bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of changes in coagulation factors in fresh frozen plasma during storage at -18°C for 5 weeks at Kisii Teaching and Referral Hospital
Authors: Ogolla Collince O. , Demba Rodgers N.
Published: April 2023

Background

Fresh frozen plasma is a critical substitute therapy in management of bleeding. Increased risk of venous thrombosis has been described to be associated with high plasma levels of several coagulation factors.

Methodology

This study was a longitudinal study involving time series analysis of fresh frozen plasma stored at -18°C for five weeks. A sample of 180 ml plasma was obtained from the blood centrifuged at 4000rpm which was aliquoted into three parts each containing 60ml. The first aliquot was used to assess the changes in coagulation factors in FFP at baseline during the first week of sample collection, the second aliquot was used to assess the changes in coagulation factors in FFP storage at -18°C temp after three weeks of storage, the third aliquot was used to assess the changes in coagulation factors in FFP storage at -18°C temp after five weeks of storage. Coagulation factor analysis was performed using Erba Mannheim ECL 105 coagulation analyzer, India factor results recorded. Thawing for subsequent coagulation factor analysis and serial testing of stored cryoprecipitate and fresh frozen plasma was done using Stericox Plasma Thawing Bath at 37°C, for 45 mins before before analyzing the samples. Standard storage conditions for the aliquots were monitored and maintained to ensure homogeneity.

Results

The findings showed significant changes in the coagulation factors in FFP during storage at -18 for a period to five weeks with chi-square value of 216.000 and asymptomatic significance value (p-value) <0.0001* less than the standard alpha 0.05.

Conclusion

There was a constant decrease of coagulation factors in fresh frozen plasma during storage at -18°C for 5 weeks at Kisii Teaching and Referral Hospital, Kisii County.
Combination treatment of persistent COVID-19 in immunocompromised patients with remdesivir, nirmaltrevir/ritonavir and tixegavimab/cilgavimab
Authors: Brosh-Nissimov Tal , Ma’aravi Nir , Leshin-Carmel Daniel , Edel Yonatan , Barouch Sharon Ben , Segman Yafit , Cahan Amos , Barenboim Erez
Published: April 2023

Background

Little data exists to guide the treatment of persistent COVID-19 in immunocompromised patients. We have employed a unique protocol combining tixegavimab/cilgavimab, and short-term combination antivirals including remdesivir.

Methods

A retrospective single-center analysis of persistent COVID-19 in immunocompromised patients. Response was assessed by symptom resolution, declining C-reactive protein (CRP) levels and increasing SARS-CoV-2-PCR cycle-threshold (Ct) values.

Results

Fourteen patients were included, including 2 kidney transplant recipients, 11 with B-cell lymphoproliferative disease, treated with anti-CD20 or ibrutinib, and 1 with rheumatoid arthritis, treated with anti-CD20. Median Ct-value was 27 (interquartile range (IQR):24-32). All patients received tixegavimab/cilgavimab and a 5-day course of remdesivir. Eleven also received nirmaltrevir/ritonavir and one received molnupiravir. Median follow-up was 45 days (IQR:12-89). Eleven patients had complete responses including symptom resolution, decrease in CRP, and increase in Ct values (all with either a negative PCR or Ct value>30 on day 4-16). Three patients had a partial response with relapses requiring re-admission. One had died, and two responded to prolonged antiviral treatments.

Conclusions

A combination of monoclonal antibodies with antivirals has led to complete resolution of persistent COVID-19 in most severely-immunocompromised patients. Controlled studies will further direct the treatment of these patients, while more effective antivirals are urgently needed.

Key points

Some immunocompromised patients develop persistent symptomatic SARS-CoV-2 infection. Combination of monoclonal antibodies plus one or more antivirals cured 11/14 patients. Non-responders benefitted from prolonged combination antiviral treatment. Controlled trials are needed to find optimal treatment of persistent COVID-19.
Endothelial Nitric Oxide Synthase Regulates Lymphatic Valve Specification By Controlling β - catenin Signaling During Embryogenesis
Authors: Iyer Drishya , Mastrogiacomo Diandra , Li Kunyu , Banerjee Richa , Yang Ying , Scallan Joshua P.
Published: April 2023

Objective

Lymphatic valves play a critical role in ensuring unidirectional lymph transport. Loss of lymphatic valves or dysfunctional valves are associated with several diseases including lymphedema, lymphatic malformations, obesity, and ileitis. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. In blood vessels, eNOS (gene name:Nos3) is a well characterized shear stress signaling effector, but its role in lymphatic valve development remains unexplored.

Approach and Results

We used globalNos3−/−mice and cultured hdLECs to investigate the role of eNOS in lymphatic valve development, which requires oscillatory shear stress signaling. Our data reveal a 45% reduction in lymphatic valve specification cell clusters and that loss of eNOS protein inhibited activation of β-catenin and its nuclear translocation. Genetic knockout or knockdown of eNOS led to downregulation of β-catenin target proteinsin vivoandin vitro. However, pharmacological inhibition of NO production did not reproduce these effects. Coimmunoprecipitation experiments reveal that eNOS forms a complex with β-catenin and their association is enhanced by oscillatory shear stress. Finally, genetic ablation of the Foxo1 gene enhanced FOXC2 expression and rescued the loss of valve specification in the eNOS knockouts.

Conclusion

In conclusion, we demonstrate a novel, nitric oxide-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS forms a complex with β-catenin to regulate its nuclear translocation and thereby transcriptional activity.
Novel technology to develop non-transmissible live influenza virus vaccines through alterations in M2/M42 ion channel expression
Authors: Kapczynski Darrell R. , Segovia Karen , Chrzastek Klaudia , Conceicao Carina , Suarez David L. , Vervelde Lonneke , Digard Paul
Published: April 2023

Continued global outbreaks of H5Nx highly pathogenic avian influenza viruses (HPAIV) have been reported in poultry since the emergence of the Asian Goose/Guangdong lineage of HPAIV H5N1 in 1996. Consequently, vaccines have been developed and employed to protect commercial and non-commercial poultry flocks. However, constant changes in virus immunogenetics makes vaccine candidates that prevent morbidity, mortality, reduce shedding, and prevent transmission a moving target. Here, we tested the effects of disrupting the mRNA splice sites and thus expression of either of the two isoforms of the viral ion channel M2 and M42 expressed by the H5N2 low pathogenic avian influenza virus (LPAIV) progenitor of the 1983 Pennsylvania HPAIV outbreak. Both G52C (ΔM2) and G145A (ΔM42) versions of the A/chicken/Pennsylvania/1/83 (Ck/Penn) virus replicated wellin vitroandin ovo, but showed altered virion morphology, with the G145A virus exhibiting filamentous budding. The G52C and G145A viruses also infected chickens efficiently and stimulated robust immune responses; however, unlike the wild type virus, they did not transmit to naïve-contact birds. In protection studies, vaccination of birds with G52C or G145A viruses protected 100% of birds from lethal challenge with homologous and distant heterologous H5 HPAIV strains from North American and Asian lineages and significantly reduced virus shedding compared to controls. Furthermore, the live virus vaccines decreased virus shedding 10,000-fold more than corresponding inactivated forms of the vaccine virus. Taken together, these studies demonstrate a strategy for developing a non-transmittable but highly protective live attenuated virus for AIV.
Comprehensive proteomic analysis of JC polyomavirus-infected human astrocytes and their excreted vesicles
Authors: Oberholster Larise , Mathias Amandine , Perriot Sylvain , Blaser Emma , Canales Mathieu , Jones Samuel , Culebras Lucas , Gimenez Marie , Kaynor G. Campbell , Sapozhnik Alexey , Richetin Kevin , Goelz Susan , Pasquier Renaud Du
Published: April 2023

JC polyomavirus (JCPyV) is an opportunistic virus that remains in a latent state in the kidneys of more than half of the human adult population. In rare cases of severe immune suppression, the virus is able to establish a lytic infection of glial cells in the brain, resulting in a debilitating, demyelinating disease known as progressive multifocal leukoencephalopathy (PML). Because of the exceptional species and tissue specificity of the virus, appropriate models of JCPyV infection in the brain are lacking, thus hampering progress towards the development of novel antiviral strategies and biomarkers of disease activity. While PML has traditionally been characterized as a lytic infection of oligodendrocytes, more recent findings suggest an important role for astrocytes during the initial stages of disease. Here, using human induced pluripotent stem cell (hiPSC) derived-astrocytes coupled with a multiparametric approach, we show that 1. JCPyV readily infects and replicates in astrocytes, 2. JCPyV strongly dysregulates the cell biology and 3. these findings adequately reflectex vivofindings. We perform an in-depth characterization of the effect of JCPyV on the cell proteome over time, demonstrating a strong dysregulation of the cell cycle and activation of the DNA damage response. Furthermore, we show that the proteomic signature observed for infected astrocytes is extended to excreted vesicles, underlining their potential to gain valuable insights into JCPyV propagation in the brain.
Wearable-ome meets epigenome: A novel approach to measuring biological age with wearable devices
Authors: Sugden Cameron , du Preez Franco B , Olivier Laurence R , Deffur Armin
Published: April 2023

Aging is an inevitable process of cellular and physiological decline. These markers of age can be measured on the molecular and functional level. Wearable devices offer a non-invasive continuous measure of physiological and behavioural features and how they pertain to aging. Wearable data can be used to extrapolate information derived from epigenetic biological age predictions and its underlying biology. LifeQ-enabled wearable devices were worn for 40 days to harvest data on 48 human participants. Thereafter blood was drawn and methylation levels determined using the Illumina EPIC array. Multiple epigenetic clock ages were calculated and compared with wearable features. Activity minutes correlated with VO2max (p = 0.003), subendocardial viability ratio (SEVR, p < 0.01), blood pressure index (BPI, p = 0.02), resting heart rate (RHR, p < 0.01) and heart outflow (HO, p < 0.01). Sedentary time correlated with RHR (p < 0.01), VO2max (p = 0.01), SEVR (p = 0.04), and HO (p = 0.04). VO2max, SEVR, small artery resistance (SAR), BPI and large artery stiffness index (LASI) correlated with multiple epigenetic age clock outputs and chronological age but were most strongly correlated with PCPhenoAge. VO2max, (p = 0.04) RHR (p < 0.01) and LASI (p = 0.04) were significantly correlated with PCPhenoAge acceleration. Weighted gene correlation network analysis (WGCNA) of the differentially methylated positions of PCPhenoAge acceleration was used to construct modules, identifying 3 modules correlating with wearable features. Behavioural features impact physiological state, measured by the wearable, which are associated with epigenetic age and age acceleration. Signal from the underlying biology of age acceleration can be picked up by the wearable, presenting a case that wearable devices can capture portions of biological aging.
An Azapeptide Platform in Conjunction with Covalent Warheads to Uncover High-Potency Inhibitors for SARS-CoV-2 Main Protease
Authors: Khatua Kaustav , Alugubelli Yugendar R. , Yang Kai S. , Vulupala Veerabhadra R. , Blankenship Lauren R. , Coleman Demonta D. , Atla Sandeep , Chaki Sankar P. , Geng Zhi Zachary , Ma Xinyu R. , Xiao Jing , Chen Peng-Hsun Chase , Cho Chia-Chuan Dean , Vatansever Erol C. , Ma Yuying , Yu Ge , Neuman Benjamin W. , Xu Shiqing , Liu Wenshe Ray
Published: April 2023

Main protease (MPro) of SARS-CoV-2, the viral pathogen of COVID-19, is a crucial nonstructural protein that plays a vital role in the replication and pathogenesis of the virus. Its protease function relies on three active site pockets to recognize P1, P2, and P4 amino acid residues in a substrate and a catalytic cysteine residue for catalysis. By converting the P1 Cα atom in an MProsubstrate to nitrogen, we showed that a large variety of azapeptide inhibitors with covalent warheads targeting the MProcatalytic cysteine could be easily synthesized. Through the characterization of these inhibitors, we identified several highly potent MProinhibitors. Specifically, one inhibitor, MPI89 that contained an aza-2,2-dichloroacetyl warhead, displayed a 10 nM EC50value in inhibiting SARS-CoV-2 from infecting ACE2+A549 cells and a selectivity index of 875. The crystallography analyses of MProbound with 6 inhibitors, including MPI89, revealed that inhibitors used their covalent warheads to covalently engage the catalytic cysteine and the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 represents one of the most potent MProinhibitors developed so far, suggesting that further exploration of the azapeptide platform and the aza-2,2-dichloroacetyl warhead is needed for the development of potent inhibitors for the SARS-CoV-2 MProas therapeutics for COVID-19.
Dietary protein shapes the profile and repertoire of intestinal CD4+T cells
Authors: Lockhart Ainsley , Reed Aubrey , Castro Tiago Rezende de , Herman Calvin , Canesso Maria Cecilia Campos , Mucida Daniel
Published: April 2023

The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring CD4+T cells. Combining antigenically defined diets with gnotobiotic models, we show that food and microbiota distinctly influence the profile and T cell receptor repertoire of intestinal CD4+T cells. Independent of the microbiota, dietary proteins contributed to accumulation and clonal selection of antigen-experienced CD4+T cells at the intestinal epithelium, imprinting a tissue specialized transcriptional program including cytotoxic genes on both conventional and regulatory CD4+T cells (Tregs). This steady state CD4+T cell response to food was disrupted by inflammatory challenge, and protection against food allergy in this context was associated with Treg clonal expansion and decreased pro-inflammatory gene expression. Finally, we identified both steady state epithelium-adapted CD4+T cells and tolerance-induced Tregs that recognize dietary antigens, suggesting that both cell types may be critical for preventing inappropriate immune responses to food.
Native and engineered human megakaryocytic extracellular vesicles for targeted non-viral cargo delivery to blood stem cells
Authors: Das Samik , Thompson Will , Papoutsakis E. Terry
Published: April 2023

Native and engineered extracellular vesicles (EVs) generated from human megakaryocytes (huMkEVs) or from the human megakaryocytic cell line CHRF (CHEVs) interact with tropism delivering their cargo to both human and murine hematopoietic stem and progenitor cells (HSPCs). 24 hours after intravenous infusion of huMkMPs into NOD-scidIL2Rγnull(NSG™) mice, they induced a nearly 50% increase in murine platelet counts relative to saline control, thus demonstrating the potential of these EVs, which can be stored frozen, for treating thrombocytopenias. PKH26-labeled huMkMPs or CHEVs localized to the HSPC-rich bone marrow preferentially interacting with murine HSPCs. Using engineered huMkEVs or CHEVs, their receptor-mediated tropism for HSPCs was explored to functionally deliver synthetic cargo, notably plasmid DNA coding for a fluorescent reporter, to murine HSPCs bothin vitroandin vivo.These data demonstrate the potential of these EVs as a non-viral, HSPC-specific cargo vehicle for gene therapy applications to treat hematological diseases.

Native and engineered human megakaryocytic extracellular vesicles for targeted non-viral cargo delivery to blood stem cells

(Table of Contents):

Graphical Overview: Native and engineered human megakaryocytic extracellular vesicles (huMkEVs) for provide targeted non-viral cargo delivery to blood stem cells.

We demonstrate that huMkEVs as a transformational cargo-delivery system to blood stem cells (hematopoietic stem and progenitor cells, HSPCs) in NOD-scid IL2Rγnull(NSG™) mice. Intravenous delivery of native huMkEVs enhancesde novoplatelet biogenesis by inducing megakaryocytic differentiation of murine HSPCs, thus demonstrating the desirable strong tropism of huMkEVs for murine HSPCs. Based on this tropism, we demonstrate that engineered huMkEVs can deliver functional plasmid-DNA cargo specifically to HSPCs.
Why flying insects gather at artificial light
Authors: Fabian Samuel T , Sondhi Yash , Allen Pablo , Theobald Jamie , Lin Huai-Ti
Published: April 2023

For millennia, humans have watched nocturnal insects flying erratically around fires and lamps. Explanations have included theories of “lunar navigation” and “escape to light”. However, without three-dimensional flight data to test them rigorously, this odd behaviour has remained unexplained. We employed high-resolution motion capture in the laboratory and stereo-videography in the field to reconstruct the 3D kinematics of insect flights around artificial lights. Contrary to the expectation of attraction, insects do not steer directly toward the light. Instead, insects turn their dorsum toward the light, generating flight bouts perpendicular to the source. Under natural sky light, tilting the dorsum towards the brightest visual hemisphere helps maintain proper flight attitude and control. Near artificial sources, however, this highly conserved dorsal-light-response can produce continuous steering around the light and trap an insect. Our guidance model demonstrates that this dorsal tilting is sufficient to create the seemingly erratic flight paths of insects near lights and is the most plausible model for why flying insects gather at artificial lights.
Astrovirus replication is dependent on induction of double membrane vesicles through a PI3K-dependent, LC3-independent pathway
Authors: Bub Theresa , Hargest Virginia , Tan Shaoyuan , Smith Maria , Vazquez-Pagan Ana , Flerlage Tim , Brigleb Pamela H. , Meliopoulos Victoria , Lindenbach Brett , Cortez Valerie , Crawford Jeremy Chase , Schultz-Cherry Stacey
Published: April 2023

Human astrovirus is a positive sense, single stranded RNA virus. Astrovirus infection causes gastrointestinal symptoms and can lead to encephalitis in immunocompromised patients. Positive strand RNA viruses typically utilize host intracellular membranes to form replication organelles, which are potential antiviral targets. Many of these replication organelles are double membrane vesicles (DMVs). Here we show that astrovirus infection leads to an increase in DMV formation, and this process is replication-dependent. Our data suggest that astrovirus infection induces rearrangement of endoplasmic reticulum fragments, which may become the origin for DMV formation. Transcriptional data suggested that formation of DMVs during astrovirus infection requires some early components of the autophagy machinery. Results indicate that the upstream class III phosphatidylinositol 3-kinase (PI3K) complex, but not LC3 conjugation machinery, is utilized in DMV formation. Inhibition of the PI3K complex leads to significant reduction in viral replication and release from cells. Elucidating the role of autophagy machinery in DMV formation during astrovirus infection reveals a potential target for therapeutic intervention for immunocompromised patients.

Importance

These studies provide critical new evidence that astrovirus replication requires formation of double membrane vesicles, which utilize class III PI3K, but not LC3 conjugation autophagy machinery for biogenesis. These results are consistent with replication mechanisms for other positive sense RNA viruses. This suggests that targeting PI3K could be a promising therapeutic option for not only astrovirus, but other positive sense RNA virus infections.
Spatial proteomics of human diabetic kidney disease, from health to class III
Authors: Kondo Ayano , McGrady Monee , Nallapothula Dhiraj , Ali Hira , Trevino Alexandro E. , Lam Amy , Preska Ryan , D’Angio H. Blaize , Wu Zhenqin , Lopez Lauren , Badhesha Harshanna Kaur , Vargas Chenoa Rochel , Ramesh Achyuta , Wiegley Nasim , Han Seung Seok , Dall’Era Marc , Jen Kuang-Yu , Mayer Aaron T. , Afkarian Maryam
Published: April 2023

Aims/Hypothesis

Diabetic kidney disease (DKD) remains a significant cause of morbidity and mortality in people with diabetes. Though animal models have taught us much about the molecular mechanisms of DKD, translating these findings to human disease requires greater knowledge of the molecular changes caused by diabetes in human kidneys. Establishing this knowledge base requires building carefully curated, reliable, and complete repositories of human kidney tissue, as well as tissue proteomics platforms capable of simultaneous, spatially resolved examination of multiple proteins.

Methods

We used the multiplexed immunofluorescence platform CO-Detection by indexing (CODEX) to image and analyze the expression of 21 proteins in 23 tissue sections from 12 individuals with diabetes and healthy kidneys (DM, 5 individuals), DKD classes IIA, and IIB (2 individuals per class), IIA-B intermediate (2 individuals), and III (one individual).

Results

Analysis of the 21-plex immunofluorescence images revealed 18 cellular clusters, corresponding to 10 known kidney compartments and cell types, including proximal tubules, distal nephron, podocytes, glomerular endothelial and peritubular capillaries, blood vessels, including endothelial cells and vascular smooth muscle cells, macrophages, cells of the myeloid lineage, broad CD45+ inflammatory cells and the basement membrane. DKD progression was associated with co-localized increase in collagen IV deposition and infiltration of inflammatory cells, as well as loss of native proteins of each nephron segment at variable rates. Compartment-specific cellular changes corroborated this general theme, with compartment-specific variations. Cell type frequency and cell-to-cell adjacency highlighted (statistically) significant increase in inflammatory cells and their adjacency to tubular and αSMA+ cells in DKD kidneys. Finally, DKD progression was marked by substantial regional variability within single tissue sections, as well as variability across patients within the same DKD class. The sizable intra-personal variability in DKD severity impacts pathologic classifications, and the attendant clinical decisions, which are usually based on small tissue biopsies.

Conclusions/Interpretations

High-plex immunofluorescence images revealed changes in protein expression corresponding to differences in cellular phenotypic composition and microenvironment structure with DKD progression. This initial dataset demonstrates the combined power of curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools in revealing pathophysiology of human DKD.
Color appearance of iridescent objects
Authors: Doerschner Katja , Ennis Robert , Börner Philipp , Maile Frank J. , Gegenfurtner Karl R.
Published: April 2023

Iridescent objects and animals are quite mesmerizing to look at, since they feature multiple intense colors whose distribution can vary quite dramatically as a function of viewing angle. These properties make them a particularly interesting and unique stimulus to experimentally investigate the factors that contribute to single color impressions of multi-colored objects. Our stimuli were 3D printed shapes of varying complexity that were covered with three different types of iridescent coatings. For each shape-color combination, participants performed single- and multi-color matches for different views of the stationary object, as well as single color matches for a corresponding rotating stimulus. In the multi-color matching task, participants subsequently rated the size of the surface area on the object that was covered by the match-identified color. Results show that single-color appearance of iridescent objects varied with shape complexity, view, and object motion. Moreover, hue similarity of color settings in the multi color match task best predicted single color appearance, however this predictor was weaker for predicting single color matches in the motion condition. Taken together our findings suggest that the single color appearance of iridescent objects may be modulated by chromatic factors, spatial-relations and the characteristic dynamics of color changes that are typical for this type of material.
GTP signaling links metabolism, DNA repair, and responses to genotoxic stress
Authors: Zhou Weihua , Zhao Zitong , Lin Angelica , Yang John , Xu Jie , Kari Wilder-Romans , Yang Annabel , Li Jing , Solanki Sumeet , Speth Jennifer , Walker Natalie , Scott Andrew J. , Kothari Ayesha U. , Yao Yangyang , Peterson Erik R. , Korimerla Navyateja , Werner Christian K. , Liang Jessica , Jacobson Janna , Palavalasa Sravya , Obrien Alexandra M. , Elaimy Ameer L. , Ferris Sean P. , Zhao Shuang G. , Sarkaria Jann N. , Győrffy Balázs , Zhang Shuqun , Al-Holou Wajd N , Umemura Yoshie , Morgan Meredith A. , Lawrence Theodore S. , Lyssiotis Costas A. , Peters-Golden Marc , Shah Yatrik M. , Wahl Daniel R.
Published: April 2023

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.
Understanding the link between functional profiles and intelligence through dimensionality reduction and graph analysis
Authors: Alberti F. , Menardi A. , Margulies D.S. , Vallesi A.
Published: April 2023

There is a growing interest in neuroscience for how individual-specific structural and functional features of the cortex relate to cognitive traits. This work builds on previous research which, using classical high-dimensional approaches, has proven that the interindividual variability of functional connectivity profiles reflects differences in fluid intelligence. To provide an additional perspective into this relationship, the present study uses a recent framework for investigating cortical organization:functional gradients.This approach places local connectivity profiles within a common low-dimensional space whose axes are functionally interretable dimensions. Specifically, this study uses a data-driven approach focussing on areas where FC variability is highest across individuals to model different facets of intelligence. For one of these loci, in the right ventral-lateral prefrontal cortex (vlPFC), we describe an association between fluid intelligence and relative functional distance from sensory and high-cognition systems. Furthermore, the topological properties of this region indicate that with decreasing functional affinity with the latter, its functional connections are more evenly distributed across all networks. Participating in multiple functional networks may reflect a better ability to coordinate sensory and high-order cognitive systems.

Significant Statement

The human brain is highly variable. In particular, the way brain regions communicate to one another – that is, how they arefunctionallyconnected – constitutes a neural fingerprint of the individual. In this study, we make use of a recent methodological approach to characterize the connectivity patterns of transmodal (closely linked to abstract processing) and unimodal (closely linked to sensory processing) brain regions in an attempt to explain how this balance affects intelligence. We show that the more the functional profile of executive control regions is distant to that of abstract processing, the better they are at integrating information coming from widespread neural systems, ultimately leading to better cognitive performance.
Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury
Authors: Bandres Maria F. , Gomes Jefferson L. , McPherson Jacob G.
Published: April 2023

Electrical stimulation of spinal networks below a spinal cord injury (SCI) is a promising approach to restore functions compromised by inadequate excitatory neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared motor pathways and spinal motor networks rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by SCI. Debilitating spasms, spasticity, and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. But whereas spasms and spasticity can often be managed pharmacologically, SCI-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from etiologies other than SCI, and it has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for motor rehabilitation. Thus, we reasoned that spinal stimulation intended to increase transmission in motor pathways may simultaneously reduce transmission in spinal pain pathways. Using a well-validated pre-clinical model of SCI that results in severe bilateral motor impairments and SCI-related neuropathic pain, we show that the responsiveness of neurons integral to the development and persistence of the neuropathic pain state can be enduringly reduced by motor-targeted spinal stimulation while preserving spinal responses to non-pain-related sensory feedback. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with SCI.
Venomous Noodles: evolution of toxins in Nemertea through positive selection and gene duplication
Authors: Sonoda G.G , Tobaruela E.C. , Norenburg J.L. , Fabi J.P. , Andrade S.C.S.
Published: April 2023

Some, probably most and perhaps all, members of the phylum Nemertea are venomous, documented so far from marine and benthic specimens. Although the toxicity of these animals has been long known, systematic studies on characterization of toxins, mechanisms of toxicity and toxin evolution for this group are relatively scarce compared to other venomous groups. Here we present the first investigation of the molecular evolution of toxins in Nemertea. Using a proteo-transcriptomic approach, we described toxins in the body and poisonous mucus of the pilidiophoranLineus sanguineusand the hoplonemerteanNemertopsis pamelaroeae. Using these new and publicly available transcriptomes, we investigated the molecular evolution of six selected toxin gene families. In addition, we have also characterizedin silicothe toxin genes found in the interstitial hoplonemertean,Ototyphlonemertes erneba, a first record for meiofaunal taxa. We identified 99 toxin transcripts in the pilidiophoranL. sanguineus,including previously known toxins, such as thealpha-nemertidesand theCytotoxins-A. However, for each of the hoplonemerteans, no more than 30 toxin transcripts were found. Genomic alignments and tree reconciliation methods supported the occurrence of at least one gene duplication in each analyzed toxin gene. Evidence of positive selection was observed in all investigated toxin genes. We hypothesized that an increased rate of gene duplications observed for Pilidiophora could be involved with the origin and expansion of toxin genes. Studies concerning the natural history of Nemertea are still needed to understand the evolution of their toxins. Nevertheless, our results show evolutionary mechanisms similar to those observed in other venomous groups.
Deletion ofPax1scoliosis-associated regulatory elements leads to a female-biased tail abnormality
Authors: Ushiki Aki , Sheng Rory R. , Zhang Yichi , Zhao Jingjing , Nobuhara Mai , Murray Elizabeth , Ruan Xin , Rios Jonathan J. , Wise Carol A. , Ahituv Nadav
Published: April 2023

Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A GWAS identified a female-specific AIS susceptibility locus near thePAX1gene. Here, we used mouse enhancer assays, three mouse enhancer knockouts and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterized a sequence, PEC7, that overlaps the AIS-associated variant, and found it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, and deletion of both sequences led to a kinky phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicated several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism.
MUSSEL: Enhanced Bayesian Polygenic Risk Prediction Leveraging Information across Multiple Ancestry Groups
Authors: Jin Jin , Zhan Jianan , Zhang Jingning , Zhao Ruzhang , O’Connell Jared , Jiang Yunxuan ,   23andMe Research Team, Buyske Steven , Gignoux Christopher , Haiman Christopher , Kenny Eimear E. , Kooperberg Charles , North Kari , Koelsch Bertram L. , Wojcik Genevieve , Zhang Haoyu , Chatterjee Nilanjan
Published: April 2023

Polygenic risk scores (PRS) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across different populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in the summary statistics from genome-wide association studies (GWAS) across multiple ancestry groups. MUSSEL conducts Bayesian hierarchical modeling under a MUltivariate Spike-and-Slab model for effect-size distribution and incorporates an Ensemble Learning step using super learner to combine information across different tuning parameter settings and ancestry groups. In our simulation studies and data analyses of 16 traits across four distinct studies, totaling 5.7 million participants with a substantial ancestral diversity, MUSSEL shows promising performance compared to alternatives. The method, for example, has an average gain in prediction R2across 11 continuous traits of 40.2% and 49.3% compared to PRS-CSx and CT-SLEB, respectively, in the African Ancestry population. The best-performing method, however, varies by GWAS sample size, target ancestry, underlying trait architecture, and the choice of reference samples for LD estimation, and thus ultimately, a combination of methods may be needed to generate the most robust PRS across diverse populations.
Biology of Coital Behavior: Looking Through the Lens of Mathematical Genomics
Authors: Sil Moumita , Nawn Debaleena , Hassan Sk. Sarif , Chakraborty Subhajit , Goswami Arunava , Basu Pallab , Roopesh Lalith , Wu Emma , Lundstrom Kenneth , Uversky Vladimir N.
Published: April 2023

Research has shown that genetics and epigenetics regulate mating behavior across multiple species. Previous studies have generally focused on the signaling pathways involved and spatial distribution of the associated receptors. However a thorough quantitative characterization of the receptors involved may offer deeper insight into mating behavioral patterns. Here oxytocin, arginine-vasopressin 1a, dopamine 1, and dopamine 2 receptors were investigated across 76 vertebrate species. The receptor sequences were characterized by polarity-based randomness, amino acid frequency-based Shannon entropy and Shannon sequence variability, intrinsic protein disorder, binding affinity, stability and pathogenicity of homology-based SNPs, structural and physicochemical features. Hierarchical clustering of species was derived based on structural and physicochemical features of the four receptor sequences separately, which eventually led to proximal relationships among 29 species. Humans were found to be significantly distant phylogenetically from the prairie voles, a representative of monogamous species based on coital behavior. Furthermore, the mouse (polygamous), the prairie deer mouse (polygamous), and the prairie vole (monogamous) although being proximally related (based on quantitative genomics of receptors), differed in their coital behavioral pattern, mostly, due to behavioral epigenetic regulations. This study adds a perspective that receptor genomics does not directly translate to behavioral patterns.
Large genetic variability of maize leaf palatability to european corn borer : metabolic insights
Authors: Sanane Inoussa , Nicolas Stephane D. , Bauland Cyril , Marion-Poll Frédéric , Noûs Camille , Legrand Judith , Dillmann Christine
Published: April 2023

Maize is the most-produced cereal in the world, but its production faces constraints such as parasitic attacks from stemborers. We evaluated the resistance of a core-collection of 18 maize lines by measuring their palatability to European Corn Borer (ECB) larvae fed on maize leaf discs. Using an original consumption test device that takes into account the variability of larvae behaviour, we were able to phenotype the resistance of the 18 maize lines. We matched consumption data to existing enzymatic and metabolomic data that characterized the maize core-collection and identified some metabolites such as caffeoyl-lquinate, trocopherol, digalactosylglycerol and tyrosine that are positively or negatively correlated with the palatability to ECB larvae. Altogether, our results confirm the metabolic complexity involved in the establishment of plant defenses. Metabolic changes associated to leaf palatability mostly concern membrane and cell wall composition. Some of them, pointing-out to the phenylpropanoids pathway, were observed independently of plant developmental pace and plant earliness.
Effect of disease prevalence and growth stage on symptoms severity in theTurnip mosaic virus - Arabidopsis thalianapathosystem
Authors: de la Iglesia Francisca , Elena Santiago F.
Published: April 2023

Plants emit volatile organic compounds (VOCs) in response to biotic and abiotic stimuli that provide information about their physiological status to other individuals in the community. Nearby receivers adjust their own defenses in response to these chemical cues. The majority of studies to date has concentrated on the communication of abiotic stressors (e.g. salinity or drought) or herbivory. Less attention had received the role of VOCs during microbial infections and almost nothing has been done for viruses. Here we investigated the function of VOCs during turnip mosaic virus infection ofArabidopsis thaliana. First, we looked at the influence of two factors on the kinetics of symptoms progression in receivers, namely the prevalence of infection in the population and the growth stage of the receiver plants at inoculation. We found that young plants were more sensitive to the protective effect of VOCs than older ones, and that high infection prevalence results in a slower disease progression in receivers. Second, we tested the possibility that jasmonates could be VOC candidates. To do this, we examined the kinetics of symptoms progression in jasmonate-insensitive and wild-type plants, and the results showed that the protective effect vanished in the mutant plants. Third, we investigated the possibility that root communication would be also relevant. We found that the kinetics of symptom progression across receivers was further slowed down in an age-dependent manner when plants were planted in the same pot. Together, these preliminary findings point to a potential function for disease prevalence in plant communities in regulating the severity of symptoms, this effect being mediated by VOCs.
Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain
Authors: Harris Noah J , Jenkins Meredith L , Nam Sung-Eun , Rathinaswamy Manoj K , Parson Matthew AH , Ranga-Prasad Harish , Dalwadi Udit , Moeller Brandon E , Sheekey Eleanor , Hansen Scott D , Yip Calvin K , Burke John E
Published: April 2023

PI3Kγ is a critical immune signaling enzyme activated downstream of diverse cell surface molecules, including Ras, PKCβ activated by the IgE receptor, and Gβγ subunits released from activated GPCRs. PI3Kγ can form two distinct complexes, with the p110γ catalytic subunit binding to either a p101 or p84 regulatory subunit, with these complexes being differentially activated by upstream stimuli. Here using a combination of cryo electron microscopy, HDX-MS, and biochemical assays we have identified novel roles of the helical domain of p110γ in regulating lipid kinase activity of distinct PI3Kγ complexes. We defined the molecular basis for how an allosteric inhibitory nanobody potently inhibits kinase activity through rigidifying the helical domain and regulatory motif of the kinase domain. The nanobody did not block either p110γ membrane recruitment or Ras/Gβγ binding, but instead decreased ATP turnover. We also identified that p110γ can be activated by dual PKCβ helical domain phosphorylation leading to partial unfolding of an N-terminal region of the helical domain. PKCβ phosphorylation is selective for p110γ-p84 compared to p110γ-p101, driven by differential dynamics of the helical domain of these different complexes. Nanobody binding prevented PKCβ mediated phosphorylation. Overall, this works shows an unexpected allosteric regulatory role of the helical domain of p110γ that is distinct between p110γ-p84 and p110γ-p101 and reveals how this can be modulated by either phosphorylation or allosteric inhibitory binding partners. This opens possibilities of future allosteric inhibitor development for therapeutic intervention.
LinRace: single cell lineage reconstruction using paired lineage barcode and gene expression data
Authors: Pan Xinhai , Li Hechen , Putta Pranav , Zhang Xiuwei
Published: April 2023

Understanding how single cells divide and differentiate into different cell types in developed organs is one of the major tasks of developmental and stem cell biology. Recently, lineage tracing technology using CRISPR/Cas9 genome editing has enabled simultaneous readouts of gene expressions and lineage barcodes in single cells, which allows for the reconstruction of the cell division tree, and even the detection of cell types and differentiation trajectories at the whole organism level. While most state-of-the-art methods for lineage reconstruction utilize only the lineage barcode data, methods that incorporate gene expression data are emerging, aiming to improve the accuracy of lineage reconstruction. However, effectively incorporating the gene expression data requires a reasonable model on how gene expression data changes along generations of divisions. Here, we present LinRace (LineageReconstruction with asymmetric cell division model), a method that integrates the lineage barcode and gene expression data using the asymmetric cell division model and infers cell lineage under a framework combining Neighbor Joining and maximum-likelihood heuristics. On both simulated and real data, LinRace outputs more accurate cell division trees than existing methods. Moreover, Lin Race can output the cell states (cell types) of ancestral cells, which is rarely performed with existing lineage reconstruction methods. The information on ancestral cells can be used to analyze how a progenitor cell generates a large population of cells with various functionalities. LinRace is available at:https://github.com/ZhangLabGT/LinRace.
Using dynamic oral dosing of rifapentine and rifabutin to simulate exposure profiles of long-acting formulations in a mouse model of tuberculosis preventive therapy
Authors: Chang Yong S. , Li Si-Yang , Pertinez Henry , Betoudji Fabrice , Lee Jin , Rannard Steven P. , Owen Andrew , Nuermberger Eric L. , Ammerman Nicole C.
Published: April 2023

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have anti-tuberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We utilized a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally-determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that has utility beyond latent tuberculosis infection.
Senescence suppresses the integrated stress response and activates a stress-enhanced secretory phenotype
Authors: Payea Matthew J. , Dar Showkat A. , Anerillas Carlos , Martindale Jennifer L. , Belair Cedric , Munk Rachel , Malla Sulochan , Fan Jinshui , Piao Yulan , Yang Xiaoling , Rehman Abid , Banskota Nirad , Abdelmohsen Kotb , Gorospe Myriam , Maragkakis Manolis
Published: April 2023

Senescence is a state of indefinite cell cycle arrest associated with aging, cancer, and age-related diseases. Here, using label-based mass spectrometry, ribosome profiling and nanopore direct RNA sequencing, we explore the coordinated interaction of translational and transcriptional programs of human cellular senescence. We find that translational deregulation and a corresponding maladaptive integrated stress response (ISR) is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames. Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. Furthermore, absent a response, stress augments the senescence secretory phenotype, thus intensifying a proinflammatory state that exacerbates disease. Our results reveal a novel mechanism that senescent cells exploit to evade an adaptive stress response and remain viable.