bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the outcomes of donor-recipient age differences in young adults undergoing liver transplantation
Authors: Snyder Abigail , Kojima Lisa , Imaoka Yuki , Akabane Miho , Kwong Allison , Melcher Marc L. , Sasaki Kazunari
Published: February 2023

The current liver allocation system may be disadvantaging younger adult recipients as it does not incorporate the donor-recipient age difference. Given the longer life expectancy of younger recipients, the influences of older donor grafts on their long-term prognosis should be elucidated. This study sought to reveal the long-term prognostic influence of the donor-recipient age difference in young adult recipients. Adult patients who received initial liver transplants from deceased donors between 2002 and 2021 were identified from the UNOS database. Young recipients (patients 45 years old or below) were categorized into 4 groups: donor age younger than the recipient, 0–9 years older, 10–19 years older, or 20 years older or above. Older recipients were defined as patients 65 years old or above. To examine the influence of the age difference in long-term survivors, conditional graft survival analysis was conducted on both younger and older recipients. Among 91,952 transplant recipients, 15,170 patients were 45 years old or below (16.5%); these were categorized into 6,114 (40.3%), 3,315 (21.9%), 2,970 (19.6%), and 2,771 (18.3%) for groups 1–4, respectively. Group 1 demonstrated the highest probability of survival, followed by groups 2, 3, and 4 for the actual graft survival and conditional graft survival analyses. In younger recipients who survived at least 5 years post-transplant, inferior long-term survival was observed when there was an age difference of 10 years or above (86.9% vs. 80.6%, log-rank p<0.01), whereas there was no difference in older recipients (72.6% vs. 74.2%, log-rank p=0.89). In younger patients who are not in emergent need of a transplant, preferential allocation of younger aged donor offers would optimize organ utility by increasing postoperative graft survival time.
Radiographic Sigmoid Sinus Wall Abnormalities and Pulsatile Tinnitus: A Case-Control Study
Authors: Cass Nathan D. , Lindquist Nathan R. , Patro Ankita , Smetak Miriam R. , Perkins Elizabeth L. , O'Malley Matthew R. , Bennett Marc L. , Haynes David S. , Tawfik Kareem O.
Published: February 2023

Objective

Compare incidence of sigmoid sinus wall abnormalities (SSWAs) and other radiographic abnormalities in patients with pulsatile tinnitus (PT) versus controls.

Study Design

Retrospective case-control.

Setting

Tertiary referral center.

Patients

Adults with PT and high-resolution computed tomography imaging were compared with adults undergoing cochlear implant workup including high-resolution computed tomography imaging.

Main Outcome Measures

Incidence of SSWA in PT cohort (n = 141) compared with control (n = 149, n = 298 ears). Secondary outcome measures included differences in demographics and in other radiographic abnormalities between cohorts.

Results

Patients with PT had a higher incidence of SSWA (34% versus 9%, p < 0.001) and superior canal dehiscence (23% versus 12%, p = 0.017) than controls. Spearman product component correlations demonstrated that ipsilateral PT was weakly associated with SSWA (r = 0.354, p < 0.001). When SSWA was present in the PT cohort (n = 48 patients, n = 59 ears), in 31 cases (64.6%), the SSWA correlated with PT laterality (e.g., left SSWA, left PT); in 12 (25.0%), SSWA partially correlated with PT laterality (e.g., bilateral SSWA, right PT); and in 5 (10.4%), the SSWA did not correlate with PT laterality (e.g., right SSWA, left PT).

Conclusions

For our patients with both PT and SSWA, the SSWA is likely a contributing factor in approximately 65% of cases. For a third of patients with PT and concomitant SSWA, the association between the two is either not causative or not solely causative. Surgeons counseling patients with PT and SSWA may be optimistic overall regarding sigmoid resurfacing procedures but must appreciate the possibility of treatment failure, likely because of untreated comorbid conditions.
Mortality difference from Klebsiella aerogenes vs Enterobacter cloacae bloodstream infections
Authors: Chou Andrew , Sucgang Richard , Hamill Richard J. , Zechiedrich Lynn , Trautner Barbara W.
Published: February 2023

Members of the order Enterobacterales, including

Escherichia coli

,

Klebsiella

species and

Enterobacter

species, are important pathogens in healthcare-associated infections. Higher mortality has been reported from infections due to

Klebsiella pneumoniae

than from

E. coli

, but prior studies comparing

Enterobacter aerogenes

(recently renamed

Klebsiella aerogenes

) bacteraemia and

Enterobacter cloacae

complex bacteraemia have yielded conflicting results regarding whether clinical outcomes differ. We found bacteraemia with

K. aerogenes

was independently associated with greater risk of 30-day mortality than bacteraemia with

Enterobacter cloacae

complex.
Viral infectivity in pediatric SARS-CoV-2 clinical samples does not vary by age
Authors: Schmidt Madaline M , Despres Hannah W , Shirley David J , Bose Michael E , McCaul Kate C , Crothers Jessica W , Henrickson Kelly J , Lee Benjamin , Bruce Emily A
Published: February 2023

At the start of the SARS-CoV-2 pandemic, there was much uncertainty about the role of children in infection and transmission dynamics. Through the course of the pandemic, it became clear that children were susceptible to SARS-CoV-2 infection, however they were experiencing a notable lack of severe disease outcomes as compared to the adult population. This trend held true with the emergence of new SARS-CoV-2 variants, even in pediatric populations that were ineligible to be vaccinated. The difference in disease outcomes has prompted questions about the virologic features of SARS-CoV-2 infection in this population. In order to determine if there was any difference in the infectivity of the virus produced by children infected with COVID-19, we compared viral RNA levels (clinical RT-qPCR CTs) and infectious virus titers from 144 SARS-CoV-2 positive clinical samples collected from children ages 0 to 18 years old. We found that age had no impact on the infectiousness of SARS-CoV-2 within our cohort, with children of all ages able to produce high levels of infectious virus.
Clostridioides difficile infection: traversing host–pathogen interactions in the gut
Authors: Cheng Jeffrey K. J. , Unnikrishnan Meera
Published: February 2023

C. difficile

is the primary cause for nosocomial infective diarrhoea. For a successful infection,

C. difficile

must navigate between resident gut bacteria and the harsh host environment. The perturbation of the intestinal microbiota by broad-spectrum antibiotics alters the composition and the geography of the gut microbiota, deterring colonization resistance, and enabling

C. difficile

to colonize. This review will discuss how

C. difficile

interacts with and exploits the microbiota and the host epithelium to infect and persist. We provide an overview of

C. difficile

virulence factors and their interactions with the gut to aid adhesion, cause epithelial damage and mediate persistence. Finally, we document the host responses to

C. difficile

, describing the immune cells and host pathways that are associated and triggered during

C. difficile

infection.
Predicting Breast Cancer Events in Ductal Carcinoma In Situ (DCIS) using Generative Adversarial Network Augmented Deep Learning Model
Authors: Ghose Soumya , Cho Sanghee , Ginty Fiona , McDonough Elizabeth , Davis Cynthia , Zhang Zhanpan , Mitra Jhimli , Harris Adrian L. , Thike Aye Aye , Tan Puay Hoon , Gökmen-Polar Yesim , Badve Sunil S.
Published: February 2023

Standard clinicopathological parameters (age, growth pattern, tumor size, margin status and grade) have been shown to have limited value in predicting recurrence in ductal carcinoma in situ (DCIS) patients. Early and accurate recurrence prediction would facilitate a more aggressive treatment policy for high-risk patients (mastectomy or adjuvant radiation therapy), and simultaneously reduce over-treatment of low-risk patients. Generative adversarial networks (GAN) are a class of DL models in which two adversarial neural networks, generator and discriminator, compete with each other to generate high quality images. In this work, we have developed a deep learning (DL) classification network that predicts breast cancer events (BCEs) in DCIS patients using hematoxylin and eosin (H&E) images. The DL classification model was trained on 67 patients using image patches from the actual DCIS cores and GAN generated image patches to predict breast cancer events (BCEs). The hold-out validation dataset (n= 66) had an AUC of 0.82. Bayesian analysis further confirmed the independence of the model from classical clinico-pathological parameters. DL models of H&E images may be used as a risk stratification strategy for DCIS patients to personalize therapy.

Simple Summary

Ductal carcinoma in situ (DCIS) patients have an excellent overall survival rate and over-treatment is always a cause for concern due to potential side-effects. Standard clinicopathological parameters have limited value in predicting breast cancer events (BCEs) and stratification of high and low risk patients. Herein, we have developed a deep learning (DL) classification framework to predict BCEs in DCIS patients. A generative adversarial network (GAN) augmented deep learning (DL) classification of histological features associated with aggressive disease was trained on hematoxylin and eosin (H&E) tissue microarray (TMA) images of DCIS to predict BCEs. The area under the curve (AUC) for BCE’s in the validation set was 0.82. Early and accurate prediction of DCIS BCEs would facilitate a personalized approach to therapy.
Sub-second fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans
Authors: Sands L. Paul , Jiang Angela , Liebenow Brittany , DiMarco Emily , Laxton Adrian W. , Tatter Stephen B. , Montague P. Read , Kishida Kenneth T.
Published: February 2023

In the mammalian brain, midbrain dopamine neuron activity is hypothesized to encode reward prediction errors that promote learning and guide behavior by causing rapid changes in dopamine levels in target brain regions. This hypothesis (and alternatives regarding dopamine’s role in punishment-learning) has limited direct evidence in humans. We report intracranial, sub-second measurements of dopamine release in human striatum measured while volunteers (i.e., patients undergoing deep brain stimulation (DBS) surgery) performed a probabilistic reward- and punishment-learning choice task designed to test whether dopamine release encodes only reward prediction errors or whether dopamine release may also encode adaptive punishment-learning signals. Results demonstrate that extracellular dopamine levels can encode both reward and punishment prediction errors, but may do so via by independent valence-specific pathways in the human brain.

One-Sentence Summary

Dopamine release encodes reward and punishment prediction errors via independent pathways in the human brain.
Estimating single cell clonal dynamics in human blood using coalescent theory
Authors: Johnson Brian , Shuai Yubo , Schweinsberg Jason , Curtius Kit
Published: February 2023

While evolutionary approaches to medicine show promise, measuring evolution itself is difficult due to experimental constraints and the dynamic nature of body systems. In cancer evolution, continuous observation of clonal architecture is impossible, and longitudinal samples from multiple timepoints are rare. Increasingly available DNA sequencing datasets at single cell resolution enable the reconstruction of past evolution using mutational history, allowing for a better understanding of dynamics prior to detectable disease. We derive methods based on coalescent theory for estimating the net growth rate of clones from either reconstructed phylogenies or the number of shared mutations. Using single-cell datasets from blood, we apply and validate our analytical methods for estimating the net growth rate of hematopoietic clones, eliminating the need for complex simulations. We show that our estimates may have broad applications to improve mechanistic understanding and prognostic ability. Compared to clones with a single or unknown driver mutation, clones with multiple drivers have significantly increased growth rates (median 0.94 vs. 0.25 per year; p = 1.6 × 10-6). Further, stratifying patients with a myeloproliferative neoplasm (MPN) by the growth rate of their fittest clone shows that higher growth rates are associated with shorter time from clone initiation to MPN diagnosis (median 13.9 vs. 26.4 months; p = 0.0026).
Acquired epithelial WNT secretion drives niche independence of developing gastric cancer
Authors: Teriyapirom Isaree , Kim Jihoon , Lee Heetak , Merker Sebastian R. , Andersson-Rolf Amanda , Jahn Stephan R. , Ada Anne-Marlen , Kim Sang-Min , Lim Joo Yeon , Schmäche Tim , Wetterling Nancy , Stegert Saskia , Park Ji-Yeon , Cheong Jae-Ho , Kim Hyunki , Stange Daniel E. , Koo Bon-Kyoung
Published: February 2023

Recent studies have shed light on the signaling pathways required for gastric tissue maintenance and how aberrations in these key pathways lead to gastric cancer development. Although it has been shown that the WNT pathway is important for gastric epithelial homeostasis, the identity and source of the responsible canonical WNT ligands remain unknown. Furthermore, it is unclear how gastric cancer acquires WNT niche independence - an important early step in tumorigenesis. Using human and mouse gastric organoids andin vivomouse models, we found that mesenchymal WNT2B and WNT7B maintain gastric epithelium in homeostasis. Next, mouse genetic studies and single-cell multi-omics analyses revealed that activation of MAPK signaling induces secretion of WNT7B in the epithelium itself. We further confirmed that in human gastric cancer, MAPK pathway activation through HER2 overexpression or copy number gains ofWNT2confers WNT independence. Importantly, the epithelium-intrinsic WNT expression could be therapeutically inhibited. Taken together, our results reveal that normal gastric epithelial turnover relies on WNT ligands secreted by niche mesenchymal cells, while transformation involves acquisition of a WNT secretory phenotype in the epithelium - representing a potential target for therapeutic interventions.
Multimodal decoding of human liver regeneration
Authors: Matchett KP , Wilson-Kanamori JR , Portman JR , Kapourani CA , Fercoq F , May S , Mackey JBG , Brice M , Zajdel E , Beltran M , Sutherland EF , Wilson GC , Wallace SJ , Kitto L , Younger NT , Dobie R , Oniscu GC , Wigmore SJ , Ramachandran P , Vallejos CA , Carragher NO , Simpson KJ , Kendall TJ ,   Acute Liver Failure Study Group, Rule JA , Lee WM , Hoare M , Weston CJ , Marioni JC , Teichmann ST , Bird TG , Carlin LM , Henderson NC
Published: February 2023

The liver has a unique ability to regenerate1,2, however in the setting of acute liver failure (ALF) this regenerative capacity is often overwhelmed and emergency liver transplantation is the only curative option3-5. To advance our understanding of human liver regeneration and to inform design of pro-regenerative therapies, we use paired single-nuclei RNA sequencing (snRNA-seq) combined with spatial profiling of healthy and ALF explant human livers to generate the first single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+migratory hepatocyte subpopulation which emerges during human liver regeneration, and a corollary migratory hepatocyte subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Importantly, interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. 4-D intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 expression reduces HGF-induced human and mouse hepatocyte migrationin vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Taken together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation which mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may open up new areas of therapeutic discovery in regenerative medicine.
Traumatic brain injury-induced fear generalization in mice involves hippocampal memory trace dysfunction and is alleviated by (R,S)-ketamine
Authors: McGowan Josephine C. , Ladner Liliana R. , Shubeck Claire X. , Tapia Juliana , LaGamma Christina T. , Anqueira-González Amanda , DeFrancesco Ariana , Chen Briana K. , Hunsberger Holly C. , Sydnor Ezra J. , Logan Ryan W. , Yu Tzong-Shiue , Kernie Steven G. , Denny Christine A.
Published: February 2023

INTRODUCTION

Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI.

METHODS

To identify the neural ensembles mediating fear generalization, we utilized the ArcCreERT2x enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact (CCI) model of TBI. Mice were then administered a contextual fear discrimination (CFD) paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice.

RESULTS

TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the DG, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination and this behavioral improvement was reflected in DG memory trace activity.

CONCLUSIONS

These data show that TBI induces fear generalization by altering fear memory traces, and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.
Secreted soluble factors from tumor-activated mesenchymal stromal cells confer platinum chemoresistance to ovarian cancer cells
Authors: Carmi Yifat Koren , Khamaisi Hazem , Adawi Rina , Gopas Jacob , Mahajna Jamal
Published: February 2023

Ovarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemotherapy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging in the treatment of patients, most of who will experience relapse, mainly due to chemoresistance. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and can also be mediated by the tumor microenvironment (TME).

In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5 respectively, and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells.

Various OC cells exhibit variable sensitivity to CM activity. Moreover, exposure of OC to CM affected ERK1/2 phosphorylation in a non-consistent pattern and in a cell-specific manner, and does not correlate with platinum chemoresistance. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (SuPAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Exposure to increasing concentrations of HGF resulted in increased proliferation and reduced platinum sensitivity. Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF’s ability to promote platinum resistance and restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM.

Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells.
ReConPlot – an R package for the visualization and interpretation of genomic rearrangements
Authors: Espejo Valle-Inclan Jose , Cortes-Ciriano Isidro
Published: February 2023

Whole-genome sequencing studies of human tumours have revealed that complex forms of structural variation, collectively known as complex genome rearrangements (CGR), are pervasive across diverse cancer types. Detection, classification, and mechanistic interpretation of CGR requires the visualization of complex patterns of somatic copy number aberrations (SCNAs) and structural variants (SVs). However, there is a lack of tools specifically designed to facilitate the visualization and study of CGR. We present ReConPlot (REarrangement and COpy Number PLOT), an R package that provides functionalities for the joint visualization of SCNAs and SVs across one or multiple chromosomes. ReConPlot is based on the popular ggplot2 package, thus allowing customization of plots and the generation of publication-quality figures with minimal effort. Overall, ReConPlot facilitates the exploration, interpretation, and reporting of complex genome rearrangement patterns. Code availability: The R package ReConPlot is available at https://github.com/cortes-ciriano-lab/GenomicRearrangementPlot. Detailed documentation and a tutorial with examples are provided with the package.
Heat stress response and transposon control in plant shoot stem cells
Authors: Nguyen Vu Hoang , Mittelsten Scheid Ortrun , Gutzat Ruben
Published: February 2023

Post-embryonic plant development must be coordinated in response to and with environmental feedback. Development of above-ground organs is orchestrated from stem cells in the center of the shoot apical meristem (SAM). Heat can pose significant stress to plants and induces a rapid heat response, developmental alterations, chromatin decondensation, and activation of transposable elements (TEs). However, most plant heat-stress studies are conducted with whole plants, not resolving cell-type-specific responses. Heat stress consequences in stem cells are of particular significance, as they can potentially influence the next generation. Here we use fluorescent-activated nuclear sorting to isolate and characterize stem cells after heat exposure and after a recovery period in wild type and mutants defective in TE defense and chromatin compaction. Our results indicate that stem cells can suppress the heat response pathways that dominate surrounding somatic cells and maintain their developmental program. Furthermore, mutants defective in DNA methylation recover less efficiently from heat stress and persistently activate heat response factors and heat-inducible TEs. Heat stress also induces epimutations at the level of DNA methylation, and we find hundreds of DNA methylation changes three weeks after stress. Our results underline the importance of disentangling cell type-specific environmental responses for understanding plant development.
Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-damage-sensing-dependent Cell Protection
Authors: Centeno Daniel , Farsinejad Sadaf , Kochetkova Elena , Volpari Tatiana , Gladych-Macioszek Alexandra , Klupczynska – Gabryszak Agnieszka , Polotaye Teagan , Greenberg Michael , Kung Douglas , Hyde Emily , Alshehri Sarah , Pavlovic Tonja , Sullivan William , Plewa Szymon , Vakifahmetoglu-Norberg Helin , Monsma Frederick J , Muller Patricia A. J. , Matysiak Jan , Zaborowski Mikolaj , DiFeo Analisa , Norberg Erik , Martin Laura A. , Iwanicki Marcin
Published: February 2023

Taurine, a non-proteogenic amino acid, and commonly used nutritional supplement can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We have found that OC ascites-derived cells contained significantly more intracellular taurine than cell cultures modeling OC. In culture, elevation of intracellular taurine concentration to OC ascites-cells-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant- or wild-type p53 binding to DNA, and activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine’s suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine’s ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine’s cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth, metabolism, and activate cell protective mechanisms involving mTOR and DNA damage sensing signal transduction.
Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown
Authors: Nageshan Rishi Kumar , Ortega Raquel , Krogan Nevan , Cooper Julia Promisel
Published: February 2023

Persisting replication intermediates can confer mitotic catastrophe if left unresolved. Loss of the fission yeast telomere protein Taz1 (ortholog of mammalian TRF1/TRF2) causes telomeric replication fork stalling and in turn, telomere entanglements that stretch between the segregating chromosomes at anaphase. At ≤20°C, these entanglements fail to resolve, resulting in lethality. Rif1, a conserved DNA replication/repair protein, localizes between the segregating chromosomes and specifically hinders the resolution of telomere entanglements without affecting their formation. During anaphase, the spindle and the last segments of segregating chromatin are encased by the nuclear envelope (NE), creating a microdomain termed the anaphase midregion. In the final stages of fission yeast mitosis, this midregion undergoes local NE breakdown. Here we demonstrate that in response totaz1Δtelomeric entanglements, Rif1 delays midregion NE breakdown, and this delay disfavors entanglement resolution. Accordingly, gene deletions that hasten midregion NE breakdown phenocopy, and are epistatic with,rif1+deletion. Conversely, gene deletions that delay midregion NE breakdown block thetaz1Δtelomere detanglement afforded by loss of Rif1. Overexpression of Rif1 in a wild type background causes cold-specific NE defects and lethality, which are rescued by treatment with a membrane fluidizing agent. We propose that delayed NE breakdown normally favors the resolution of simple entanglements, arising from incomplete replication, by delaying exposure to the cytoplasm. In contrast, resolution of more complex entanglements involving strand invasion, like entanglements between nonsistertaz1Δtelomeres, requires more rapid exposure to the cytoplasm. These observations uncover an unexpected coordination between NE remodeling and DNA processing events that can prevent or promote aneuploidy.
Phylogenomic analysis of the Lake Kronotskoe species flock of Dolly Varden charr reveals genetic and developmental signatures of sympatric radiation
Authors: Woronowicz Katherine C. , Esin Evgeny V. , Markevich Grigorii N. , Martinez Crisvely Soto , McMenamin Sarah K. , Daane Jacob M. , Harris Matthew P. , Shkil Fedor N.
Published: February 2023

Recent adaptive radiations provide evolutionary case studies, which provide the context to parse the relationship between genomic variation and the origins of distinct phenotypes. Sympatric radiations of the charr complex (genusSalvelinus) present a trove for phylogenetics as charrs have repeatedly diversified into multiple morphs with distinct feeding specializations. However, species flocks normally comprise only two to three lineages. Dolly Varden charr inhabiting Lake Kronotske represent the most extensive radiation described for the charr genus, containing at least seven lineages, each with defining morphological and ecological traits. Here, we perform the first genome-wide analysis of this species flock to parse the foundations of adaptive change. Our data support distinct, reproductively isolated lineages with little evidence of hybridization. We also find that specific selection on thyroid signaling and craniofacial genes forms a genomic basis for the radiation. Thyroid hormone is further implicated in subsequent lineage partitioning events. These results delineate a clear genetic basis for the diversification of specialized lineages, and highlight the role of developmental mechanisms in shaping the forms generated during adaptive radiation.

Significance Statement

Dolly Varden Charr (Salvelinus malma) radiation in Lake Kronotskoe provides a unique case study of the genetics of adaptation and morphological evolution. We provide first genomic and experimental analyses of this radiation and show that major axes of change may be shaped by developmental constraints.
Can deep learning predict human intelligence from structural brain MRI?
Authors: Hussain Mohammad Arafat , LaMay Danielle , Grant Ellen , Ou Yangming
Published: February 2023

Can brain structure predict human intelligence? T1-weighted structural brain magnetic resonance images (sMRI) have been correlated with intelligence. Nevertheless, population-level association does not fully account for individual variability in intelligence. To address this, individual prediction studies emerge recently. However, they are mostly on predicting fluid intelligence (the ability to solve new problems). Studies are lacking to predict crystallized intelligence (the ability to accumulate knowledge) or general intelligence (fluid and crystallized intelligence combined). This study tests whether deep learning of sMRI can predict an individual subject’s verbal, comprehensive, and full-scale intelligence quotients (VIQ, PIQ, FSIQ), which reflect both fluid and crystallized intelligence. We performed a comprehensive set of 432 experiments, using different input images, six deep learning models, and two outcome settings, on 850 autistic and healthy subjects 6-64 years of age. Results show promise with statistical significance, and also open up questions inviting further future studies.
How Healthy Older Adults Enact Lateral Maneuvers While Walking
Authors: Desmet David M. , Kazanski Meghan E. , Cusumano Joseph P. , Dingwell Jonathan B.
Published: February 2023

Background

Walking requires frequent maneuvers to navigate changing environments with shifting goals. Humans accomplish maneuvers and simultaneously maintain balance primarily by modulating their foot placement, but a direct trade-off between these two objectives has been proposed. As older adults rely more on foot placement to maintain lateral balance, they may be less able to adequately adapt stepping to perform lateral maneuvers.

Research Question

How do older adults adapt stepping to enact lateral lane-change maneuvers, and how do physical and perceived ability influence their task performance?

Methods

Twenty young (21.7 ± 2.6 yrs) and 18 older (71.6 ± 6.0 yrs) adults walked on a motorized treadmill in a virtual environment. Following an audible and visual cue, participants switched between two parallel paths, centered 0.6m apart, to continue walking on their new path. We quantified when participants initiated the maneuver following the cue, as well as their step width, lateral position, and stepping variability ellipses at each maneuver step.

Results

Young and older adults did not differ in when they initiated the maneuver, but participants with lower perceived ability took longer to do so. Young and older adults also did not exhibit differences in step width or lateral positions at any maneuver step, but participants with greater physical ability reached their new path faster. While only older adults exhibited stepping adaptations prior to initiating the maneuver, both groups traded-off stability for maneuverability to enact the lateral maneuver.

Significance

Physical and perceived balance ability, rather than ageper se, differentially influenced maneuver task performance. Humans must make decisions related to the task of walking itself and do so based on both physical and perceived factors. Understanding and targeting these interactions may help improve walking performance among older adults.
Patient-specific simulation of Retinal Hemangioblastoma provides new perspectives on the role of antiangiogenic therapy
Authors: Pradelli Franco , Minervini Giovanni , Tosatto Silvio C.E.
Published: February 2023

Retinal Hemangioblastoma (RH) is the most frequent manifestation of the von Hippel-Lindau syndrome (VHL), a rare disease associated with the germline mutation of the von Hippel-Lindau protein (pVHL). An emblematic feature of RH is the high vascularity, which is easily explained by the overexpression of angiogenic factors (AFs) arising from the pVHL impairment. The introduction of Optical Coherence Tomography Angiography (OCTA) allowed observing this feature with exceptional detail. However, our understanding of RH is limited by the absence of an animal model fully recapitulating the tumor. Here, we exploit a cancer mathematical model as an alternative way to explore RH development and angiogenesis. We derived our model from the agreed pathology for this tumor and compared our results with patient-specific OCTA images. Our simulations closely resemble the medical images, proving the capability of our model to recapitulate RH pathology. Our results also suggest that angiogenesis in RH occurs suddenly when the tumor reaches a critical mass, with full capillary invasion in the order of days. These findings open a new perspective on the critical role of time in antiangiogenic therapy in RH, which has resulted ineffective. Indeed, it might be that when RH is diagnosed, angiogenesis is already too advanced to be effectively targeted with this mean.
A portable regulatory RNA array design enables tunable and complex regulation across diverse bacteria
Authors: Liu Baiyang , Cuba Samaniego Christian , Bennett Matthew R. , Franco Elisa , Chappell James
Published: February 2023

A lack of composable and tunable gene regulators has hindered efforts to engineer non-model bacteria and consortia. To address this, we explore the broad-host potential of small transcription activating RNA (STAR) and propose a novel design strategy to achieve tunable gene control. First, we demonstrate that STARs optimized forE. colifunction across different Gram-negative species and can actuate using phage RNA polymerase, suggesting that RNA systems acting at the level of transcription are portable. Second, we explore a novel RNA design strategy that uses arrays of tandem and transcriptionally fused RNA regulators to precisely alter regulator concentration from 1 to 8 copies. This provides a simple means to predictably tune output gain across species and does not require access to large regulatory part libraries. Finally, we show RNA arrays can be used to achieve tunable cascading and multiplexing circuits across species, analogous to the motifs used in artificial neural networks.
Identification of anti-fungal bioactive terpenoids from the bioenergy crop switchgrass (Panicum virgatum)
Authors: Li Xingxing , Chou Ming-Yi , Bonito Gregory M. , Last Robert L.
Published: February 2023

Plant derived bioactive small molecules have attracted attention of scientists across fundamental and applied scientific disciplines. We seek to understand the influence of these phytochemicals on functional phytobiomes. Increased knowledge of specialized metabolite bioactivities could inform strategies for sustainable crop production. Our recent investigations of metabolomes of the upland and lowland ecotypes of the bioenergy crop switchgrass (Panicum virgatum) revealed large differences in types and abundances of terpenoid specialized metabolites. We hypothesized that – consistent with accumulating evidence that switchgrass genotype impacts microbiome assembly – differential terpenoid accumulation contributes to switchgrass ecotype-specific microbiome composition. An initialin vitroplate-based disc diffusion screen of 18 switchgrass root derived fungal isolates revealed differential responses to upland- and lowland-isolated metabolites. To identify specific fungal growth-modulating metabolites, we tested fractions from root extracts on three ecologically important fungal isolates –Linnemania elongata, Trichodermasp. andFusariumsp. Saponins and diterpenoids were identified as the most prominent antifungal metabolites. Finally, analysis of liquid chromatography-purified terpenoids revealed fungal inhibition structure – activity relationships (SAR). Saponin antifungal activity was primarily determined by the number of sugar moieties – saponins glycosylated at a single core position were inhibitory whereas saponins glycosylated at two core positions were inactive. Saponin core hydroxylation and acetylation were also associated with reduced activity. Diterpenoid activity required the presence of an intact furan ring for strong fungal growth inhibition. This study demonstrates that switchgrass genotype-specific metabolites differentially inhibit fungal isolates from the root and rhizosphere, supporting the hypothesis that these small molecules contribute to microbiome assembly and function.
BERBERINE BRIDGE ENZYME-LIKE OXIDASES OF CELLODEXTRINS AND MIXED-LINKED β-GLUCANS CONTROL SEED COAT FORMATION
Authors: Costantini Sara , Benedetti Manuel , Pontiggia Daniela , Giovannoni Moira , Cervone Felice , Mattei Benedetta , De Lorenzo Giulia
Published: February 2023

A member of the Arabidopsis Berberine Bridge Enzyme-like (BBE-l) protein family named CELLODEXTRIN OXIDASE 2 (CELLOX2) has been characterized in this paper and shown to display structural and enzymatic features similar to the previously characterized CELLOX1. These include the capability to oxidize the mixed-linked β-1→3/β-1→4-glucans (MLGs), recently described as cell wall-derived damage-associated molecular patterns (DAMPs) that activate plant immunity. The two paralogous genes show a different expression profile. UnlikeCELLOX1, CELLOX2is not expressed in seedlings or in adult plants and is not involved in immunity againstBotrytis cinerea.Both genes are expressed in a concerted manner in the seed coat during development: whereasCELLOX2transcripts are detected mainly during the heart stage,CELLOX1transcripts are detected later, when the expression ofCELLOX2decreases. Analysis of seeds ofcellox1andcellox2knock-out mutants show alterations in the structure of the coat and mucilage, but not in their monosaccharide composition. We propose that the cell wall structure of specific organs is not only the result of a coordinated synthesis/degradation of polysaccharides but also of their exposure to enzymatic oxidation. Our results also reinforce the view that the family of BBE-l proteins is at least in part devoted to the control of the activity of cell wall-derived oligosaccharides acting as DAMPs.

SENTENCE

Two Arabidopsis BBE–like oxidases of the cell wall DAMPs cellodextrins and mixed-linked β-glucans inactivate their elicitor activity. Seed coat and mucilage are altered in null mutants of two enzymes.
Differentially deregulated microRNAs contribute to ultraviolet radiation-induced photocarcinogenesis through immunomodulation: An-analysis of microRNAs expression profiling
Authors: Agarwal Anshu , Kansal Vikash , Farooqi Humaira , Singh Vijay Kumar , Prasad Ram
Published: February 2023

MicroRNAs (miRNAs) are short non-coding RNA molecules (18-25 nucleotides) that regulate several fundamental biological processes. Emerging evidence has shown more than 1500 miRNAs functions in the cell cycle, proliferation, apoptosis, oxidative stress, immune response, DNA damage, and epigenetics alterations. miRNAs are bidirectionally in nature and act as a tumor suppressor and as an oncogene through crosstalk between tumor cells and immune cells. Although the roles of miRNAs in several cancers are well studied, little is known about ultraviolet B (UVB) radiation-induced skin cancer. Here, we performed a comprehensive screening of 1281 miRNAs in tumor tissues and compared their expression with normal skin. Our results demonstrate that the expression levels of 587 miRNAs were altered in tumor tissues compared to their expression in normal skin. The expression of 337 miRNAs was upregulated from 1.5-12 folds, while the expression of 250 miRNAs was downregulated up to 1.5-10 folds in tumors. Further, intraperitoneal injection of a mimic of down-regulated miR-15b (30nM) and an inhibitor of upregulated miR-133a (20nM) protect UVB-induced suppression of contact hypersensitivity (CHS) response. In conclusion, we identified a network of altered miRNAs in tumors that can serve as prognostic biomarkers and therapeutic targets to manage photocarcinogenesis effectively.
Norwegian general population normative data for the EORTC questionnaires; the core QLQ-C30, the sexual health questionnaire QLQ-SHQ22, and sexual domains of the QLQ-BR23/BR45
Authors: Åsberg R.E , Nilsen M , Hjermstad M.J , Reinertsen K.V , Karlsen J , Giskeødegård G.F , Reidunsdatter R.J.
Published: February 2023

Objective

The aim of this study was to provide gender-, age-, and morbidity-specific Norwegian general population normative values for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires QLQ-C30, the sexual health questionnaire QLQ-SHQ22, and the sexual domains of the breast modules QLQ-BR23 and QLQ-BR45.

Methods

A random nation-wide sample stratified by gender and age groups (18–29, 30-39, 40–49, 50–59, 60–69 and ≥70 years) was drawn from the Norwegian National Population Register. Participants were notified through National online health services (HelseNorge) and by postal mail. The survey included sociodemographic background information, HRQoL assessed by the EORTC questionnaires, and morbidity by The Self-Administered Comorbidity Questionnaire. Multivariable linear regression was carried out to estimate the associations of age, sex, and morbidity with the EORTC scale and item scores.

Results

Of the 15,627 eligible individuals, 5.135 (33%) responded. Women and persons with morbidities reported lower functioning and higher symptom burden than men and persons without morbidities, respectively, on nearly all EORTC scales. Sex differences were most prominent forEmotional Functioning, Pain, Fatigue, andInsomnia(QLQ-C30),Body Image, Sexual Functioning(QLQ-BR23/45),Importance of Sexual Activity, Libido, andFatigue(QLQ-SHQ22). The score differences between persons with and without morbidity were highly significant and largest among the youngest and middle-aged groups.

Conclusion

The present study is the first to provide normative values for the EORTC sexual health questionnaire QLQ-SHQ22 and the sexual subscales of the QLQ-BR23 and QLQ-BR45, for all separately in age groups by sex and morbidity.
A unifying principle for global greenness patterns and trends
Authors: Cai Wenjia , Zhu Ziqi , Harrison Sandy P. , Ryu Youngryel , Wang Han , Zhou Boya , Prentice Iain Colin
Published: February 2023

Vegetation cover regulates the exchanges of energy, water and carbon between land and atmosphere. Remotely-sensed fractional absorbed photosynthetically active radiation (fAPAR), a land-surface greenness metric, depends on carbon allocation to foliage while also controlling photon flux for photosynthesis. Greenness is thus both a driver and an outcome of gross primary production (GPP). An equation with just two (globally) fitted parameters describes annual maximum fAPAR (fAPARmax) as the smaller of a water-limited value, transpiring a constant fraction of annual precipitation, and an energy-limited value, maximizing annual plant growth. This minimalist description reproduces global greenness patterns, and the consistent temporal trends among remote-sensing products, as accurately as the best-performing dynamic global vegetation models. Widely observed greening is attributed to the influence of rising carbon dioxide on the light- and water-use efficiencies of GPP, augmented by wetting in some dry regions and warming in high latitudes. Limited regions show browning, attributed to drying.
MDTOMO: Continuous conformational variability analysis in cryo electron subtomogram data using flexible fitting based on Molecular Dynamics simulations
Authors: Vuillemot Rémi , Rouiller Isabelle , Jonić Slavica
Published: February 2023

Cryo electron tomography (cryo-ET) allows observing macromolecular complexes in their native environment. The common routine of subtomogram averaging (STA) allows obtaining the three-dimensional (3D) structure of abundant macromolecular complexes, and can be coupled with discrete classification to reveal conformational heterogeneity of the sample. However, the number of complexes extracted from cryo-ET data is usually small, which restricts the discrete-classification results to a small number of enough populated states and, thus, results in a largely incomplete conformational landscape. Alternative approaches are currently being investigated to explore the continuity of the conformational landscapes thatin situcryo-ET studies could provide. In this article, we present MDTOMO, a method for analyzing continuous conformational variability in cryo-ET subtomograms based on Molecular Dynamics (MD) simulations. MDTOMO allows obtaining an atomic-scale model of conformational variability and the corresponding free-energy landscape, from a given set of cryo-ET subtomograms. The article presents the performance of MDTOMO on a synthetic ABC exporter dataset and anin situSARS-CoV-2 spike dataset. MDTOMO allows analyzing dynamic properties of molecular complexes to understand their biological functions, which could also be useful for structure-based drug discovery.