bluuebunny/crossref_metadata_2025 huggingface dataset:
Ambulatory urine biomarkers associations with acute kidney injury and hospitalization in people with HIV
Authors: Lai Mason , Scherzer Rebecca , Shlipak Michael G. , Madden Erin , Vittinghoff Eric , Tse Warren , Parikh Chirag R. , Villalobos Celia P. Corona , Monroy-Trujillo Jose Manuel , Moore Richard D. , Estrella Michelle M.
Published: August 2023

Background:

People with HIV (PWH) generally have worse ambulatory levels of kidney injury biomarkers and excess risk of acute kidney injury (AKI) compared to persons without HIV. We evaluated whether ambulatory measures of subclinical kidney injury among PWH are associated with subsequent AKI.

Methods:

In the Predictors of Acute Renal Injury Study (PARIS), which enrolled 468 PWH from April 2016 to August 2019, we measured 10 urine biomarkers of kidney health (albumin, a1m, b2M, NGAL, IL18, KIM-1, EGF, UMOD, MCP-1, YKL40) at baseline and annually during follow-up. Using multivariable Cox regression models, we evaluated baseline and time-updated biomarker associations with the primary outcome of AKI (≥0.3 mg/dl or ≥1.5-times increase in serum creatinine from baseline) and secondary outcome of all-cause hospitalization.

Results:

At baseline, the mean age was 53 years old, and 45% self-identified as female. In time-updated models adjusting for sociodemographic factors, comorbidities, albuminuria, estimated glomerular filtration rate, and HIV-associated factors, higher KIM-1 [hazard ratio (HR) = 1.30 per twofold higher; 95% confidence interval (CI) 1.03–1.63] and NGAL concentrations (HR = 1.24, 95% CI 1.06–1.44) were associated with higher risk of hospitalized AKI. Additionally, in multivariable, time-updated models, higher levels of KIM-1 (HR = 1.19, 95% CI 1.00, 1.41), NGAL (HR = 1.13, 95% CI 1.01–1.26), and MCP-1 (HR = 1.20, 95% CI 1.00, 1.45) were associated with higher risk of hospitalization.

Conclusions:

Urine biomarkers of kidney tubular injury, such as KIM-1 and NGAL, are strongly associated with AKI among PWH, and may hold potential for risk stratification of future AKI.
Integrative Medicine: An Opportunity for Improving Quality of Care in the Inpatient Setting
Authors: Maheu Arlene R. , Ayubcha Soussan , Handley Nathan R.
Published: August 2023

As medicine shifts to a value-based focus, health care providers in inpatient settings are actively seeking approaches to providing high-quality patient care without exacerbating prevailing cost burden. Complementary and integrative medicine may offer one potential solution for this challenge. Although the benefits of utilizing integrative practices in the inpatient setting have not been explored extensively thus far, early evidence demonstrates great promise of using integrative modalities to improve symptom burden in the inpatient setting while increasing patient pain satisfaction and reducing overall costs of care. Currently, social, educational, and financial barriers exist, limiting the widespread incorporation of complementary and integrative medicine into the inpatient setting. Nonetheless, a more robust body of literature demonstrating the effectiveness of complementary and integrative medicine in reducing costs of care and improving patient outcomes may help address these limitations and lead to the acceptance of integrative practices as the standard of high-value inpatient care.
Variability in Opioid Prescribing Among Plastic Surgery Residents After Bilateral Breast Reduction
Authors: Fiscella Kimberly , Awad Amanda N. , Shihadeh Hanaa , Patel Ashit
Published: August 2023

Background

Prescription opioid misuse in the United States accounts for significant avoidable morbidity and mortality. Over one third of all prescriptions written by surgeons are for opioids. Although opioids continue to provide needed analgesia for surgical patients, there are few guidelines in the plastic surgery literature for their safe and appropriate use after surgery. The consequence is wide variability and excessive opioid prescriptions. Understanding patterns of prescribing among plastic surgery residents is a crucial step toward developing safer practice models for managing postoperative pain.

Methods

The authors performed a retrospective analysis of discharge opioid prescriptions after bilateral breast reduction at a single academic medical center from 2018 to 2021. Single factor 1-way analysis of variance was used to evaluate prescribing patterns by resident, postgraduate year, attending of record, and patient characteristics for 126 patients. A multivariate analysis was performed to determine the degree to which these factors predicted opioid prescriptions.

Results

This analysis revealed significant variability among residents prescribing opioids after bilateral breast reductions (P < 0.001) irrespective of patient comorbidities and demographics. Residents were found to be the main predictor of opioid prescriptions after surgery (P < 0.001) with a greater number of morphine milligram equivalents prescribed by the more junior residents (P < 0.001).

Conclusions

Excessive and variable opioid prescriptions among plastic surgery residents highlight the need for opioid prescribing education early in surgical training and improved oversight and communication with attending surgeons. Furthermore, implementation of evidence-based opioid-conscious analgesic protocols after common surgical procedures may improve patient safety by standardizing postoperative analgesic prescriptions.
Let-Down Rhinoplasty in Patients With Cleft Lip Nose
Authors: Tapan Mehmet , Şeker Yunus Emre , Zöhre Cihan Taylan , İşler Vedat Can , Özpar Ege Bora , Özkan Özlenen , Özkan Ömer
Published: August 2023

Background and Objectives

Rhinoplasty in patients with cleft lip nose (CLN) deformity is challenging. Cleft lip nose deformity primarily affects the nasal tip, columella, nostrils, alar base, floor, and septum. The needs of patients with CLN are quite different from those of patients who undergo primary rhinoplasty. Recently, the dorsal preservation rhinoplasty technique has gained popularity. We applied this technique to patients with CLN deformity to obtain better aesthetic and functional results.

Patients and Methods

Ten consecutive patients with indication for primary CLN reconstruction underwent let-down rhinoplasty. Rhinoplasties were performed using either the closed or open approach, with costal cartilage grafts and full-thickness skin grafts. A rhinoplasty outcome evaluation questionnaire was used to assess the results. Moreover, the use of the same questionnaire in prior patients allowed us to compare results between our previous and new techniques.

Results

The study included 6 female and 4 male patients, with ages ranging from 18 to 25 years. Only 1 patient had a history of bilateral cleft lip. Seven patients had a history of left-sided cleft lip, and 2 patients had right-sided cleft lip. Open-approach let-down rhinoplasty with costal cartilage grafts and full-thickness skin grafts was performed in 8 patients, whereas closed-approach let-down rhinoplasty with costal cartilage grafts was performed in 2 patients. Columellar struts and affected-side onlay costal cartilage grafts were used in all patients. All patients reported being satisfied with the let-down rhinoplasty outcome, and none complained of functional problems. However, nostril symmetry was not observed in some patients, particularly in patients who underwent closed-approach rhinoplasty.

Conclusions

Combining open approach, full-thickness skin graft, costal cartilage graft, and let-down rhinoplasty shows promising and satisfactory outcomes in patients with CLN. However, further studies are required to confirm this observation.
Dynamic Changes in Metabolic Status Are Associated With Risk of Ocular Motor Cranial Nerve Palsies
Authors: Choi Daye Diana , Park Kyung-Ah , Han Kyungdo , Oh Sei Yeul
Published: August 2023

Background:

To investigate whether recovery from or development of metabolic syndrome (MetS) in a population is associated with an altered risk for ocular motor cranial nerve palsy (CNP).

Methods:

This cohort study included 4,233,273 adults without a history of ocular motor cranial nerve palsy (ocular motor CNP) who underwent 2 consecutive biennial health screenings provided by the Korean National Health Insurance System between 2009 and 2011. They were followed up until December 31, 2018. Participants were categorized into a MetS-free, MetS-developed, MetS-recovered, or MetS-chronic group. A multivariable Cox proportional hazard regression model was used. Model 3 was adjusted for age, sex, smoking status, alcohol consumption, and physical activity.

Results:

Compared with the MetS-free group, the MetS-chronic group had the highest risk of ocular motor CNP (hazard ratio [HR]: 1.424; 95% confidential interval [CI]: 1.294–1.567, Model 3), followed by the MetS-developed group (HR: 1.198, 95% CI: 1.069–1.343), and the MetS-recovered group (HR: 1.168, 95% CI: 1.026–1.311) after adjusting for potential confounders. The hazard ratio of ocular motor CNP in men with chronic MetS was 1.566 (95% CI, 1.394–1.761) while that of women with chronic MetS was 1.191 (95% CI, 1.005–1.411). Among age groups, those in their 30s and 40s showed the highest association between dynamic MetS status and ocular motor CNP.

Conclusions:

In our study, recovering from MetS was associated with a reduced risk of ocular motor CNP compared with chronic MetS, suggesting that ocular motor CNP risk could be managed by changing MetS status.
Explainable AI in Deep Learning-based Detection of Aortic Elongation on Chest X-ray Images
Authors: Ribeiro Estela , Cardenas Diego A. C. , Dias Felipe M. , Krieger Jose E. , Gutierrez Marco A.
Published: August 2023

Aim

Aortic Elongation can result from age-related changes, congenital factors, aneurysms, or conditions affecting blood vessel elasticity. It is associated with cardiovascular diseases and severe complications like aortic aneurysms and dissection. We aim to assess qualitatively and quantitatively explainable methods in order to understand the decisions of a deep learning model for Aortic Elongation detection with Chest X-Ray (CXR) images.

Methods and Results

In this work, we evaluated the performance of deep learning models (DenseNet and EfficientNet) for aortic elongation detection based on transfer learning and fine-tunning techniques using CXR as input. DenseNet achieved higher accuracy (84.7% ± 0.7), precision (75.6% ± 1.3), sensitivity (88.7% ± 2.7), specificity (82.3% ± 1.6), F1-score (81.6% ± 1.0), and AUROC (93.1% ± 0.4) than EfficientNet. To gain insights into the decision-making process of the deep learning models, we employed Grad-CAM and LIME explainability methods. Through these techniques, we were able to successfully identify the expected location of aortic elongation in the x-ray images. Moreover, we used the pixel-flipping method to assess quantitatively the interpretations providing valuable insights into models behavior.

Conclusion

Our study presents a comprehensive strategy for analyzing CXR by integrating Aortic Elongation detection models with explainable methods. By incorporating explainable AI techniques, we enhanced the interpretability and understanding of the models’ decisions. This approach holds promise for aiding clinicians in timely and accurate diagnosis, potentially improving patient outcomes in clinical practice.
CCR7+ CD4 T Cell Immunosurveillance Disrupted in Chronic SIV-Induced Neuroinflammation in Rhesus Brain
Authors: Elizaldi Sonny R. , Hawes Chase E , Verma Anil , Dinasarapu Ashok R. , Lakshmanappa Yashavanth Shaan , Schlegel Brent T , Rajasundaram Dhivyaa , Li Jie , Durbin-Johnson Blythe P , Ma Zhong-Min , Beckman Danielle , Ott Sean , Lifson Jeffrey , Morrison John H. , Iyer Smita S.
Published: August 2023

CD4 T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4 T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4 T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside other CNS border tissues. Sequestering TCMcells in lymph nodes using FTY720 led to reduced CCR7+ CD4 T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL57 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4 T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4 T cells in CNS immune surveillance and their decline during chronic SIV-induced neuroinflammation highlights their responsiveness to neuroinflammatory processes.

GRAPHICAL ABSTRACT

In Brief

Utilizing single-cell and spatial transcriptomics on adult rhesus brain, we uncover a unique CCR7+ CD4 T cell subset resembling central memory T cells (TCM) within brain and border tissues, including skull bone marrow. Our findings show decreased frequencies of this subset during SIV- induced chronic neuroinflammation, emphasizing responsiveness of CCR7+ CD4 T cells to CNS disruptions.

Highlights

CCR7+ CD4 T cells survey border and parenchymal CNS compartments during homeostasis; reduced presence of CCR7+ CD4 T cells in cerebrospinal fluid leads to immune activation, implying a role in neuroimmune homeostasis.

CNS CCR7+ CD4 T cells exhibit phenotypic and functional features of central memory T cells (TCM) including production of interleukin 2 and the capacity for rapid recall proliferation. Furthermore, CCR7+ CD4 T cells reside in the skull bone marrow.

CCR7+ CD4 T cells are markedly decreased within the brain parenchyma during chronic viral neuroinflammation.
Analysis of Moonlighting Proteins Regulated by Curcumin and Resveratrol in Cancer
Authors: Sumantran Venil N. , Kannadasan Anand Babu
Published: August 2023

Multitasking proteins or moonlighting proteins (MLP) play a major role in human disease and many are drug targets. MLPs have a single polypeptide with two different biochemical functions and often have different cellular localizations. Analysis of MultitaskProtDB-II and Comparative Toxicogenomics databases and Gene Ontology and STRING analysis, showed that curcumin and resveratrol regulate 3 groups of MLPs. Group 1 MLPs drive epithelial mesenchymal transition (EMT), whereas MLPs in groups 2 and 3 regulate tumour growth and suppression, respectively. The 3 groups of MLPs form a complex self-regulating network due to regulatory interactions between MLPs and the presence of transcription factors (CTNNB1, p53, NRF2) with their regulators and targets. Curcumin and/or resveratrol downregulate MLPs which drive EMT (CTNNB1, FASN, SMADs 2,3,4, MECP2, MMP2, TGFβR1, HES1) and promote growth and inflammation (MMP2, EGFR, FGF2, MDR1). Second, curcumin and/or resveratrol modulate pleiotropic, regulatory ‘hub’ MLPs (GSK3β, NOTCH1, HMGB1). Third, both phytochemicals upregulate tumour suppressor CDH1, and CYCS, which triggers apoptosis. Fourth, both phytochemicals modulate p53 expression, activity, and independently downregulate tumorigenic gene targets of p53 in groups 1 and 2. This dual mechanism can permit regulation of p53 activity in cells with wild type or mutant p53. Fifth, moonlighting functions of specific MLPs can cause unpredictable effects. These results add insights into synergistic and pleiotropic anti-cancer mechanisms of curcumin and resveratrol. It has clinical relevance because both phytochemicals are chemo-preventive agents and chemosensitizers in clinical trials.
Identification of Potential Therapeutic targets for Stroke and Its Subtypes by Integrating Proteomes and Genetics from Human Plasma
Authors: Liu Hanchen , Zhang Xiaoxi , Ma Hongyu , Nguyen Thanh N. , Hua Weilong , Mo Shaojun , Huang Qinghai , Liu Jianmin , Zhou Yu , Yang Pengfei
Published: August 2023

Background

Previous genome-wide association studies (GWAS) have identified several risk genes for stroke; however, it remains unclear how they confer risk for the disease. We conducted an integrative analysis to identify candidate genes for stroke and stroke subtypes by integrating blood-derived multi-omics data with genetic data.

Method

We systematically integrated the latest stroke GWAS database (73,652 patients and 1,234,808 controls) with human plasma proteomes (N=7,213) and performed proteome-wide association studies (PWAS), Mendelian randomization (MR), Bayesian colocalization analysis, and transcriptome-wide association study (TWAS) to prioritize genes that associate the risk of stroke and its subtypes with their expression and protein abundance in plasma. Cell-type specificity and functional enrichment analysis using single-cell RNA sequencing (scRNA-seq) and Gene Ontology (GO) databases were then performed to select target genes. A two-step MR analysis was followed to explore the potential mechanisms.

Results

We found that the protein abundance of seven genes (MMP12, F11, SH3BGRL3, ENGASE, SCARA5, SWAP70,andSPATA20) in the plasma was associated with stroke and its subtypes, with six genes (MMP12, F11, SH3BGRL3, SCARA5, SWAP70,andSPATA20) causally related with stroke and its subtypes (P < 0.05/proteins identified for PWAS; P < 0.05/8 for MR; posterior probability of hypothesis 4 ≥ 75 % for Bayesian colocalization). The effect ofF11, SH3BGRL, SPATA20,andSWAP70on each subtype was mediated by Factor XI inhibitors (FXI), atrial fibrillation, T2D, and SBP respectively (p<0.05). We also found thatSCARA5andSWAP70were related to stroke and ischemic stroke at the transcriptome level.

Conclusions

Our present proteomic findings have identified new causal genes in the pathogenesis of stroke, which may offer potential future therapeutic targets for stroke prevention.
Characterization of Identified Dopaminergic Neurons in the Mouse Forebrain and Midbrain
Authors: Lau Maggy Yu Hei , Gadiwalla Sana , Jones Susan , Galliano Elisa
Published: August 2023

Dopaminergic (DA) neurons play pivotal roles in diverse brain functions, spanning movement, reward processing, and sensory perception. DA neurons are most abundant in the midbrain (Substantia Nigra pars compacta, SNC, and Ventral Tegmental Area, VTA) and the olfactory bulb (OB) in the forebrain. Interestingly, a subtype of OB DA neurons is capable of regenerating throughout life, while a second class is exclusively born during embryonic development. Emerging evidence in SNC and VTA also indicates substantial heterogeneity in terms of morphology, connectivity, and function. To further investigate this heterogeneity and directly compare form and function of midbrain and forebrain DA neurons, we performed immunohistochemistry and whole-cell patch-clamp recordings inex vivobrain slices from juvenile DAT-tdTomato mice. After confirming the penetrance and specificity of the dopamine transporter (DAT) Cre line, we compared soma shape, passive membrane properties, voltage sags and action potential firing across midbrain and forebrain DA subtypes. We found that each DA subgroup within midbrain and forebrain was highly heterogeneous, and that DA neurons across the two brain areas are also substantially different. These findings complement previous work in rats as well as gene expression andin vivodatasets, further questioning the existence of a single “dopaminergic” neuronal phenotype.
Impact of Infectious Diseases on Wild Bovidae Populations in Thailand: Insights from Population Modelling and Disease Dynamics
Authors: Horpiencharoen Wantida , Marshall Jonathan C. , Muylaert Renata L. , John Reju Sam , Hayman David T. S.
Published: August 2023

The wildlife and livestock interface is vital for wildlife conservation and habitat management. Infectious diseases maintained by domestic species may impact threatened species such as Asian bovids, as they share natural resources and habitats. To predict the population impact of infectious diseases with different traits, we used stochastic mathematical models to simulate the population dynamics 100 times over 100 years for a model gaur (Bos gaurus) population with and without disease. We simulated repeated introductions from a reservoir, such as domestic cattle. We selected six bovine infectious diseases; anthrax, bovine tuberculosis, hemorrhagic septicaemia, lumpy skin disease, foot and mouth disease and brucellosis, all of which have caused outbreaks in wildlife populations. From a starting population of 300, the disease-free population increased by an average of 228% over 100 years. Brucellosis with frequency-dependent transmission showed the highest average population declines (−97%), with population extinction occurring 16% of the time. Foot and mouth disease with frequency-dependent transmission showed the lowest impact, with an average population increase of 200%. Overall, acute infections with very high or low fatality had the lowest impact, whereas chronic infections produced the greatest population decline. These results may help disease management and surveillance strategies support wildlife conservation.
Comparative GWAS identifies a role for Mendel’s green pea gene in the nonphotochemical quenching kinetics of sorghum, maize, and arabidopsis
Authors: Sahay Seema , Shrestha Nikee , Dias Henrique Moura , Mural Ravi V. , Grzybowski Marcin , Schnable James C. , Głowacka Katarzyna
Published: August 2023

Photosynthetic organisms must cope with rapid fluctuations in light intensity. Nonphotochemical quenching (NPQ) enables the dissipation of excess light energy as heat under high light conditions, whereas its relaxation under low light maximizes photosynthetic productivity. We quantified variation in NPQ kinetics across a large sorghum (Sorghum bicolor) association panel in four environments, uncovering significant genetic control for NPQ. A genome-wide association study (GWAS) identified 20 unique regions in the sorghum genome associated with NPQ. We detected strong signals from the sorghum ortholog ofArabidopsis thaliana SUPPRESSOR OF VARIEGATION3(SVR3) involved in plastid–nucleus signaling and tolerance to cold. By integrating GWAS results for NPQ across maize (Zea mays) and sorghum association panels, we identified a second gene,NON-YELLOWING 1(NYE1), originally identified by Gregor Mendel in pea (Pisum sativum) and involved in the degradation of photosynthetic pigments in light-harvesting complexes, along withOUTER ENVELOPE PROTEIN 37(OEP37), that encodes a transporter in chloroplast envelope. Analysis ofnye1insertion alleles inA. thalianaconfirmed the effect of this gene on NPQ kinetics across monocots and eudicots. We extended our comparative genomics GWAS framework across the entire maize and sorghum genomes, identifying four additional loci involved in NPQ kinetics. These results provide a baseline for engineering crops with improved NPQ kinetics and increasing the accuracy and speed of candidate gene identification for GWAS in species with high linkage disequilibrium.
High quality genome assembly of the brown hare (Lepus europaeus) with chromosome-level scaffolding
Authors: Michell Craig , Collins Joanna , Laine Pia K. , Fekete Zsofia , Tapanainen Riikka , Wood Jonathan M. D. , Goffart Steffi , Pohjoismaki Jaakko L. O.
Published: August 2023

We present here a high-quality genome assembly of the brown hare (Lepus europaeus Pallas), based on a fibroblast cell line of a male specimen from Liperi, Eastern Finland. This brown hare genome represents the first Finnish contribution to the European Reference Genome Atlas pilot effort to generate reference genomes for European biodiversity. The genome was assembled using 25X PacBio HiFi sequencing data and scaffolded utilizing a Hi-C chromosome structure capture approach. After manual curation, the assembled genome length was 2,930,972,003 bp with N50 scaffold of 125.8 Mb. 93.16% of the assembly could be assigned to 25 identified chromosomes (23 autosomes plus X and Y), matching the published karyotype. The chromosomes were numbered according to size. The genome has a high degree of completeness based on the BUSCO score (mammalia_odb10 database), Complete: 96.1% [Single copy: 93.1%, Duplicated: 3.0%], Fragmented 0.8%, and Missing 2.9%. The mitochondrial genome of the cell line was sequenced and assembled separately. The brown hare genome is particularly interesting as this species readily hybridizes with the mountain hare (Lepus timidus L.) at the species contact zone in northern Eurasia, producing fertile offspring and resulting in gene flow between the two species. In addition to providing a useful comparison for population studies, the genome can offer insight into the chromosomal evolution among Glires in general and Lagomorpha in particular. The chromosomal assembly of the genome also demonstrates that the cell line has not acquired karyotypic changes during culture.
From neglecting to including cultivar-specificper setemperature responses: Extending the concept of thermal time for plant development modeling
Authors: Roth Lukas , Binder Martina , Kirchgessner Norbert , Tschurr Flavian , Yates Steven , Hund Andreas , Kronenberg Lukas , Walter Achim
Published: August 2023

Predicting plant development, a longstanding goal in plant physiology, involves two interwoven components: continuous growth and the progression of growth stages (phenology). Current models, like thermal time, assume species-level growth responses to temperature. We challenge this assumption, suggesting that cultivar-specific temperature responses significantly affect phenology. To investigate, we collected field-based growth and phenology data in winter wheat and soybean over multiple years. We used diverse models, from linear to neural networks, to assess growth responses to temperature at various trait and covariate levels. Cultivar-specific non-linear models best explained phenology-related cultivar-environment interactions. With cultivar-specific models, additional relations to other stressors than temperature were found. The availability of the presented field phenotyping tools allows incorporating cultivar-specific temperature response functions in future plant physiology studies, which will deepen our understanding of key factors that influence plant development. Consequently, this work has implications for crop breeding and cultivation under adverse climatic conditions.
Rice yellow mottle virusis a suitable amplicon vector an efficient production of an anti-leishmianiasis vaccine inNicotiana benthamianaleaves
Authors: Bamogo PKA , Tiendrébéogo F , Brugidou C , Sérémé D , Djigma FW , Simporé J , Lacombe S
Published: August 2023

The suitability of rice yellow mottle virus RYMV as a gene expression vector in plant was assessed using a construct carrying promastigote surface antigen (PSA) C-terminal coding sequence of the parasite protozoan Leishmania. RYMV ORF1 encoding P1 protein has been deleted from the RYMV native genome. The C-terminal PSA gene was substituted for the viral coat protein. PSA is present at the surface of the parasite and displays vaccine properties against canine and human leishmaniosis. RYMV-based vector allowed PSA expression inNicotiana benthamiana. Q-pcr analysis showed that chimeric RYMV carrying PSA gene is able to replicate inN. benthamianaleaves. P19 silencing suppressor in combination with the lacked viral vector ORF encoding RYMV Coat Protein (CP) enhanced significantly RYMV tool replication inN. benthamiana. RYMV CP played a key role on viral RNA stabilization and acts as a weak silencing suppressor.

The original RYMV-based expression vector allowed PSA protein expression enhancement in N. benthamianawithout any symptoms. RYMV-based vector could be suitable for functional genomic studies in monocots by VIGS (Viral Induced Gene Silencing) technology.
Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth
Authors: Zhang Ying , Chen Kaijing , Tang Seng Chuan , Cai Yichao , Nambu Akiko , See Yi Xiang , Fu Chaoyu , Raju Anandhkumar , Lebeau Benjamin , Ling Zixun , Mutwil Marek , Lakshmanan Manikandan , Osato Motomi , Tergaonkar Vinay , Fullwood Melissa Jane
Published: August 2023

Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form “super-silencers” and whether they are linked to cancer progression. Here, through interrogating two putative silencer components ofFGF18gene, we found that two nearby silencers can cooperate via compensatory chromatin interactions to form a “super-silencer”. Furthermore, double knockout of two silencers exhibited synergistic upregulation ofFGF18expression and changes of cell identity. To perturb the “super-silencers”, we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 (“GR”). We found that GR led to severe loss of TADs and loops, while the use of one inhibitor by itself only showed mild changes. Such changes in TADs and loops were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GSK343 and X5050 synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects bothin vitroandin vivo. Overall, our data demonstrated the first example of a “super-silencer” and showed that combinational usage of GSK343 and X5050 to disrupt “super-silencers” could potentially lead to cancer ablation.
Modelling Osteoarthritis pathogenesis through Mechanical Loading in an Osteochondral Unit-on-Chip
Authors: Mainardi Andrea , Börsch Anastasiya , Occhetta Paola , Ivanek Robert , Ehrbar Martin , Krattiger Lisa , Oertle Philipp , Loparic Marko , Martin Ivan , Rasponi Marco , Barbero Andrea
Published: August 2023

A cure for osteoarthritis (OA), the most prevalent musculoskeletal disease, remains an unmet need. Investigating the molecular and cellular processes leading to OA is challenged by the absence of human models that capture the complex interplay among different tissues in the joint under pathophysiological mechanical loading.

In this study, we have engineered an OsteoChondral Unit (OCU)-on-chip system where composite hyaline cartilage - mineralized osseous microtissue analogues are exposed to controlled, tissue-specific compression regimes akin to those of the OCUin vivo. Through single-cell transcriptomic analysis, we demonstrate the critical relevance of the mineralized layer in inducing chondrocyte subpopulations implicated in the progression of OA.

Upon exposure to hyperphysiological loading, the OCU-on-chip captures early phenotypic traits of OA pathogenesis, comprising alterations of subchondral mineral content and acquisition of previously described OA genetic signatures.

This system enabled to identify novel upstream drivers of OA metabolic changes, including mechanically induced ribosomal alterations, as well as associated molecular targets towards the development of disease-modifying OA therapies.
The Diversity of NLRs inBrassica rapaPan-genome
Authors: Liu Shuhao , Zhu Yimeng , Ke Boyang , Wang Jun , Peng Xianjia , Zhang Shaoke , Zhao Ruoxuan , Wang Haizheng , Lou Jing , Li Jiaruo , Zheng Yunhong , Huang Tao , Wang Siyao , Lang Zebin , Wang Leye , Sun Xizhe , Wang Chunyang
Published: August 2023

The speciesBrassica rapais mainly cultivated as a vegetable crop with high economic value. But infectious diseases, such as soft rot disease and clubroot disease can cause severe yield losses. Introducing resistance genes through breeding is an efficient and sustainable way to reduce the susceptibility and improve the yield of crops. Nucleotide-Binding Leucine-Rich Repeat (NLR) genes are the main types of resistance genes. They can recognize pathogen effectors and initiate downstream immune response. However, the intraspecific diversity ofNLRgenes inBrassica rapahas remained unknown. Based on domain similarity search and machine learning pipeline, we identified 2188 NLRs in 17 accessions ofBrassica rapagenomes, which constitute the species-wide pan-NLRome inBrassica rapa. The diversity of the four types ofNLRgenes are significantly different in the aspects of chromosome location, number stability, integrated domains (IDs), evolutionary trajectory, and positive selection sites. Phylogenetic analyses show TNL-type NLRs whose N terminus contain Toll/interleukin-1 receptor (TIR) domain experienced accession-specific expansion. Moreover, the expanded TNL-type NLRs carry more positively selected amino acid residues which are mainly located on the protein surface based on their 3D structures. These evidences might imply their important biological function in perceiving pathogen effectors. Taken together, our study provides better insights into the diversity and variation ofNLRgenes inBrassica rapapangemone, which can facilitate the biofunction assigning, cloning, and subsequent application in breeding programs.
Liquid Crystalline Layering and Divalent Cations Cooperatively Enhance DNA Condensation
Authors: Kodikara Sineth G. , Gyawali Prabesh , Gleeson James T. , Jakli Antal , Sprunt Samuel , Balci Hamza
Published: August 2023

The layered liquid crystalline (LC) phases formed by DNA molecules which include rigid and flexible segments (‘gapped DNA’) enable the study of both end-to-end stacking and side-to-side lateral interactions that drive the condensation of DNA molecules. The resulting layer structure exhibits long-range inter-layer and intra-layer positional correlations. Using synchrotron small-angle x-ray scattering (SAXS) measurements, we investigate the impact of divalent Mg2+cations on the stability of the inter- and intra-layer DNA ordering as a function of temperature between 5-65 °C and for different terminal base pairings at the blunt ends of the gapped DNA constructs, which mediate the strength of the attractive end-to-end interaction. We demonstrate that the stabilities at a fixed DNA concentration of both inter-layer and intra-layer order are significantly enhanced even at a few mM Mg2+concentration. The stability continues to increase up to ∼30 mM Mg2+concentration, but at higher (∼100 mM) Mg2+content repulsion between positive ions counteracts and reverses the increase. On the other hand, sufficiently strong base-stacking interactions promote intra-layer order even in the absence of multivalent cations, which demonstrates the impact of liquid crystal layering on the DNA condensation process. We discuss the implications of these results in terms cation-mediated DNA-DNA attraction.
Task success in trained spiking neuronal network models coincides with emergence of cross-stimulus-modulated inhibition
Authors: Zhu Yuqing , Smith Chadbourne M.B. , Tang Mufeng , Scherr Franz , MacLean Jason N.
Published: August 2023

The neocortex is composed of spiking neuronal units interconnected in a sparse, recurrent network. Neuronal networks exhibit spiking activity that transforms sensory inputs into appropriate behavioral outputs. In this study, we train biologically realistic spiking neural network (SNN) models to identify the architectural changes which enable task-appropriate computations. Specifically, we employ a binary state change detection task, where each state is defined by motion entropy. This task mirrors behavioral paradigms that mice perform in the lab. SNNs are composed of excitatory and inhibitory units randomly interconnected with connection likelihoods and strengths matched to observations from mouse neocortex. Following training, we discover that SNNs selectively adjust firing rates depending on state, and that excitatory and inhibitory connectivity between input and recurrent layers change in accordance with this rate modulation. Input channels that exhibit bias to one specific motion entropy input develop stronger connections to recurrent excitatory units during training, while channels that exhibit bias to the other input develop stronger connections to inhibitory units. Furthermore, recurrent inhibitory units which positively modulated firing rates to one input strengthened their connections to recurrent units of the opposite modulation. This specific pattern of cross-modulation inhibition emerged as the optimal solution when imposing Dale’s law throughout training of the SNNs. Removing this constraint led to the absence of the emergence of this architectural solution. This work highlights the critical role of interneurons and the specific architectural patterns of inhibition in shaping dynamics and information processing within neocortical circuits.
Regulating temperature and humidity inhibits the disease severity of tomato
Authors: Li Tianzhu , Li Jianming
Published: August 2023

The environment significantly impacts the interactions between plants and pathogens, thus remarkably affecting crop disease occurrence. Regulating the environmental conditions in greenhouses to inhibit plant diseases is conducive to the development of green ecological agriculture. However, how to specific regulate the temperature and humidity to reduce plant diseases remain unclear. In this study, different methods of temperature and humidity regulation were performed. Histological observation and dual RNA–seq analysis showed that increasing temperature and decreasing humidity at 24 h post inoculation (hpi) for 12 h could effectively inhibit disease severity of tomatoes. The regulation induced the expression of heat shock proteins (HSPs) and defense–related genes of tomatoes in response toB. cinerea. Bcl–2–associated athanogenes (BAGs) may be involved in tomato resistance toB. cinereamediated by temperature and humidity regulation. In addition, the infection process and the expression of toxin–related genes ofB. cinereasuch as sesquiterpene botrydial (BOT) and polyketide botcinic acid (BOA) was inhibited. Overall, we obtained the optimal regulation method of temperature and humidity to alleviate tomato gray mold, and preliminarily explored its mechanisms of inhibiting the disease.
High-quality genome of the zoophytophagous stink bug,Nesidiocoris tenuis, informs their food habit adaptation
Authors: Shibata Tomofumi , Shimoda Masami , Kobayashi Tetsuya , Arai Hiroshi , Owashi Yuta , Uehara Takuya
Published: August 2023

The zoophytophagous stink bug,Nesidiocoris tenuis, is a promising natural enemy of micropests such as whiteflies and thrips. This bug possesses both phytophagous and entomophagous food habits, enabling it to obtain nutrition from both plants and insects. This trait allows us to maintain its population density in agricultural fields by introducing insectary plants, even when the pest prey density is extremely low. However, if the bugs’ population becomes too dense, they can sometimes damage crop plants. This dual character seems to arise from the food preferences and chemosensation of this predator. To understand the genomic landscape ofN. tenuis, we examined the whole genome sequence of a commercially available Japanese strain. We used long-read sequencing and Hi-C analysis to assemble the genome at the chromosomal level. We then conducted a comparative analysis of the genome with previously reported genomes of phytophagous and hematophagous stink bugs to focus on the genetic factors contributing to this species’ herbivorous and carnivorous tendencies. Our findings suggest that the gustatory gene set plays a pivotal role in adapting to food habits, making it a promising target for selective breeding. Furthermore, we identified the whole genomes of microorganisms symbiotic with this species through genomic analysis. We believe that our results shed light on the food habit adaptations ofN. tenuisand will accelerate breeding efforts based on new breeding techniques for natural enemy insects, including genomics and genome editing.
Disruption of the PAR3/INSC/LGN complex causes microtubule instability and peripheral neuropathy
Authors: Yeh Jui-Yu , Chao Hua-Chuan , Hung Yu-Chien , Tzou Fei-Yang , Hsiao Cheng-Tsung , Chou Cheng-Ta , Tsai Yu-Shuen , Liao Yi-Chu , Huang Shu-Yi , Kennerson Marina , Lee Yi-Chung , Chan Chih-Chiang
Published: August 2023

PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209T>G (p.Met70Arg) in the INSC (INSC) gene. Modelling theINSCM70Rvariant inDrosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of theINSCM70Rmutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlights a potential therapeutic target for INSC-associated CMT2.

One-Sentence Summary

PAR3/INSC/LGN dysfunction causes peripheral neuropathy and is potentially treatable by stabilizing the microtubule network.
Transcriptional dysregulation and impaired neuronal activity inFMR1knock-out and Fragile X patients’ iPSC-derived models
Authors: Maussion Gilles , Rocha Cecilia , Abdian Narges , Yang Dimitri , Turk Julien , Valenzuela Dulce Carrillo , Pimentel Luisa , You Zhipeng , Morquette Barbara , Nicouleau Michael , Deneault Eric , Higgins Samuel , Chen Carol X.-Q. , Reintsch Wolfgang , Stanley Ho , Soubannier Vincent , Lépine Sarah , Modrusan Zora , Lund Jessica , Stephenson William , Schubert Rajib , Durcan Thomas M.
Published: August 2023

The lack of fragile X mental retardation protein (FMRP) protein, due to a repression of theFMR1gene, causes Fragile X syndrome (FXS), one of the most prevalent forms of syndromic autisms. TheFMR1gene codes for an RNA binding protein involved in the regulation of gene expression through RNA processing, control of local translation, and protein-protein interactions; processes that are crucial for proper brain development.

Taking advantage of induced pluripotent stem cells (iPSCs) and CRISPR-Cas9 genome editing technologies, we generated iPSC-derived cortical neural progenitors and cortical neurons from anFMR1knock-out and patient cell line with the aim of identifying common phenotypes between the two cellular models. Using RNA sequencing, quantitative PCR and multielectrode array approaches, we assessed how the absence of the functionalFMR1gene affects the transcriptional profiles and the activities of iPSC-derived cortical neuronal progenitor cells (NPCs) and neurons with both models.

We observed thatFMR1KO and FXS patient cells have a decrease in their mean firing rate; a cellular activity that can also be blocked by tetrodotoxin (TTX) application in wild-type active neurons. Relative to wild-type neurons, inFMR1KO neurons, increased expression of presynaptic mRNA and transcription factors involved in the forebrain specification and decreased levels of mRNA coding AMPA and NMDA subunits were observed. Intriguingly, 40% of the differentially expressed genes were commonly deregulated between NPCs and differentiating neurons with significant enrichments in FMRP targets and Autism Related Genes found amongst downregulated genes. This implies that an absence of functional FMRP affects transcriptional profiles at the NPC stage, resulting in impaired activity and differentiation of the progenitors into mature neurons over time.

These findings from theFMR1KO lines were also shared with FXS patients’ iPSC-derived cells that also present with an impairment in activity and neuronal differentiation, illustrating the critical role of FMRP protein in neuronal development.
E-cigarette vapour induces cellular senescence in primary lung fibroblasts and may contribute to lung pathology
Authors: Bozier Jack , Wang Baoming , de Vries Maaike , Brandsma Corry-Anke , van den Berge Maarten , Timens Wim , Heijink Irene H. , Oliver Brian G.G. , Woldhuis Roy R.
Published: August 2023

Cellular senescence has been recognized to play a role in COPD pathophysiology. Non-aerosolized E-liquid treatment of a lung fibroblast foetal cell line resulted in cellular senescence induction, but this has not been assessed using E-vapour exposure and using primary lung fibroblasts. Therefore, we investigated whether E-vapour exposure induces cellular senescence in primary human lung fibroblasts and whether this affects their tissue repair function.

Primary human lung fibroblasts were stimulated with E-cigarette vapour extracts, and cigarette smoke extract (CSE) and Paraquat (PQ) as positive controls. IL-8 secretion was measured to confirm a stimulatory response. Multiple senescence markers (p16, p21, SA-β-gal, and proliferation) were assessed and the tissue repair function was assessed using a scratch assay. Finally, we tried to validate our findings in an E-cigarette-exposed mouse model.

Upon stimulation with CSE, PQ, and E-vapour extracts, cellular senescence was induced, which seemed dose-dependent and nicotine-independent. E-vapour-induced senescence resulted in an impaired tissue repair function. No significant difference was observed in the E-cigarette-exposed mouse model.

In this study, we identify E-cigarette vapours’ potential to induce cellular senescence in primary human lung fibroblasts and that this affects their tissue repair function, which further adds to the identified risks of E-cigarette use.