bluuebunny/crossref_metadata_2025 huggingface dataset:
Pretransplant Malnutrition, Particularly With Muscle Depletion Is Associated With Adverse Outcomes After Kidney Transplantation
Authors: Lorden Heather , Engelken Jessa , Sprang Katrina , Rolfson Megan , Mandelbrot Didier , Parajuli Sandesh
Published: April 2024

Background.

Kidney transplant centers lack consistent diagnostic malnutrition tools. The Academy of Nutrition and Dietetics and American Society of Parenteral Nutrition Adult Malnutrition Criteria (AMC) is the widely accepted and utilized tool by Registered Dietitian Nutritionists (RDNs) to diagnose malnutrition.

Methods.

In this single-center, retrospective observational study, we evaluated the outcomes of prekidney transplant malnutrition based on Academy of Nutrition and Dietetics and American Society of Parenteral Nutrition AMC, as well as the individual components of the AMC, on posttransplant outcomes including length of stay, delayed graft function (DGF), early readmission, cardiovascular events, acute rejection, death-censored graft failure, and death. Bivariable and multivariable logistic regression models were used to assess the association of malnutrition or its components with outcomes of interest.

Results.

A total of 367 recipients were included, of whom 36 (10%) were malnourished (23 moderately and 13 severely) at pretransplant evaluation. In adjusted models, pretransplant malnutrition was significantly associated with increased risk for early readmission (adjusted odds ratio 2.86; 95% confidence interval: 1.14-7.21; P = 0.03) and with DGF (adjusted odds ratio 8.33; 95% confidence interval: 1.07-64.6; P = 0.04). Muscle depletion was also associated with an increased risk for readmission and with DGF. Fat depletion and reduced functionality in the adjusted model were only associated with increased risk for readmission.

Conclusions.

Malnutrition could be an important consideration for selecting kidney transplant recipients because it was associated with poor clinical outcomes. A multidisciplinary approach with the involvement of RDNs to outline a nutrition intervention plan may help mitigate some of the poor outcomes.
Genome-wide annotation of transcript boundaries using bacterial Rend-seq datasets
Authors: Lawaetz Andreas C. , Cowley Lauren A. , Denham Emma L.
Published: April 2024

Accurate annotation to single-nucleotide resolution of the transcribed regions in genomes is key to optimally analyse RNA-seq data, understand regulatory events and for the design of experiments. However, currently most genome annotations provided by GenBank generally lack information about untranslated regions. Additionally, information regarding genomic locations of non-coding RNAs, such as sRNAs, or anti-sense RNAs is frequently missing. To provide such information, diverse RNA-seq technologies, such as Rend-seq, have been developed and applied to many bacterial species. However, incorporating this vast amount of information into annotation files has been limited and is bioinformatically challenging, resulting in UTRs and other non-coding elements being overlooked or misrepresented. To overcome this problem, we present pyRAP (python Rend-seq Annotation Pipeline), a software package that analyses Rend-seq datasets to accurately resolve transcript boundaries genome-wide. We report the use of pyRAP to find novel transcripts, transcript isoforms, and RNase-dependent sRNA processing events. In Bacillus subtilis we uncovered 63 novel transcripts and provide genomic coordinates with single-nucleotide resolution for 2218 5′UTRs, 1864 3′UTRs and 161 non-coding RNAs. In Escherichia coli, we report 117 novel transcripts, 2429 5′UTRs, 1619 3′UTRs and 91 non-coding RNAs, and in Staphylococcus aureus, 16 novel transcripts, 664 5′UTRs, 696 3′UTRs, and 81 non-coding RNAs. Finally, we use pyRAP to produce updated annotation files for B. subtilis 168, E. coli K-12 MG1655, and S. aureus 8325 for use in the wider microbial genomics research community.
Streptococcus pyogenespharyngitis elicits diverse antibody responses to key vaccine antigens influenced by the imprint of past infections
Authors: Osowicki Joshua , Frost Hannah R , Azzopardi Kristy I , Whitcombe Alana L , McGregor Reuben , Carlton Lauren H. , Baker Ciara , Fabri Loraine , Pandey Manisha , Good Michael F , Carapetis Jonathan R. , Walker Mark J , Smeesters Pierre R , Licciardi Paul V , Moreland Nicole J , Hill Danika L , Steer Andrew C
Published: April 2024

Knowledge gaps regarding human immunity toStreptococcus pyogeneshave impeded vaccine development. To address these gaps and evaluate vaccine candidates, we established a human challenge model ofS. pyogenespharyngitis. Here, we analysed antibody responses in serum and saliva against 19 antigens to identify characteristics distinguishing 19 participants who developed pharyngitis and 6 who did not. Pharyngitis elicited serum IgG responses to key vaccine antigens and a muted mucosal IgA response, whereas the 6 participants without pharyngitis had more pronounced IgA responses and minimal IgG responses. Serum IgG responses to pharyngitis in adult participants resembled those observed in children and were inversely correlated with the magnitude of pre-existing responses. While a straightforward correlate of protection was not evident, baseline antibody signatures distinguished clinical and immunological outcomes following experimental challenge. This highlights the influence of a complex humoral imprint from previous exposure, relevant for interpreting immunogenicity in forthcoming vaccine trials.
An adapted typology of tree-related microhabitats including tropical forests
Authors: Nußer Ronja , Bianco Giovanni , Kraus Daniel , Larrieu Laurent , Feldhaar Heike , Schleuning Matthias , Müller Jörg
Published: April 2024

Tree-related microhabitats (TreMs) describe the microhabitats that a tree can provide for a multitude of other taxonomic groups and have been proposed as an important indicator for forest biodiversity (Asbeck et al., 2021). So far, the focus of TreM studies has been on temperate forests, although many trees in the tropics harbour exceptionally high numbers of TreMs. In this study, TreMs in the lowland tropical forests of the Choco (Ecuador) and in the mountain tropical forests of Mount Kilimanjaro (Tanzania) were surveyed. Our results extend the existing typology of TreMs of Larrieu et al. (2018) to include tropical forests and enabled a comparison of the relative recordings and diversity of TreMs between tropical and temperate forests. A new TreM form, Root formations, and three new TreM groups, concavities build by fruits or leaves, dendrotelms, and root formations, were established. In total, 15 new TreM types in five different TreM groups were specified. The relative recordings of most TreMs were similar between tropical and temperate forests. However,ivy and lianas,andfernswere more common in the lowland rainforest than in temperate forests, andbark microsoil,limb breakage,andfoliose and fruticose lichensin tropical montane forest than in lowland rainforest. Mountain tropical forests hosted the highest diversity for common and dominant TreM types, and lowland tropical forest the highest diversity for rare TreMs. Our extended typology of tree-related microhabitats can support studies of forest-dwelling biodiversity in tropical forests. Specifically, given the ongoing threat to tropical forests, TreMs can serve as an additional tool allowing rapid assessments of biodiversity in these hyperdiverse ecosystems.
Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline
Authors: Cheng Keren , Seita Yasunari , Whelan Eoin C. , Yokomizo Ryo , Hwang Young Sun , Rotolo Antonia , Krantz Ian D. , Kaur Maninder , Ginsberg Jill P. , Lal Priti , Luo Xunda , Pierorazio Phillip M. , Linn Rebecca L. , Ryeom Sandra , Sasaki Kotaro
Published: April 2024

Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory primordial germ cells, but exhibit enhanced germline and pluripotency programs, and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister Killian syndrome patients mosaic for i(12p) to model seminoma, we identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular and signaling programs driving seminoma transformation, and the newly developed in vitro platform permits evaluation of additional signals required for seminoma tumorigenesis.
FInCH: FIJI plugin for automated and scalable whole-image analysis of protein expression and cell morphology
Authors: Lee Cody A. , Moreno Carmen Sánchez , Badyaev Alexander V.
Published: April 2024

Study of morphogenesis and its regulation requires analytical tools that enable simultaneous assessment of processes operating at cellular level, such as synthesis of transcription factors (TF), with their effects at the tissue scale. Most current studies conduct histological, cellular and immunochemical (IHC) analyses in separate steps, introducing inevitable biases in finding and alignment of areas of interest at vastly distinct scales of organization, as well as image distortion associated with image repositioning or file modifications. These problems are particularly severe for longitudinal analyses of growing structures that change size and shape. Here we introduce a python-based application for automated and complete whole-slide measurement of expression of multiple TFs and associated cellular morphology. The plugin collects data at customizable scale from the cell-level to the entire structure, records each data point with positional information, accounts for ontogenetic transformation of structures and variation in slide positioning with scalable grid, and includes a customizable file manager that outputs collected data in association with full details of image classification (e.g., ontogenetic stage, population, IHC assay). We demonstrate the utility and accuracy of this application by automated measurement of morphology and associated expression of eight TFs for more than six million cells recorded with full positional information in beak tissues across 12 developmental stages and 25 study populations of a wild passerine bird. Our script is freely available as an open-source Fiji plugin and can be applied to IHC slides from any imaging platforms and transcriptional factors.

Graphical abstract

Specifications table
The effects of parasitism on sex allocation of a hermaphroditic acorn barnacle
Authors: Tamechika Masami M. , Yamada Hiroyuki , Ijiri Shigeho , Yusa Yoichi
Published: April 2024

Sex allocation theory predicts the adaptive allocation of resources to male versus female reproduction in simultaneous hermaphrodites in response to individual characteristics or environmental factors. Because parasites uptake resources from their hosts, their presence could affect the sex allocation of the hosts. We investigated the effects of infestation status and infestation intensity by the rhizocephalan barnacleBoschmaella japonicaon reproduction, including sex allocation, of the host intertidal barnacleChthamalus challengeri. Feeding activity was also examined as a factor related to resource intake. Both male and female reproductive investment decreased with increasing parasite infestation, and the sex allocation of large infested hosts was more male-biased than that of large uninfested hosts. Moreover, in contrast to the model prediction that male investment does not change under resource limitation, male investment decreased in infested hosts whose resources were taken by parasites. This reduction in male investment could be explained by changes in mating group size, since infested hosts have shorter penises and consequently are able to access fewer mating partners.
Scale-free dynamics of cerebrospinal fluid regions is associated with Alzheimer’s disease-related pathology
Authors: Guo Qiwei , Hua Lin , Zhao Zhiying , Yuan Zhen
Published: April 2024

Cerebrospinal Fluid (CSF) clearance is one of the central mechanisms for removal of amyloid-β (Aβ) and tau proteins from the central nervous system that are closely linked to Alzheimer’s Disease (AD) pathology. Conventional functional imaging studies in AD have primarily focused on activities in the brain while ignoring macroscopic cerebrospinal fluid (CSF) activities. In the current study, we utilized a public dataset from the Alzheimer’s Disease Neuroimaging Initiative. Our analysis spanned both brain and cerebrospinal fluid (CSF) areas. We compared the scale-free dynamics in fMRI signals across three groups: cognitively normal individuals (CN), people with Alzheimer’s Disease (AD), and those with mild cognitive impairments (MCI). Scale-free dynamics are patterns of brain activity that remain consistent across different time scales. Our comparison focused on the Hurst exponent (H), a measure derived from detrended fluctuation analysis (DFA), to characterize these dynamics. This comparison revealed clusters in the fourth ventricle and subarachnoid space (medioventral channel along the spinal axis). In these CSF-filled structures, H was significantly higher in AD group comparing to CN. Moreover, H in these two clusters correlated with AD pathological biomarkers including CSF Aβ and tau in the AD group. These findings suggested scale-free properties of macroscopic CSF flow as a potential imaging biomarker for AD. This biomarker can be readily acquired from common resting-state fMRI scans and therefore may be valuable for AD diagnosis.
Interplay of genotypic and thermal sex determination shapes climatic distribution in herpetofauna
Authors: Nemesházi Edina , Bókony Veronika
Published: April 2024

Sex is a fundamental trait of all sexually reproducing organisms, and sex-determination systems show a great diversity across the tree of life. A growing body of evidence shows that genotypic and temperature-dependent sex determination (GSD and TSD, respectively) can coexist, which theoretically can have wide-ranging consequences for demography and population persistence, especially under climate change. Temperature-induced sex reversal, resulting from combined effects of sex chromosomes and environmental temperatures on sexual development, can explain the frequent transitions between GSD and TSD, and even between different GSD systems, that happened multiple times in ectothermic vertebrates. However, general lack of empirical data on the prevalence of sex reversal has long constrained the assessment of its evolutionary-ecological significance. Here we analysed an exhaustive compilation of available data to demonstrate that the climatic distribution of extant species is explained by the combination of their sex-chromosome system (GSD) and temperature reaction norm (TSD) across the phylogeny of amphibians and some reptiles. This pattern is in accordance with predictions of the ‘asymmetrical sex reversal’ theory, underscoring the importance of temperature-induced sex reversal in phylogeography, evolution, and species conservation under the threat of climate change, and highlighting the need for more empirical research on sex reversal in nature.
Glia-Mediated Antigen Presentation In The Retina During Degeneration
Authors: Intonti Simona , Kokona Despina , Zinkernagel Martin S. , Stein Jens V. , Enzmann Volker , Conedera Federica M.
Published: April 2024

Glia antigen-presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. The intricate mechanisms underlying their local coordination and activation remain unclear.

Our study integrates an animal model of retinal injury, retrospective analysis of human retinas, and in vitro experiments to elucidate insights into the pivotal role of antigen presentation in neuroimmunology during retinal degeneration, uncovering the involvement of various glial cells, notably Müller glia, and microglia. Glial cells act as sentinels, detecting antigens released during degeneration and interacting with T-cells via MHC molecules, which are essential for immune responses. Microglia function as APCs via the MHC class II pathway, upregulating key molecules such as Csf1r and cytokines. In contrast, Müller cells act as atypical APCs through the MHC class I pathway, exhibiting upregulated antigen processing genes and promoting a CD8+T-cell response. Distinct cytokine signaling pathways, including TNF-α and IFN, contribute to the immune balance. Human retinal specimens corroborate these findings, demonstrating glial activation and MHC expression correlating with degenerative changes. In vitro assays also confirmed differential T-cell migration responses to activated microglia and Müller cells, highlighting their role in shaping the immune milieu within the retina. These insights emphasize the complex interplay between glial cells and T-cells, influencing the inflammatory environment and potentially modulating degenerative processes.

In summary, our study emphasizes the involvement of retinal glial cells in modulating the immune response after insults to the retinal parenchyma. Thus, unraveling the intricacies of glia-mediated antigen presentation in retinal degeneration is essential for developing precise therapeutic interventions for retinal pathologies.
Coated crystalline essential amino acid supplementation supports high soybean meal inclusion in diets for Nile tilapia (Oreochromis niloticus) with improved protein retention and nutrient assimilation
Authors: Davies Simon J. , Bell Matt E.
Published: April 2024

The aquaculture industry has previously relied on high-quality fishmeal (FM) to produce diets of excellent standards. However, plant-based proteins such as soybean are more cost-effective for low-value fish species, for example, tilapia and carp, and fishmeal use has been significantly diminished. Previous studies have mainly addressed standard soybean meal (SBM) sources in aquafeeds. A 55-day feeding trial was conducted to investigate the replacement of fish meal with soybean meal concentrate in Nile tilapia (Oreochromis niloticus)using a semi-purified diet approach against a Low Temperature (LT) fishmeal as a primary reference protein. Four diets with different levels of soybean meal were evaluated and compared to a control diet of 100 % fish meal. Three diets containing 20, 40, and 80 % soybean protein concentrate (SBPC) were examined. The fourth diet consisted of 80 % SBPC and two essential amino acids: lysine and methionine (80SBPCAA) in a coated form. The average daily growth values highlight similar daily growth rates when tilapia was fed 100FM and 40SBPC. No significant differences were observed in the final mean weight for all soybean-fed tilapia, but they were marginally lower than the 100FM control diet group. The 80SBPC diet showed the poorest feed conversion ratio (FCR) at 1.31 and protein efficiency ratio (PER) at 2.19. However, the 80SBPCAAdiet showed a significantly improved result for per cent weight gain compared to the 80SBPC-fed tilapia. Also, protein efficiency ratio was significantly higher at 2.47 and had a better Apparent Net Protein Utilization (ANPU) value of 28.51 % compared to un-supplemented 80SBPC-fed tilapia (25.48 %). These results confirmed that high-quality fishmeal can be substituted by up to 40 % SBPC alone and without any detrimental effects on growth or carcass composition. Further studies on plant proteins and supplementary amino acids as a suitable alternative for replacing high-quality fishmeal may promote a more sustainable aquaculture industry.
A Comprehensive Collection of Pain and Opioid Use Disorder Compounds for High-Throughput Screening and Artificial Intelligence-Driven Drug Discovery
Authors: Hu Xin , Shinn Paul , Itkin Zina , Ye Lin , Zhang Ya-Qin , Shen Min , Ford-Scheimer Stephanie , Hall Matthew D.
Published: April 2024

As part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, the National Center for Advancing Translational Sciences (NCATS) is dedicated to the development of new pharmacological tools and investigational drugs for managing and treating pain, as well as the prevention and treatment of opioid misuse and addiction. In line with these objectives, we created a comprehensive, annotated small molecule library including drugs, probes, and tool compounds that act on published pain and addiction-relevant targets. Nearly 3,000 small molecules associated with approximately 200 known and hypothesized HEAL targets have been assembled, curated, and annotated in one collection. Physical samples of the library compounds have been acquired and plated in 1536-well format, enabling rapid and efficient high throughput screen (HTS) against a wide range of assays. The creation of the HEAL Targets and Compounds Library, coupled with an integrated computational platform for AI-driven machine learning (ML), structural modeling, and virtual screening (VS), provides a valuable source for strategic drug repurposing, innovative profiling, and hypothesis testing of novel targets related to pain and opioid use disorder (OUD). The library is available to investigators for screening pain and OUD-relevant phenotypes.
Tagging of Exo70 at the N-terminus compromises its assembly with the exocyst complex and changes its spatiotemporal behavior at the plasma membrane
Authors: Gosain Hiteshika , Seebohm Guiscard , Holtmannspötter Michael , Kurre Rainer , Busch Karin B.
Published: April 2024

The vesicle-tethering exocyst complex is a key regulator of cell polarity. The subunit Exo70 is required for the targeting of the exocyst complex to the plasma membrane. While the N-terminus of Exo70 is important for its regulation by GTPases, the C-terminus binds to PI(4,5)P2 and Arp2/3. Here, we compare N- and C-terminal tagged Exo70 with respect to subcellular localization, dynamics and function in cell membrane expansion. Using high-resolution imaging, we determined the spatial distribution and dynamics in different sub-compartments of un-polarized and polarized cells. With lattice light-sheet microscopy, we show that HaloTag-Exo70, but not Exo70-HaloTag, promotes the outgrowth of filopodia-like structures from the axon of hippocampal neurons. Fluorescence lifetime imaging of sfGFP-Exo70 and molecular modeling results suggest that the assembly of sfGFP-Exo70 with the exocyst complex is reduced. This is supported by single particle tracking data showing higher mobility of N- than C-terminal tagged Exo70 at the plasma membrane. The distinct spatiotemporal properties of N-terminal tagged Exo70 were correlated with pronounced filopodia formation in unpolarized cells and neurons, a process that is less reliant on exocyst complex formation. We therefore propose that N-terminal tagging of Exo70 shifts its activity to processes that are less exocyst-dependent.

Why it matters

In the life sciences, the high-resolution visualization of processes in living cells is of great interest. To tag proteins, they are fused with fluorescent proteins, usually at the N- or C-terminus of the amino acid sequence. We show here that the position of the tag alters the function and interaction of Exo70, a polypeptide involved in vesicle fusion, but also in membrane bending and expansion. Using state-of-the-art microscopic techniques, single particle localization and tracking, fluorescence lifetime imaging microscopy and co-localization in combination with modeling, we conclude that N-terminal tagging of Exo70 impairs its assembly with the exocyst complex and instead promotes the interaction of free Exo70 with the actin skeleton, which favors controlled membrane expansion into filipodia.
Heart rate changes related to risky selections and outcomes in a rat gambling task
Authors: Fukushima Fumiya , Tamura Atsushi , Kuga Nahoko , Sasaki Takuya
Published: April 2024

Risk-taking behavior is crucial for animals to increase their potential outcomes and is considered to alter arousal states in the brain and body represented by heart rates. In this study, we monitored changes in heart rate as rats performed a gambling task in which they selected either a certain outcome with 100% probability (sure option) or a probabilistic double outcome with 50% probability (risky option). We found that when rats selected risky options, they exhibited significantly greater decreases in their instantaneous heart rates immediately before selection than when they selected certain options. In addition, we observed significantly larger increases in instantaneous heart rates when the rats were informed of the larger number of outcomes after selecting the risky options than after selecting the sure options. These results demonstrate that animals can dynamically alter their instantaneous heart rates in response to risky selection and outcomes.
Atlas of Cynomolgus Macaque Hematopoiesis
Authors: Oshima Shinichiro , Sinha Rahul , Takeuchi Kazuhiro , Mizuta Ken , Nakamura Tomonori , Ito Ryoji , Kawamoto Ikuo , Iwatani Chizuru , Nakaya Masataka , Tsuchiya Hideaki , Bhagat Shruti , Tsukiyama Tomoyuki , Takaori-Kondo Akifumi , Saitou Mitinori , Murakawa Yasuhiro , Yamamoto Ryo
Published: April 2024

Self-renewal and differentiation are inherent properties of hematopoietic stem cells (HSCs) that are necessary to support hematopoiesis; however, the underlying mechanisms, especially in human, remain unclear. Here, using the cynomolgus macaque as a surrogate model, we develop a new gating strategy to isolate with high purity transplantable cynomolgus HSCs and generated a single-cell transcriptomic map of cynomolgus HSCs and progenitor cells — that covering gestational periods previously not analyzed in human. We show that hematopoietic cells from the late-1stto early-3rdtrimester fetal liver and late-2ndtrimester and thereafter bone marrow have repopulating potential, closely mimicking humans. Unexpectedly however, we found unlike in human, cynomolgus HSCs express CD38 but not CD33, indicating that these cellular counterparts are molecularly distinct. Our transcriptomic analysis reveals the presence of a direct differentiation pathway from HSCs to megakaryocyte lineages, lineage-primed multipotent progenitors and also identified putative HSC surface markers. Taken together, our comprehensive dataset highlights not only the utility of cynomolgus monkeys as model systems to study hematopoiesis but also their potential for translational applications.
Temporal tissue dynamics from a spatial snapshot
Authors: Somer Jonathan , Mannor Shie , Alon Uri
Published: April 2024

Physiological and pathological processes such as inflammation or cancer emerge from the interactions between cells over time. However, methods to follow cell populations over time within the native context of a human tissue are lacking, because a biopsy offers only a single snapshot. Here we present one-shot tissue dynamics reconstruction (OSDR), an approach to estimate a dynamical model of cell populations based on a single tissue sample. OSDR uses spatial proteomics to learn how the composition of cellular neighborhoods influences division rate, providing a dynamical model of cell population change over time. We apply OSDR to human breast cancer data, and reconstruct two fixed points of fibroblasts and macrophage interactions. These fixed points correspond to hot and cold fibrosis, in agreement with co-culture experiments that measured these dynamics directly. We then use OSDR to discover a pulse-generating excitable circuit of T and B cells in the tumor microenvironment, suggesting temporal flares of adaptive anti-cancer responses. Finally, we study longitudinal biopsies from a triple negative breast cancer clinical trial, where OSDR predicts the collapse of the tumor cell population in responders versus non-responders based on early treatment biopsies. OSDR can be applied to a wide range of spatial proteomics assays to enable analysis of tissue dynamics based on patient biopsies.
Chromosome level genome reference of the Caucasian dwarf gobyKnipowitschiacf.caucasica, a new alien Gobiidae invading the River Rhine
Authors: Schoenle Alexandra , Guiglielmoni Nadège , Mainz Tobias , Greve Carola , Hamadou Alexander Ben , Heermann Lisa , Borcherding Jost , Waldvogel Ann-Marie
Published: April 2024

The Caucasian dwarf gobyKnipowitschiacf.caucasicais a new invasive alien Gobiidae spreading in the Lower Rhine since 2019. Little is known about the invasion biology of the species and further investigations to reconstruct the invasion history are lacking genomic resources. We assembled a high-quality chromosome-scale reference genome ofKnipowitschiacf.caucasicaby combining PacBio, Omni-C and Illumina technologies. The size of the assembled genome is 956.58 Mb with a N50 scaffold length of 43 Mb, which includes 92.3 % complete Actinopterygii Benchmarking Universal Single-Copy Orthologs. 98.96 % of the assembly sequence was assigned to 23 chromosome-level scaffolds, with a GC-content of 42.83 %. Repetitive elements account for 53.08 % of the genome. The chromosome-level genome contained 26,404 transcripts with 23,210 multi-exons, of which 26,260 genes were functionally annotated. In summary, the high-quality genome assembly provides a fundamental basis to understand the adaptive advantage of the species.
Predicting organoid morphology through a phase field model: insights into cell division and lumenal pressure
Authors: Tanida Sakurako , Fuji Kana , Lu Linjie , Guyomar Tristan , Lee Byung Ho , Honigmann Alf , Grapin-Botton Anne , Riveline Daniel , Hiraiwa Tetsuya , Nonomura Makiko , Sano Masaki
Published: April 2024

Organoids are ideal systems to predict the phenotypes of organs. However, there is currently a lack of understanding regarding the generalized rules that enable use of simple cellular principles to make morphological predictions of entire organoids. Therefore, we employed a phase field model with the following basic components: the minimum conditions for the timing and volume of cell division, lumen nucleation rules, and lumenal pressure. Through our model, we could compute and generate a myriad of organoid phenotypes observed till date. We propose morphological indices necessary to characterize the shapes and construct phase diagrams and show their dependencies on proliferation time and lumen pressure. Additionally, we introduced the lumen-index parameter, which helped in examining the criteria to maintain organoids as spherical structures comprising a single layer of cells and enclosing an intact lumen. Finally, we predict a star-like organoid phenotype that did not undergo differentiation, suggesting that the volume constraint during cell division may determine the final phenotype. In summary, our approach provides researchers with guidelines to test the mechanisms of self-organization and predict the shape of organoid.

Author summary

In nature, a wide variety of organ morphologies are observed. Owing to the complexity of the process underlying the acquisition of organs’ morphology, it is challenging to investigate the mechanisms that lead to such variations. A promising approach to study these variations is the use of “computational organoid” study, which is the computational-based study of self-organizing shapes in multicellular assemblies and fluid-filled cavities called lumens that develop from a few proliferating cells. This study explores general mechanisms that dictate how various mechanical factors affect the growing self-organized multicellular assembly. We relied on computer simulations of the mathematical model called multicellular phase-field model with lumens and explored the mechanical factor effects, such as the lumen pressure while considering the time and volume conditions required for cell division. These simulations generated and categorized a wide range of organoid phenotypes based on the varying lumen pressure and cell division conditions. These phenotypes were characterized into seven distinct classes, based on the morphological index sets, including a cellular monolayer/multilayer surrounding single or multiple lumens and branch formation. These phenotypes were obtained without the assumption of differentiation. Our study elucidates the mechanisms underlying the organoid and organ formation with different shapes, thereby highlighting the significance of mechanical forces in shaping these complex biological structures.
Prefrontal encoding of an internal model for emotional inference
Authors: Gu Xiaowei , Johansen Joshua P.
Published: April 2024

A key function of brain systems mediating emotion is to learn to anticipate unpleasant experiences based on predictive sensory cues in the environment. While organisms readily associate sensory stimuli with aversive outcomes, higher-order forms of emotional learning and memory require inference to extrapolate the circumstances surrounding directly experienced aversive events to other indirectly related contexts and sensory patterns which weren’t a part of the original experience. To achieve this type of learning requires internal models of emotion which flexibly track directly experienced and inferred aversive associations. While the brain mechanisms of simple forms of aversive learning have been well studied in areas such as the amygdala, whether and how the brain represents internal models of emotionally relevant associations is not known. Here we report that neurons in the rodent dorsomedial prefrontal cortex (dmPFC) encode an internal model of emotion by linking sensory stimuli in the environment with aversive events, whether they were directly or indirectly associated with that experience. These representations are flexible, and updating the behavioral significance of individual features of the association selectively modifies corresponding dmPFC representations. While dmPFC population activity encodes all salient associations, dmPFC neurons projecting to the amygdala specifically represent and are required to express inferred associations. Together, these findings reveal how internal models of emotion are encoded in dmPFC to regulate subcortical systems for recall of inferred emotional memories.
EEG Analyses of visual cue effects on executed movements
Authors: Suwandjieff Patrick , Müller-Putz Gernot R.
Published: April 2024

Background

In electroencephalographic (EEG) or electrocorticographic (ECoG) experiments, visual cues are commonly used for timing synchronization but may inadvertently induce neural activity and cognitive processing, posing challenges when decoding self-initiated tasks.

New Method

To address this concern, we introduced four new visual cues (Fade, Rotation, Reference, and Star) and investigated their impact on brain signals. Our objective was to identify a cue that minimizes its influence on brain activity, facilitating cue-effect free classifier training for asynchronous applications, particularly aiding individuals with severe paralysis.

Results

22 able-bodied, right-handed participants aged 18-30 performed hand movements upon presentation of the visual cues. Analysis of time-variability between movement onset and cue-aligned data, grand average MRCPs, and classification outcomes revealed significant differences among cues. Rotation and Reference cue exhibited favorable results in minimizing temporal variability, maintaining MRCP patterns, and achieving comparable accuracy to self-paced signals in classification.

Comparison with Existing Methods

Our study contrasts with traditional cue-based paradigms by introducing novel visual cues designed to mitigate unintended neural activity. We demonstrate the effectiveness of Rotation and Reference cue in eliciting consistent and accurate MRCPs during motor tasks, surpassing previous methods in achieving precise timing and high discriminability for classifier training.

Conclusions

Precision in cue timing is crucial for training classifiers, where both Rotation and Reference cue demonstrate minimal variability and high discriminability, highlighting their potential for accurate classifications in online scenarios. These findings offer promising avenues for refining brain-computer interface systems, particularly for individuals with motor impairments, by enabling more reliable and intuitive control mechanisms.
Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson's Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder
Authors: Dautan Daniel , Paslawski Wojciech , Montejo Sergio , Doyon Daniel , Marangiu Roberta , Kaplitt Michael G , Chen Rong , Dawson Valina L. , Zhang Xiaoqun , Dawson Ted M. , Svenningsson Per
Published: April 2024

Parkinson's disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient's quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mouse model involving injection of alpha-synuclein (aSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism. Using anatomical mapping of aSyn-PFF propagation and behavioral and physiological characterizations, we unveil a correlation between post-injection time the temporal dynamics of aSyn propagation and non-motor/motor manifestations of the disease. We highlight the concurrent presence of aSyn aggregates in key brain regions, expressing acetylcholine or dopamine, involved in sleep duration, wakefulness, and particularly REM-associated atonia corresponding to REM behavioral disorder-like symptoms. This study presents a novel and in-depth exploration into the multifaceted nature of PD, unraveling the complex connections between aSynucleinopathies, gut-brain connectivity, and the emergence of non-motor phenotypes.
Upregulated expression of ubiquitin ligase TRIM21 promotes PKM2 nuclear translocation and astrocyte activation in experimental autoimmune encephalomyelitis
Authors: Yang Luting , Hu Chunqing , Chen Xiaowen , Zhang Jie , Feng Zhe , Xiao Yanxin , He Weitai , Cui Tingting , Zhang Xin , Yang Yang , Zhang Yaling , Yan Yaping
Published: April 2024

Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. However, the role and molecular mechanism of metabolic reprogramming in activation of astrocytes have not been clarified. Here, we found that PKM2, a notoriously known rate-limiting enzyme of glycolysis, displayed nuclear translocation in astrocytes of EAE (experimental autoimmune encephalomyelitis) mice, an animal model of multiple sclerosis. Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines. Most importantly, we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. TRIM21 interacted with PKM2, promoted its nuclear translocation and stimulated its nuclear activity to phosphorylate STAT3, NF-κB and interact with c-myc. Further single-cell RNA sequencing and immunofluorescence staining demonstrated that TRIM21 expression was upregulated in astrocytes of EAE. TRIM21 overexpressing in primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58. Moreover, intracerebroventricular injection of a lentiviral vector to knockdown TRIM21 in astrocytes or intraperitoneal injection of TEPP-46, which inhibit the nuclear translocation of PKM2, effectively decreased disease severity, CNS inflammation and demyelination in EAE. Collectively, our study provides novel insights into the pathological function of nuclear glycolytic enzyme PKM2 and ubiquitination-mediated regulatory mechanism that are involved in astrocyte activation. Targeting this axis may be a potential therapeutic strategy for the treatment of astrocyte-involved neurological disease.
Neuroanatomical dissection of the MC3R circuitry regulating energy rheostasis
Authors: Possa-Paranhos Ingrid Camila , Butts Jared , Pyszka Emma , Nelson Christina , Cho Dajin , Sweeney Patrick
Published: April 2024

Although mammals resist both acute weight loss and weight gain, the neural circuitry mediating bi-directional defense against weight change is incompletely understood. Global constitutive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioral response to both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain following anabolic challenges and increased weight loss following anorexic challenges (i.e. impaired energy rheostasis). However, the brain regions mediating this phenotype remain incompletely understood.

Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase to selectively delete MC3R from medial hypothalamus (MH) in adult mice. Behavioral assays were performed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anorexic challenges. Complementary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific medial hypothalamic brain regions mediating the role of MC3R in energy homeostasis. Finally, we performed RNAscope in situ hybridization to map changes in the mRNA expression of MC3R, POMC, and AgRP following energy rheostatic challenges.

Our results demonstrate that MC3R deletion in MH increased feeding and weight gain following acute high fat diet feeding in males, and enhanced the anorexic effects of semaglutide, in a sexually dimorphic manner. Additionally, activation of DMH MC3R neurons increased energy expenditure and locomotion. Together, these results demonstrate that MC3R mediated effects on energy rheostasis result from the loss of MC3R signaling in the medial hypothalamus of adult animals and suggest an important role for DMH MC3R signaling in energy rheostasis.

Key Points:

MC3R signaling regulates energy rheostasis in adult mice

Medial hypothalamus regulates energy rheostasis in adult mice

Energy rheostasis alters mRNA levels of AgRP and MC3R in DMH

DMH MC3R neurons increase locomotion and energy expenditure

MC3R expression in DMH is sexually dimorphic
Force-Enhanced Sensitive Detection of New DNA-Interactive Agents from Microorganisms at the Single-Molecule Level
Authors: Liu Tianyu , Cai Teng , Liu Hongwei , Li Aiying , Yin Meng , Mei Yan , Zhou Yueyue , Fan Sijun , Lu Yao , Wan Luosheng , You Huijuan , Cai Xiaofeng
Published: April 2024

The discovery of microbial-derived DNA-interacting agents, which hold broad therapeutic potential, is inherently challenging due to the limited sensitivity and specificity of conventional methodologies. Our study introduces a pioneering application of single-molecule stretching assay (SMSA) in natural product chemistry to identify DNA-intercalating agents directly from microbial cultures or extracts. We demonstrate that mechanical force can enhance sensitivity by increasing both the binding affinityKa and the quantity of ligands bound. The changes induced by intercalators in the counter length and overstretching transition of dsDNA yield a distinctive and highly specific signature indicative of DNA intercalative binding, thereby enabling straightforward detection of DNA intercalators even in trace amounts from microbial cultures. This methodology eliminates the need for extensive large-scale fermentation and purification processes, thus offering a more streamlined approach to DNA-intercalating natural product discovery. By applying SMSA to 17 microorganisms, we identified two DNA intercalator-producing strains:Streptomyces tanashiensisandTalaromyces funiculosus. Subsequently, three DNA intercalators, namely medermycin, kalafungin, and ligustrone B, were isolated and characterized. Among them, medermycin and kalafungin showed significant inhibitory effects against HCT-116 cancer cells, withIC50values of 52 ± 6 nM and 70 ± 7 nM, respectively.
Perfusion-Independent Tissue Hypoxia in Cardiac Hypertrophy in Mice Measured by64Cu-CTS PET Imaging
Authors: Baark Friedrich , Michaels Aidan M. , Waters Edward C. T. , Rigby Alex , Kim Jana , Yu Zilin , Pell Victoria R. , Clark James E. , Blower Philip J. , Eykyn Thomas R. , Southworth Richard
Published: April 2024

Background

Hypoxia is central to many cardiac pathologies, but clinically its presence can only be inferred by indirect biomarkers including hypoperfusion and energetic compromise. Imaging hypoxia directly could offer new opportunities for the diagnosis and sub-stratification of cardiovascular diseases.

Objectives

To determine whether [64Cu]CuCTS Positron Emission Tomography (PET) can identify hypoxia in a murine model of cardiac hypertrophy.

Methods

Male C57BL/6 mice underwent abdominal aortic constriction (AAC) to induce cardiac hypertrophy, quantified by echocardiography over 4 weeks. Hypoxia and perfusion were quantified in vivo using [64Cu]CuCTS and [64Cu]CuGTSM PET, respectively, and radiotracer biodistribution was quantified post-mortem. Cardiac radiotracer retention was correlated with contractile function (measured by echocardiography), cardiac hypertrophy (measured by histology), HIF-1α stabilization and NMR-based metabolomics. The effect of anesthesia on [64Cu]CuCTS uptake was additionally investigated in a parallel cohort of mice injected with radiotracer while conscious.

Results

Hearts showed increased LV wall thickness, reduced ejection fraction and fractional shortening following AAC. [64Cu]CuCTS retention was 317% higher in hypertrophic myocardium (p<0.001), despite there being no difference in perfusion measured by64CuGTSM. Radiotracer retention correlated on an animal-by-animal basis with severity of hypertrophy, contractile dysfunction, HIF1α stabilization and metabolic signatures of hypoxia. [64Cu]CuCTS uptake in hypertrophic hearts was significantly higher when administered to conscious animals.

Conclusions

[64Cu]CuCTS PET can quantify cardiac hypoxia in hypertrophic myocardium, independent of perfusion, suggesting the hypoxia is caused by increased oxygen diffusion distances at the subcellular level. Alleviation of cardiac workload by anesthesia in preclinical models partially alleviates this effect.