bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACT:

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.
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

ABSTRACTPurposeTranscription-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 DesignThe 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.ResultsAOH1996 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).ConclusionsTherapeutic 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

ABSTRACTDe 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

AbstractThe 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

AbstractBackgroundIn 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.MethodWe 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.ResultsThe 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.ConclusionsUtilizing 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

AbstractPost-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

AbstractWe 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

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

AbstractBackgroundCumulative 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 & MethodsWe 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.ResultsHigher 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.ConclusionsThe 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

ABSTRACTThe 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

AbstractRNA-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

AbstractOrganismal 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

AbstractDeep 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 StatementDespite 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.