifferentiation of chicken fibroblasts in 3D to produce muscle mass and deposit fat into the same cells without the co-culture or mixture of different cells or fat substances. The immortalized chicken embryonic fibroblasts were implanted into the hydrogel scaffold and the cell proliferation and myogenic transdifferentiation were conducted in 3D to produce the whole-cut meat mimics. Compare to 2D, cells grown in 3D matrix showed elevated myogenesis and collagen production. We further induced fat deposition in the transdifferentiated muscle cells and the triglyceride content could be manipulated to match and exceed the levels of chicken meat. The gene expression analysis indicated that both lineage-specific and multi-functional signalings could contribute to the generation of muscle/fat matrix. Overall, we were able to precisely modulate muscle, fat, and extracellular matrix contents according to balanced or specialized meat preferences. These findings provide new avenues for customized cultured meat production with desired intramuscular fat contents that can be tailored to meet the diverse demands of consumers.
An antimicrobial drug recommender system using MALDI-TOF MS and dual-branch neural networks
Authors: De Waele Gaetan , Menschaert Gerben , Waegeman Willem
Published: May 2024

Timely and effective use of antimicrobial drugs can improve patient outcomes, as well as help safeguard against resistance development. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is currently routinely used in clinical diagnostics for rapid species identification. Mining additional data from said spectra in the form of antimicrobial resistance (AMR) profiles is, therefore, highly promising. Such AMR profiles could serve as a drop-in solution for drastically improving treatment efficiency, effectiveness, and costs.This study endeavours to develop the first machine learning models capable of predicting AMR profiles for the whole repertoire of species and drugs encountered in clinical microbiology. The resulting model can be interpreted as a drug recommender system for infectious diseases. We find that our dual-branch method delivers considerably higher performance compared to previous approaches. In addition, experiments show that the models can be efficiently fine-tuned to data from other clinical laboratories. MALDI-TOF-based AMR recommender systems can, hence, greatly extend the value of MALDI-TOF MS for clinical diagnostics.All code supporting this study is distributed on PyPI and is packaged under: https://github.com/gdewael/maldi-nn
Insights into metabolic heterogeneity of colorectal cancer gained from fluorescence lifetime imaging
Authors: Komarova Anastasia D , Sinyushkina Snezhana D , Shchechkin Ilia D , Druzhkova Irina N , Smirnova Sofia A , Terekhov Vitaliy M , Mozherov Artem M , Ignatova Nadezhda I , Nikonova Elena E , Shirshin Evgeny A , Shimolina Liubov E , Gamayunov Sergey V , Shcheslavskiy Vladislav I , Shirmanova Marina V
Published: May 2024

Heterogeneity of tumor metabolism is an important, but still poorly understood aspect of tumor biology. Present work is focused on the visualization and quantification of cellular metabolic heterogeneity of colorectal cancer using fluorescence lifetime imaging (FLIM) of redox cofactor NAD(P)H. FLIM-microscopy of NAD(P)H was performed in vitro in four cancer cell lines (HT29, HCT116, CaCo2 and CT26), in vivo in the four types of colorectal tumors in mice and ex vivo in patients’ tumor samples. The dispersion and bimodality of the decay parameters were evaluated to quantify the intercellular metabolic heterogeneity. Our results demonstrate that patients’ colorectal tumors have significantly higher heterogeneity of energy metabolism compared with cultured cells and tumor xenografts, which was displayed as a wider and frequently bimodal distribution of a contribution of a free (glycolytic) fraction of NAD(P)H within a sample. Among patients’ tumors, the dispersion was larger in the high-grade and early stage ones, without, however, any association with bimodality. These results indicate that cell-level metabolic heterogeneity assessed from NAD(P)H FLIM has a potential to become a clinical prognostic factor.
Deciphering the actin structure-dependent preferential cooperative binding of cofilin
Authors: Ngo Kien Xuan , Vu Huong T , Umeda Kenichi , Trinh Minh-Nhat , Kodera Noriyuki , Uyeda Taro Q.P.
Published: May 2024

The mechanism underlying the preferential and cooperative binding of cofilin and the expansion of clusters toward the pointed-end side of actin filaments remains poorly understood. To address this, we conducted a principal component analysis based on available filamentous actin (F-actin) and C-actin (cofilins were excluded from cofilactin) structures and compared to monomeric G-actin. The results strongly suggest that C-actin, rather than F-ADP-actin, represented the favourable structure for binding preference of cofilin. High-speed atomic force microscopy explored that the shortened bare half helix adjacent to the cofilin clusters on the pointed end side included fewer actin protomers than normal helices. The mean axial distance (MAD) between two adjacent actin protomers along the same long-pitch strand within shortened bare half helices was longer (5.0–6.3 nm) than the MAD within typical helices (4.3–5.6 nm). The inhibition of torsional motion during helical twisting, achieved through stronger attachment to the lipid membrane, led to more pronounced inhibition of cofilin binding and cluster formation than the presence of inorganic phosphate (Pi) in solution. F-ADP-actin exhibited more naturally supertwisted half helices than F-ADP.Pi-actin, explaining how Pi inhibits cofilin binding to F-actin with variable helical twists. We propose that protomers within the shorter bare helical twists, either influenced by thermal fluctuation or induced allosterically by cofilin clusters, exhibit characteristics of C-actin like structures with an elongated MAD, leading to preferential and cooperative binding of cofilin.g
Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability
Authors: Abbott Keene L. , Ali Ahmed , Reinfeld Bradley I. , Deik Amy , Subudhi Sonu , Landis Madelyn D. , Hongo Rachel A. , Young Kirsten L. , Kunchok Tenzin , Nabel Christopher S. , Crowder Kayla D. , Kent Johnathan R. , Madariaga Maria Lucia L. , Jain Rakesh K. , Beckermann Kathryn E. , Lewis Caroline A. , Clish Clary B. , Muir Alexander , Rathmell W. Kimryn , Rathmell Jeffrey C. , Vander Heiden Matthew G.
Published: May 2024

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.
Expression of most retrotransposons in human blood correlates with biological aging
Authors: Tsai Yi-Ting , Seymen Nogayhan , Thompson I Richard , Zou Xinchen , Mumtaz Warisha , Gerlevik Sila , Mufti Ghulam J , Karimi Mohammad M
Published: May 2024

Retrotransposons (RTEs) have been postulated to reactivate with age and contribute to aging through activated innate immune response and inflammation. Here, we analyzed the relationship between RTE expression and aging using published transcriptomic and methylomic datasets of human blood. Despite no observed correlation between RTE activity and chronological age, the expression of most RTE classes and families except short interspersed nuclear elements (SINEs) correlated with biological age-associated gene signature scores. Strikingly, we found that the expression of SINEs was linked to upregulated DNA repair pathways in multiple cohorts. We also observed DNA hypomethylation with aging and the significant increase in RTE expression level in hypomethylated RTEs except for SINEs. Additionally, our single-cell transcriptomic analysis suggested a role for plasma cells in aging mediated by RTEs. Altogether, our multi-omics analysis of large human cohorts highlights the role of RTEs in biological aging and suggests possible mechanisms and cell populations for future investigations.
Expression of Most Retrotransposons in Human Blood Correlates with Biological Aging
Authors: Tsai Yi-Ting , Seymen Nogayhan , Thompson Ian R. , Zou Xinchen , Mumtaz Warisha , Gerlevik Sila , Mufti Ghulam J. , Karimi Mohammad M.
Published: May 2024

Retrotransposons (RTEs) have been postulated to reactivate with age and contribute to aging through activated innate immune response and inflammation. Here, we systematically analyzed the relationship between RTEs expression and aging using published transcriptomic and methylomic datasets of human blood. Despite no observed correlation between RTEs activity and chronological age, most RTE classes and families except short interspersed nuclear elements (SINEs) correlate with age-associated gene signature scores. Strikingly, we found that the expression of SINEs is linked to upregulated DNA repair pathways in multiple cohorts. DNA hypomethylation with aging was observed across RTE classes and associated with increased RTEs expression in most RTE classes and families except SINEs. Additionally, our single-cell transcriptomic analysis suggests a role for plasma cells in aging mediated by RTEs. Altogether, our multi-omics analysis of large human cohorts highlights the role of RTEs in biological aging and suggests possible mechanisms and cell populations for future investigations.
Implicit motor adaptation patterns in a redundant motor task manipulating a stick with both hands
Authors: Kobayashi Toshiki , Nozaki Daichi
Published: May 2024

The remarkable ability of the motor system to adapt to novel environments has traditionally been investigated using kinematically non-redundant tasks, such as planar reaching movements. This limitation prevents the study of how the motor system achieves adaptation by altering the movement patterns of our redundant body. To address this issue, we developed a redundant motor task in which participants reached for targets with the tip of a virtual stick held with both hands. Despite the redundancy of the task, participants consistently employed a stereotypical strategy of flexibly changing the tilt angle of the stick depending on the direction of tip movement. Thus, this baseline relationship between tip-movement direction and stick-tilt angle constrained both the physical and visual movement patterns of the redundant system. Our task allowed us to systematically investigate how the motor system implicitly changed both the tip-movement direction and the stick-tilt angle in response to imposed visual perturbations. Both types of perturbations, whether directly affecting the task (tip-movement direction) or not (stick-tilt angle around the tip), drove adaptation, and the patterns of implicit adaptation were guided by the baseline relationship. Consequently, tip-movement adaptation was associated with changes in stick-tilt angle, and intriguingly, even seemingly ignorable stick-tilt perturbations significantly influenced tip-movement adaptation, leading to tip-movement direction errors. These findings provide a new understanding that the baseline relationship plays a crucial role not only in how the motor system controls movement of the redundant system, but also in how it implicitly adapts to modify movement patterns.
Additional feedforward mechanism of Parkin activation via binding of phospho-UBL and RING0 in trans
Authors: Lenka Dipti , Dahe Shakti , Antico Odetta , Sahoo Pritiranjan , Prescott Alan R. , Muqit Miratul M. K. , Kumar Atul
Published: May 2024

Loss of function Parkin mutations lead to early-onset of Parkinson’s disease. Parkin is an auto-inhibited ubiquitin E3 ligase activated by phosphorylation of its ubiquitin-like (Ubl) domain and ubiquitin by PINK1. Herein, we show a competitive binding mode of the phospho-Ubl and RING2 domains on the RING0 domain, which regulates Parkin activity. We show that phosphorylated Parkin can directly complex with unmodified Parkin, leading to the activation of autoinhibited Parkin in trans. Furthermore, we show that the activator element (ACT) of Parkin is required to maintain the enzyme’s kinetics, and the removal of ACT slows the enzyme catalysis. We also demonstrate that ACT can activate Parkin in trans but less efficiently than when present in the cis molecule. Furthermore, crystal structure reveals a new donor ubiquitin binding pocket that plays a crucial role in function. This study provides new molecular insights into Parkin activation, which may aid the development of Parkin activators as a therapeutic strategy against Parkinson’s.
Feature sequence-based genome mining uncovers the hidden diversity of bacterial siderophore pathways
Authors: Gu Shaohua , Shao Yuanzhe , Rehm Karoline , Bigler Laurent , Zhang Di , He Ruolin , Xu Ruichen , Shao Jiqi , Jousset Alexandre , Friman Ville-Petri , Bian Xiaoying , Wei Zhong , Kümmerli Rolf , Li Zhiyuan
Published: May 2024

Microbial secondary metabolites are a rich source for pharmaceutical discoveries and play crucial ecological functions. While tools exist to identify secondary metabolite clusters in genomes, precise sequence-to-function mapping remains challenging because neither function nor substrate specificity of biosynthesis enzymes can accurately be predicted. Here, we developed a knowledge-guided bioinformatic pipeline to solve these issues. We analyzed 1928 genomes of Pseudomonas bacteria and focused on iron-scavenging pyoverdines as model metabolites. Our pipeline predicted 188 chemically different pyoverdines with nearly 100% structural accuracy and the presence of 94 distinct receptor groups required for the uptake of iron-loaded pyoverdines. Our pipeline unveils an enormous yet overlooked diversity of siderophores (151 new structures) and receptors (91 new groups). Our approach, combining feature sequence with phylogenetic approaches, is extendable to other metabolites and microbial genera, and thus emerges as powerful tool to reconstruct bacterial secondary metabolism pathways based on sequence data.
The actomyosin system is essential for the integrity of the endosomal system in bloodstream form Trypanosoma brucei
Authors: Link Fabian , Jung Sisco , Malzer Xenia , Zierhut Felix , Konle Antonia , Borges Alyssa , Batters Christopher , Weiland Monika , Poellmann Mara , Nguyen An Binh , Kullmann Johannes , Veigel Claudia , Engstler Markus , Morriswood Brooke
Published: May 2024

The actin cytoskeleton is a ubiquitous feature of eukaryotic cells, yet its complexity varies across different taxa. In the parasitic protist Trypanosoma brucei, a rudimentary actomyosin system consisting of one actin gene and two myosin genes has been retained despite significant investment in the microtubule cytoskeleton. The functions of this highly simplified actomyosin system remain unclear, but appear to centre on the endomembrane system. Here, advanced light and electron microscopy imaging techniques, together with biochemical and biophysical assays, were used to explore the relationship between the actomyosin and endomembrane systems. The class I myosin (TbMyo1) had a large cytosolic pool and its ability to translocate actin filaments in vitro was shown here for the first time. TbMyo1 exhibited strong association with the endosomal system and was additionally found on glycosomes. At the endosomal membranes, TbMyo1 colocalised with markers for early and late endosomes (TbRab5A and TbRab7, respectively), but not with the marker associated with recycling endosomes (TbRab11). Actin and myosin were simultaneously visualised for the first time in trypanosomes using an anti-actin chromobody. Disruption of the actomyosin system using the actin-depolymerising drug latrunculin A resulted in a delocalisation of both the actin chromobody signal and an endosomal marker, and was accompanied by a specific loss of endosomal structure. This suggests that the actomyosin system is required for maintaining endosomal integrity in T. brucei.
TMEM16 and OSCA/TMEM63 proteins share a conserved potential to permeate ions and phospholipids
Authors: Lowry Augustus J , Liang Pengfei , Song Mo , Wan Yuichun , Pei Zhen-Ming , Yang Huanghe , Zhang Yang
Published: May 2024

The calcium-activated TMEM16 proteins and the mechanosensitive/osmolarity-activated OSCA/TMEM63 proteins belong to the Transmembrane Channel/Scramblase (TCS) superfamily. Within the superfamily, OSCA/TMEM63 proteins, as well as TMEM16A and TMEM16B, are thought to function solely as ion channels. However, most TMEM16 members, including TMEM16F, maintain an additional function as scramblases, rapidly exchanging phospholipids between leaflets of the membrane. Although recent studies have advanced our understanding of TCS structure–function relationships, the molecular determinants of TCS ion and lipid permeation remain unclear. Here, we show that single mutations along the transmembrane helix (TM) 4/6 interface allow non-scrambling TCS members to permeate phospholipids. In particular, this study highlights the key role of TM 4 in controlling TCS ion and lipid permeation and offers novel insights into the evolution of the TCS superfamily, suggesting that, like TMEM16s, the OSCA/TMEM63 family maintains a conserved potential to permeate ions and phospholipids.
TMEM16 and TMEM63/OSCA proteins share a conserved potential to permeate ions and phospholipids
Authors: Lowry Augustus J. , Liang Pengfei , Serena Wan Y.C. , Pei Zhen-Ming , Yang Huanghe , Zhang Yang
Published: May 2024

The calcium-activated TMEM16 proteins and the mechanosensitive/osmolarity-activated OSCA/TMEM63 proteins belong to the Transmembrane Channel/Scramblase (TCS) superfamily. Within the superfamily, OSCA/TMEM63 proteins, as well as TMEM16A and TMEM16B, likely function solely as ion channels. However, the remaining TMEM16 members, including TMEM16F, maintain an additional function as scramblases, rapidly exchanging phospholipids between leaflets of the membrane. Although recent studies have advanced our understanding of TCS structure-function relationships, the molecular determinants of TCS ion and lipid permeation remain unclear. Here we show that single lysine mutations in transmembrane helix (TM) 4 allow non-scrambling TCS members to permeate phospholipids. This study highlights the key role of TM 4 in controlling TCS ion and lipid permeation and offers novel insights into the evolution of the TCS superfamily, suggesting that, like TMEM16s, the OSCA/TMEM63 family maintains a conserved potential to permeate ions and phospholipids.
JAK-STAT pathway activation compromises nephrocyte function in a Drosophila high-fat diet model of chronic kidney disease
Authors: Zhao Yunpo , Duan Jianli , van de Leemput Joyce , Han Zhe
Published: May 2024

Chronic kidney disease is a major healthy issue and is gaining prevalence. Using a
Drosophila
model for chronic kidney disease we show that a high-fat diet (HFD) disrupts the slit diaphragm filtration structure in nephrocytes, the fly functional equivalent of mammalian podocytes. The structural disruption resulted in reduced filtration function in the affected nephrocytes. We demonstrate that a HFD activates the JAK-STAT pathway in nephrocytes, which has previously been linked to diabetic kidney disease. JAK-STAT activation was initiated by increased expression and release of the adipokine, Upd2, from the fat body. This leptin-like hormone is a known ligand of JAK-STAT. Both genetic and pharmacological inhibition of JAK-STAT restored nephrocyte HFD-associated dysfunction. Altogether, our study reveals the importance of the JAK-STAT signaling pathway in the adipose tissue−nephrocyte axis and its contribution to HFD-associated nephropathy. These findings open new avenues for intervention in treating diabetic nephropathy and chronic kidney disease.
Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex
Authors: Francavilla Ruggiero , Chattopadhyaya Bidisha , Kamda Jorelle Linda Damo , Jadhav Vidya , Kourrich Saïd , Michaud Jacques L , Di Cristo Graziella
Published: May 2024

SYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical excitatory neurons development; recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, is unknown. Here, we examined whether, and how, embryonic-onset
Syngap1
haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adult primary auditory cortex (A1). We found that
Syngap1
haploinsufficiency affects the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons in adult Layer IV A1, whilst Somatostatin (SST)+ interneurons were mostly resistant to
Syngap1
haploinsufficiency. Further, the AMPA component of thalamocortical evoked-EPSC was decreased in PV+ cells from mutant mice. Finally, we found that the selective blocking of voltage-gated D-type K+ currents was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest that
Syngap1
plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult A1, which could in turn contribute to the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.
The microbiome interacts with the circadian clock and dietary composition to regulate metabolite cycling in the gut
Authors: Zhang Yueliang , Li Yongjun , Noya Sara B. , Sehgal Amita
Published: May 2024

The gut microbiome plays a key role in the maintenance of host metabolic homeostasis and health. Most metabolic processes cycle with a 24 hour rhythm, but the extent to which the microbiome influences metabolite cycling under different conditions, such as variations in dietary composition, is largely unknown. In this study, we utilized high temporal resolution metabolite profiling of the
Drosophila
gut to investigate the role of the microbiome in metabolite cycling. Although the microbiome was previously shown to dampen transcript cycling in the gut, we find that in contrast it increases the number of oscillating metabolites. Interestingly, effects of microbiome loss on metabolite cycling are reduced in a time restricted feeding (TF) paradigm. Conversely, promotion of cycling by TF is reduced in microbiome-containing flies, suggesting that TF compensates for deficits in the microbiome to some extent. In a clock mutant background, loss of the microbiome increases cycling of some classes of metabolites but profoundly affects phase of all of them, indicating the host clock modulates effects of the microbiome on cycling and maintains phase in the face of microbial changes. Lastly, a high protein diet increases microbiome-dependent metabolite cycling but a high sugar diet suppresses such cycling while altering phase. Indeed, we observe that amino acid metabolism is the metabolic pathway most affected by changes in the gut microbiome, the circadian clock and timed feeding. Collectively, our observations highlight a key role of the gut microbiome in contributing to host metabolite cycling, and reveal a complex interaction with internal and external factors.
A direct experimental test of Ohno’s hypothesis
Authors: Mihajlovic Ljiljana , Iyengar Bharat Ravi , Baier Florian , Barbier Içvara , Iwaszkiewicz Justyna , Zoete Vincent , Wagner Andreas , Schaerli Yolanda
Published: May 2024

Gene duplication drives evolution by providing raw material for proteins with novel functions. The oldest and historically most influential hypothesis about the evolutionary fate and potential of duplicated genes has been proposed by Susumu Ohno in 1970. This hypothesis essentially posits that gene duplication can help genes tolerate new mutations and thus facilitates the evolution of new phenotypes Competing hypotheses argue that deleterious mutations will usually inactivate gene duplicates too rapidly for Ohno’s hypothesis to work. Here, we provide a first direct experimental test of Ohno’s hypothesis. Specifically, we evolved one or two genes encoding a fluorescent protein in
Escherichia coli
through multiple rounds of mutagenesis and selection. We then analyzed the genotypic and phenotypic evolutionary dynamics of the evolving populations through high-throughput DNA sequencing, biochemical assays, and engineering of selected variants. In support of Ohno’s hypothesis, populations carrying two gene copies displayed higher mutational robustness than those carrying a single gene copy. As a consequence, the double-copy populations experienced relaxed purifying selection, evolved higher phenotypic and genetic diversity, carried more mutations and accumulated combinations of key beneficial mutations earlier. However, their phenotypic evolution was not accelerated, possibly because one gene copy rapidly became inactivated by deleterious mutations. Our work provides an experimental platform to test models of evolution by gene duplication, and it supports alternatives to Ohno’s hypothesis.
CTFFIND5 provides improved insight into quality, tilt, and thickness of TEM samples
Authors: Elferich Johannes , Kong Lingli , Zottig Ximena , Grigorieff Nikolaus
Published: May 2024

Images taken by transmission electron microscopes are usually affected by lens aberrations and image defocus, among other factors. These distortions can be modeled in reciprocal space using the contrast transfer function (CTF). Accurate estimation and correction of the CTF is essential for restoring the high-resolution signal in cryogenic electron microscopy (cryoEM). Previously, we described the implementation of algorithms for this task in the cisTEM software package (Grant et al., 2018). Here we show that taking sample characteristics, such as thickness and tilt, into account can improve CTF estimation. This is particularly important when imaging cellular samples, where measurement of sample thickness and geometry derived from accurate modeling of the Thon ring pattern helps judging the quality of the sample. This improved CTF estimation has been implemented in CTFFIND5, a new version of the cisTEM program CTFFIND. We evaluated the accuracy of these estimates using images of tilted aquaporin crystals and eukaryotic cells thinned by focused ion beam milling. We estimate that with micrographs of sufficient quality CTFFIND5 can measure sample tilt with an accuracy of 3° and sample thickness with an accuracy of 5 nm.
CTFFIND5 provides improved insight into quality, tilt and thickness of TEM samples
Authors: Elferich Johannes , Kong Lingli , Zottig Ximena , Grigorieff Nikolaus
Published: May 2024

Images taken by transmission electron microscopes are usually affected by lens aberrations and image defocus, among other factors. These distortions can be modeled in reciprocal space using the contrast transfer function (CTF). Accurate estimation and correction of the CTF is essential for restoring the high-resolution signal in an image and has been one of the key aspects of the “resolution revolution” in cryogenic electron microscopy (cryoEM). Previously, we described the implementation of algorithms for this task in the
cis
TEM software package (Grant
et al
., 2018). Here we show that taking sample characteristics, such as thickness and tilt, into account can improve CTF estimation. This is particularly important when imaging cellular samples, where measurement of sample thickness and geometry derived from accurate modeling of the Thon ring pattern helps judging the quality of the sample. This improved CTF estimation has been implemented in CTFFIND5, a new version of the
cis
TEM program CTFFIND. We evaluated the accuracy of these estimates using images of tilted aquaporin crystals and eukaryotic cells thinned by focused ion beam milling. We estimate that with micrographs of sufficient quality CTFFIND5 can measure sample tilt with an accuracy of 3° and sample thickness with an accuracy of 5 nm.
Turnaround Time and Barriers in Treatment of Newly Diagnosed Cancer Patients: A Research Protocol
Authors: Pal Harshali Himmat , Pankwase Jitesh
Published: May 2024

Introduction: The journey from cancer diagnosis to treatment initiation is a critical period in a patient’s life. Timely treatment is often associated with better outcomes, yet numerous challenges and barriers can impede the process. Need of the Study: This research will hold significant implications for healthcare providers, policymakers, and, most importantly, cancer patients. By uncovering the obstacles and delays in cancer treatment, this protocol will provide the information needed to streamline the process, potentially leading to earlier interventions, improved patient experiences, and enhanced treatment outcomes. Aim: To comprehensively understand and address the factors influencing the turnaround time and the barriers encountered by cancer patients in accessing treatment. Materials and Methods: This study will employ a mixed-methods research design, combining both quantitative and qualitative approaches. It will encompass 89 patients at Siddharth Gupta Memorial Cancer Hospital (SGMCH), situated in Sawangi (Meghe), Wardha, Maharashtra, India. The estimated duration for this study is from December 2023 to October 2024. Factors influencing the turnaround time and the barriers encountered by cancer patients in accessing treatment will be evaluated. Primary data will be collected directly from newly diagnosed cancer patients using structured surveys/questionnaires. Secondary data sources include medical records, hospital, and healthcare system data. Statistical analysis will be done using Chi-square for qualitative measurement, Independent t-test, and Analysis of Variance (ANOVA) for the quantitative measurement. A p-value of <0.05 will be considered significant.
Radioprotection Compliance Rules Study in Dakar's Hospitals, Senegal
Authors: Ndoye EL Hadji Oumar , Diop Al Housseynou , Badiane Serigne Moussa
Published: May 2024

This work aims to promote greater safety in the use of X-rays in our hospitals. The effects of radiation have continued to arouse keen interest mixed with concern. Due to their ionizing power, these radiations lead to cascades of reactions in the body causing genetic mutations, cancer phenomena and even cell death, among others. We thus distinguish between threshold effects (deterministic) and random effects (stochastic). This work is a quantitative study based on a questionnaire intended for majors in radiology services in Dakar.
 This study was carried out in the Dakar region over a period of two (02) months from July 15, 2022 to September 15, 2022. By analyzing the results, we’ve noted that standard radiography and computed tomography are the two most frequently performed radiological examinations in all the services studied with respectively 60.9 o/o and 30.4 o/o of the radiological examinations carried out daily. It is appeared that radiation protection in radiology departments has limits. It is therefore urgent to overcome them and to encourage the development of radiation protection in parallel with the evolution of the technical platform. Compliance with the rules and regulations constitutes a requirement for the protection of people exposed to ionizing radiation. The national radiation protection authority should take steps to harmonize the control protocols for radiology department equipment for optimal monitoring of radiation protection measures. It would be important to install a maintenance unit in each health structure with a radiology department which would be under the responsibility of the national authority responsible for radiation protection.
Sanctions are provided for in the event of breaches of laws and regulations by the Senegalese authorities.
Applications of Fractional Time Delayed Grey Model in Primary Energy Consumption Prediction
Authors: He Qingping , Hao Yiwu
Published: May 2024

The prediction of total energy consumption is crucial across various domains including the economy, environment, market, and geopolitics. Accurate forecasts can guide policy-making, investment decisions, and international strategies, contributing to sustainable development and energy security. Fractional models have been proven to better capture the long-term memory effects and complex dynamic characteristics of systems, with time delay playing a crucial role in capturing dynamic behaviors. Such models enhance the accuracy and reliability of predicting future trends and behaviors. For the prediction of primary energy consumption in South and Central America, the Middle East, and Africa, this study opts for the existing fractional time delayed grey model, optimizing the fractional order using the particle swarm optimization algorithm. Experimental results demonstrate that in most cases, the predictive capability of the fractional time delayed grey model surpasses that of other grey models. This indicates the effectiveness and reliability of the model in forecasting energy consumption, providing valuable references and foundations for decision-making in relevant fields.
Relations of proactive and reactive dimensions of aggression to overt and covert narcissism in nonclinical adolescents
Authors: Fossati Andrea , Borroni Serena , Eisenberg Nancy , Maffei Cesare
Published: November 2009

In recent years, there has been increasing acknowledgment of the multidimensionality of narcissism and that different types of narcissism may relate differently to other domains of functioning. Similarly, aggression—a frequently discussed correlate of narcissism—is a heterogeneous construct. In this study, the relations of proactive and reactive aggression with overt and covert manifestations of narcissism were examined in a sample of 674 Italian high school students (mean age=15.5 years, SD=2.1 years). Overt narcissism was positively related to both proactive and reactive subtypes of aggression, whereas covert narcissism related only to reactive aggression. Vanity, Authority, Exhibitionism, and Exploitativeness were the components of overt narcissism related to Proactive Aggression (all remained unique correlates when controlling for Reactive Aggression), whereas Reactive Aggression was associated with the Exhibitionism, Superiority, and Entitlement subscales (only the latter was uniquely related when controlling for Proactive Aggression). Aggr. Behav. 36:21–27, 2010. © 2009 Wiley‐Liss, Inc.
Evaluating Carrier Accumulation in Degraded Bulk Heterojunction Organic Solar Cells by a Thermally Stimulated Current Technique
Authors: Kawano Kenji , Adachi Chihaya
Published: November 2009

Here, the initial photo‐degradation of encapsulated P3HT:PCBM bulk heterojunction organic solar cells is investigated. The degraded device is recovered by thermal annealing treatment. Thermally stimulated current measurements reveal that the cause of photo‐degradation is carrier accumulation and that the degraded organic solar cell has two broad trap levels, of 0.71 and 0.81 eV. These traps are independent of the thickness of the photoactive layers, the mixing ratio of the photoactive materials and the cathode materials. In addition, it is confirmed that there is a close relationship between the degree of degradation and the amount of accumulated charge carriers.
Gold‐ and Silver‐Catalyzed Intramolecular Hydroamination of Terminal Alkynes: Water‐Triggered Chemo‐ and Regioselective Synthesis of Fused Tricyclic Xanthines
Authors: Ye Deju , Zhang Xu , Zhou Yu , Zhang Dengyou , Zhang Lei , Wang Hengshuai , Jiang Hualiang , Liu Hong
Published: November 2009

A simple, convenient and green synthetic approach to diverse fused tricyclic xanthines has been developed via gold(I) complex‐catalyzed intramolecular hydroamination or silver(I)‐catalyzed isomerization‐hydroamination of terminal alkynes under microwave irradiation in water. The first synthesis of N9‐annelated xanthines has also been reported.