bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-148a deletion protects from bone loss in physiological and estrogen-deficient mice by targeting NRP1
Authors: Pan Bin , Zheng Lin , Liu Shijie , Fang Jiawei , Lou Chao , Hu Xingyu , Ye Lin , Lai Hehuan , Gao Jiawei , Zhang Yejin , Ni Kainan , He Dengwei
Published: November 2022

Bone metabolic homeostasis is largely dependent on the dynamic balance between osteoblasts and osteoclasts. MicroRNAs (miRNAs) play critical roles in regulating bone metabolism. In this study, we explored the role of a new miRNA (miR-148a) in osteoporosis. We compared the bone phenotype between miR-148a knockout (KO) mice and the wild-type (WT) littermates. We found miR-148a KO mice exhibited an increased bone mass phenotype and decreased osteoclastogenesis compared to the WT group. In vitro, miR-148a overexpression promoted osteoclastogenesis and bone resorption function. Mechanistically, NRP1 was identified as a novel direct target of miR-148a, and NRP1 silencing reversed the effect of miR-148a knockout. In OVX and calvarial osteolysis models, miR-148a KO protects mice against excessive bone resorption, while miR-148a agomiR/AAV-shNRP1 accelerates pathologic bone loss. Finally, the miR-148a level was found to be positively correlated with β-CTX in postmenopausal osteoporosis (PMOP) serum specimens. In summary, our findings revealed that miR-148a genetic deletion ameliorates bone loss under physiological and pathological conditions by targeting NRP1. In osteoclast-related bone metabolic diseases such as PMOP, miR-148a may be an attractive therapeutic target in the future.
Estimation of stillbirths attributable to ambient fine particles in 137 countries
Authors: Xue Tao , Tong Mingkun , Li Jiajianghui , Wang Ruohan , Guan Tianjia , Li Jiwei , Li Pengfei , Liu Hengyi , Lu Hong , Li Yanshun , Zhu Tong
Published: November 2022

Gestational exposure to ambient fine particles (PM2.5) increases the risk of stillbirth, but the related disease burden is unknown, particularly in low- and middle-income countries (LMICs). We combine state-of-the-art estimates on stillbirths, and multiple exposure–response functions obtained from previous meta-analyses or derived by a self-matched case-control study in 54 LMICs. 13,870 stillbirths and 32,449 livebirths are extracted from 113 geocoded surveys from the Demographic and Health Surveys. Each stillbirth is compared to livebirth(s) of the same mother using a conditional logit regression. We find that 10-µg/m3 increase of PM2.5 is associated with an 11.0% (95% confidence interval [CI] 6.4, 15.7) increase in the risk of stillbirth, and the association is significantly enhanced by maternal age. Based on age-specific nonlinear PM2.5–stillbirth curves, we evaluate the PM2.5-related stillbirths in 137 countries. In 2015, of 2.09 (95% CI: 1.98, 2.20) million stillbirths, 0.83 (0.54, 1.08) million or 39.7% (26.1, 50.8) are attributable to PM2.5 exposure exceeding the reference level of 10 μg/m3. In LMICs, preventing pregnant women from being exposed to PM2.5 can improve maternal health.
A population-based serological study of post-COVID syndrome prevalence and risk factors in children and adolescents
Authors: Dumont Roxane , Richard Viviane , Lorthe Elsa , Loizeau Andrea , Pennacchio Francesco , Zaballa María-Eugenia , Baysson Hélène , Nehme Mayssam , Perrin Anne , L’Huillier Arnaud G. , Kaiser Laurent , Barbe Rémy P. , Posfay-Barbe Klara M. , Stringhini Silvia ,   SEROCoV-KIDS study group, Amrein Deborah , Azman Andrew S. , Bal Antoine , Balavoine Michael , Berthelot Julie , Bleich Patrick , Boehm Livia , Bryand Gaëlle , Bucolli Viola , Collombet Prune , Cudet Alain , Davidovic Vladimir , de Mestral Vargas Carlos , D’Ippolito Paola , Dubos Richard , Eckerle Isabella , Favier Marion , El Merjani Nacira , Francioli Natalie , Graindorge Clément , Harnal Séverine , Hurst Samia , Kherad Omar , Lamour Julien , Lescuyer Pierre , Martinez Chantal , Mermet Stéphanie , Noël Natacha , Perez-Saez Javier , Pittet Didier , Portier Jane , Poulain Géraldine , Pugin Caroline , Pullen Nick , Rinaldi Frederic , Rizzo Jessica , Rochat Deborah , Sahyoun Cyril , Sakvarelidze Irine , Samir Khadija , Ramirez Hugo Alejandro Santa , Schrempft Stephanie , Semaani Claire , Testini Stéphanie , Tisserand Yvain , Rivas Deborah Urrutia , Verolet Charlotte , Villers Jennifer , Violot Guillemette , Vuilleumier Nicolas , Yerly Sabine , Zavlanou Christina , Guessous Idris
Published: November 2022

Post-COVID syndrome remains poorly studied in children and adolescents. Here, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status. Children from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), aged 6 months to 17 years, were tested for anti-SARS-CoV-2 N antibodies (December 2021-February 2022) and parents filled in a questionnaire on persistent symptoms in their children (lasting over 12 weeks) compatible with post-COVID. Of 1034 children tested, 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). Stratifying per age group, only adolescents displayed a substantial risk of having post-COVID symptoms (ΔaPrev = 8.3%, 95%CI: 3.5;13.5). Identified risk factors for post-COVID syndrome were older age, having a lower socioeconomic status and suffering from chronic health conditions, especially asthma. Our findings show that a significant proportion of seropositive children, particularly adolescents, experienced persistent COVID symptoms. While there is a need for further investigations, growing evidence of pediatric post-COVID urges early screening and primary care management.
Shedding light on the base-pair opening dynamics of nucleic acids in living human cells
Authors: Yamaoki Yudai , Nagata Takashi , Kondo Keiko , Sakamoto Tomoki , Takami Shohei , Katahira Masato
Published: November 2022

Base-pair opening is a fundamental property of nucleic acids that plays important roles in biological functions. However, studying the base-pair opening dynamics inside living cells has remained challenging. Here, to determine the base-pair opening kinetics inside living human cells, the exchange rate constant ($${k}_{{{{{{\rm{ex}}}}}}}$$

k

ex

) of the imino proton with the proton of solvent water involved in hairpin and G-quadruplex (GQ) structures is determined by the in-cell NMR technique. It is deduced on determination of $${k}_{{{{{{\rm{ex}}}}}}}$$

k

ex

values that at least some G-C base pairs of the hairpin structure and all G-G base-pairs of the GQ structure open more frequently in living human cells than in vitro. It is suggested that interactions with endogenous proteins could be responsible for the increase in frequency of base-pair opening. Our studies demonstrate a difference in dynamics of nucleic acids between in-cell and in vitro conditions.
Genetically personalised organ-specific metabolic models in health and disease
Authors: Foguet Carles , Xu Yu , Ritchie Scott C. , Lambert Samuel A. , Persyn Elodie , Nath Artika P. , Davenport Emma E. , Roberts David J. , Paul Dirk S. , Di Angelantonio Emanuele , Danesh John , Butterworth Adam S. , Yau Christopher , Inouye Michael
Published: November 2022

Understanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 individuals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4312 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 92 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases.
EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis
Authors: Verma Ayushi , Singh Akhilesh , Singh Manish Pratap , Nengroo Mushtaq Ahmad , Saini Krishan Kumar , Satrusal Saumya Ranjan , Khan Muqtada Ali , Chaturvedi Priyank , Sinha Abhipsa , Meena Sanjeev , Singh Anup Kumar , Datta Dipak
Published: November 2022

Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC’s poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor SP1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.
Lamellar carbon nitride membrane for enhanced ion sieving and water desalination
Authors: Wang Yang , Lian Tingting , Tarakina Nadezda V. , Yuan Jiayin , Antonietti Markus
Published: November 2022

Membrane-based water treatment processes offer possibility to alleviate the water scarcity dilemma in energy-efficient and sustainable ways, this has been exemplified in filtration membranes assembled from two-dimensional (2D) materials for water desalination purposes. Most representatives however tend to swell or disintegrate in a hydrated state, making precise ionic or molecular sieving a tough challenge. Here we report that the chemically robust 2D carbon nitride can be activated using aluminum polycations as pillars to modulate the interlayer spacing of the conjugated framework, the noncovalent interaction concomitantly affords a well-interlinked lamellar structure, to be carefully distinguished from random stacking patterns in conventional carbon nitride membranes. The conformally packed membrane is characterized by adaptive subnanochannel and structure integrity to allow excellent swelling resistance, and breaks permeability-selectivity trade-off limit in forward osmosis due to progressively regulated transport passage, achieving high salt rejection (>99.5%) and water flux (6 L m−2 h−1), along with tunable permeation behavior that enables water gating in acidic and alkaline environments. These findings position carbon nitride a rising building block to functionally expand the 2D membrane library for applications in water desalination and purification scenarios.
HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation
Authors: Oberoi Jasmeen , Guiu Xavi Aran , Outwin Emily A. , Schellenberger Pascale , Roumeliotis Theodoros I. , Choudhary Jyoti S. , Pearl Laurence H.
Published: November 2022

Activation of client protein kinases by the HSP90 molecular chaperone system is affected by phosphorylation at multiple sites on HSP90, the kinase-specific co-chaperone CDC37, and the kinase client itself. Removal of regulatory phosphorylation from client kinases and their release from the HSP90-CDC37 system depends on the Ser/Thr phosphatase PP5, which associates with HSP90 via its N-terminal TPR domain. Here, we present the cryoEM structure of the oncogenic protein kinase client BRAFV600E bound to HSP90-CDC37, showing how the V600E mutation favours BRAF association with HSP90-CDC37. Structures of HSP90-CDC37-BRAFV600E complexes with PP5 in autoinhibited and activated conformations, together with proteomic analysis of its phosphatase activity on BRAFV600E and CRAF, reveal how PP5 is activated by recruitment to HSP90 complexes. PP5 comprehensively dephosphorylates client proteins, removing interaction sites for regulatory partners such as 14-3-3 proteins and thus performing a ‘factory reset’ of the kinase prior to release.
IL6 supports long-term expansion of hepatocytes in vitro
Authors: Guo Ren , Jiang Mengmeng , Wang Gang , Li Bing , Jia Xiaohui , Ai Yan , Chen Shanshan , Tang Peilan , Liu Aijie , Yuan Qianting , Xie Xin
Published: November 2022

Hepatocytes are very difficult to expand in vitro. A few studies have demonstrated that chemical cocktails with growth factors or Wnt ligands can support long-term expansion of hepatocytes via dedifferentiation. However, the culture conditions are complex, and clonal expansion of hepatic progenitors with full differentiation capacity are rarely reported. Here, we discover IL6, combined with EGF and HGF, promotes long-term expansion (>30 passages in ~150 days with theoretical expansion of ~1035 times) of primary mouse hepatocytes in vitro in simple 2D culture, by converting hepatocytes into induced hepatic progenitor cells (iHPCs), which maintain the capacity of differentiation into hepatocytes. IL6 also supports the establishment of single hepatocyte-derived iHPC clones. The summation of the downstream STAT3, ERK and AKT pathways induces a number of transcription factors which support rapid growth. This physiological and simple way may provide ideas for culturing previously difficult-to-culture cell types and support their future applications.
Ultrastrong MXene films via the synergy of intercalating small flakes and interfacial bridging
Authors: Wan Sijie , Li Xiang , Chen Ying , Liu Nana , Wang Shijun , Du Yi , Xu Zhiping , Deng Xuliang , Dou Shixue , Jiang Lei , Cheng Qunfeng
Published: November 2022

Titanium carbide MXene combines high mechanical and electrical properties and low infrared emissivity, making it of interest for flexible electromagnetic interference (EMI) shielding and thermal camouflage film materials. Conventional wisdom holds that large MXene is the preferable building block to assemble high-performance films. However, the voids in the films comprising large MXene degrade their properties. Although traditional crosslinking strategies can diminish the voids, the electron transport between MXene flakes is usually disrupted by the insulating polymer bonding agents, reducing the electrical conductivity. Here we demonstrate a sequential densification strategy to synergistically remove the voids between MXene flakes while strengthening the interlayer electron transport. Small MXene flakes were first intercalated to fill the voids between multilayer large flakes, followed by interfacial bridging of calcium ions and borate ions to eliminate the remaining voids, including those between monolayer flakes. The obtained MXene films are compact and exhibit high tensile strength (739 MPa), Young’s modulus (72.4 GPa), electrical conductivity (10,336 S cm−1), and EMI shielding capacity (71,801 dB cm2 g−1), as well as excellent oxidation resistance and thermal camouflage performance. The presented strategy provides an avenue for the high-performance assembly of other two-dimensional flakes.
Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy
Authors: Gharbi Severine Isabelle , Pelletier Laura A. , Espada Alfonso , Gutiérrez Jesus , Sanfeliciano Sonia Maria Gutiérrez , Rauch Charles T. , Ganado Maria Patricia , Baquero Carmen , Zapatero Elisabet , Zhang Aiping , Benach Jordi , Russell Anna-Maria , Cano Leticia , Gomez Sandra , Broughton Howard , Pulliam Nicholas , Perez Carmen Maria , Torres Raquel , Debets Marjoke F. , de Dios Alfonso , Puig Oscar , Hilgers Mark T. , Lallena Maria Jose
Published: November 2022

Despite the biological and therapeutic relevance of CDK4/6 for the treatment of HR+, HER2- advanced breast cancer, the detailed mode of action of CDK4/6 inhibitors is not completely understood. Of particular interest, phosphorylation of CDK4 at T172 (pT172) is critical for generating the active conformation, yet no such crystal structure has been reported to date. We describe here the x-ray structure of active CDK4-cyclin D3 bound to the CDK4/6 inhibitor abemaciclib and discuss the key aspects of the catalytically-competent complex. Furthermore, the effect of CDK4/6 inhibitors on CDK4 T172 phosphorylation has not been explored, despite its role as a potential biomarker of CDK4/6 inhibitor response. We show mechanistically that CDK4/6i stabilize primed (pT172) CDK4-cyclin D complex and selectively displace p21 in responsive tumor cells. Stabilization of active CDK4-cyclin D1 complex can lead to pathway reactivation following alternate dosing regimen. Consequently, sustained binding of abemaciclib to CDK4 leads to potent cell cycle inhibition in breast cancer cell lines and prevents rebound activation of downstream signaling. Overall, our study provides key insights demonstrating that prolonged treatment with CDK4/6 inhibitors and composition of the CDK4/6-cyclin D complex are both critical determinants of abemaciclib efficacy, with implications for this class of anticancer therapy.
Analytical and numerical modeling of optical second harmonic generation in anisotropic crystals using ♯SHAARP package
Authors: Zu Rui , Wang Bo , He Jingyang , Wang Jian-Jun , Weber Lincoln , Chen Long-Qing , Gopalan Venkatraman
Published: November 2022

Electric-dipole optical second harmonic generation (SHG) is a second-order nonlinear process that is widely used as a sensitive probe to detect broken inversion symmetry and local polar order. Analytical modeling of the SHG polarimetry of a nonlinear optical material is essential to extract its point group symmetry and the absolute nonlinear susceptibilities. Current literature on SHG analysis involves numerous approximations and a wide range of (in)accuracies. We have developed an open-source package called the Second Harmonic Analysis of Anisotropic Rotational Polarimetry (♯SHAARP.si) which derives analytical and numerical solutions of reflection SHG polarimetry from a single interface (.si) for bulk homogeneous crystals with arbitrary symmetry group, arbitrary crystal orientation, complex and anisotropic linear dielectric tensor with frequency dispersion, a general SHG tensor and arbitrary light polarization. ♯SHAARP.si enables accurate modeling of polarimetry measurements in reflection geometry from highly absorbing crystals or wedge-shaped transparent crystals. The package is extendable to multiple interfaces.
Effects of non-Newtonian viscosity on arterial and venous flow and transport
Authors: Lynch Sabrina , Nama Nitesh , Figueroa C. Alberto
Published: November 2022

It is well known that blood exhibits non-Newtonian viscosity, but it is generally modeled as a Newtonian fluid. However, in situations of low shear rate, the validity of the Newtonian assumption is questionable. In this study, we investigated differences between Newtonian and non-Newtonian hemodynamic metrics such as velocity, vorticity, and wall shear stress. In addition, we investigated cardiovascular transport using two different approaches, Eulerian mass transport and Lagrangian particle tracking. Non-Newtonian solutions revealed important differences in both hemodynamic and transport metrics relative to the Newtonian model. Most notably for the hemodynamic metrics, in-plane velocity and vorticity were consistently larger in the Newtonian approximation for both arterial and venous flows. Conversely, wall shear stresses were larger for the non-Newtonian case for both the arterial and venous models. Our results also indicate that for the Lagrangian metrics, the history of accumulated shear was consistently larger for both arterial and venous flows in the Newtonian approximation. Lastly, our results also suggest that the Newtonian model produces larger near wall and luminal mass transport values compared to the non-Newtonian model, likely due to the increased vorticity and recirculation. These findings demonstrate the importance of accounting for non-Newtonian behavior in cardiovascular flows exhibiting significant regions of low shear rate and recirculation.
Evaluation of input geological parameters and tunnel strain for strain-softening rock mass based on GSI
Authors: Cui Lan , Sheng Qian , Zhang Jun , Dong You-kou , Guo Zhen-shan
Published: November 2022

The regression analysis method is being widely adopted to analyse the tunnel strain, most of which ignore the strain-softening effect of the rock mass and fail to consider the influence of support pressure, initial stress state, and rock mass strength classification in one fitting equation. This study aims to overcome these deficiencies with a regression model used to estimate the tunnel strain. A group of geological strength indexes (GSI) are configured to quantify the input strength parameters and deformation moduli for the rock mass with a quality ranging from poor to excellent. A specific semi-analytical procedure is developed to calculate the tunnel strain around a circular opening, which is validated by comparison with those using existing methods. A nonlinear regression model is then established to analyse the obtained tunnel strain, combining twelve fitting equations to relate the tunnel strain and the factors including the support pressure, GSI, initial stress state, and critical softening parameter. Particularly, three equations are for the estimation of the critical tunnel strain, critical support pressure, and tunnel strain under elastic behaviour, respectively; and the other nine equations are for the tunnel strain with different strain-softening behaviours. The relative significance between the GSI, the initial stress and the support pressure on the tunnel strain is assessed.
Recent and rapid ecogeographical rule reversals in Northern Treeshrews
Authors: Juman Maya M. , Millien Virginie , Olson Link E. , Sargis Eric J.
Published: November 2022

Two of the most-studied ecogeographical rules describe patterns of body size variation within species. Bergmann’s rule predicts that individuals have larger body sizes in colder climates (typically at higher latitudes), and the island rule predicts that island populations of small-bodied species average larger in size than their mainland counterparts (insular gigantism). These rules are rarely tested in conjunction or assessed across space and time simultaneously. We investigated these patterns in the Northern Treeshrew (Tupaia belangeri) using museum specimens collected across a wide spatial and temporal range. Contrary to Bergmann’s rule, size increases with temperature in T. belangeri, a signal that is highly consistent across space and time. We also show that these rules are intertwined: Bergmann’s rule is reversed on the mainland but holds on islands, and therefore the island rule is upheld at higher, but not lower, latitudes. Moreover, we demonstrate a rapid reversal of both rules over time. The mechanism behind these inversions remains unclear, though temperature and precipitation are significant predictors of body size. Ecogeographical rules rely on the assumption of a constant relationship between size and the factors driving its variation. Our results highlight the need to question this assumption and reevaluate these rules in the context of accelerating and uneven climate change.
Incidence and challenges in management of hemodialysis catheter-related infections
Authors: Hajji Meriam , Neji Manel , Agrebi Sahar , Nessira Saoussen Ben , Hamida Fethi Ben , Barbouch Samia , Harzallah Amel , Abderrahim Ezzedine
Published: November 2022

Catheter-related infections (CRI) are a major cause of morbidity and mortality in chronic hemodialysis (HD) patients. In this paper, we share our experience with CRI in HD patients. We recorded 49 cases of CRI among 167 patients during a period of 40 months (January 2018–April 2021). The incidence of CRI was 3.7 per 1000 catheter-days. The revealing symptoms were dominated by fever or chills (90%). Inflammatory signs were observed in 74% of cases with respectively concurrent exit-site (51%) and tunnel infection (6%). The biological inflammatory syndrome was found in 74% of patients (average CRP level = 198.9 mg/l). Blood cultures were performed in all cases and were positive in 65% of cases. Thirteen patients have been diagnosed with Infection complications, which were respectively infective endocarditis in 7 cases, septic arthritis in 3 cases, infective myositis in one case, cerebral thrombophlebitis in 1 case and mediastinitis in 1 case. The death occurred in eleven patients, it was due to septic shock in 9 cases, pulmonary embolism in one case and neurologic alterations related to cerebral thrombophlebitis. The mean seniority in HD was 16.5 months in the group with CRI and 3.7 months in the group without CRI (p < 0.04). We did not notice significant difference in mortality between tunnelled and non-tunnelled catheters. CRI does not seem to be more severe in patients with diabetes. Duration of use of the HD catheter (p < 0.007) and ferritin level (p < 0.0001) were independent factors that predispose to CRI in our population.
Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury through a sirtuin-3 mediated increase in fatty acid oxidation
Authors: Hall Andrew R. , Karwi Qutuba G. , Kumar Sanjeev , Dongworth Rachel , Aksentijević Dunja , Altamimi Tariq R. , Fridianto Kevin Timothy , Chinda Kroekkiat , Hernandez-Resendiz Sauri , Mahmood Mohammad U. , Michelakis Evangelos , Ramachandra Chrishan J. , Ching Jianhong , Vicencio Jose M. , Shattock Michael J. , Kovalik Jean-Paul , Yellon Derek M. , Lopaschuk Gary , Hausenloy Derek J.
Published: November 2022

Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury (IRI) but the mechanisms are unknown. Here, we investigate the role of the mitochondrial NAD+-dependent deacetylase, Sirtuin-3 (SIRT3), which has been shown to influence fatty acid oxidation and cardiac outcomes, as a potential mediator of this effect. Fasting was shown to shift metabolism from glucose towards fatty acid oxidation. This change in metabolic fuel substrate utilisation increased myocardial infarct size in wild-type (WT), but not SIRT3 heterozygous knock-out (KO) mice. Further analysis revealed SIRT3 KO mice were better adapted to starvation through an improved cardiac efficiency, thus protecting them from acute myocardial IRI. Mitochondria from SIRT3 KO mice were hyperacetylated compared to WT mice which may regulate key metabolic processes controlling glucose and fatty acid utilisation in the heart. Fasting and the associated metabolic switch to fatty acid respiration worsens outcomes in WT hearts, whilst hearts from SIRT3 KO mice are better adapted to oxidising fatty acids, thereby protecting them from acute myocardial IRI.
Fully automated condyle segmentation using 3D convolutional neural networks
Authors: Jha Nayansi , Kim Taehun , Ham Sungwon , Baek Seung-Hak , Sung Sang-Jin , Kim Yoon-Ji , Kim Namkug
Published: November 2022

The aim of this study was to develop an auto-segmentation algorithm for mandibular condyle using the 3D U-Net and perform a stress test to determine the optimal dataset size for achieving clinically acceptable accuracy. 234 cone-beam computed tomography images of mandibular condyles were acquired from 117 subjects from two institutions, which were manually segmented to generate the ground truth. Semantic segmentation was performed using basic 3D U-Net and a cascaded 3D U-Net. A stress test was performed using different sets of condylar images as the training, validation, and test datasets. Relative accuracy was evaluated using dice similarity coefficients (DSCs) and Hausdorff distance (HD). In the five stages, the DSC ranged 0.886–0.922 and 0.912–0.932 for basic 3D U-Net and cascaded 3D U-Net, respectively; the HD ranged 2.557–3.099 and 2.452–2.600 for basic 3D U-Net and cascaded 3D U-Net, respectively. Stage V (largest data from two institutions) exhibited the highest DSC of 0.922 ± 0.021 and 0.932 ± 0.023 for basic 3D U-Net and cascaded 3D U-Net, respectively. Stage IV (200 samples from two institutions) had a lower performance than stage III (162 samples from one institution). Our results show that fully automated segmentation of mandibular condyles is possible using 3D U-Net algorithms, and the segmentation accuracy increases as training data increases.
Disease-related compound identification based on deeping learning method
Authors: Yang Bin , Bao Wenzheng , Wang Jinglong , Chen Baitong , Iwamori Naoki , Chen Jiazi , Chen Yuehui
Published: November 2022

Acute lung injury (ALI) is a serious respiratory disease, which can lead to acute respiratory failure or death. It is closely related to the pathogenesis of New Coronavirus pneumonia (COVID-19). Many researches showed that traditional Chinese medicine (TCM) had a good effect on its intervention, and network pharmacology could play a very important role. In order to construct "disease-gene-target-drug" interaction network more accurately, deep learning algorithm is utilized in this paper. Two ALI-related target genes (REAL and SATA3) are considered, and the active and inactive compounds of the two corresponding target genes are collected as training data, respectively. Molecular descriptors and molecular fingerprints are utilized to characterize each compound. Forest graph embedded deep feed forward network (forgeNet) is proposed to train. The experimental results show that forgeNet performs better than support vector machines (SVM), random forest (RF), logical regression (LR), Naive Bayes (NB), XGBoost, LightGBM and gcForest. forgeNet could identify 19 compounds in Erhuang decoction (EhD) and Dexamethasone (DXMS) more accurately.
Incorporating social determinants of health into the mathematical modeling of HIV/AIDS
Authors: de Oliveira Robson Bruniera , Rubio Felipe Alves , Anderle Rodrigo , Sanchez Mauro , de Souza Luis Eugenio , Macinko James , Dourado Ines , Rasella Davide
Published: November 2022

Currently, it is estimated that 37.6 million people are living with the HIV/AIDS virus worldwide, placing HIV/AIDS among the ten leading causes of death, mostly among low- and lower-middle-income countries. Despite the effective intervention in the prevention and treatment, this reduction did not occur equally among populations, subpopulations and geographic regions. This difference in the occurrence of the disease is associated with the social determinants of health (SDH), which could affect the transmission and maintenance of HIV. With the recognition of the importance of SDH in HIV transmission, the development of mathematical models that incorporate these determinants could increase the accuracy and robustness of the modeling. This article aims to propose a theoretical and conceptual way of including SDH in the mathematical modeling of HIV/AIDS. The theoretical mathematical model with the Social Determinants of Health has been developed in stages. For the selection of SDH that were incorporated into the model, a narrative literature review was conducted. Secondly, we proposed an extended model in which the population (N) is divided into Susceptible (S), HIV-positive (I), Individual with AIDS (A) and individual under treatment (T). Each SDH had a different approach to embedding in the model. We performed a calibration and validation of the model. A total of 31 SDH were obtained in the review, divided into four groups: Individual Factors, Socioeconomic Factors, Social Participation, and Health Services. In the end, four determinants were selected for incorporation into the model: Education, Poverty, Use of Drugs and Alcohol abuse, and Condoms Use. the section “Numerical simulation” to simulate the influence of the poverty rate on the AIDS incidence and mortality rates. We used a Brazilian dataset of new AIDS cases and deaths, which is publicly available. We calibrated the model using a multiobjective genetic algorithm for the years 2003 to 2019. To forecast from 2020 to 2035, we assumed two lines of poverty rate representing (i) a scenario of increasing and (ii) a scenario of decreasing. To avoid overfitting, we fixed some parameters and estimated the remaining. The equations presented with the chosen SDH exemplify some approaches that we can adopt when thinking about modeling social effects on the occurrence of HIV. The model was able to capture the influence of the employment/poverty on the HIV/AIDS incidence and mortality rates, evidencing the importance of SDOH in the occurrence of diseases. The recognition of the importance of including the SDH in the modeling and studies on HIV/AIDS is evident, due to its complexity and multicausality. Models that do not take into account in their structure, will probably miss a great part of the real trends, especially in periods, as the current on, of economic crisis and strong socioeconomic changes.
Spatial and temporal changes in moth assemblages along an altitudinal gradient, Jeju-do island
Authors: Choi Sei-Woong , An Jeong-Seop , Lee Jae-Young , Koo Kyung Ah
Published: November 2022

Montane species on islands attract attention due to their small and isolated populations and limited dispersal potential, making them vulnerable to extinction. We investigated the diversity pattern of moth assemblages over the 12-years-period (2009–2020) at 11 study plots on an island mountain (Mount Hallasan, Jeju-do Island, South Korea) to assess the changes in the moth assemblages in terms of species composition, richness, and abundances. We expected to find a decline in the number of species at these sites, given the reported decline in similar taxa in other temperate regions, such as Europe and North America. In contrast, we found that the numbers of species and individuals of moth populations on the island mountain have not significantly changed, except at the high-elevation sites, where the number of species has increased. Our results also show that the numbers of species and individuals are closely related to energy availability, actual evapotranspiration. Moreover, we found that the species composition during the study period has not been greatly changed, except at the lowermost and uppermost elevations. The mechanism driving this high dissimilarity of moth assemblages differed: the low-elevation site experienced high temporal turnover, and the high elevation sites also experienced high temporal turnover and nestedness resulting from active species replacement due to a recent forest fire and vegetation changes and the geographic and ecological constraints of the high elevations. To date, the moth species diversity of the temperate forests of the island mountain is not showing a drastic change. However, we observed that the moth assemblages had changed the number of species and individuals at low and high elevations. Given the biological and ecological limitations of moths (ectothermic organisms with limited habitat range) and considering the results of our study, we infer that climate change has impacted the diversity and species composition of moths on the island mountain.
Effect of a temperature gradient on the behaviour of an endangered Mexican topminnow and an invasive freshwater fish
Authors: Gomez-Maldonado Sebastian , Camacho-Cervantes Morelia
Published: November 2022

Climate change and biological invasions are two of the major threats to biodiversity. They could act synergistically to the detriment of natives as non-native species may be more plastic and resilient when facing changing environments. The twoline skiffia (Skiffia bilineata) is an endangered Mexican topminnow that cohabits with invasive guppies (Poecilia reticulata) in some areas in central Mexico. Guppies have been found to take advantage from associating with the twoline skiffia and are considered partially responsible for the decline of its populations. Refuge use and exploratory behaviours are trade-offs between being safe from the unknown and the opportunity to explore novel areas in search for better resources or to disperse. The aim of this study is to investigate how a change in temperature affects the refuge use and exploratory behaviours for both species. We found that temperature affects the refuge use of twoline skiffias, and the swimming activity of both species. Skiffias explored the rock more than guppies regardless of the temperature scenario. Also, smaller fish spent more time performing exploratory behaviours than bigger ones. Our study is the first to test the effect of temperature on the refuge use and exploratory behaviour of a goodeid species, and our results contribute to the idea that some natives could be more affected by climate change than some invaders.
Innovative multi-material tool use in the pant-hoot display of a chimpanzee
Authors: Watson Stuart K. , Lambeth Susan P. , Schapiro Steven J.
Published: November 2022

‘Pant-hoot displays’ are a species-typical, multi-modal communicative behaviour in chimpanzees in which pant-hoot vocalisations are combined with varied behavioural displays. In both captivity and the wild, individuals commonly incorporate striking or throwing elements of their environment into these displays. In this case study, we present five videos of an unenculturated, captive, adult male chimpanzee combining a large rubber feeding tub with excelsior (wood wool) in a multi-step process, which was then integrated into the subject’s pant-hoot displays as a percussive tool or ‘instrument’. During the construction process, the subject demonstrated an understanding of the relevant properties of these materials, ‘repairing’ the tub to be a more functional drum when necessary. We supplement these videos with a survey of care staff from the study site for additional detail and context. Although care must be taken in generalising data from a single individual, the behaviour reported here hints at three intriguing features of chimpanzee communicative cognition: (1) it suggests a degree of voluntary control over vocal production, (2) it is a so-far unique example of compound tool innovation and use in communicative behaviour and (3) it may represent an example of forward planning in communicative behaviour. Each of these would represent hitherto undocumented dimensions of flexibility in chimpanzee communication, mapping fertile ground for future research.
Comparative metabolomic profiling of women undergoing in vitro fertilization procedures reveals potential infertility-related biomarkers in follicular fluid
Authors: Dabaja Mohamed Ziad , dos Santos Aline Amaro , Christofolini Denise Maria , Barbosa Caio Parente , de Oliveira Diogo Noin , de Oliveira Arthur Noin , Melo Carlos Fernando Odir Rodrigues , Guerreiro Tatiane Melina , Catharino Rodrigo Ramos
Published: November 2022

Infertility is a worldwide concern, affecting one in six couples throughout their reproductive period. Therefore, enhancing the clinical tools available to identify the causes of infertility may save time, money, and emotional distress for the involved parties. This study aims to annotate potential biomarkers in follicular fluid that are negatively affecting pregnancy outcomes in women suffering infertility-related diseases such as endometriosis, tuboperitoneal factor, uterine factor, and unexplained infertility, using a metabolomics approach through high-resolution mass spectrometry. Follicular fluid samples collected from women who have the abovementioned diseases and managed to become pregnant after in vitro fertilization procedures [control group (CT)] were metabolically compared with those from women who suffer from the same diseases and could not get pregnant after the same treatment [infertile group (IF)]. Mass spectrometry analysis indicated 10 statistically relevant differential metabolites in the IF group, including phosphatidic acids, phosphatidylethanolamines, phosphatidylcholines, phosphatidylinositol, glucosylceramides, and 1-hydroxyvitamin D3 3-d-glucopyranoside. These metabolites are associated with cell signaling, cell proliferation, inflammation, oncogenesis, and apoptosis, and linked to infertility problems. Our results indicate that understanding the IF’s metabolic profile may result in a faster and more assertive female infertility diagnosis, lowering the costs, and increasing the probability of a positive pregnancy outcome.
Cyanophages as an important factor in the early evolution of oxygenic photosynthesis
Authors: Ślesak Ireneusz , Ślesak Halina
Published: November 2022

Cyanophages are viruses that infect cyanobacteria. An interesting feature of many of them is the presence ofpsbAandpsbD, genes that encode D1 and D2 proteins, respectively. The D1 and D2 are core proteins of the photosystem II (PSII) in cyanobacteria, algae and plants and influence the proper function of oxygenic photosynthesis (OP) in all oxyphototrophs on Earth. The frequent occurrence ofpsbAandpsbDin cyanophages raises the question whether these genes coevolved with hosts during the early stages of cyanophage and cyanobacterial evolution, or whether they are direct descendants of genes adopted from the genomes of cyanobacterial hosts. The phylogeny of D1/D2 proteins encoded in the genomes of selected cyanophages and oxyphototrophs was reconstructed. In addition, common ancestral sequences of D1 and D2 proteins were predicted for cyanophages and oxyphototrophs. Based on this, the reconstruction of the 3D structures of D1 and D2 proteins was performed. In addition, the ratio of non-synonymous to synonymous (dN/dS) nucleotide substitutions in the coding sequences (CDSs) ofpsbAandpsbDwas determined. The results of the predicted spatial structures of the D1 and D2 proteins and purifying selection for the CDSs ofpsbAandpsbDsuggest that they belong to the ancient proteins, which may have formed the primordial PSII. It cannot be ruled out that they involved in water oxidation in cyanobacteria-like organisms at early stages of the evolution of life on Earth and coevolved with ancient cyanophages. The data are also discussed in the context of the origin of viruses.
Training with noninvasive brain–machine interface, tactile feedback, and locomotion to enhance neurological recovery in individuals with complete paraplegia: a randomized pilot study
Authors: Nicolelis Miguel A. L. , Alho Eduardo J. L. , Donati Ana R. C. , Yonamine Seidi , Aratanha Maria A. , Bao Guillaume , Campos Debora S. F. , Almeida Sabrina , Fischer Dora , Shokur Solaiman
Published: November 2022

In recent years, our group and others have reported multiple cases of consistent neurological recovery in people with spinal cord injury (SCI) following a protocol that integrates locomotion training with brain machine interfaces (BMI). The primary objective of this pilot study was to compare the neurological outcomes (motor, tactile, nociception, proprioception, and vibration) in both an intensive assisted locomotion training (LOC) and a neurorehabilitation protocol integrating assisted locomotion with a noninvasive brain–machine interface (L + BMI), virtual reality, and tactile feedback. We also investigated whether individuals with chronic-complete SCI could learn to perform leg motor imagery. We ran a parallel two-arm randomized pilot study; the experiments took place in São Paulo, Brazil. Eight adults sensorimotor-complete (AIS A) (all male) with chronic (> 6 months) traumatic spinal SCI participated in the protocol that was organized in two blocks of 14 weeks of training and an 8-week follow-up. The participants were allocated to either the LOC group (n = 4) or L + BMI group (n = 4) using block randomization (blinded outcome assessment). We show three important results: (i) locomotion training alone can induce some level of neurological recovery in sensorimotor-complete SCI, and (ii) the recovery rate is enhanced when such locomotion training is associated with BMI and tactile feedback (∆Mean Lower Extremity Motor score improvement for LOC =  + 2.5, L + B =  + 3.5; ∆Pinprick score: LOC =  + 3.75, L + B =  + 4.75 and ∆Tactile score LOC =  + 4.75, L + B =  + 9.5). (iii) Furthermore, we report that the BMI classifier accuracy was significantly above the chance level for all participants in L + B group. Our study shows potential for sensory and motor improvement in individuals with chronic complete SCI following a protocol with BMIs and locomotion therapy. We report no dropouts nor adverse events in both subgroups participating in the study, opening the possibility for a more definitive clinical trial with a larger cohort of people with SCI.

Trial registration: http://www.ensaiosclinicos.gov.br/ identifier RBR-2pb8gq.
Chronic gut inflammation impairs contextual control of fear
Authors: Matisz C. E. , Patel M. , Hong N. S. , McDonald R. J. , Gruber A. J.
Published: November 2022

Chronic inflammatory diseases are highly comorbid with anxiety in humans. The extent to which chronic inflammation is responsible for this relationship remains to be determined. We therefore tested the hypothesis that prolonged, but not brief, gut inflammation is sufficient to evoke anxiety-related behaviours in mice. We used the discriminative fear to context conditioning paradigm to assess fear generalization, which is a prominent feature of anxiety disorders. Gut inflammation was induced by exposure to dextran sodium sulfate (DSS) in the drinking water, a well-established rodent model of ulcerative colitis evoking prolonged inflammation. Neither acute (1 × 5 day cycle) nor chronic (3 × 5 day cycles) exposure to DSS affected fear responses when tested shortly after conditioning. Mice in all groups generated more fear responses (freezing) in a chamber previously paired with mild shock, as compared to a chamber with no pairing. This suggests DSS exposure had no effect on acquisition or expression of conditioned fear. Acute and control animals showed this same contextual control of freezing when tested 9 days later. In contrast, at this remote time point, the chronically treated animals exhibited increased freezing in the unpaired chamber such that freezing was equivalent in both contexts. These animals, however, showed intact preference for the unpaired chamber when allowed to freely move between chambers. These data suggest that some mnemonic process engaged after training, such as memory consolidation, is affected by past chronic inflammation so as to generalize negative associations and engage fearful responding in inappropriate contexts, despite intact knowledge that the chambers have different affective associations sufficient for place preference.