bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative transcriptomics reveals divergence in pathogen response gene families amongst 20 forest tree species
Authors: Lu Mengmeng , Cao Min , Yang Jie , Swenson Nathan G
Published: October 2023

Forest trees provide critical ecosystem services for humanity that are under threat due to ongoing global change. Measuring and characterizing genetic diversity are key to understanding adaptive potential and developing strategies to mitigate negative consequences arising from climate change. In the area of forest genetic diversity, genetic divergence caused by large-scale changes at the chromosomal level has been largely understudied. In this study, we used the RNA-seq data of 20 co-occurring forest trees species from genera including Acer, Alnus, Amelanchier, Betula, Cornus, Corylus, Dirca, Fraxinus, Ostrya, Populus, Prunus, Quercus, Ribes, Tilia, and Ulmus sampled from Upper Peninsula of Michigan. These data were used to infer the origin and maintenance of gene family variation, species divergence time, as well as gene family expansion and contraction. We identified a signal of common whole genome duplication events shared by core eudicots. We also found rapid evolution, namely fast expansion or fast contraction of gene families, in plant–pathogen interaction genes amongst the studied diploid species. Finally, the results lay the foundation for further research on the genetic diversity and adaptive capacity of forest trees, which will inform forest management and conservation policies.
The safety and efficacy of decortication for stage III drug-resistant tuberculous empyema
Authors: Yao Li , Wang Bing , Chen Xianxiang , Liu Qibin , Sheng Jian , Liu Xiaoyu , Dai Xiyong , Jiang Yuhui
Published: October 2023

OBJECTIVES

The goal of this study was to evaluate the safety and efficacy of decortication for stage III drug-resistant tuberculous empyema (TE).

METHODS

We analysed all patients with stage III TE who underwent decortication between March 2015 and October 2019 at Wuhan Pulmonary Hospital. The patients were divided into 2 groups according to drug-susceptibility testing of bronchoscopy lavage fluid, pleural effusion and tissue specimens, including a drug-resistant group and a drug-sensitive group. We collected and compared the preoperative, perioperative and postoperative data from the 2 groups to evaluate the safety and efficacy of decortication for stage III drug-resistant TE.

RESULTS

In total, 135 cases met the inclusion criteria and were enrolled, including 30 cases in the drug-resistant group and 105 cases in the drug-sensitive group. No deaths were recorded for the entire study population. Compared to the drug-sensitive group, the drug-resistant group had longer operation times (259.8 ± 78.4 min vs 187.2 ± 56.0 min, P = 0.00), a larger volume of intraoperative blood loss [300 (200,400) ml vs 200 (130, 300) ml, P = 0.00] and a higher intraoperative transfusion rate (5/30, 16.7% vs 4/105, 3.8%, P = 0.04). The rate of complications was significantly higher in the drug-resistant group (23; 76.7%) than in the drug-sensitive group (53; 50.5%) (P = 0.01). Recurrence was not reported in any of the patients. Twenty-three (76.7%) patients in the drug-resistant group and 90 (85.7%) patients in the drug-sensitive group recovered to an “excellent” level, and 3 cases in each group recovered to a “poor” level; there was no significant difference between the 2 groups in surgical effects (P = 0.21).

CONCLUSIONS

Decortication is a safe, effective and feasible option for patients with stage III drug-resistant TE, although the operation is difficult and risky.
Exploring drivers and challenges influencing antibiotic prescribing in outpatient settings and possible mitigation strategies in the United Arab Emirates: a qualitative study
Authors: Sadeq Ahmed A , Issa Farah Ahmed , Bakhit Mina , Al-Tamimi Maitha Abdul-Aziz , Babiker Zahir Osman Eltahir , Alshabebi Raghad S Ismail , Abdallah Jehad , Nsutebo Emmanuel Fru , Moukarzel Marleine B , Abukhater Rawan , Conway Barbara R , Bond Stuart E , Khan Sidra , Aldeyab Mamoon A
Published: October 2023

Objectives

Healthcare institutions implement antimicrobial stewardship (AMS) programmes to optimize the use of antibiotics. The focus is often on inpatient rather than outpatient settings. We aimed to explore perceptions of AMS stakeholders on effective interventions for appropriate antibiotic use in outpatient settings, and the role of clinical pharmacists in the AMS multidisciplinary team.

Methods

A qualitative semi-structured interview study using thematic analysis by two researchers independently. Participants that practice AMS programmes were recruited from healthcare facilities in the United Arab Emirates (UAE). Interviews were conducted face to face or online and transcribed verbatim.

Results

Four themes emerged: (i) Perceived factors leading to unnecessary or inappropriate antibiotic prescribing and their impact on patients and the community; (ii) current outpatient AMS activities and perceived barriers and facilitators for their sustainability; (iii) suggested outpatient AMS strategies to be implemented in outpatient settings; and (iv) perceived future AMS implementation barriers and suggested mitigation strategies.

Conclusions

Several AMS interventions, together with the presence of a clinical pharmacist, may be effective in improving antibiotic use in UAE outpatient settings. Future research should investigate the most appropriate AMS strategy considering barriers and possible mitigation strategies to ensure sustainability.
Pediatric Infectious Diseases Milestones: A Step in the Right Direction to Evaluate Subspecialty Learners
Authors: Thomas Sanya J , Anderson Marsha S , Adderson Elisabeth E , Edgar Laura , Curtis Donna , Dong Sara W , Fatemi Yasaman , Hecht Shaina M , James Scott H , Lehman Alice , Michelow Ian C , Perez Norma , Sattler Matthew M , Myers Angela L , Martin-Blais Rachel
Published: October 2023

We share the work of the ACGME Pediatric Infectious Diseases Working Group in creating the Pediatric Infectious Diseases-Specific Milestones and discuss key considerations that lead to the reformation of competencies to better assess learners in Pediatric Infectious Diseases.
The FAST Galactic Plane Pulsar Snapshot Survey – III. Timing results of 30 newly discovered pulsars
Authors: Su W Q , Han J L , Wang P F , Yuan J P , Wang Chen , Zhou D J , Wang Tao , Yan Yi , Jing W C , Yang Z L , Cai N N , Chen Xue , Xu Jun , Xie Lang , Wang H G , Xu R X , You X P
Published: October 2023

Timing observations are crucial for determining the basic parameters of newly discovered pulsars. Using the Five-hundred-meter Aperture Spherical radio Telescope (FAST) with the L-band 19-beam receiver covering the frequency range of 1.0–1.5 GHz, the FAST Galactic Plane Pulsar Snapshot (GPPS) Survey has discovered more than 600 faint pulsars with flux densities of only a few or a few tens of μJy at 1.25 GHz. To obtain accurate position, spin parameters and dispersion measure of a pulsar, and to calculate derived parameters such as the characteristic age and surface magnetic field, we collect available FAST pulsar data obtained either through targeted follow-up observations or through coincidental survey observations with one of the 19 beams of the receiver. From these data we obtain time of arrival (TOA) measurements for 30 newly discovered pulsars as well as for 13 known pulsars. We demonstrate that the TOA measurements acquired by the FAST from any beams of the receiver in any observation mode (e.g. the tracking mode or the snapshot mode) can be combined to get timing solutions. We update the ephemerides of 13 previously known pulsars and obtain the first phase-coherent timing results for 30 isolated pulsars discovered in the FAST GPPS Survey. Notably, PSR J1904+0853 is an isolated millisecond pulsar, PSR J1906+0757 is a disrupted recycled pulsar, and PSR J1856+0211 has a long period of 9.89 s that can constrain pulsar death lines. Based on these timing solutions, all available FAST data have been added together to obtain the best pulse profiles for these pulsars.
Efficacy and Safety of Darolutamide in Combination With Androgen-Deprivation Therapy and Docetaxel in Black Patients From the Randomized ARASENS Trial
Authors: Shore Neal D , Hussain Maha , Saad Fred , Fizazi Karim , Sternberg Cora N , Crawford David , Tombal Bertrand , Nordquist Luke , Cookson Michael , Verholen Frank , Jhaveri Jay , Srinivasan Shankar , Smith Matthew R
Published: October 2023

Background

In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS.

Patients and Methods

Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety.

Results

In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%).

Conclusion

In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.
Non-Native Plant Viruses Prevalent in Remnant Natural Plant Communities Harm Native Perennial Hosts
Authors: Shates Tessa M. , Gebiola Marco , Sun Penglin , Aung Oaksoe , Helo Amani , Kenney Jaimie R. , Malmstrom Carolyn M. , Mauck Kerry E.
Published: October 2023

Plant viruses are ubiquitous throughout plant communities, but research on viral impacts largely focuses on crops. Little is known about how viruses influence wild plants in their native habitats. To address this gap, we examined virus interactions with wild drought-tolerant perennials in California desert natural areas encroached upon by agriculture. We used metagenomics, targeted diagnostics, and phylogenetics to assess virus diversity and clade relationships, and experiments to investigate viral influence on hosts. We focused on three herbaceous perennials ( Cucurbita foetidissima, C. palmata, and Datura wrightii) and tested the hypothesis that these wild species accumulate virus infections typically found in crops and transmitted by polyphagous insects. We predicted that such infections might be retained across seasons and potentially impair plant performance. Virome profiling revealed a rich community of previously characterized virus species (12 total), with virus community structure varying by site and host species. The dominant viruses in the wild hosts were non-native crop pathogens, including cucurbit aphid-borne yellows virus (CABYV) and cucurbit yellow stunting disorder virus (CYSDV). Targeted testing revealed that CABYV infected as many as 88% of sampled wild Cucurbita individuals, with dual CABYV–CYSDV infections common in natural areas adjacent to desert agriculture. CABYV infections reduced shoot and root production in greenhouse experiments with the two wild Cucurbita species. Phylogenetic analyses suggest that CABYV was introduced to California multiple times from other continents. Our findings provide concerning evidence of ways in which human activities can alter virus pressure on wild plants and potentially contribute to plant decline.
High-Quality Genome Resource of Nothophoma quercina Causing Brown Spot Disease in Pears
Authors: Liu Lun , Ma Panpan , Luo Tingyue , Sun Yu , Tang Xiaomei , Heng Wei , Jia Bing , Zhu Liwu , Ye Zhenfeng
Published: October 2023

Brown spot, a serious disease caused by Nothophoma quercina, results in small, brown, round-to-oval lesions on the leaves and is a major concern in the pear industry. We previously reported a new pathogenic strain NqHH of Nothophoma quercina, which was isolated from ‘Huanghua’ pear ( Pyrus pyrifolia Nakai, cultivar Huanghua) leaves. However, genome information regarding this pathogen is limited. Herein, we detected the genome-wide sequence of the NqHH strain using the Illumina NovaSeq 6000 and PacBio Sequel Ⅱ systems. The genome of NqHH was estimated to be 35.3 Mb with an N50 length of 1.37 Mb, encoding for 11,659 predicted protein-coding genes. This genome sequence provides valuable information for the selection of pathogenic effectors and comparative genomics of brown spot disease in pears.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Pharmacogenetic Testing in Patients with Autism Spectrum Disorder Evaluated in a Precision Medicine Clinic
Authors: Goodson Rachel , Wagner Jennifer , Sandritter Tracy , Staggs Vincent S. , Soden Sarah , Nadler Cy
Published: October 2023

Objective:

This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results.

Methods:

Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital's precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients' co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories.

Results:

Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status.

Conclusion:

In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.
The impact of health literacy on adolescent and young adult pediatric liver transplant recipients
Authors: Baranwal Prerana , Sathe Mihika , Lobritto Steven J. , Vittorio Jennifer
Published: October 2023

Pediatric liver transplant recipients have increased rates of morbidity and mortality following transfer to adult health care providers. The role of health literacy (HL) has not been adequately assessed in this population and may be an unrecognized barrier to successful health care transition. We sought to determine the impact of HL for patients and their caregivers on measures of transition readiness (TR), adherence, health-related quality of life, and medical outcomes following pediatric liver transplant. This is a single-center study of pediatric liver transplant recipients transplanted between the ages of 12 and 26 from October 2016 through August 2020. Patients and caregivers completed 4 surveys to evaluate TR, health-related quality of life, and HL. Clinical outcomes were stratified based on the presence or absence of adequate HL. Limited HL was identified in 57.0% of recipients and 47.4% of caregivers. Patients with limited HL were more likely to be younger in age (p = 0.004), Hispanic (p = 0.003), and less likely to have obtained a high school diploma or equivalent (p < 0.001). Patients with adequate HL demonstrated significantly higher levels of TR (p < 0.001). Patient HL did not impact health-related quality of life, adherence, or medical outcomes. Caregiver HL did not impact patient outcomes or adherence, though higher levels of caregiver education were associated with adequate patient HL (p = 0.049). This study demonstrates that limited HL is associated with decreased measures of TR. Inadequate HL may be an unrecognized barrier to a successful health care transition. Regular assessment of HL may provide an opportunity for intervention prior to transfer of care. Future studies should investigate the impact of these interventions on long-term medical outcomes.
Escape the Room! Utilizing Gamification in a Preceptor Training Workshop
Authors: Coughlin Vincenza , Ho Mary Rose , Alvarez Guisela
Published: October 2023

Gamification is an innovative pedagogy involving immersive technology that acknowledges learner-centric milieus and dynamic teaching practices. Gamification is positioned well in nursing education because learners can translate tools from team experiences, communication, and critical thinking questions into the healthcare setting. This article introduces an escape-the-room format that was constructed for a preceptor program at a large academic medical center. The results of the implementation encourage gamification as an engaging methodology in clinical education.
Second Victim Phenomenon Educational Program Evaluation
Authors: Copley Dianna Jo , Burchill Christian N. , Lindell Deborah , Dolansky Mary A.
Published: October 2023

Second victim phenomenon (SVP) occurs when nurses who are involved in an unanticipated adverse event become victimized and traumatized by the event. Following a needs assessment, an SVP education program was implemented, including adverse events and SVP experiences, available support, and a case study. Evaluation indicated nurses had improved knowledge and attitude and increased practice intent. Education that promotes awareness is the first step to support nurses who experience events that can precipitate SVP.
Using a Flipped Classroom Model to Deliver Cardiovascular Nursing Education
Authors: Pollack Daniel , Chong Khrizna , Bahru Rahel
Published: October 2023

The COVID-19 pandemic served as a catalyst to change a didactic class training series consisting of passive lecture-based learning to a flipped classroom model with active learning techniques for newly hired nurses to a cardiovascular center. The purpose of this quality improvement project is to measure if utilizing a flipped classroom model to teach new cardiovascular nurses elicits the same class evaluation measurements compared to a traditional in-person didactic learning model.
Therapeutic Targeting of Oncogene-induced Transcription-Replication Conflicts in Pancreatic Ductal Adenocarcinoma
Authors: Smith Shanna J. , Meng Fan , Lingeman Robert G. , Li Caroline M. , Li Min , Boneh Galyah , Seppälä Toni T. , Phan Thuy , Li Haiqing , Burkhart Richard A , Parekh Vishwas , Rahmanuddin Syed , Melstrom Laleh G. , Hickey Robert J. , Chung Vincent , Liu Yilun , Malkas Linda H. , Raoof Mustafa
Published: October 2023

Purpose

Transcription-replication conflicts (TRCs) are a major source of endogenous replication stress in cancer. We previously discovered that pancreatic ductal adenocarcinoma (PDAC) demonstrates uniquely high levels of TRCs compared to other common solid tumors. Here, we characterize the mechanism of action, oncogene-dependency, PDAC subtype-specificity, and preclinical activity of a TRC-targeting small molecule – AOH1996 – in a spectrum of PDAC models. We also provide first clinical evidence of the activity of AOH1996 in a PDAC patient.

Experimental Design

The oncogene-dependent toxicity of AOH1996 was examined in KRAS(G12D) inducible systems. Next, the effect of AOH1996 was evaluated on replication fork progression, TRCs, DNA damage response, cell cycle progression, and apoptosis in PDAC cell lines. PDAC subtype-specific responses were evaluated in organoid cultures, andin vivoefficacy was evaluated in murine and patient-derived xenografts. Efficacy in a PDAC patient was evaluated by radiographic response assessment and progression-free survival.

Results

AOH1996 demonstrated dose-dependent cytotoxicity that was exquisitely dependent on oncogenic KRAS(G12D) induction. Cytotoxicity of AOH1996 was evident in several human and murine PDAC cell lines (Average IC50 across cell lines 0.72μM). Mechanistically, AOH1996 inhibited replication fork progression and promoted TRCs through enhanced interaction between RNA Polymerase II and Proliferating cell nuclear antigen which resulted in transcription-dependent DNA damage and global transcription shutdown. AOH1996 demonstrated activity in all organoid lines tested with varying potency (IC50 406nM – 2μM). Gene expression analysis demonstrated that organoids with replication stress high or very strongly basal signature were most vulnerable to AOH1996. In PDAC mouse model studies, AOH1996 reduced tumor growth rate, enhanced tumor-selective DNA damage and prolonged survival (Median 14 days vs. 21 days, P=0.04) without observable toxicity. The first patient with chemotherapy-refractory PDAC who was treated with AOH1996 monotherapy demonstrated early evidence of efficacy (49% shrinkage of the two hepatic metastases with stabilization of disease at other sites).

Conclusions

Therapeutic targeting of TRCs using small molecule inhibition is safe and effective in preclinical models. Pre-clinical data along with proof-of-concept activity in a patient with chemotherapy-refractory PDAC provides rationale for further clinical development of TRC targeting strategies.
The structural landscape of the immunoglobulin fold by large-scalede novodesign
Authors: Roel-Touris Jorge , Carcelén Lourdes , Marcos Enrique
Published: October 2023

De novodesigning immunoglobulin-like frameworks that allow for functional loop diversification shows great potential for crafting antibody-like scaffolds with fully customizable structures and functions. In this work, we combinedde novoparametric design with deep-learning methods for protein structure prediction and design to explore the structural landscape of 7-stranded immunoglobulin domains. After screening folding of nearly 4 million designs, we have assembled a structurally diverse library of ∼50,000 immunoglobulin domains with high-confidence AlphaFold2 predictions and structures diverging from naturally occurring ones. The designed dataset enabled us to identify structural requirements for the correct folding of immunoglobulin domains, shed light on β-sheet-β-sheet rotational preferences and how these are linked to functional properties. Our approach eliminates the need for preset loop conformations and opens the route to large-scalede novodesign of immunoglobulin-like frameworks.
Hidden in the sand: phylogenomics unravel an unexpected evolutionary history on the desert-adapted vipers of the genusCerastes
Authors: Mochales-Riaño Gabriel , Burriel-Carranza Bernat , Barros Margarida Isabel , Velo-Antón Guillermo , Talavera Adrián , Spilani Loukia , Tejero-Cicuéndez Héctor , Crochet Pierre-André , Piris Alberto , García-Cardenete Luis , Busais Salem , Els Johannes , Shobrak Mohammed , Brito José Carlos , Šmíd Jiří , Carranza Salvador , Martínez-Freiría Fernando
Published: October 2023

The desert vipers of the genusCerastesare a small clade of medically important venomous snakes within the family Viperidae. According to published morphological and molecular studies, the group is comprised by four species: two morphologically similar and phylogenetically sister taxa, the African horned viper (Cerastes cerastes) and the Arabian horned viper (Cerastes gasperettii); a more distantly related species, the Saharan sand viper (Cerastes vipera), and the enigmatic Böhme’s sand viper (Cerastes boehmei), only known from a single specimen in captivity allegedly captured in Central Tunisia. In this study, we analyzed one mitochondrial marker (COI) as well as genome-wide data (ddRAD sequencing) from 28 and 41 samples, respectively, covering the entire distribution range of the genus to explore the population genomics, phylogenomic relationships and introgression patterns within the genusCerastes. Additionally, and to provide insights into the mode of diversification of the group, we carried out niche overlap analyses considering climatic and habitat variables. Both nuclear phylogenomic reconstructions and population structure analyses have unveiled an unexpected evolutionary history for the genusCerastes, which sharply contradicts the morphological similarities and previously published mitochondrial approaches.Cerastes cerastesandC. viperaare recovered as sister taxa whilstC. gasperettiiis a sister taxon to the clade formed by these two species. We found a relatively high niche overlap (OI > 0.7) in both climatic and habitat variables betweenC. cerastesandC. vipera, contradicting a potential scenario of sympatric speciation. These results are in line with the introgression found between the northwestern African populations ofC. cerastesandC. vipera. Finally, our genomic data confirms the existence of a lineage ofC. cerastesin Arabia. All these results highlight the importance of genome-wide data over few genetic markers to study the evolutionary history of species.
Connecting Cancers to Chromosomal Locations Through Copy Number Variations
Authors: Sayad Saed , Hiatt Mark , Mustafa Hazem
Published: October 2023

Background

In 1960, scientists Peter Nowell and David Hungerford made a groundbreaking discovery by identifying the first genetic abnormality linked to cancer using cytogenetics. This discovery marked the beginning of research into many other genetic changes associated with cancer. These changes in chromosomes are like fingerprints, revealing how genes go haywire in cancer and destabilize the cell’s genetic makeup. In this paper, we focus on a clear connection between changes in the number of copies of certain genes at specific spots on chromosomes (called copy number variations or CNVs) and their role in various types of cancer.

Method

We obtained copy number data from various cancers cell lines through the DepMap portal website (https://depmap.org/portal/download/) and conducted diverse statistical analyses. Our approach involved comparing a single cancer cell line (primary disease) against the non-cancer cells. We used t-test to identify the top 100 genes that exhibited significant alterations in their copy number levels, both upregulated and downregulated. To enhance our understanding, we then linked these selected top 100 genes to their respective positions on the chromosomes.

Results

The top 100 upregulated genes associated with different cancers exhibit distinct chromosomal locations. For example all top 100 upregulated genes in Acute Myeloid Leukemia and Non-Hodgkin Lymphoma are on chromosome 17. Similarly, the top 100 downregulated genes linked to various cancers have their designated chromosomal locations.

Conclusions

Utilizing the DepMap copy number data, we have unveiled a distinctive linkage between cancer types and their specific chromosomal locales. The significance of these observed associations, when substantiated by biological evidence, holds the potential to significantly enhance our comprehension of cancer’s origins. Furthermore, such confirmation could pave the way for the development of more efficacious diagnostic, prognostic, and therapeutic strategies, promising a brighter outlook in the fight against cancer.
Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19
Authors: Li Chaofan , Qian Wei , Wei Xiaoqin , Narasimhan Harish , Wu Yue , Arish Mohd , Cheon In Su , Sharifi Kamya , Kern Ryan , Vassallo Robert , Sun Jie
Published: October 2023

Post-acute sequelae of SARS-CoV-2 infection (PASC) represents an urgent public health challenge, with its impact resonating in over 60 million individuals globally. While a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood studies, with few focusing on samples derived from post-COVID affected tissues. Further, clinical studies alone often provide correlative insights rather than causal relationships. Thus, it is essential to compare clinical samples with relevant animal models and conduct functional experiments to truly understand the etiology of PASC. In this study, we have made comprehensive comparisons between bronchoalveolar lavage fluid (BAL) single-cell RNA sequencing (scRNAseq) data derived from clinical PASC samples and relevant PASC mouse models. This revealed a strong pro-fibrotic monocyte-derived macrophage response in respiratory PASC (R-PASC) in both humans and mice, and abnormal interactions between pulmonary macrophages and respiratory resident T cells. IFN-γ emerged as a key node mediating the immune anomalies in R-PASC. Strikingly, neutralizing IFN-γ post the resolution of acute infection reduced lung inflammation, tissue fibrosis, and improved pulmonary gas-exchange function in two mouse models of R-PASC. Our study underscores the importance of performing comparative analysis to understand the root cause of PASC for developing effective therapies.
Draft Genomes of FourKluyveromyces marxianusIsolates Retrieved from the Elaboration Process of Henequén (Agave fourcroydes) Mezcal
Authors: Lozano-Aguirre Luis , Avitia Morena , Lappe-Oliveras Patricia , Licona-Cassani Cuauhtémoc , Cevallos Miguel Ángel , Le Borgne Sylvie
Published: October 2023

We report the draft genomes of fourKluyveromyces marxianusisolates obtained from the elaboration process of henequén (Agave fourcroydes) mezcal, a Mexican alcoholic beverage. The average nucleotide identity (ANI) analysis revealed that isolates derived from agave plants are distinct from those from other environments, including agave fermentations.
Effectiveness of one dose of MVA-BN vaccine against mpox infection in males in Ontario, Canada: A target trial emulation
Authors: Navarro Christine , Lau Cindy , Buchan Sarah A. , Burchell Ann N. , Nasreen Sharifa , Friedman Lindsay , Okpokoro Evaezi , Austin Peter C. , Tan Darrell HS , Gubbay Jonathan B. , Kwong Jeffrey C. , Mishra Sharmistha
Published: October 2023

Background

Limited evidence is available on the real-world effectiveness of modified vaccinia Ankara-Bavarian Nordic vaccine (MVA-BN) against mpox infection.

Methods

We emulated a target trial using linked databases in Ontario, Canada to estimate the effectiveness of one dose of MVA-BN. Our study included males aged ≥18 years who: (1) had a history of syphilis testing and a laboratory-confirmed bacterial sexually transmitted infection (STI) in the prior year; or (2) filled a prescription for HIV pre-exposure prophylaxis in the prior year. On each day between June 12, 2022 and October 27, 2022, males who had been vaccinated 15 days prior were matched 1:1 with unvaccinated males by age, geographic region, prior HIV diagnosis, number of bacterial STI diagnoses in the previous three years, and receipt of any non- MVA-BN vaccine in the previous year. We used a Cox proportional hazards model to estimate the hazard ratio comparing the incidence of mpox between the two groups, and calculated vaccine effectiveness as (1–HR)x100.

Results

Each group included 3,204 males. A total of 71 mpox infections were diagnosed over the study period, with 0.09 (95% confidence interval [CI], 0.05–0.13) per 1000 person-days for the vaccinated group and 0.20 (95%CI, 0.15–0.27) per 1000 person-days for the unvaccinated group. Estimated vaccine effectiveness of one dose of MVA-BN against mpox infection was 59% (95%CI, 31–76%).

Conclusions

This study, conducted in the context of a targeted vaccination program and evolving outbreak, suggests that one dose of MVA-BN is moderately effective in preventing mpox infection.
Cross-Tissue Specificity of Pediatric DNA Methylation Associated with Cumulative Family Adversity
Authors: Chan Meingold Hiu-ming , Merrill Sarah M. , Fatima Fizza , MacIsaac Julie L. , Obradović Jelena , Boyce W. Thomas , Kobor Michael S.
Published: October 2023

Background

Cumulative family adversity (cumulative FA), characterized by co-occurring stressors in a family context, may be biologically embedded through DNA methylation (DNAm) and contribute to later health outcomes.

Materials & Methods

We compared epigenome-wide DNAm associated with cumulative FA in buccal epithelial cells (BECs;n=218) and peripheral blood mononuclear cells (PBMCs;n=51) from 7-13-year-old children in Canada, accounting for sex, age, predicted cell-type proportion, and genetic ancestry.

Results

Higher levels of cumulative FA were associated with DNAm at seven sites, primarily in stress- and immune-related genes, only in PBMCs. Negative mother-child interaction contributed to this association.

Conclusions

The findings of this study suggested that PBMC DNAm can be used as a marker for biological embedding of cumulative FA.
Sex Differences In The Interaction Between Alcohol And mTORC1
Authors: Ehinger Yann , Phamluong Khanhky , Ron Dorit
Published: October 2023

The kinase mechanistic target of rapamycin complex 1 (mTORC1) plays an essential role in learning and memory by promoting mRNA to protein translation of a subset of synaptic proteins at dendrites. We generated a large body of data in male rodents indicating that mTORC1 is critically involved in mechanisms that promote numerous adverse behaviors associated with alcohol use disorder (AUD) including heavy alcohol use. For example, we found that mTORC1 is activated in the nucleus accumbens (NAc) and orbitofrontal cortex (OFC) of male mice and rats that were subjected to 7 weeks of intermittent access to 20% alcohol two-bottle choice (IA20%2BC). We further showed that systemic or intra-NAc administration of the selective mTORC1 inhibitor, rapamycin, decreases alcohol seeking and drinking, whereas intra-OFC administration of rapamycin reduces alcohol seeking and habit in male rats. This study aimed to assess mTORC1 activation in these corticostriatal regions of female mice and to determine whether the selective mTORC1 inhibitor, rapamycin, can be used to reduce heavy alcohol use in female mice. We found that mTORC1 is not activated by 7 weeks of intermittent 20% alcohol binge drinking and withdrawal in the NAc and OFC. Like in males, mTORC1 signaling was not activated by chronic alcohol intake and withdrawal in the medial prefrontal cortex (mPFC) of female mice. Interestingly, Pearson correlation comparisons revealed that the basal level of mTORC1 activation between the two prefrontal regions, OFC and mPFC were correlated and that the drinking profile predicts the level of mTORC1 activation in the mPFC after 4-hour binge drinking. Finally, we report that administration of rapamycin does not attenuate heavy alcohol drinking in female animals. Together, our results suggest a sex-dependent contribution of mTORC1 to the neuroadaptation that drives alcohol use and abuse.
Introgressions lead to reference bias in wheat RNA-Seq analysis
Authors: Coombes Benedict , Lux Thomas , Akhunov Eduard , Hall Anthony
Published: October 2023

RNA-Seq is a fundamental technique in genomics, yet reference bias, where transcripts derived from non-reference alleles are quantified less accurately, can undermine the accuracy of RNA-Seq quantification and thus the conclusions made downstream. Reference bias in RNA-Seq analysis has yet to be explored in complex polyploid genomes despite evidence that they are often a complex mosaic of wild relative introgressions, which introduce blocks of highly divergent genes. Here we use hexaploid wheat as a model complex polyploid, using both simulated and experimental data to show that RNA-Seq alignment in wheat suffers from widespread reference bias which is largely driven by divergent introgressed genes. This leads to underestimation of gene expression and incorrect assessment of homoeologue expression balance. By incorporating gene models from ten wheat genome assemblies into a pantranscriptome reference, we present a novel method to reduce reference bias, which can be readily scaled to capture more variation as new genome and transcriptome data becomes available.
Mitochondrial background can explain variable costs of immune deployment
Authors: Kutzer Megan A. M. , Cornish Beth , Jamieson Michael , Zawistowska Olga , Monteith Katy M. , Vale Pedro F.
Published: October 2023

Organismal health and survival depend on the ability to mount an effective immune response against infection. Yet, immune defence may be energy-demanding, resulting in fitness costs if investment in immune function deprives other physiological processes of resources. While evidence of costly immunity resulting in reduced longevity and reproduction is common, the role of energy-producing mitochondria on the magnitude of these costs is unknown. Here we employedDrosophila melanogastercybrid lines, where several mitochondrial genotypes (mitotypes) were introgressed onto a single nuclear genetic background, to explicitly test the role of mitochondrial variation on the costs of immune stimulation. We exposed female flies carrying one of nine distinct mitotypes to either a benign, heat-killed bacterial pathogen (stimulating immune deployment while avoiding pathology), or to a sterile control, and measured lifespan, fecundity, and locomotor activity. We observed mitotype-specific costs of immune stimulation and identified a positive genetic correlation between lifespan and the proportion of time cybrids spent moving while alive. Our results suggests that costs of immunity are highly variable depending on the mitochondrial genome, adding to a growing body of work highlighting the important role of mitochondrial variation in host-pathogen interactions.
Spatially specific, closed-loop infrared thalamocortical deep brain stimulation
Authors: Coventry Brandon S , Lawlor Georgia L , Bagnati Christina B , Krogmeier Claudia , Bartlett Edward L
Published: October 2023

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson’s disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically-mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to mid-infrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Significance Statement

Despite initial clinical successes, electrical deep brain stimulation (DBS) is fraught with off-target current spillover into tissue outside of therapeutic targets, giving rise to patient side effects and the reduction of therapeutic efficacy. In this study, we validate infrared neural stimulation (INS) as a spatially constrained optical DBS paradigm by quantifying dose-response profiles and robust information transfer through INS driven thalamocortical circuits. We show that INS elicits biophysically relevant responses which are spatially constrained compared to conventional electrical stimulation, potentially reducing off-target side effects. Leveraging the spatial specificity of thalamocortical INS, we used deep reinforcement learning to close the loop on thalamocortical INS and showed the ability to drive subject-specific thalamocortical circuits to target response states in real time.
Trade-offs, trade-ups, and high mutational parallelism underlie microbial adaptation to extreme feast/famine
Authors: Behringer Megan G. , Ho Wei-Chin , Miller Samuel F , Worthan Sarah B. , Cen Zeer , Stikeleather Ryan , Lynch Michael
Published: October 2023

Microbes are robust organisms capable of rapidly adapting to complex stress, enabling the colonization of harsh environments. In nature, microbes are regularly challenged by starvation, which is a particularly complex stress because resource limitation often co-occurs with changes in pH, osmolarity, and toxin accumulation created by metabolic waste. Often overlooked are the additional complications introduced by eventual resource replenishment as successful microbes must withstand rapid environmental shifts before swiftly capitalizing on replenished resources to avoid invasion by competing species. To understand how microbes navigate trade-offs between growth and survival, ultimately adapting to thrive in environments with extreme fluctuations, we experimentally evolved 16Escherichia colipopulations for 900 days to repeated feast/famine cycles of 100-day starvation before resource replenishment. Using longitudinal population-genomic analysis, we found that evolution in response to extreme feast/famine is characterized by narrow adaptive trajectories with high mutational parallelism and notable mutational order. Genetic reconstructions reveal that early mutations result in trade-offs for biofilm and motility but trade-ups for growth and survival, as these mutations conferred correlated advantages during both short-term and long-term culture. Our results demonstrate how microbes can navigate the adaptive landscapes of regularly fluctuating conditions and ultimately follow mutational trajectories that confer benefits across diverse environments.
The Maintenance of Deleterious Variation in Wild Chinese Rhesus Macaques
Authors: Steux Camille , Szpiech Zachary A.
Published: October 2023

Understanding how deleterious variation is shaped and maintained in natural populations is important in conservation and evolutionary biology, as decreased fitness caused by these deleterious mutations can potentially lead to an increase in extinction risk. It is known that demographic processes can influence these patterns. For example, population bottlenecks and inbreeding increase the probability of inheriting identical-by-descent haplotypes from a recent common ancestor, creating long tracts of homozygous genotypes called runs of homozygosity (ROH), which have been associated with an accumulation of mildly deleterious homozygotes. Counter intuitively, positive selection can also maintain deleterious variants in a population through genetic hitchhiking.

Here we analyze the whole genomes of 79 wild Chinese rhesus macaques across five sub-species and characterize patterns of deleterious variation with respect to ROH and signals of recent positive selection. We show that the fraction of homozygotes occurring in long ROH is significantly higher for deleterious homozygotes than tolerated ones, whereas this trend is not observed for short and medium ROH. This confirms that inbreeding, by generating these long tracts of homozygosity, is the main driver of the high burden of homozygous deleterious alleles in wild macaque populations. Furthermore, we show evidence that homozygous LOF variants are being purged. Next, we identify 7 deleterious variants at high frequency in regions putatively under selection near genes involved with olfaction and other processes.

Our results shed light on how evolutionary processes can shape the distribution of deleterious variation in wild non-human primates.

Significance

Our results offer insights into the relationship between demographic and evolutionary processes and the maintenance of deleterious alleles in wild rhesus macaques. We demonstrate how inbreeding and recent positive selection can contribute to the maintenance of deleterious variants in wild non-human primate populations. Given that deleterious variation can reduce individuals reproductive fitness and contribute to extinction risks, this study is particularly relevant in the context of conservation of wild endangered species.
Dissecting glial scar formation by spatial point pattern and topological data analysis
Authors: Manrique-Castano Daniel , Bhaskar Dhananjay , ElAli Ayman
Published: October 2023

Glial scar formation represents a fundamental response to central nervous system (CNS) injury. It is mainly characterized by a well-defined spatial rearrangement of reactive astrocytes and microglia. The mechanisms underlying glial scar formation have been extensively studied, yet quantitative descriptors of the spatial arrangement of reactive glial cells remain limited. Here, we present a novel approach using point pattern analysis (PPA) and topological data analysis (TDA) to quantify spatial patterns of reactive glial cells after experimental ischemic stroke in mice. We provide open and reproducible tools usingRandJuliato quantify spatial intensity, cell covariance and conditional distribution, cell-to-cell interactions, and short/long-scale arrangement, which collectively disentangle the arrangement patterns of the glial scar. This approach unravels a substantial divergence in the distribution of reactive astrocytes and microglia after injury that conventional analysis methods cannot fully characterize. PPA and TDA are valuable tools for studying the complex spatial arrangement of reactive glia and other nervous cells following CNS injuries and have potential applications for evaluating glial-targeted restorative therapies.