bluuebunny/crossref_metadata_2025 huggingface dataset:
Retina-derived signals control pace of neurogenesis in visual brain areas but not circuit assembly
Authors: Sherman Shachar , Arnold-Ammer Irene , Schneider Martin W. , Kawakami Koichi , Baier Herwig
Published: September 2023

Brain development is orchestrated by both innate and experience-dependent mechanisms, but their relative contributions are difficult to disentangle. Here we asked if and how central visual areas are altered in a vertebrate brain depleted of any and all signals from retinal ganglion cells throughout development. We transcriptionally profiled neurons in pretectum, thalamus and other retinorecipient areas of larval zebrafish and searched for changes in lakritz mutants that lack all retinal connections. Although individual genes are dysregulated, the complete set of 77 neuronal types develops in apparently normal proportions, at normal locations, and along normal differentiation trajectories. Strikingly, the cell-cycle exits of proliferating progenitors in these areas are delayed, and a greater fraction of early postmitotic precursors remain uncommitted or are diverted to a pre-glial fate. Optogenetic stimulation targeting groups of neurons normally involved in processing visual information evokes behaviors indistinguishable from wildtype. In conclusion, we show that signals emitted by retinal axons influence the pace of neurogenesis in visual brain areas, but do not detectably affect the specification or wiring of downstream neurons.
Twisted moiré photonic crystal enabled optical vortex generation through bound states in the continuum
Authors: Zhang Tiancheng , Dong Kaichen , Li Jiachen , Meng Fanhao , Li Jingang , Munagavalasa Sai , Grigoropoulos Costas P. , Wu Junqiao , Yao Jie
Published: September 2023

The twisted stacking of two layered crystals has led to the emerging moiré physics as well as intriguing chiral phenomena such as chiral phonon and photon generation. In this work, we identified and theoretically formulated a non-trivial twist-enabled coupling mechanism in twisted bilayer photonic crystal (TBPC), which connects the bound state in the continuum (BIC) mode to the free space through the twist-enabled channel. Moreover, the radiation from TBPC hosts an optical vortex in the far field with both odd and even topological orders. We quantitatively analyzed the twist-enabled coupling between the BIC mode and other non-local modes in the photonic crystals, giving rise to radiation carrying orbital angular momentum. The optical vortex generation is robust against geometric disturbance, making TBPC a promising platform for well-defined vortex generation. As a result, TBPCs not only provide a new approach to manipulating the angular momentum of photons, but may also enable novel applications in integrated optical information processing and optical tweezers. Our work broadens the field of moiré photonics and paves the way toward the novel application of moiré physics.
Efficient optimization with higher-order Ising machines
Authors: Bybee Connor , Kleyko Denis , Nikonov Dmitri E. , Khosrowshahi Amir , Olshausen Bruno A. , Sommer Friedrich T.
Published: September 2023

A prominent approach to solving combinatorial optimization problems on parallel hardware is Ising machines, i.e., hardware implementations of networks of interacting binary spin variables. Most Ising machines leverage second-order interactions although important classes of optimization problems, such as satisfiability problems, map more seamlessly to Ising networks with higher-order interactions. Here, we demonstrate that higher-order Ising machines can solve satisfiability problems more resource-efficiently in terms of the number of spin variables and their connections when compared to traditional second-order Ising machines. Further, our results show on a benchmark dataset of Boolean k-satisfiability problems that higher-order Ising machines implemented with coupled oscillators rapidly find solutions that are better than second-order Ising machines, thus, improving the current state-of-the-art for Ising machines.
All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ
Authors: Koren Shon A. , Ahmed Selim Nada , De la Rosa Lizbeth , Horn Jacob , Farooqi M. Arsalan , Wei Alicia Y. , Müller-Eigner Annika , Emerson Jacen , Johnson Gail V. W. , Wojtovich Andrew P.
Published: September 2023

Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.
A systematic analysis of marine lysogens and proviruses
Authors: Yi Yi , Liu Shunzhang , Hao Yali , Sun Qingyang , Lei Xinjuan , Wang Yecheng , Wang Jiahua , Zhang Mujie , Tang Shan , Tang Qingxue , Zhang Yue , Liu Xipeng , Wang Yinzhao , Xiao Xiang , Jian Huahua
Published: September 2023

Viruses are ubiquitous in the oceans, exhibiting high abundance and diversity. Here, we systematically analyze existing genomic sequences of marine prokaryotes to compile a Marine Prokaryotic Genome Dataset (MPGD, consisting of over 12,000 bacterial and archaeal genomes) and a Marine Temperate Viral Genome Dataset (MTVGD). At least 40% of the MPGD genomes contain one or more proviral sequences, indicating that they are lysogens. The MTVGD includes over 12,900 viral contigs or putative proviruses, clustered into 10,897 viral genera. We show that lysogens and proviruses are abundant in marine ecosystems, particularly in the deep sea, and marine lysogens differ from non-lysogens in multiple genomic features and growth properties. We reveal several virus-host interaction networks of potential ecological relevance, and identify proviruses that appear to be able to infect (or to be transferred between) different bacterial classes and phyla. Auxiliary metabolic genes in the MTVGD are enriched in functions related to carbohydrate metabolism. Finally, we experimentally demonstrate the impact of a prophage on the transcriptome of a representative marine Shewanella bacterium. Our work contributes to a better understanding of the ecology of marine prokaryotes and their viruses.
AlphaFold-Multimer predicts cross-kingdom interactions at the plant-pathogen interface
Authors: Homma Felix , Huang Jie , van der Hoorn Renier A. L.
Published: September 2023

Adapted plant pathogens from various microbial kingdoms produce hundreds of unrelated small secreted proteins (SSPs) with elusive roles. Here, we used AlphaFold-Multimer (AFM) to screen 1879 SSPs of seven tomato pathogens for interacting with six defence-related hydrolases of tomato. This screen of 11,274 protein pairs identified 15 non-annotated SSPs that are predicted to obstruct the active site of chitinases and proteases with an intrinsic fold. Four SSPs were experimentally verified to be inhibitors of pathogenesis-related subtilase P69B, including extracellular protein-36 (Ecp36) and secreted-into-xylem-15 (Six15) of the fungal pathogens Cladosporium fulvum and Fusarium oxysporum, respectively. Together with a P69B inhibitor from the bacterial pathogen Xanthomonas perforans and Kazal-like inhibitors of the oomycete pathogen Phytophthora infestans, P69B emerges as an effector hub targeted by different microbial kingdoms, consistent with a diversification of P69B orthologs and paralogs. This study demonstrates the power of artificial intelligence to predict cross-kingdom interactions at the plant-pathogen interface.
A digital twin for DNA data storage based on comprehensive quantification of errors and biases
Authors: Gimpel Andreas L. , Stark Wendelin J. , Heckel Reinhard , Grass Robert N.
Published: September 2023

Archiving data in synthetic DNA offers unprecedented storage density and longevity. Handling and storage introduce errors and biases into DNA-based storage systems, necessitating the use of Error Correction Coding (ECC) which comes at the cost of added redundancy. However, insufficient data on these errors and biases, as well as a lack of modeling tools, limit data-driven ECC development and experimental design. In this study, we present a comprehensive characterisation of the error sources and biases present in the most common DNA data storage workflows, including commercial DNA synthesis, PCR, decay by accelerated aging, and sequencing-by-synthesis. Using the data from 40 sequencing experiments, we build a digital twin of the DNA data storage process, capable of simulating state-of-the-art workflows and reproducing their experimental results. We showcase the digital twin’s ability to replace experiments and rationalize the design of redundancy in two case studies, highlighting opportunities for tangible cost savings and data-driven ECC development.
Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex
Authors: Salamon Iva , Park Yongkyu , Miškić Terezija , Kopić Janja , Matteson Paul , Page Nicholas F. , Roque Alfonso , McAuliffe Geoffrey W. , Favate John , Garcia-Forn Marta , Shah Premal , Judaš Miloš , Millonig James H. , Kostović Ivica , De Rubeis Silvia , Hart Ronald P. , Krsnik Željka , Rasin Mladen-Roko
Published: September 2023

Abnormalities in neocortical and synaptic development are linked to neurodevelopmental disorders. However, the molecular and cellular mechanisms governing initial synapse formation in the prenatal neocortex remain poorly understood. Using polysome profiling coupled with snRNAseq on human cortical samples at various fetal phases, we identify human mRNAs, including those encoding synaptic proteins, with finely controlled translation in distinct cell populations of developing frontal neocortices. Examination of murine and human neocortex reveals that the RNA binding protein and translational regulator, CELF4, is expressed in compartments enriched in initial synaptogenesis: the marginal zone and the subplate. We also find that Celf4/CELF4-target mRNAs are encoded by risk genes for adverse neurodevelopmental outcomes translating into synaptic proteins. Surprisingly, deleting Celf4 in the forebrain disrupts the balance of subplate synapses in a sex-specific fashion. This highlights the significance of RNA binding proteins and mRNA translation in evolutionarily advanced synaptic development, potentially contributing to sex differences.
Mechanically enhanced biogenesis of gut spheroids with instability-driven morphomechanics
Authors: Lin Feng , Li Xia , Sun Shiyu , Li Zhongyi , Lv Chenglin , Bai Jianbo , Song Lin , Han Yizhao , Li Bo , Fu Jianping , Shao Yue
Published: September 2023

Region-specific gut spheroids are precursors for gastrointestinal and pulmonary organoids that hold great promise for fundamental studies and translations. However, efficient production of gut spheroids remains challenging due to a lack of control and mechanistic understanding of gut spheroid morphogenesis. Here, we report an efficient biomaterial system, termed micropatterned gut spheroid generator (μGSG), to generate gut spheroids from human pluripotent stem cells through mechanically enhanced tissue morphogenesis. We show that μGSG enhances the biogenesis of gut spheroids independent of micropattern shape and size; instead, mechanically enforced cell multilayering and crowding is demonstrated as a general, geometry-insensitive mechanism that is necessary and sufficient for promoting spheroid formation. Combining experimental findings and an active-phase-field morphomechanics theory, our study further reveals an instability-driven mechanism and a mechanosensitive phase diagram governing spheroid pearling and fission in μGSG. This work unveils mechanobiological paradigms based on tissue architecture and surface tension for controlling tissue morphogenesis and advancing organoid technology.
Multimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization
Authors: Bie Fenglong , Wang Zhijie , Li Yulong , Guo Wei , Hong Yuanyuan , Han Tiancheng , Lv Fang , Yang Shunli , Li Suxing , Li Xi , Nie Peiyao , Xu Shun , Zang Ruochuan , Zhang Moyan , Song Peng , Feng Feiyue , Duan Jianchun , Bai Guangyu , Li Yuan , Huai Qilin , Zhou Bolun , Huang Yu S. , Chen Weizhi , Tan Fengwei , Gao Shugeng
Published: September 2023

Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.
Vaccination of cattle with the Babesia bovis sexual-stage protein HAP2 abrogates parasite transmission by Rhipicephalus microplus ticks
Authors: Silva Marta G. , Bastos Reginaldo G. , Laughery Jacob M. , Alzan Heba F. , Rathinasamy Vignesh A. , Cooke Brian M. , Suarez Carlos E.
Published: September 2023

The apicomplexan parasite Babesia bovis is responsible for bovine babesiosis, a poorly controlled tick-borne disease of global impact. The widely conserved gametocyte protein HAPLESS2/GCS1 (HAP2) is uniquely expressed on the surface of B. bovis sexual stage parasites and is a candidate for transmission-blocking vaccines (TBV). Here, we tested whether vaccination of calves with recombinant HAP2 (rHAP2) interferes with the transmission of B. bovis by competent ticks. Calves vaccinated with rHAP2 (n = 3), but not control animals (n = 3) developed antibodies specific to the vaccine antigen. Vaccinated and control animals were infested with Rhipicephalus microplus larvae and subsequently infected with virulent blood stage B. bovis parasites by needle inoculation, with all animals developing clinical signs of acute babesiosis. Engorged female ticks fed on the infected calves were collected for oviposition, hatching, and obtention of larvae. Transmission feeding was then conducted using pools of larvae derived from ticks fed on rHAP2-vaccinated or control calves. Recipient calves (n = 3) exposed to larvae derived from control animals, but none of the recipient calves (n = 3) challenged with larvae from ticks fed on rHAP2-vaccinated animals, developed signs of acute babesiosis within 11 days after tick infestation. Antibodies against B. bovis antigens and parasite DNA were found in all control recipient animals, but not in any of the calves exposed to larvae derived from HAP2-vaccinated animals, consistent with the absence of B. bovis infection via tick transmission. Overall, our results are consistent with the abrogation of parasite tick transmission in rHAP2-vaccinated calves, confirming this antigen as a prime TBV candidate against B. bovis.
Using spectral characterization to identify healthcare-associated infection (HAI) patients for clinical contact precaution
Authors: Cui Jiaming , Cho Sungjun , Kamruzzaman Methun , Bielskas Matthew , Vullikanti Anil , Prakash B. Aditya
Published: September 2023

Healthcare-associated infections (HAIs) are a major problem in hospital infection control. Although HAIs can be suppressed using contact precautions, such precautions are expensive, and we can only apply them to a small fraction of patients (i.e., a limited budget). In this work, we focus on two clinical problems arising from the limited budget: (a) choosing the best patients to be placed under precaution given a limited budget to minimize the spread (the isolation problem), and (b) choosing the best patients to release when limited budget requires some of the patients to be cleared from precaution (the clearance problem). A critical challenge in addressing them is that HAIs have multiple transmission pathways such that locations can also accumulate ‘load’ and spread the disease. One of the most common practices when placing patients under contact precautions is the regular clearance of pathogen loads. However, standard propagation models like independent cascade (IC)/susceptible-infectious-susceptible (SIS) cannot capture such mechanisms directly. Hence to account for this challenge, using non-linear system theory, we develop a novel spectral characterization of a recently proposed pathogen load based model, 2-Mode-SIS model, on people/location networks to capture spread dynamics of HAIs. We formulate the two clinical problems using this spectral characterization and develop effective and efficient algorithms for them. Our experiments show that our methods outperform several natural structural and clinical approaches on real-world hospital testbeds and pick meaningful solutions.
Monomeric streptavidin phage display allows efficient immobilization of bacteriophages on magnetic particles for the capture, separation, and detection of bacteria
Authors: Carmody Caitlin M. , Nugen Sam R.
Published: September 2023

Immobilization of bacteriophages onto solid supports such as magnetic particles has demonstrated ultralow detection limits as biosensors for the separation and detection of their host bacteria. While the potential impact of magnetized phages is high, the current methods of immobilization are either weak, costly, inefficient, or laborious making them less viable for commercialization. In order to bridge this gap, we have developed a highly efficient, site-specific, and low-cost method to immobilize bacteriophages onto solid supports. While streptavidin–biotin represents an ideal conjugation method, the functionalization of magnetic particles with streptavidin requires square meters of coverage and therefore is not amenable to a low-cost assay. Here, we genetically engineered bacteriophages to allow synthesis of a monomeric streptavidin during infection of the bacterial host. The monomeric streptavidin was fused to a capsid protein (Hoc) to allow site-specific self-assembly of up to 155 fusion proteins per capsid. Biotin coated magnetic nanoparticles were functionalized with mSA-Hoc T4 phage demonstrated in an E. coli detection assay with a limit of detection of < 10 CFU in 100 mLs of water. This work highlights the creation of genetically modified bacteriophages with a novel capsid modification, expanding the potential for bacteriophage functionalized biotechnologies.
The Dictyostelium discoideum FimA protein, unlike yeast and plant fimbrins, is regulated by calcium similar to mammalian plastins
Authors: Ishida Hiroaki , Woodman Andrew G. , Kitada Naoya , Aizawa Tomoyasu , Vogel Hans J.
Published: September 2023

Plastins, also known as fimbrins, are highly conserved eukaryotic multidomain proteins that are involved in actin-bundling. They all contain four independently folded Calponin Homology-domains and an N-terminal headpiece that is comprised of two calcium-binding EF-hand motifs. Since calcium-binding has been shown to be integral to regulating the activity of the three mammalian plastin proteins, we decided to study the properties of the headpiece regions of fimbrins from the model plant Arabidopsis thaliana, the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe and the amoeba Dictyostelium discoideum. Of these protein domains only the FimA headpiece from the amoeba protein possesses calcium binding properties. Structural characterization of this protein domain by multidimensional NMR and site-directed mutagenesis studies indicates that this EF-hand region of FimA also contains a regulatory ‘switch helix’ that is essential to regulating the activity of the human L-plastin protein. Interestingly this regulatory helical region seems to be lacking in the plant and yeast proteins and in fimbrins from all other nonmotile systems. Typical calmodulin antagonists can displace the switch-helix from the FimA headpiece, suggesting that such drugs can deregulate the Ca2+-regulation of the actin-bunding in the amoeba, thereby making it a useful organism for drug screening against mammalian plastins.
The hydrodynamic performance of duck feet for submerged swimming resembles oars rather than delta-wings
Authors: Ribak Gal , Gurka Roi
Published: September 2023

Waterfowl use webbed feet to swim underwater. It has been suggested that the triangular shape of the webbed foot functions as a lift-generating delta wing rather than a drag-generating oar. To test this idea, we studied the hydrodynamic characteristics of a diving duck’s (Aythya nyroca) foot. The foot’s time varying angles-of-attack (AoAs) during paddling were extracted from movies of ducks diving vertically in a water tank. Lift and drag coefficients of 3D-printed duck-foot models were measured as a function of AoA in a wind-tunnel; and the near-wake flow dynamics behind the foot model was characterized using particle image velocimetry (PIV) in a flume. Drag provided forward thrust during the first 80% of the power phase, whereas lift dominated thrust production at the end of the power stroke. In steady flow, the transfer of momentum from foot to water peaked at 45° < AoA < 60°, due to an organized wake flow pattern (vortex street), whereas at AoAs > 60° the flow behind the foot was fully separated, generating high drag levels. The flow characteristics do not constitute the vortex lift typical of delta wings. Rather, duck feet seem to be an adaptation for propulsion at a wide range of AoAs, on and below the water surface.
Classification of cancer cells at the sub-cellular level by phonon microscopy using deep learning
Authors: Pérez-Cota Fernando , Martínez-Arellano Giovanna , La Cavera Salvatore , Hardiman William , Thornton Luke , Fuentes-Domínguez Rafael , Smith Richard J. , McIntyre Alan , Clark Matt
Published: September 2023

There is a consensus about the strong correlation between the elasticity of cells and tissue and their normal, dysplastic, and cancerous states. However, developments in cell mechanics have not seen significant progress in clinical applications. In this work, we explore the possibility of using phonon acoustics for this purpose. We used phonon microscopy to obtain a measure of the elastic properties between cancerous and normal breast cells. Utilising the raw time-resolved phonon-derived data (300 k individual inputs), we employed a deep learning technique to differentiate between MDA-MB-231 and MCF10a cell lines. We achieved a 93% accuracy using a single phonon measurement in a volume of approximately 2.5 μm3. We also investigated means for classification based on a physical model that suggest the presence of unidentified mechanical markers. We have successfully created a compact sensor design as a proof of principle, demonstrating its compatibility for use with needles and endoscopes, opening up exciting possibilities for future applications.
A pancancer analysis of the oncogenic role of cyclin B1 (CCNB1) in human tumors
Authors: Dai Peng , Xiong Lecai , Wei Yanhong , Wei Xiaoyan , Zhou Xuefeng , Zhao Jinping , Tang Hexiao
Published: September 2023

Aberrant levels of the G2/M cyclin cyclin B1 (gene CCNB1) have been associated with multiple cancers; however, the literature lacks a focused and comprehensive analysis of the regulation of this important regulator of cell proliferation in cancer. Through this work, we performed a pancancer analysis of the levels of CCNB1 and dissected aspects of regulation and how this correlates with cancer prognosis. We comprehensively evaluated the expression and promoter methylation of CCNB1 across 38 cancers based on RNA sequencing data obtained from the Cancer Genome Atlas (TCGA). The correlation of CCNB1 with prognosis and the tumor microenvironment was explored. Using lung adenocarcinoma data, we studied the potential upstream noncoding RNAs involved in the regulation of CCNB1 and validated the protein levels and prognostic value of CCNB1 for this disease site. CCNB1 was highly expressed, and promoter methylation was reduced in most cancers. Gene expression of CCNB1 correlated positively with poor prognosis of tumor patients, and these results were confirmed at the protein level using lung adenocarcinoma. CCNB1 expression was associated with the infiltration of T helper cells, and this further correlated with poor prognosis for certain cancers, including renal clear cell carcinoma and lung adenocarcinoma. Subsequently, we identified a specific upstream noncoding RNA contributing to CCNB1 overexpression in lung adenocarcinoma through correlation analysis, expression analysis and survival analysis. This study provides a comprehensive analysis of the expression and methylation status of CCNB1 across several forms of cancer and provides further insight into the mechanistic pathways regulating Cyclin B1 in the tumorigenesis process.
Permeability evolution of Bentheim Sandstone at simulated georeservoir conditions
Authors: Fazio Marco , Chandler Michael R. , Sauter Martin
Published: September 2023

Bentheim Sandstone is considered a suitable conventional georeservoir rock even at great depth because of its mineral composition, homogeneity, micro- and macrostructure, and is also used as a reference material in rock deformation tests. However, a full characterization of the permeability at representative depths has never been performed. Here we report new experimental data where the permeability of Bentheim Sandstone is measured both with a simultaneous variation and with a sequential variation of three different variables to simulate georeservoir conditions. The results indicate a decrease in permeability with simulated increasing depth until 2–3 km, followed by a partial permeability recovery until 4–5 km depth. During the exhumation path, initially, permeability is unaffected, but at shallow depths, a sharp increase in permeability is observed, likely due to microcracking. These variations are a consequence of a complex interaction between stress, pore pressure and temperature, highlighting the importance of experiments considering all three variables when studying the evolution of permeability at depth. These results will aid with the accurate estimation of permeability at different georeservoir conditions.
Validating virtual administration of neuropsychological testing in Parkinson disease: a pilot study
Authors: Gallagher Julia , Mamikonyan Eugenia , Xie Sharon X. , Tran Baochan , Shaw Sarah , Weintraub Daniel
Published: September 2023

COVID-19 has highlighted the need for remote cognitive testing, but the reliability and validity of virtual cognitive testing in Parkinson disease (PD) is unknown. Therefore, we assessed PD participants enrolled in an observational, cognition-focused study with an extensive cognitive battery completed both in-person and via video conference close in time. Data for 35 PD participants with normal cognition to mild dementia were analyzed. Only one test (semantic verbal fluency) demonstrated a difference in score by administration type, with a significantly better score virtually. Only three tests demonstrated good reliability for in-person versus virtual testing, but reliability values for visit 1 versus visit 2 were similarly low overall. Trail Making Test B was successfully administered virtually to only 18 participants due to technical issues. Virtual and in-person cognitive testing generate similar scores at the group level, but with poor to moderate reliability for most tests. Mode of test administration, learning effects, and technical difficulties explained little of the low test–retest reliability, indicating possible significant short-term variability in cognitive performance in PD in general, which has implications for clinical care and research. In-person cognitive testing with a neuropsychologist remains the gold standard, and it remains to be determined if virtual cognitive testing is feasible in PD.
Palaeoenvironments and hominin evolutionary dynamics in southeast Asia
Authors: Bacon Anne-Marie , Bourgon Nicolas , Dufour Elise , Demeter Fabrice , Zanolli Clément , Westaway Kira E. , Joannes-Boyau Renaud , Duringer Philippe , Ponche Jean-Luc , Morley Mike W. , Suzzoni Eric , Frangeul Sébastien , Boesch Quentin , Antoine Pierre-Olivier , Boualaphane Souliphane , Sichanthongtip Phonephanh , Sihanam Daovee , Huong Nguyen Thi Mai , Tuan Nguyen Anh , Fiorillo Denis , Tombret Olivier , Patole-Edoumba Elise , Zachwieja Alexandra , Luangkhoth Thonglith , Souksavatdy Viengkeo , Dunn Tyler E. , Shackelford Laura , Hublin Jean-Jacques
Published: September 2023

Secure environmental contexts are crucial for hominin interpretation and comparison. The discovery of a Denisovan individual and associated fauna at Tam Ngu Hao 2 (Cobra) Cave, Laos, dating back to 164–131 ka, allows for environmental comparisons between this (sub)tropical site and the Palearctic Denisovan sites of Denisova Cave (Russia) and Baishiya Karst Cave (China). Denisovans from northern latitudes foraged in a mix of forested and open landscapes, including tundra and steppe. Using stable isotope values from the Cobra Cave assemblage, we demonstrate that, despite the presence of nearby canopy forests, the Denisovan individual from Cobra Cave primarily consumed plants and/or animals from open forests and savannah. Using faunal evidence and proxy indicators of climates, results herein highlight a local expansion of rainforest at ~ 130 ka, raising questions about how Denisovans responded to this local climate change. Comparing the diet and habitat of the archaic hominin from Cobra Cave with those of earlyHomo sapiensfrom Tam Pà Ling Cave (46–43 ka), Laos, it appears that only our species was able to exploit rainforest resources.
Transcriptome-wide marker gene expression analysis of stress-responsive sulfate-reducing bacteria
Authors: Jawaharraj Kalimuthu , Peta Vincent , Dhiman Saurabh Sudha , Gnimpieba Etienne Z. , Gadhamshetty Venkataramana
Published: September 2023

Sulfate-reducing bacteria (SRB) are terminal members of any anaerobic food chain. For example, they critically influence the biogeochemical cycling of carbon, nitrogen, sulfur, and metals (natural environment) as well as the corrosion of civil infrastructure (built environment). The United States alone spends nearly $4 billion to address the biocorrosion challenges of SRB. It is important to analyze the genetic mechanisms of these organisms under environmental stresses. The current study uses complementary methodologies, viz.,transcriptome-wide marker gene panel mapping and gene clustering analysis to decipher the stress mechanisms in four SRB. Here, the accessible RNA-sequencing data from the public domains were mined to identify the key transcriptional signatures. Crucial transcriptional candidate genes ofDesulfovibriospp. were accomplished and validated the gene cluster prediction. In addition, the unique transcriptional signatures ofOleidesulfovibrio alaskensis(OA-G20) at graphene and copper interfaces were discussed using in-house RNA-sequencing data. Furthermore, the comparative genomic analysis revealed 12,821 genes with translation, among which 10,178 genes were in homolog families and 2643 genes were in singleton families were observed among the 4 genomes studied. The current study paves a path for developing predictive deep learning tools for interpretable and mechanistic learning analysis of the SRB gene regulation.
Biomechanical performance evaluation of a modified proximal humerus locking plate for distal humerus shaft fracture using finite element analysis
Authors: Lee Jung-Soo , Kim Kwang Gi , Yoon Yong-Cheol
Published: September 2023

The extra-articular distal humerus plate (EADHP) has been widely used for surgical treatment of distal humerus shaft fracture (DHSF). However, the surgical approach, fixation methods, and implant positions of the EADHP remain controversial owing to iatrogenic radial nerve injury and complaints such as skin irritation related to the plate. Anterior plating with a modified (upside-down application) proximal humerus locking plate (PHILOS) has been proposed as an alternative, However, research on its biomechanical performance remain insufficient and were mostly based on retrospective studies. This study quantitatively compared and evaluated the biomechanical performance between posterior plating with the EADHP and anterior plating with a modified PHILOS using finite element analysis (FEA). The FEA simulation results that both the EADHP and PHILOS had adequate biomechanical performance and stability under axial, bending, and varus force load conditions. The PHILOS has a fixed stability comparable to that of the EADHP, and fixation was achieved using only four locking screws within a fixed range of 30 mm just above the olecranon fossa. The results show that the PHILOS could be an option for the fixation of a DHSF when considering the dissection range and complaints (e.g. skin irritation) associated with the EADHP.
CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor
Authors: Duan Lei , Tadi Mehrdad Jafari , Maki Carl G.
Published: September 2023

P53 represses transcription by activating p21 expression and promoting formation of RB1-E2F1 and RBL1/RBL2-DREAM transcription repressor complexes. The DREAM complex is composed of DP1, RB-family proteins RBL1 or RBL2 (p107/p130), E2F4/5, and MuvB. We recently reported RBL2-DREAM contributes to improved therapy responses in p53 wild-type NSCLC cells and improved outcomes in NSCLC patients whose tumors express wild-type p53. In the current study we identified CSE1L as a novel inhibitor of the RBL2-DREAM pathway and target to activate RBL2-DREAM in NSCLC cells. CSE1L is an oncoprotein that maintains repression of genes that can be reactivated by HDAC inhibitors. Mocetinostat is a HDAC inhibitor in clinical trials with selectivity against HDACs 1 and 2. Knockdown of CSE1L in NSCLC cells or treatment with mocetinostat increased p21, activated RB1 and RBL2, repressed DREAM target genes, and induced toxicity in a manner that required wild-type p53. Lastly, we found high levels of CSE1L and specific DREAM-target genes are candidate markers to identify p53 wild-type NSCLCs most responsive to mocetinostat. Thus, we identified CSE1L as a critical negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC that can be indirectly targeted with HDAC1/2 inhibitors (mocetinostat) in current clinical trials. High expression of CSE1L and DREAM target genes could serve as a biomarker to identify p53 wild-type NSCLCs most responsive to this HDAC1/2 inhibitor.
Overuse of the psychoactive analgesics’ opioids and gabapentinoid drugs in patients having surgery for nerve entrapment disorders
Authors: Dahlin Lars B. , Perez Raquel , Nyman Erika , Zimmerman Malin , Merlo Juan
Published: September 2023

Knowledge about risks for overuse of psychoactive analgesics in patients having primary surgery for carpal tunnel syndrome (CTS) or ulnar nerve entrapment (UNE), or both, is limited. We investigated if patients with those nerve entrapment disorders have a higher risk of overuse of psychoactive analgesics (i.e., opioids and gabapentinoid drugs) before, after, and both before and after surgery than observed in the general population after accounting for demographical and socioeconomic factors. Using a large record linkage database, we analysed 5,966,444 individuals (25–80 years), residing in Sweden December 31st, 2010–2014, of which 31,380 underwent surgery 2011–2013 for CTS, UNE, or both, applying logistic regression to estimate relative risk (RR) and 95% confidence interval (CI). Overall, overuse of the psychoactive analgesics was low in the general population. Compared to those individuals, unadjusted RR (95% CI) of overuse ranged in patients between 2.77 (2.57–3.00) with CTS after surgery and 6.21 (4.27–9.02) with both UNE and CTS after surgery. These risks were only slightly reduced after adjustment for demographical and socioeconomic factors. Patients undergoing surgery for CTS, UNE, or both, have a high risk of overuse of psychoactive analgesics before, after, and both before and after surgery.
Associations between physical size and space are strongly asymmetrical
Authors: Richter Melanie , Wühr Peter
Published: September 2023

The spatial–size association of response codes (SSARC) effect describes the phenomenon that left responses are faster and more accurate to small stimuli whereas right responses are faster and more accurate to large stimuli, as compared to the opposite mapping. The effect indicates associations between the mental representations of physical size and space. Importantly, the theoretical accounts of SSARC effects make different predictions about the reciprocity and/or symmetry of spatial–size associations. To investigate the reciprocity of SSARC effects, we compared compatibility effects in two verbal choice-response tasks: a size–location (typical SSARC) task and a location–size (reciprocal SSARC) task. In the size–location task, participants responded verbally to a small/large stimulus by saying “left”/“right”. In the location–size task, participants responded verbally to a left-/right-side stimulus by saying “small”/“large”. Participants completed both tasks with a compatible (small–left, large–right; left–small, right–large) and an incompatible (small–right, large–left; left–large, right–small) mapping. A regular SSARC effect emerged in the size–location task. However, no reciprocal SSARC effect emerged in the location–size task if outliers were excluded. If outliers were not excluded, small reciprocal SSARC effects occurred. Associations underlying the SSARC effect are thus strongly asymmetrical: Physical (stimulus) size can prime spatial responses much more strongly than spatial (stimulus) position can prime size-related responses. The finding of asymmetrical associations between size and space is in line with some theoretical accounts of the SSARC effect but at odds with others.
Prevalence of low trabecular bone score and its association with disease severity and activity in patients with axial spondyloarthritis
Authors: Saisirivechakun Pannarat , Mahakkanukrauh Ajanee , Pongchaiyakul Chatlert , Boonya-ussadorn Trirat , Narongroeknawin Pongthorn , Pakchotanon Rattapol , Assavatanabodee Paijit , Chaiamnuay Sumapa
Published: September 2023

Axial spondyloarthritis (axSpA) increases the risk of osteoporosis and vertebral fractures. Bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) has limitations in axSpA patients. Trabecular bone score (TBS) indirectly assesses bone microarchitecture and can be used to predict fracture risk. However, few studies have investigated the role of TBS in axSpA patients. The objective of this study were to compare TBS between axSpA patients and 1:1 sex- and age-matched healthy volunteers and determine factors associated with low TBS in axSpA patients. A cross-sectional study was conducted in two tertiary-care hospitals. A total of 137 axSpA patients and healthy volunteers were enrolled. Demographics, disease characteristics, and risk factors for osteoporosis were recorded. TBS, BMD at the lumbar spine, hip, and vertebral fractures were assessed by DXA. Low TBS was defined as a TBS value < 1.230. Factors associated with low TBS were examined by logistic regression. Most patients were male (75.9%) and tested positive for HLA-B27 (88.3%). The mean (SD) age was 42.8 (12.0) years. The mean (SD) of TBS in the axSpA patients was lower than those in the healthy volunteers [1.402 (0.107) vs 1.440 (0.086), respectively; p = 0.002]. The mean (SD) of lumbar BMD in the axSpA patients was higher than in healthy volunteers [1.186 (0.212) vs 1.087 (0.124), p < 0.001], whereas the mean (SD) of femoral neck BMD in the axSpA group was lower than that in the healthy volunteers [0.867 (0.136) vs 0.904 (0.155), p = 0.038]. Disease severity as indicated by sacroiliac joint fusion and a high ASDAS score were associated with low TBS with the odds ratios (95% confidence interval) of 11.8 (1.2–115.4) and 5.2 (1.6–16.9), respectively. In conclusion, axSpA patients had a higher prevalence of low TBS than healthy volunteers. Sacroiliac joint fusion and a high ASDAS score were associated with low TBS.
A fixed 20:1 combination of cafedrine/theodrenaline increases cytosolic Ca2+ concentration in human tracheal epithelial cells via ryanodine receptor-mediated Ca2+ release
Authors: Schmidt Götz , Rienas Gerrit , Müller Sabrina , Richter Katrin , Sander Michael , Koch Christian , Henrich Michael
Published: September 2023

Mucociliary clearance is a pivotal physiological mechanism that protects the lung by cleaning the airways from pollution and colonization, thereby preventing infection. Ciliary function is influenced by various signal transduction cascades, and Ca2+ represents a key second messenger. A fixed 20:1 combination of cafedrine and theodrenaline has been widely used to treat perioperative hypotension and emergency hypotensive states since the 1960s; however, its effect on the intracellular Ca2+ concentration ([Ca2+]i) of respiratory epithelium remains unknown. Therefore, human tracheal epithelial cells were exposed to the clinically applied 20:1 mixture of cafedrine/theodrenaline and the individual substances separately. [Ca2+]i was assessed by FURA-2 340/380 fluorescence ratio. Pharmacological inhibitors were applied to elucidate relevant signal transduction cascades, and reverse transcription polymerase chain reaction (RT-PCR) was performed on murine tracheal epithelium to analyze ryanodine receptor (RyR) subtype expression. All three pharmacological preparations instantaneously induced a steep increase in [Ca2+]i that quickly returned to its baseline value despite the persistence of each substance. Peak [Ca2+]i following the administration of 20:1 cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone increased in a dose-dependent manner, with median effective concentrations of 0.35 mM (7.32 mM cafedrine and 0.35 mM theodrenaline), 3.14 mM, and 3.45 mM, respectively. When extracellular Ca2+ influx was inhibited using a Ca2+-free buffer solution, the peak [Ca2+]i following the administration of cafedrine alone and theodrenaline alone were reduced but not abolished. No alteration in [Ca2+]i compared with baseline [Ca2+]i was observed during β-adrenergic receptor inhibition. Depletion of caffeine-sensitive stores and inhibition of RyR, but not IP3 receptors, completely abolished any increase in [Ca2+]i. However, [Ca2+]i still increased following the depletion of mitochondrial Ca2+ stores using 2,4-dinitrophenol. RT-PCR revealed RyR-2 and RyR-3 expression on murine tracheal epithelium. Although our experiments showed that cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone release Ca2+ from intracellular stores through mechanisms that are exclusively triggered by β-adrenergic receptor stimulation, which most probably lead to RyR activation, clinical plasma concentrations are considerably lower than those used in our experiments to elicit an increase in [Ca2+]i; therefore, further studies are needed to evaluate the ability of cafedrine/theodrenaline to alter mucociliary clearance in clinical practice.
Prediction of some milk production traits using udder and teat measurements with a spotlight on their genetic background in Friesian cows
Authors: Saleh Ahmed. A. , Easa Ahmed A. , EL-Hedainy Dalia K. , Rashad Amr M. A.
Published: September 2023

The aggregate udder shape (Bowl, Round, Cup), udder measurements (udder width, UW, udder front depth, UFD, udder rear depth, URD, udder levelness, ULV, udder heights, UH) and teat measurements (teat diameters, TD, front teat length, FTL, rear teat length, RTL, distance between front teats, DFT and distance between rear teats, DRT) were measured on 1300 Friesian cows located in a commercial farm under subtropical conditions (Egypt) to appraise udder and teats status and to evaluate the possible relationships with some milk production characteristics in conjunction with udder shape, age at first calving, sire and inbreeding effects on udder morphological traits and milk production ability. For such an available sample size, parity had affected (P < 0.01) UFD, TD, FTL and RTL. In addition, udder shape affected (P < 0.01) UW, UFD, URD, ULV and DFT. None of the other studied factors affected milk production traits. The bowl udder shape (P < 0.01) yielded a high total milk yield (3267.19 kg), adjusted milk yield (2443.01 kg) and lactation length (480.70 d) compared to other udder shapes. The genetic correlations of UW with total milk yield and persistency were strongly positive (0.86 and 0.93, respectively). However, strong negative genetic correlations were found between UW with peak milk yield and lactation length (− 0.92 and − 0.80, respectively), between RTL with peak milk yield (− 0.92) and DRT with persistency (− 0.79). As found from the stepwise multiple regression, UW and URD can be used as good indicators for predicting milk yield and lactation length. Additionally, this study spotlights the genetic background of udder characteristics based on reliable studies and the QTL database for cattle as a first step toward applying this knowledge side by side with phenotypic traits to improve the productivity of the Holstein breed under subtropical conditions.
Serpin E1 mediates the induction of renal tubular degeneration and premature senescence upon diabetic insult
Authors: Chen Bo Han , Lu Xiao Qing , Liang Xian Hui , Wang Pei
Published: September 2023

As a leading cause of chronic kidney disease, diabetic kidney disease (DKD) involves insidious but progressive impairments of renal tubules, and is associated with premature renal aging. The underlying pathomechanisms remain elusive. Post hoc analyses of the publicly-available renal transcriptome revealed that TGFβ1 is overexpressed in renal tubulointerstitia in patients with DKD and positively correlated with kidney aging signaling. This finding was validated in kidney biopsy specimens collected from patients with DKD, associated with renal tubular senescence and degenerative changes. In vitro in renal tubular epithelial cells, exposure to a diabetic milieu, stimulated with high ambient glucose and TGFβ1, elicited premature senescence, as evidenced by staining for senescence-associated β-galactosidase activity and increased expression of p16INK4A, and p53. This coincided with Serpin E1 induction, in parallel with increased fibronectin accumulation and reduced expression of the epithelial marker E-cadherin, all indicative of degenerative changes. Reminiscent of the action of typical senolytics, a small molecule inhibitor of Serpin E1 substantially mitigated the pro-senescent and degenerating effects of the diabetic milieu, suggesting an essential role of Serpin E1 in mediating renal tubular senescence upon diabetic insult. Moreover, inhibition of Serpin E1 abolished the diabetic insult-triggered paracrine senescence of renal tubular cells. In consistency, in patients with DKD, renal tubular expression of Serpin E1 was upregulated and positively correlated with tubular senescence and fibrosis in renal tubulointerstitia. Collectively, diabetic insult induces renal tubular degeneration and premature senescence via, at least in part, Serpin E1 signaling.