bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical cell death in the growth plate chondrocytes ofTric-b-knockout mice
Authors: Ichimura Atsuhiko , Miyazaki Yuu , Nagatomo Hiroki , Tomizawa Masato , Kawabe Takaaki , Nakajima Nobuhisa , Okamoto Naoki , Komazaki Shinji , Kakizawa Sho , Nishi Miyuki , Takeshima Hiroshi
Published: March 2023

TRIC-A and TRIC-B proteins form homotrimeric cation-permeable channels in the sarco/endoplasmic reticulum (SR/ER) and nuclear membranes and are thought to contribute to counterionic flux coupled with store Ca2+release in various cell types. Serious mutations in theTRIC-Blocus cause autosomal recessive osteogenesis imperfecta (OI), which is characterized by insufficient bone mineralization. We have reported thatTric-b-knockout mice can be used as an OI model. Here we report irregular cell death in proliferating growth plate chondrocytes in developingTric-b-knockout bones. In the knockout chondrocytes, excess pro-collagen fibers were occasionally accumulated in severely dilated ER elements. Of the major ER stress pathways, the PERK pathway was preferentially hyperactivated in the knockout chondrocytes, and most likely altered gene expression to induce apoptosis-related proteins including CHOP and caspase 12. In Ca2+imaging experiments, the knockout chondrocytes exhibited aberrant Ca2+handling; ER Ca2+release was impaired, and intracellular Ca2+concentration was elevated. Our data suggest thatTric-bdeficiency directs growth plate chondrocytes to pro-apoptotic stages by compromising cellular Ca2+-handling and exacerbating ER stress, leading to atypical apoptotic cell death.
Scalable Solar-Driven Chemical Production by Semiconductor Biohybrids Synthesized from Wastewater Pollutants
Authors: Pi Shanshan , Yang Wenjun , Feng Wei , Yang Ruijie , Chao Weixiang , Cheng Wenbo , Cui Lei , Li Zhida , Lin Yiliang , Yang Chen , Lu Lu , Gao Xiang
Published: March 2023

Semiconductors biohybrids integrate the best of biological catalysts and semiconductor nanomaterials for solar-to-chemical conversion. To realize the potential of hybrid systems at the commercial level, it remains an urgent need for cost-competitive and environmentally friendly approaches to scaling up. Here, we successfully tackle this challenge through developing biohybrid route that co-utilize multi-pollutants in wastewater to produce semiconductor biohybridsin-situfor solar-to-chemical production. To achieve cost-effective biohybrid production, we introduced an aerobic sulfate reduction pathway intoVibrio natriegensto enable the direct utilization of the heavy metal ions (i.e., Cd2+), sulfate, and organics in the wastewater to biosynthesize functional semiconductor nanoparticles in livingV. natriegens. Furthermore, 2,3-butanediol biosynthetic pathway was introduced into theV. natriegenshybrid to couple the solar energy for enhanced bioproduction. We demonstrated the scalability of this system in a 5-L illuminated fermenter using wastewater as the feedstock, which resulted in production of 13 g/L of 2,3-butanediol. Life cycle analysis showed this specific biohybrid route had a significantly lower cost and reduced CO2emission compared to both pure sugars fermentation and fossil-based routes. In addition to providing a promising step toward sustainable commercializing semiconductor biohybrids for biomanufacturing, our work may lead to hybrid living matter toward future waste to wealth conversion.
Genetic Predisposition to Neuroblastoma Results from a Regulatory Polymorphism that Promotes the Adrenergic Cell State
Authors: Weichert-Leahey Nina , Shi Hui , Tao Ting , Oldridge Derek A , Durbin Adam D , Abraham Brian J. , Zimmerman Mark W , Zhu Shizhen , Wood Andrew C , Reyon Deepak , Joung J Keith , Young Richard A , Diskin Sharon J , Maris John M. , Look A Thomas
Published: March 2023

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like “mesenchymal” cell state and a more differentiated sympathetic “adrenergic” cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional co-factor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism G/T that affects aGATA motif in the first intron of LMO1. Here we show that wild-type zebrafish with theGATA genotype develop adrenergic neuroblastoma, while knock-in of the protectiveTATA allele at this locus reduces the penetrance of MYCN-driven tumors, which are restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrates thatTATA/TATA tumors also exhibit a mesenchymal cell state and are low risk at diagnosis. Thus, conversion of the regulatoryGATA to aTATA allele in the first intron ofLMO1reduces the neuroblastoma initiation rate by preventing formation of the adrenergic cell state, a mechanism that is conserved over 400 million years of evolution separating zebrafish and humans.
Multimodal fusion of multiple rest fMRI networks and MRI gray matter via multilink joint ICA reveals highly significant function/structure coupling in Alzheimer’s disease
Authors: Khalilullah K M Ibrahim , Agcaoglu Oktay , Sui Jing , Adali Tülay , Duda Marlena , Calhoun Vince D.
Published: March 2023

In this paper we focus on estimating the joint relationship between structural MRI (sMRI) gray matter (GM) and multiple functional MRI (fMRI) intrinsic connectivity networks (ICN) using a novel approach called multi-link joint independent component analysis (ml-jICA). The proposed model offers several improvements over the existing joint independent component analysis (jICA) model. We assume a shared mixing matrix for both the sMRI and fMRI modalities, while allowing for different mixing matrices linking the sMRI data to the different ICNs. We introduce the model and then apply this approach to study the differences in resting fMRI and sMRI data from patients with Alzheimer’s disease (AD) versus controls. The results yield significant differences with large effect sizes that include regions in overlapping portions of default mode network, and also hippocampus and thalamus. Importantly, we identify two joint components with partially overlapping regions which show opposite effects for Alzheimer’s disease versus controls, but were able to be separated due to being linked to distinct functional and structural patterns. This highlights the unique strength of our approach and multimodal fusion approaches generally in revealing potentially biomarkers of brain disorders that would likely be missed by a unimodal approach. These results represent the first work linking multiple fMRI ICNs to gray matter components within a multimodal data fusion model and challenges the typical view that brain structure is more sensitive to AD than fMRI.
GIPC3 couples to MYO6 and PDZ domain proteins and shapes the hair cell apical region
Authors: Chatterjee Paroma , Morgan Clive P. , Krey Jocelyn F. , Benson Connor , Goldsmith Jennifer , Bateschell Michael , Ricci Anthony J. , Barr-Gillespie Peter G.
Published: March 2023

GIPC3 has been implicated in auditory function. Initially localized to the cytoplasm of inner and outer hair cells of the cochlea, GIPC3 increasingly concentrated in cuticular plates and at cell junctions during postnatal development. Early postnatalGipc3KO/KOmice had mostly normal mechanotransduction currents, but had no auditory brainstem response at one month of age. Cuticular plates ofGipc3KO/KOhair cells did not flatten during development as did those of controls; moreover, hair bundles were squeezed along the cochlear axis in mutant hair cells. Junctions between inner hair cells and adjacent inner phalangeal cells were also severely disrupted inGipc3KO/KOcochleas. GIPC3 bound directly to MYO6, and the loss of MYO6 led to altered distribution of GIPC3. Immunoaffinity purification of GIPC3 from chicken inner ear extracts identified co-precipitating proteins associated with adherens junctions, intermediate filament networks, and the cuticular plate. Several of immunoprecipitated proteins contained GIPC-family consensus PDZ binding motifs (PBMs), including MYO18A, which binds directly to the PDZ domain of GIPC3. We propose that GIPC3 and MYO6 couple to PBMs of cytoskeletal and cell-junction proteins to shape the cuticular plate.

Summary statement

The PDZ-domain protein GIPC3 couples the molecular motors MYO6 and MYO18A to actin cytoskeleton structures in hair cells. GIPC3 is necessary for shaping the hair cell’s cuticular plate and hence the arrangement of the stereocilia in the hair bundle.
Predicting developmental relationships of tumor resident and circulating T cells in ovarian cancer
Authors: Carneiro Mayra S. , Bareche Yacine , Zhao Cheng , Thébault Pamela , Rahimi Kurosh , Provencher Diane , Samouélian Vanessa , Cormier Béatrice , Cailhier Jean-François , Mes-Masson Anne-Marie , Petropoulos Sophie , Stagg John , Lapointe Réjean
Published: March 2023

Characterizing T cell populations and understanding their developmental relationships may help design more effective cancer immunotherapies. We coupled single-cell transcriptomics and T cell receptor (TCR) αβ profiling of intratumoral and peripheral T cells in ovarian cancer patients to identify transcriptional programs and infer their relationship by trajectory and TCR overlap analyses. We proposed a model of differentiation pathway from an intermediate GZMH-expressing CD8 T cell subset found in the blood and tumor that progressively reinforces the exhaustion and tissue residency programs from aCCL4-expressing cluster towardsXCL1- andCXCL13-expressing terminally exhausted cells. Inferred cell communication analysis suggests that interaction withCXCL13-expressing CD4 T cells, which we refer to as Tfh-like cells, sustains the effector function of this intermediate GZMH-expressing CD8 T cell subset. Moreover, our results suggest that Tfh-like cells attract cells expressingGPR183through the production of its ligand 7α,25 dihydroxycholesterol (7α,25-HC). Finally, we demonstrated thatGPR183is highly expressed in a subset of pre-effectorGZMK-expressing CD8 T cells and plasmacytoid dendritic cells. Collectively, our results suggest that Tfh-like cells expressing IL-21 help promote antitumor immunity against ovarian tumors by coordinating the action of immune cells responsive to 7α,25-HC.
Mapping global marine biodiversity under sparse data conditions
Authors: Righetti Damiano , Vogt Meike , Gruber Nicolas , Zimmermann Niklaus E.
Published: March 2023

Sparse and spatiotemporally highly uneven sampling efforts pose major challenges to obtaining accurate species and biodiversity distributions. Here, we demonstrate how limited surveys can be integrated with global models to uncover hotspots and distributions of marine biodiversity. We test the skill of recent and advanced species distribution model setups to predict the global biodiversity of >560 phytoplankton species from 183,000 samples. Recent setups attain quasi-null skill, while models optimized for sparse data explain up to 91% of directly observed species richness variations. Using a refined spatial cross-validation approach to address data sparsity at multiple temporal resolutions we find that background choices are the most critical step. Predictor variables selected from broad sets of drivers and tuned for each species individually improve the models’ ability in identifying richness hotspots and latitude gradients. Optimal setups identify tropical hotspots, while common ones lead to polar hotspots disjunct from general marine diversity. Our results show that unless great care is taken to validate models, conservation areas in the ocean may be misplaced. Yet a game-changing advance in mapping diversity can be achieved by addressing data-sparse conditions that prevail for >80% of extant marine species.

Authorship statement

All authors designed the research and contributed to the writing. D.R. designed the multiscale validation and predictor selection methods, developed the figures with input by M.V. and N.E.Z., performed research, and wrote the first draft.
Brain Organoid Computing for Artificial Intelligence
Authors: Cai Hongwei , Ao Zheng , Tian Chunhui , Wu Zhuhao , Liu Hongcheng , Tchieu Jason , Gu Mingxia , Mackie Ken , Guo Feng
Published: March 2023

Brain-inspired hardware emulates the structure and working principles of a biological brain and may address the hardware bottleneck for fast-growing artificial intelligence (AI). Current brain-inspired silicon chips are promising but still limit their power to fully mimic brain function for AI computing. Here, we developBrainoware, living AI hardware that harnesses the computation power of 3D biological neural networks in a brain organoid. Brain-like 3Din vitrocultures compute by receiving and sending information via a multielectrode array. Applying spatiotemporal electrical stimulation, this approach not only exhibits nonlinear dynamics and fading memory properties but also learns from training data. Further experiments demonstrate real-world applications in solving non-linear equations. This approach may provide new insights into AI hardware.
Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes
Authors: Nagy Nadine , Kaber Gernot , Sunkari Vivekananda G. , Marshall Payton L. , Hargil Aviv , Kuipers Hedwich F. , Ishak Heather D. , Bogdani Marika , Hull Rebecca L. , Grandoch Maria , Fischer Jens W. , McLaughlin Tracey L. , Wight Thomas N. , Bollyky Paul L.
Published: March 2023

Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We have identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low levels of HA are present in healthy pancreatic islets. However, HA substantially accumulates in cadaveric islets of human T2D and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the major HA receptor CD44, preserve glycemic control and insulin levels in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserve glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we find that 4-MU increases the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation does not result in β-cell apoptosis. These data indicate a role for HA accumulation in diabetes pathogenesis and suggest that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.
An intact amber-free HIV-1 system for in-virus protein bioorthogonal click labeling that delineates envelope conformational dynamics
Authors: Ao Yuanyun , Grover Jonathan R. , Han Yang , Zhong Guohua , Qin Wenyi , Ghimire Dibya , Haque Anzarul , Bhattacharjee Rajanya , Zhang Baoshan , Arthos James , Lemke Edward A. , Kwong Peter D. , Lu Maolin
Published: March 2023

The HIV-1 envelope (Env) glycoprotein is conformationally dynamic and mediates membrane fusion required for cell entry. Single-molecule fluorescence resonance energy transfer (smFRET) of Env using peptide tags has provided mechanistic insights into the dynamics of Env conformations. Nevertheless, using peptide tags risks potential effects on structural integrity. Here, we aim to establish minimally invasive smFRET systems of Env on the virus by combining genetic code expansion and bioorthogonal click chemistry. Amber stop-codon suppression allows site-specifically incorporating noncanonical/unnatural amino acids (ncAAs) at introduced amber sites into proteins. However, ncAA incorporation into Env (or other HIV-1 proteins) in the virus context has been challenging due to low copies of Env on virions and incomplete amber suppression in mammalian cells. Here, we developed an intact amber-free virus system that overcomes impediments from preexisting ambers in HIV-1. Using this system, we successfully incorporated dual ncAAs at amber-introduced sites into Env on intact virions. Dual-ncAA incorporated Env retained similar neutralization sensitivities to neutralizing antibodies as wildtype. smFRET of click-labeled Env on intact amber-free virions recapitulated conformational profiles of Env. The amber-free HIV-1 infectious system also permits in-virus protein bioorthogonal labeling, compatible with various advanced microscopic studies of virus entry, trafficking, and egress in living cells.

Amber-free HIV-1 infectious systems actualized minimal invasive Env tagging for smFRET, versatile for in-virus bioorthogonal click labeling in advanced microscopic studies of virus-host interactions.
ClockBase: a comprehensive platform for biological age profiling in human and mouse
Authors: Ying Kejun , Tyshkovskiy Alexander , Trapp Alexandre , Liu Hanna , Moqri Mahdi , Kerepesi Csaba , Gladyshev Vadim N.
Published: March 2023

Aging represents the greatest risk factor for chronic diseases and mortality, but to understand it we need the ability to measure biological age. In recent years, many machine learning algorithms based on omics data, termed aging clocks, have been developed that can accurately predict the age of biological samples. However, there is currently no resource for systematic profiling of biological age. Here, we describeClockBase, a platform that features biological age estimates based on multiple aging clock models applied to more than 2,000 DNA methylation datasets and nearly 200,000 samples. We further provide an online interface for statistical analyses and visualization of the data. To show how this resource could facilitate the discovery of biological age-modifying factors, we describe a novel anti-aging drug candidate, zebularine, which reduces the biological age estimates based on all aging clock models tested. We also show that pulmonary fibrosis accelerates epigenetic age. Together,ClockBaseprovides a resource for the scientific community to quantify and explore biological ages of samples, thus facilitating discovery of new longevity interventions and age-accelerating conditions.
COVID-19 adenoviral vector vaccination elicits a robust memory B cell response with the capacity to recognize Omicron BA.2 and BA.5 variants
Authors: Fryer Holly A. , Hartley Gemma E. , Edwards Emily S.J. , Varese Nirupama , Boo Irene , Bornheimer Scott J. , Hogarth P. Mark , Drummer Heidi E. , O’Hehir Robyn E. , van Zelm Menno C.
Published: March 2023

Following the COVID-19 pandemic caused by SARS-CoV-2, novel vaccines have successfully reduced severe disease and death. Despite eliciting lower antibody responses, adenoviral vector vaccines are nearly as effective as mRNA vaccines. Therefore, protection against severe disease may be mediated by immune memory cells. We here evaluated plasma antibody and memory B cells (Bmem) targeting the Spike receptor binding domain (RBD) elicited by the adenoviral vector vaccine ChAdOx1 (AstraZeneca), their capacity to bind Omicron subvariants, and compared this to the response elicited by the mRNA vaccine BNT162b2 (Pfizer-BioNTech). Whole blood was sampled from 31 healthy adults pre-vaccination, and four weeks after dose one and dose two of ChAdOx1. Neutralizing antibodies (NAb) against SARS-CoV-2 were quantified at each timepoint. Recombinant RBDs of the Wuhan-Hu-1 (WH1), Delta, BA.2, and BA.5 variants were produced for ELISA-based quantification of plasma IgG and incorporated separately into fluorescent tetramers for flow cytometric identification of RBD-specific Bmem. NAb and RBD-specific IgG levels were over eight times lower following ChAdOx1 vaccination than BNT162b2. In ChAdOx1-vaccinated individuals, median plasma IgG recognition of BA.2 and BA.5 as a proportion of WH1-specific IgG was 26% and 17%, respectively. All donors generated resting RBD-specific Bmem, which were boosted after the second dose of ChAdOx1, and were similar in number to those produced by BNT162b2. The second dose of ChAdOx1 boosted Bmem that recognized VoC, and 37% and 39% of WH1-specific Bmem recognized BA.2 and BA.5, respectively. These data uncover mechanisms by which ChAdOx1 elicits immune memory to confer effective protection against severe COVID-19.
OsNLP4-OsD3 module integrates nitrogen-iron nutrient signals to promote rice tillering by repressing strigolactone signaling
Authors: Song Ying , Wan Guang-Yu , Wang Jing-Xian , Yu Lin-Hui , Wu Jie , Xiang Cheng-Bin
Published: March 2023

Rice tillers are a major yield component regulated by phytohormones and nutrients. How nutrients interact with phytohormones to control tillering remains largely elusive. Here, we report a novel mechanism by which the transcription factor NIN-like protein 4 (OsNLP4) integrates nitrogen (N)-iron (Fe) nutrient signals to promote tillering by repressingOsD3in strigolactone (SL) signaling. We show that the N-Fe balance modulates OsNLP4 nuclear accumulation, which is increased by Fe through H2O2reduction. Furthermore, OsNLP4 upregulates multiple H2O2scavenging genes, providing a positive regulatory loop for OsNLP4 nuclear accumulation. Our findings uncover a fundamental mechanism by which the OsNLP4-OsD3 module integrates N-Fe nutrient signals to downregulate SL signaling and thereby promote rice tillering and yield, thus facilitating sustainable agriculture worldwide.
Type I interferon signaling induces a delayed antiproliferative response in Calu-3 cells during SARS-CoV-2 infection
Authors: Cunha Juliana Bragazzi , Leix Kyle , Sherman Emily J. , Mirabelli Carmen , Kennedy Andrew A. , Lauring Adam S. , Tai Andrew W. , Wobus Christiane E. , Emmer Brian T.
Published: March 2023

Disease progression during SARS-CoV-2 infection is tightly linked to the fate of lung epithelial cells, with severe cases of COVID-19 characterized by direct injury of the alveolar epithelium and an impairment in its regeneration from progenitor cells. The molecular pathways that govern respiratory epithelial cell death and proliferation during SARS-CoV-2 infection, however, remain poorly understood. We now report a high-throughput CRISPR screen for host genetic modifiers of the survival and proliferation of SARS-CoV-2-infected Calu-3 respiratory epithelial cells. The top 4 genes identified in our screen encode components of the same type I interferon signaling complex –IFNAR1,IFNAR2,JAK1, andTYK2. The 5thgene,ACE2, was an expected control encoding the SARS-CoV-2 viral receptor. Surprisingly, despite the antiviral properties of IFN-I signaling, its disruption in our screen was associated with an increase in Calu-3 cell fitness. We validated this effect and found that IFN-I signaling did not sensitize SARS-CoV-2-infected cultures to cell death but rather inhibited the proliferation of surviving cells after the early peak of viral replication and cytopathic effect. We also found that IFN-I signaling alone, in the absence of viral infection, was sufficient to induce this delayed antiproliferative response. Together, these findings highlight a cell autonomous antiproliferative response by respiratory epithelial cells to persistent IFN-I signaling during SARS-CoV-2 infection. This response may contribute to the deficient alveolar regeneration that has been associated with COVID-19 lung injury and represents a promising area for host-targeted therapeutic development.
Reconstruction of the molecular evolution of Usutu virus in Germany: Insights into virus emersion and circulation
Authors: Bergmann Felicitas , Holicki Cora M. , Michel Friederike , Bock Sabine , Scuda Nelly , Priemer Grit , Kenklies Susanne , Siempelkamp Timo , Skuballa Jasmin , Sauerwald Claudia , Herms Louise , Muluneh Aemero , Peters Martin , Hlinak Andreas , Groschup Martin H. , Sadeghi Balal , Ziegler Ute
Published: March 2023

Usutu virus (USUV) is a mosquito-borne flavivirus that is widely distributed in southern and central Europe. The zoonotic virus circulates primarily between birds and mosquitoes, can, however, in rare cases infect other mammals including humans. In the past USUV has been associated with mass mortalities in birds, formerly blackbirds and owls. Birds commonly succumb either due to the peracute nature of the infection or due to severe encephalitis. In Germany, USUV has spread rapidly since its first detection in 2010 in mosquitoes under the presence of susceptible host and vector species.

Nonetheless, there is to date limited access to whole genome sequences resulting in the absence of in-depth phylogenetic and phylodynamic analyses. In this study, 118 wild and captive birds were screened using a nanopore sequencing platform with prior target enrichment via amplicons. Due to the high abundancy of Europe 3 and Africa 3 in Germany an ample quantity of associated whole genome sequences was generated and the most recent common ancestor could be determined for each lineage. The corresponding clock phylogeny revealed an introduction of USUV Europe 3 and Africa 3 into Germany three years prior to their first isolation in the avifauna in 2011 and 2014, respectively. Based on the clustering and temporal history of the lineages, evidence exists for the genetic evolution of USUV within Germany as well as new introductions thereof into the country.
“Ferric carboxymaltose has a higher distribution into myocardium than gadobutrol – a quantitative T1 mapping study in healthy volunteers”
Authors: Abdula Goran , Lundin Magnus , Nickander Jannike , Sörensson Peder , Sigfridsson Andreas , Themudo Raquel , Ugander Martin
Published: March 2023

Background

The dynamic tissue distribution of the clinically available intravenous iron substitution agent ferric carboxymaltose (FCM) is largely unknown. Notably, T1 mapping cardiovascular magnetic resonance (CMR) is highly sensitive for detecting myocardial iron.

Purpose

To evaluate and quantify the dynamic tissue distribution of FCM using CMR.

Materials and methods

T1 mapping was prospectively performed to determine T1 and the partition coefficient (lambda) in myocardium, liver, spleen and skeletal muscle up to 60 minutes after onset of a 15-minute-long infusion of 20 ml (50 mg iron/ml) FCM in healthy male volunteers. For comparison, myocardial lambda for gadobutrol (0.2 mmol/kg) was measured in a separate group of age-matched healthy male volunteers. The t-test was used for group comparisons.

Results

A total of 25 healthy male participants (mean±SD age 27±3 years) were evaluated. Subjects underwent CMR with intravenous FCM (n=8) or gadobutrol (n=17, age matched). T1 values of myocardium, blood, liver, spleen and skeletal muscle were all shortened after intravenous injection of FCM (p<0.001 for all). Lambda for FCM in myocardium and spleen remained constant over time after injection of FCM (mean±SEM 64±8% and 81±20%, respectively, 30 minutes after injection start), while lambda for FCM in liver and skeletal muscle increased over time. Myocardial lambda for FCM was higher than myocardial lambda for gadobutrol (64±8 vs 45±1%, p=0.003).

Conclusions

T1 mapping can detect and quantify the dynamic tissue distribution of iron from ferric carboxymaltose in the myocardium, liver, spleen and skeletal muscle. Lambda in healthy myocardium for ferric carboxymaltose was markedly higher than lambda for gadobutrol, indicating that ferric carboxymaltose distributes to a greater extent into the myocardium than extracellular contrast agents, most likely due to additional distribution into the intracellular space.
Cerebrospinal fluid 2-hydroxyglutarate (2-HG) as a monitoring biomarker for IDH-mutant gliomas
Authors: Riviere-Cazaux Cecile , Lacey Jean M. , Carlstrom Lucas P. , Laxen William J. , Munoz-Casabella Amanda , Hoplin Matthew D. , Ikram Samar , Zubair Abdullah Bin , Andersen Katherine M. , Warrington Arthur E. , Decker Paul A. , Kaufmann Timothy J. , Campian Jian L. , Eckel-Passow Jeanette E. , Kizilbash Sani H. , Tortorelli Silvia , Burns Terry C.
Published: March 2023

D-2-hydroxyglutarate (D-2-HG) is a well-established oncometabolite of isocitrate dehydrogenase (IDH) mutant gliomas. While prior studies have demonstrated that D-2-HG is elevated in the cerebrospinal fluid (CSF) of patients with IDH-mutant gliomas1,2, no study has determined if CSF D-2-HG can provide a plausible method to evaluate therapeutic response. We are obtaining CSF samples from consenting patients during their disease course via intra-operative collection and Ommaya reservoirs. D-2-HG and D/L-2-HG consistently decreased following tumor resection and throughout chemoradiation in patients monitored longitudinally. Our early experience with this strategy demonstrates the potential for intracranial CSF D-2-HG as a monitoring biomarker for IDH-mutant gliomas.
Proteins and transcriptional dysregulation of the brain extracellular matrix in Parkinson’s disease: A systematic review
Authors: Rike Wote , Stern Shani
Published: March 2023

The extracellular matrix (ECM) of the brain is a dynamic structure made up of a vast network of bioactive macromolecules that modulate cellular events. Structural, organizational and functional changes in these macromolecules due to genetic variation or environmental stressors are thought to affect the cellular functions, and may result in disease. Most mechanistic studies to date usually focus on the cellular aspects of diseases and pay less attention to the relevance of the processes governing the dynamic nature of the extracellular matrix on disease pathogenesis. Here in this review, we gathered postmortem brain tissue and induced pluripotent stem cell (iPSC)-related studies from PubMed and Google scholar to identify, summarize and describe common macromolecular alterations in the expression of brain ECM components in Parkinson’s disease (PD). According to proteomic studies, proteins such as collagens, fibronectin, annexins and tenascins were recognized to be differentially expressed in Parkinson’s disease. Transcriptomic studies displayed dysregulated pathways including ECM-receptor interaction, focal adhesion, and cell adhesion molecules in Parkinson’s disease. Limited number of relevant studies were accessed from our search indicating that much work still remains to be done to better understand the roles of the ECM in neurodegeneration and Parkinson’s disease. However, we believe that our review will elicit focused primary studies and thus, support the ongoing efforts of the discovery and development of diagnostic biomarkers as well as therapeutic agents for Parkinson’s disease.
Large-Scale Validation Study of an Improved Semi-Autonomous Urine Cytology Assessment Tool: AutoParis-X
Authors: Levy Joshua J. , Chan Natt , Marotti Jonathan D. , Kerr Darcy A. , Gutmann Edward J. , Glass Ryan E. , Dodge Caroline P. , Suriawinata Arief A. , Christensen Brock , Liu Xiaoying , Vaickus Louis J.
Published: March 2023

Adopting a computational approach for the assessment of urine cytology specimens has the potential to improve the efficiency, accuracy and reliability of bladder cancer screening, which has heretofore relied on semi-subjective manual assessment methods. As rigorous, quantitative criteria and guidelines have been introduced for improving screening practices, e.g., The Paris System for Reporting Urinary Cytology (TPS), algorithms to emulate semi-autonomous diagnostic decision-making have lagged behind, in part due to the complex and nuanced nature of urine cytology reporting. In this study, we report on a deep learning tool, AutoParis-X, which can facilitate rapid semi-autonomous examination of urine cytology specimens. Through a large-scale retrospective validation study, results indicate that AutoParis-X can accurately determine urothelial cell atypia and aggregate a wide-variety of cell and cluster-related information across a slide to yield an Atypia Burden Score (ABS) that correlates closely with overall specimen atypia, predictive of TPS diagnostic categories. Importantly, this approach accounts for challenges associated with assessment of overlapping cell cluster borders, which improved the ability to predict specimen atypia and accurately estimate the nuclear-to-cytoplasm (NC) ratio for cells in these clusters. We developed an interactive web application that is publicly available and open-source, which features a simple, easy-to-use display for examining urine cytology whole-slide images (WSI) and determining the atypia level of specific cells, flagging the most abnormal cells for pathologist review. The accuracy of AutoParis-X (and other semi-automated digital pathology systems) indicates that these technologies are approaching clinical readiness and necessitates full evaluation of these algorithms via head-to-head clinical trials.
Discovering Digital Biomarkers of Panic Attack Risk in Consumer Wearables Data
Authors: McGinnis Ellen W. , Lunna Shania , Berman Isabel , Loftness Bryn C. , Bagdon Skylar , Danforth Christopher M. , Price Matthew , Copeland William E. , McGinnis Ryan S.
Published: March 2023

Panic attacks are an impairing mental health problem that impacts more than one out of every 10 adults in the United States (US). Clinical guidelines suggest panic attacks occur without warning and their unexpected nature worsens their impact on quality of life. Individuals who experience panic attacks would benefit from advance warning of when an attack is likely to occur so that appropriate steps could be taken to manage or prevent it. Our recent work suggests that an individual’s likelihood of experiencing a panic attack can be predicted by self-reported mood and community-level Twitter-derived mood the previous day. Prior work also suggests that physiological markers may indicate a pending panic attack. However, the ability of objective physiological, behavioral, and environmental measures to predict next-day panic attacks has not yet been explored. To address this question, we consider data from 38 individuals who regularly experienced panic attacks recruited from across the US. Participants responded to daily questions about their panic attacks for 28 days and provided access to data from their Apple Watches. Results indicate that objective measures of ambient noise (louder) and resting heart rate (higher) are related to the likelihood of experiencing a panic attack the next day. These preliminary results suggest, for the first time, that panic attacks may be predictable from data passively collected by consumer wearable devices, opening the door to improvements in how panic attacks are managed and to the development of new preventative interventions.

Clinical Relevance

Objective data from consumer wearables may predict when an individual is at high risk for experiencing a next-day panic attack. This information could guide treatment decisions, help individuals manage their panic, and inform the development of new preventative interventions.
Blood lipid density decreases at the early-stage of stomach adenocarcinoma
Authors: Prakash Om , Khan Feroz
Published: March 2023

Background

Induction of cancer creates many molecular to physiological changes in the human body. Observation of these variations between normal & diseased conditions become the basis of disease diagnosis. Present study analyzed blood lipid profile, relative to changes in genotype, at the early stage of stomach adenocarcinoma.

Materials and Method

Present study was based on establishment of relationship between genotype to phenotype. Genotypic features were collected through RNAseq analysis, which was further mapped with phenotypic expression in the form of blood lipid profile.

Results

To observe the significance difference between phenotypic expressions of normal and cancerous condition, gene signatures from multiple sources of studies were mapped with blood lipid profile including: Total Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides, Non-HDL-C, and TG to HDL ratio. Significance difference found between phenotypic expression of normal and cancerous condition.

Conclusion

Through multi-signature-based population observation, it was found that blood-lipid density decreases at the early-stage of stomach adenocarcinoma. Further, blood-lipid profile can be used for early disease prediction of stomach adenocarcinoma as well as other cancer types.
metaGE: Investigating Genotype × Environment interactions through meta-analysis
Authors: De Walsche Annaïg , Vergne Alexis , Rincent Renaud , Roux Fabrice , Nicolas Stephane , Welcker Claude , Mezmouk Sofiane , Charcosset Alain , Mary-Huard Tristan
Published: March 2023

Dissecting the genetic components of Genotype-by-Environment interactions is of key importance in the context of increasing instability and plant competition due to climate change and phytosanitary treatment limitations. It is widely addressed in plants using Multi-Environment Trials (MET), in which statistical modelling for genome-wide association studies (GWAS) is promising but significantly more complex than for single-environment studies. In this context, we introduce metaGE, a flexible and computationally efficient meta-analysis approach for the joint analysis of any MET GWAS experiment. To cope with the specific requirements of the MET context, metaGE accounts for both the heterogeneity of QTL effects across environments and the correlation between GWAS summary statistics acquired on the same or related set(s) of genotypes. Compared to previous GWAS in 3 plant species and a multi-parent population, metaGE identified known and new QTLs. It provided valuable insight into the genetic architecture of several complex traits and the variation of QTL effects conditional to environmental conditions.
Intermittent Hypoxia in Neonatal Rodents Affects Facial Bone Growth
Authors: Pae Eung-Kwon , Harper Ronald M.
Published: March 2023

Preterm human infants often show periodic breathing (PB) or apnea of prematurity (AOP), breathing patterns which are accompanied by intermittent hypoxia (IH). We examined cause-effect relationships between transient IH and reduced facial bone growth using a rat model. Neonatal pups from 14 timed pregnant Sprague-Dawley rats were randomly assigned to an IH condition, with oxygen altering between 10% and 21% every 4 min for 1 h immediately after birth, or to a litter-matched control group. The IH pups were compared with their age- and sex-matched control groups in body weight (WT), size of facial bones and nor-epinephrine (NE) levels in blood at 3, 4, and 5-weeks. Markedly increased activity of osteoclasts in sub-condylar regions of 3-week-old IH-treated animals appeared, as well as increased numbers of sympathetic nerve endings in the same region of tissue sections. Male IH-pups showed significantly higher levels of NE levels in sera at 3, 4 as well as 5-week-old time points. NE levels in 4- and-5-weekold female pups did not differ significantly. Intercondylar Width, Mandible Length and Intermolar Width measures consistently declined after IH insults in 3- and 4-week-old male as well as female animals. Three-week-old male IH-pups only showed a significantly reduced (p < 0.05) body weight compared to those of 3-week controls. However, female IH-pups were heavier than age-matched controls at all 3 time-points. Trabecular bone configuration, size of facial bones, and metabolism are disturbed after an IH challenge 1 h immediately after birth. The findings raise the possibility that IH, introduced by breathing patterns such as PB or AOP, induce significantly impaired bone development and metabolic changes in human newborns. The enhanced NE outflow from IH exposure may serve a major role in deficient bone growth, and may affect bone and other tissue influenced by that elevation.
Development of a novel epigenetic clock resistant to changes in immune cell composition
Authors: Tomusiak Alan , Floro Ariel , Tiwari Ritesh , Riley Rebeccah , Matsui Hiroyuki , Andrews Nicolas , Kasler Herbert G. , Verdin Eric
Published: March 2023

Epigenetic clocks are age predictors that use machine-learning models trained on DNA CpG methylation values to predict chronological or biological age. Increases in predicted epigenetic age relative to chronological age (epigenetic age acceleration) are connected to aging-associated pathologies, and changes in epigenetic age are linked to canonical aging hallmarks. However, epigenetic clocks rely on training data from bulk tissues whose cellular composition changes with age. We found that human naive CD8+T cells, which decrease during aging, exhibit an epigenetic age 15–20 years younger than effector memory CD8+T cells from the same individual. Importantly, homogenous naive T cells isolated from individuals of different ages show a progressive increase in epigenetic age, indicating that current epigenetic clocks measure two independent variables, aging and immune cell composition. To isolate the age-associated cell intrinsic changes, we created a new clock, the IntrinClock, that did not change among 10 immune cell types tested. IntrinClock showed a robust predicted epigenetic age increase in a model of replicative senescencein vitroand age reversal during OSKM-mediated reprogramming.
A refined single cell landscape of haematopoiesis in the mouse foetal liver
Authors: Ceccacci Elena , Villa Emanuela , Santoro Fabio , Minucci Saverio , Ruhrberg Christiana , Fantin Alessandro
Published: March 2023

During prenatal life, the foetal liver is colonised by several waves of haematopoietic stem and progenitor cells (HSPCs) to act as the main haematopoietic organ. Single cell (sc) RNA-seq has been used to identify foetal liver cell types via their transcriptomic signature and to compare gene expression pattern as haematopoietic development proceeds. To obtain a refined single cell landscape of haematopoiesis in the foetal liver, we have generated a novel scRNA-seq dataset from whole mouse E12.5 liver that includes a larger number of cells than prior datasets at this stage and was obtained without cell type preselection to include all liver cell populations. We combined mining of this dataset with that of previously published datasets at other developmental stages to follow transcriptional dynamics as well as cell cycle state of developing haematopoietic lineages. Our findings corroborate several prior reports on the timing of liver colonisation by HSPCs and the emergence of differentiated lineages and provide further molecular characterisation of each cell population. Extending these findings, we demonstrate the existence of a foetal intermediate haemoglobin profile in the mouse, similar to that previously identified in humans, and a previously unidentified population of primitive erythroid cells in the foetal liver.
Classification of Parkinson’s Disease and Delineating Progression Markers from the Sebum Volatilome
Authors: Walton-Doyle Caitlin , Heim Beatrice , Sinclair Eleanor , Lim Sze Hway , Hollywood Katherine A , Milne Joy , Holzknecht Evi , Stefani Ambra , Högl Birgit , Seppi Klaus , Silverdale Monty , Poewe Werner , Barran Perdita , Trivedi Drupad K
Published: March 2023

Parkinson’s Disease (PD) has been associated with a distinct odour, which emanates from the skin and is strongest in sebum-rich areas. In this study, sebum was sampled from participants using cotton gauze and the volatile components emanating from these swabs were analysed directly with thermal desorption gas chromatography - mass spectrometry (TD GC-MS). We analysed subjects with clinically established PD (n=46) along with healthy controls (n=28) sampled from two sites. The volatilome profiles obtained for PD and control cohorts were compared with the profile of participants (n=9) with isolated REM sleep behaviour disorder (iRBD) to investigate metabolite changes in probable prodromal PD. We also compared PD participants sampled at yearly intervals for a total of three years. Volatile compounds from TD GC-MS analysis were found in different quantities between PD, control and iRBD subjects. We found 55 significant features where abundance in samples from individuals with iRBD was intermediate between that found for PD and control samples. Significant features were found to be alkanes and fatty acid methyl esters (FAMEs), with other metabolites identified as an aldehyde, purine and tropinone. In olfactory analysis of the iRBD samples three out of nine were classified PD, and on clinical follow up two of these showed PD symptoms. Further, when analysing the volatilome from longitudinal PD sampling, almost two-thirds of the significant features showed differential regulation over the three visits. Our findings support the use of sebum as an accessible biofluid rich with measurable volatile compounds which alter in abundance in individuals with PD and iRBD, as the disease progresses.
Regulatory sites in the Mon1-Ccz1 complex control Rab5 to Rab7 transition and endosome maturation
Authors: Borchers Ann-Christin , Janz Maren , Schäfer Jan-Hannes , Moeller Arne , Kümmel Daniel , Paululat Achim , Ungermann Christian , Langemeyer Lars
Published: March 2023

Maturation from early to late endosomes depends on the exchange of their marker proteins Rab5 to Rab7. This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. Efficient GEF activity of this complex on membranes depends on Rab5, thus driving Rab-exchange on endosomes. However, molecular details on the role of Rab5 in Mon1-Ccz1 activation are unclear. Here we identify key features in Mon1 involved in GEF regulation. We show that the intrinsically disordered N-terminal domain of Mon1 autoinhibits Rab5-dependent GEF-activity on membranes. Consequently, Mon1 truncations result in higher GEF activityin vitro, and a shift from Rab5 to more Rab7 positive structures inDrosophilanephrocytes and yeast, suggesting faster endosomal maturation. Using modeling, we further identify a conserved Rab5 binding site in Mon1. Mutations impairing Rab5 interaction result in poor GEF activity on membranes and growth defectsin vivo. Our analysis provides a framework to understand the mechanism of Rab-conversion and organelle maturation along the endomembrane system.

Transport of proteins via the endolysosomal pathway requires Rab5 on early endosomes, which is replaced by Rab7 on late endosomes. Here, we identify distinct regulatory sites in the Rab7 activator, the Mon1-Ccz1 complex, shedding light on the regulation of Rab5 to Rab7 transition.
Plural breeding among unrelated females and other insights on complex social structure in the cooperatively breeding Variegated Fairywren
Authors: Boersma Jordan , Thrasher Derrick J. , Welklin Joseph F. , Baldassarre Daniel T. , Webster Michael S.
Published: March 2023

Cooperatively breeding species vary widely in degree of social complexity, and disentangling relationships among group members can reveal the costs and benefits of cooperation. Here, we explore the social system of a relatively unstudied cooperatively breeding bird, the Variegated Fairywren (Malurus lamberti), and explore how social complexity and group dynamics may affect cooperation and conflict. We used a combination of field-based population monitoring and detailed social association observations to determine group membership annually across four breeding seasons (2014 – 2017), and used a ddRAD-seq genotyping method to determine genetic relationships within social groups. Social groups ranged in size from 2 – 8 individuals and nearly half of all social groups had multiple adult individuals of both sexes. Approximately two-thirds of those groups exhibited plural breeding, in which multiple females within the same social group nested individually on the same territory. Genetic relationships were diverse across social groups, and many consisted of a combination of relatives and non-relatives of each sex. Notably, although related females often were present within a social group, co-breeding females in the same social group were never closely related to each other. Given extensive variation in relatedness among group members, cooperation in the Variegated Fairywren is likely maintained by a combination of direct and indirect fitness benefits.