bluuebunny/crossref_metadata_2025 huggingface dataset:
Is ambient air pollution associated with sarcopenia? Results from a nation-wide cross-sectional study
Authors: Lai Zhihan , Yang Yin , Qian Zhengmin (Min) , Vaughn Michael G , Tabet Maya , Lin Hualiang
Published: November 2022

Background

sarcopenia is a disease that involves the degeneration of muscle strength, muscle mass and physical performance. It remains unknown whether air pollution exposure increases the risk of sarcopenia.

Methods

the baseline survey of the UK Biobank was used in this study. Sarcopenia was identified according to European Working Group on Sarcopenia in Older People 2 (EWGSOP2) and classified into non-sarcopenia and probable sarcopenia. Land use regressions were used to estimate concentrations of particulate matter (PM2.5), coarse particles (PMcoarse), PM10, PM2.5 absorbance, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Logistic regression models were applied to estimate the associations between air pollution and sarcopenia and its components.

Results

out of 352,265 participants, 28,710 (8.2%) were identified with probable sarcopenia. In adjusted models, there were increased odds of probable sarcopenia for each interquartile range increase in PM2.5 (OR: 1.06; 95% CI: 1.04, 1.07), PM10 (OR: 1.15; 95% CI: 1.13, 1.17), PMcoarse (OR: 1.02; 95% CI:1.01, 1.03), PM2.5 absorbance (OR: 1.08; 95% CI: 1.07, 1.10), NO2 (OR: 1.12; 95% CI:1.10, 1.14) and NOx (OR: 1.06; 95% CI: 1.05, 1.08).

Conclusions

this study suggests that exposure to ambient air pollution might be one risk factor of sarcopenia. Prospective studies are needed to further confirm our findings.
Development and implementation of a laboratory monitoring dashboard to reduce treatment gaps in inflammatory bowel disease
Authors: Kozlicki Miranda , Lynch Bridget , Donoho Tony , Nichols Patrick , Zuckerman Autumn D
Published: November 2022

Purpose

Patients receiving biologic therapy for inflammatory bowel disease (IBD) require routine laboratory monitoring to ensure the safety and efficacy of therapy. The purpose of this quality improvement project was to evaluate the implementation of a dashboard to prevent treatment gaps by prospectively identifying patients with IBD and outdated laboratory results receiving biologics.

Methods

We performed a pre/post analysis of dashboard implementation to assess the number of patients with overdue laboratory work resulting in treatment gaps. The dashboard combined data from the electronic health record (EHR) and pharmacy claims database to identify patients on a biologic with laboratory tests (white blood cell count, liver transaminases, C-reactive protein, and erythrocyte sedimentation rate) completed 5 or more months ago and/or a tuberculosis screen completed 11 or more months ago. After implementation, specialty pharmacists reviewed the dashboard and communicated via EHR if a new prescription and laboratory tests were needed. Messages were sent 4 weeks in advance of the next refill-eligible date. Mixed methods were used for analysis of qualitative data, including surveys, and quantitative data, assessing treatment gap length.

Results

A total of 40 patients who had outdated laboratory values and required a new prescription (15 before dashboard implementation and 25 after implementation) were included in the analysis. The frequency of a treatment gap decreased from 80% (n = 12) in the preimplementation phase to 32% (n = 8) in the postimplementation phase. The median gap length was shorter after dashboard implementation, decreasing from 21 days (range, 3-97 days) to 11 days (range, 2-23 days).

Conclusion

Utilization of a quality measures dashboard decreased treatment gaps in patients with IBD receiving biologic therapy. Integrated specialty pharmacists are uniquely positioned to monitor adherence to laboratory monitoring parameters for patients on biologics.
Phylogeny and evolution of Asparagaceae subfamily Nolinoideae: new insights from plastid phylogenomics
Authors: Ji Yunheng , Landis Jacob B , Yang Jin , Wang Shuying , Zhou Nian , Luo Yan , Liu Haiyang
Published: November 2022

Background and aims

Asparagaceae subfamily Nolinoideae is an economically important plant group, but the deep relationships and evolutionary history of the lineage remain poorly understood. Based on a large data set including 37 newly sequenced samples and publicly available plastomes, this study aims to better resolve the inter-tribal relationships of Nolinoideae, and to rigorously examine the tribe-level monophyly of Convallarieae, Ophiopogoneae and Polygonateae.

Methods

Maximum likelihood (ML) and Bayesian inference (BI) methods were used to infer phylogenetic relationships of Nolinoideae at the genus level and above. The diversification history of Nolinoideae was explored using molecular dating.

Key results

Both ML and BI analyses identically recovered five clades within Nolinoideae, respectively corresponding to Dracaeneae + Rusceae, Polygonateae + Theropogon, Ophiopogoneae, Nolineae, and Convallarieae excluding Theropogon, and most deep nodes were well supported. As Theropogon was embedded in Polygonateae, the plastome phylogeny failed to resolve Convallarieae and Polygonateae as reciprocally monophyletic. Divergence time estimation showed that the origins of most Nolinoideae genera were dated to the Miocene and Pliocene. The youthfulness of Nolinoideae genera is well represented in the three herbaceous tribes (Convallarieae, Ophiopogoneae and Polygonateae) chiefly distributed in temperate areas of the Northern Hemisphere, as the median stem ages of all 14 genera currently belonging to them were estimated at <12.37 Ma.

Conclusions

This study recovered a robust backbone phylogeny, providing new insights for better understanding the evolution and classification of Nolinoideae. Compared with the deep relationships recovered by a previous study based on transcriptomic data, our data suggest that ancient hybridization or incomplete lineage sorting may have occurred in the early diversification of Nolinoideae. Our findings will provide important reference for further study of the evolutionary complexity of Nolinoideae using nuclear genomic data. The recent origin of these herbaceous genera currently belonging to Convallarieae, Ophiopogoneae and Polygonateae provides new evidence to support the hypothesis that the global expansion of temperate habitats caused by the climate cooling over the past 15 million years may have dramatically driven lineage diversification and speciation in the Northern Hemisphere temperate flora.
miR-4461 inhibits liver cancer stem cells expansion and chemoresistance via regulating SIRT1
Authors: Yang Daji , Zhang Ping , Yang Ziting , Hou Guojun , Yang Ziyu
Published: November 2022

MicroRNAs (miRNAs) were involved in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. We show here that miR-4461 expression is reduced in liver cancer stem cells (CSCs) and predicts the poor prognosis of HCC patients. Knockdown of miR-4461 enhances the self-renewal and tumorigenicity of liver CSCs. Conversely, forced miR-4461 expression inhibits liver CSCs self-renewal and tumorigenesis. Mechanically, miR-4461 directly targets sirtuin 1 (SIRT1) via binding to its 3ʹ untranslated region in liver CSCs. The correlation of miR-4461 and SIRT1 was confirmed in human HCC patients’ tissues. Additionally, we found that miR-4461 overexpression hepatoma cells are more sensitive to cisplatin treatment. Patient-derived xenografts also showed that miR-4461 high HCC xenografts are sensitive to cisplatin treatment. Clinical cohort analysis further confirmed that HCC patients with high miR-4461 benefited more from transcatheter arterial chemoembolization treatment. In conclusion, our findings revealed the crucial role of miR-4461 in liver CSCs expansion and cisplatin response, rendering miR-4461 as an optimal target for the prevention and intervention of HCC.
Co-viewing an Educational Video: A Pilot Study About Mother–DHH Child Interaction
Authors: Cambra Cristina , Silvestre Núria , Losilla Josep-Maria
Published: November 2022

This study analyzes the mother–child interaction that takes place after co-viewing an educational video, comparing a group of 12 Spanish hearing mothers of deaf or hard of hearing (DHH) 7- to 9-year-olds and a group of 12 Spanish mothers of an age-matched cohort of children with typical hearing (TH). The results show that, in order to ascertain what the children have understood from the video, the mothers of the DHH children ask significantly more questions than the mothers of children with TH. Regarding the strategies that they use to prompt their children to explain the video, the mothers of the DHH children make reference most of all to shared experiences and focus their attention on contents of the video, whereas the mothers of children with TH tend to encourage their children to begin or continue the explanation of the video. The age of the hearing mothers was not found to have any effect on these results.
Body Composition in Late Midlife as a Predictor of Accelerated Age-associated Deficit-accumulation From Late Midlife into Old Age: A Longitudinal Birth Cohort Study
Authors: Haapanen Markus J , Mikkola Tuija M , Kortelainen Lauri , Jylhävä Juulia , Wasenius Niko S , Kajantie Eero , Eriksson Johan G , von Bonsdorff Mikaela B
Published: November 2022

Background

Body mass index (BMI) may not be an optimal predictor of frailty as its constituents, lean and fat mass, may have opposite associations with frailty.

Methods

A linear mixed model analysis was performed in the Helsinki Birth Cohort Study (n = 2 000) spanning from 57 to 84 years. A 39-item frailty index (FI) was calculated on three occasions over 17 years. Body composition in late midlife included BMI, percent body fat (%BF), waist-to-hip ratio (WHR), lean mass index (LMI), and fat mass index (FMI).

Results

Mean FI levels increased by 0.28%/year among men and by 0.34%/year among women. Among women, per each kg/m2 higher BMI and each unit higher %BF the increases in FI levels per year were 0.013 percentage points (PP) steeper (95% CI = 0.004, 0.023) and 0.009 PP steeper (95% CI = 0.002, 0.016) from late midlife into old age. Among men, per each 0.1-unit greater WHR the increase in FI levels was 0.074 PP steeper per year (95% CI = −0.0004, 0.148). Cross-sectionally, greater FMI and LMI in late midlife were associated with higher FI levels but the direction of the association regarding LMI changed after adjustment for FMI. The categories “high FMI and high LMI” and “high FMI and low LMI” showed the highest FI levels relative to the category “low FMI and low LMI”.

Conclusions

In late midlife, greater adiposity (%BF) among women and abdominal obesity (WHR) among men may predispose to higher levels of frailty from late midlife into old age. Greater lean mass alone may be protective of frailty, but not in the presence of high fat mass.
Molecular basis of diseases induced by the mitochondrial DNA mutation m.9032T>C
Authors: Baranowska Emilia , Niedzwiecka Katarzyna , Panja Chiranjit , Charles Camille , Dautant Alain , di Rago Jean-Paul , Tribouillard-Tanvier Déborah , Kucharczyk Roza
Published: November 2022

The mitochondrial DNA mutation m.9032T>C was previously identified in patients presenting with NARP (Neuropathy Ataxia Retinitis Pigmentosa). Their clinical features had a maternal transmission and patient’s cells showed a reduced oxidative phosphorylation capacity, elevated reactive oxygen species (ROS) production and hyperpolarization of the mitochondrial inner membrane, providing evidence that m.9032T>C is truly pathogenic. This mutation leads to replacement of a highly conserved leucine residue with proline at position 169 of ATP synthase subunit a (L169P). This protein and a ring of identical c-subunits (c-ring) move protons through the mitochondrial inner membrane coupled to ATP synthesis. We herein investigated the consequences of m.9032T>C on ATP synthase in a strain of Saccharomyces cerevisiae with an equivalent mutation (L186P). The mutant enzyme assembled correctly but was mostly inactive as evidenced by a  > 95% drop in the rate of mitochondrial ATP synthesis and absence of significant ATP-driven proton pumping across the mitochondrial membrane. Intragenic suppressors selected from L186P yeast restoring ATP synthase function to varying degrees (30–70%) were identified at the original mutation site (L186S) or in another position of the subunit a (H114Q, I118T). In light of atomic structures of yeast ATP synthase recently described, we conclude from these results that m.9032T>C disrupts proton conduction between the external side of the membrane and the c-ring, and that H114Q and I118T enable protons to access the c-ring through a modified pathway.
Different atomic contrasts in HAADF images and EELS maps of rutile TiO2
Authors: Iwashimizu Chisaki , Haruta Mitsutaka , Nemoto Takashi , Kurata Hiroki
Published: November 2022

High-angle annular dark-field (HAADF) imaging and elemental mapping at the atomic scale by scanning transmission electron microscopy (STEM) combined with electron energy-loss spectroscopy (EELS) are widely used for material characterization, in which quantitative understanding of the contrast of the image is required. Here, we report an unexpected image contrast in the elemental mapping of rutile TiO2, where the Ti L2,3 map shows an anisotropic elliptical shape that extends along the long axis in the octahedral structure, while the atomic contrast of Ti columns in the HAADF image is almost circular. Multi-slice simulation reveals that unique electron channeling related to the rutile structure and the difference of the potentials between HAADF and EELS cause the different atomic contrasts in the two images.
Arthroscope-assisted reduction of humeral head impression fracture: a case report
Authors: Kachi Takuma , Shitara Hitoshi , Ichinose Tsuyoshi , Sasaki Tsuyoshi , Hamano Noritaka , Chikuda Hirotaka
Published: November 2022

We experienced a case of humeral head impression fracture accounting for approximately 20% of the anterior articular surface. Open reduction and internal fixation of the proximal humeral fracture combined with arthroscope-assisted reduction and internal fixation of the humeral head impression fracture were performed, and good clinical and radiographic outcomes were obtained. Untreated impression fracture may be a potential risk for subluxation or osteoarthritis. However, our arthroscopic approach is minimally invasive and allows for the prevention of these risks.
Paraphimosis as a complication of monkeypox infection
Authors: Mahtani Arun Umesh , Engome Yolande Mbome , Haider Muhammad , Vu Thu Minh , Delp Crystal , Katayifci Edip Cemil , Surahio Muzhafar , Khalil Ambreen , Elemam Azza
Published: November 2022

We discuss a case report of a 38-year-old uncircumcised male on pre-exposure prophylaxis for human immunodeficiency virus who presents to the emergency department for painful lesions over his penile region following unprotected sexual intercourse. Following the development of these lesions he developed painless, itchy pustules over his bilateral arms and back. He also had extensive pain and swelling over his penile region, which prevented him from unretracting his foreskin. Chlamydia trachomatis, Herpes simplex virus, Neisseria gonorrhoeae, and syphilis tests were negative. He was positive for orthopoxvirus using polymerase chain reaction. A diagnosis of paraphimosis as a complication of monkeypox infection was made.
Cardiac perforation during minimally invasive repair of pectus excavatum: a rare complication
Authors: Senica Simone Oliver , Gasparella Paolo , Soldatenkova Ksenija , Smits Lauris , Ābola Zane
Published: November 2022

Life-threatening complications (LTCs) and negative results of surgical treatments often go unreported. Minimally invasive repair of pectus excavatum (MIRPE) represents a procedure with a low incidence of adverse outcomes. However, 15 potentially fatal cases of MIRPE-related heart injury have been published. We report a case of cardiac perforation (CP) during MIRPE. A 12-year-old female was admitted for elective repair of a severe asymmetric pectus excavatum. Preoperative computed tomography showed a Haller index of 4.9. MIRPE was performed under bilateral video-assisted thoracoscopy. After the placement of the pectus bar, cardiac arrhythmias, hypotension and bilateral hemothorax occurred. Emergency thoracotomy without pectus bar removal showed CP. The wound sites were repaired and the pectus bar was eventually successfully implanted. The patient was discharged on postoperative day 11. After 10 months, she remains asymptomatic. Reporting rare complications is essential for accurate calculations of the true prevalence of LTCs, maintaining high alertness in pediatric surgeons.
Antineutrophil cytoplasmic antibody associated vasculitis: a converging diagnosis from neuropathy and testicular infarcts
Authors: Mercer Ross , White Angus , Bates Christopher
Published: November 2022

Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis encompasses a group of rare multi-system affecting diseases that can present with unremitting cases of common conditions. We present a case of a middle-aged gentleman admitted under Urology with epidymo-orchitits on multiple occasions. Ultrasound revealed segmental testicular infarcts, and he was managed conservatively. He re-presented shortly after discharge to the medical assessment unit with ulnar nerve paraesthesia, thought to be due to ulnar nerve entrapment syndrome. Less than 1 week later he was re-admitted again, with severe peripheral nerve pain in all limbs and multifocal weakness. Initial history and examination gave a provisional diagnosis of mononeuritis multiplex. Following investigations and treatment, this was deemed to be caused by a converging diagnosis of C-ANCA PR3 positive vasculitis, a small vessel vasculitis. This case highlights that patients with unremitting cases of epididymo-orchitis with testicular infarcts may benefit from autoimmune screening.
Refugee settlements, sewage pollution, COVID-19 and the unfolding cholera outbreak in Lebanon
Authors: Kassem Issmat I , Osman Marwan , Jaafar Hadi , El Omari Khaled
Published: November 2022

We have previously documented that the unsanitary conditions in the Syrian refugee settlements and pollution in Lebanon were suitable for the proliferation of infectious diseases. Here, we discuss how cholera is spreading rapidly across Lebanon, where a Syrian man from an informal settlement is thought to be the index case.
JWST/NIRCam observations of stars and H ii regions in z ≃ 6–8 galaxies: properties of star-forming complexes on 150 pc scales
Authors: Chen Zuyi , Stark Daniel P , Endsley Ryan , Topping Michael , Whitler Lily , Charlot Stéphane
Published: November 2022

The onset of the JWST-era provides a much-improved opportunity to characterize the resolved structure of early star-forming systems. Previous Spitzer observations of z ≳ 6 galaxies revealed the presence of old stars and luminous H ii regions (via [O iii]+H β emission), but the poor resolution stunted our ability to map their locations with respect to the star-forming regions identified in the rest-UV. In this paper, we investigate the internal structure of 12 of the most luminous z ≃ 6–8 galaxies in the EGS field observed with recent JWST/NIRCam imaging. The systems appear clumpy in the rest-UV, with more than half of the light coming from ≃ 107 to 109 M⊙ star-forming complexes that are ≃150–480 pc in size. The clumps tend to be dominated by young stars (median = 36 Myr), but we also find large variations in clump ages within individual galaxies. The [O iii]+H β EW varies significantly across individual galaxies (reflecting differences in stellar and gas properties), but the H ii regions largely track the UV-bright complexes. Perhaps surprisingly, the rest-optical continuum is just as clumpy as the UV, and we do not find older (and redder) nuclear stellar components that were previously undetected or faint in the UV. The majority of the stellar mass in bright 6 < z < 8 galaxies appears to be contained in the ≳150 pc-scale clumpy star-forming complexes, reflecting the very active phase of assembly that is common in reionization-era galaxies.
Talimogene laherparepvec monotherapy for head and neck melanoma patients
Authors: Franke Viola , Stahlie Emma H.A. , Klop Willem M.C. , Zuur Charlotte L. , Berger Danique M.S. , van der Hiel Bernies , van de Wiel Bart A. , Wouters Michel W.J.M. , van Houdt Winan J. , van Akkooi Alexander C.J.
Published: December 2022

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1, intralesionally administered in patients with stage IIIB/C-IVM1a unresectable melanoma. When surgery is not a treatment option in the head and neck region, T-VEC can be an elegant alternative to systemic immunotherapy. Ten patients with metastatic melanoma in the head and neck region started treatment with T-VEC monotherapy at the Netherlands Cancer Institute. We collected data on response, adverse events (AEs), and baseline characteristics. For response evaluation, we used clinical evaluation with photography, 3-monthly PET/computed tomography (PET/CT) using 18F-fluoro-2-D-deoxyglucose, and histological biopsies. Median age at baseline was 78.2 (35–97) years with a median follow-up of 11.6months. Of these 10 patients, 5 had a complete response (CR), 3 had a partial response, 1 had stable disease and 1 showed progressive disease (PD) as their best response. Best overall response rate (ORR) was 80%. Median progression-free survival was 10.8 months (95% confidence interval, 2.2–19.4). Grade 1 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms, and injection site pain. PET-CT and histological biopsies proved to be clinically useful tools to evaluate treatment response for T-VEC monotherapy, confirming pCR or PD to stage IV disease requiring systemic treatment. ORR for T-VEC monotherapy for melanoma in the head and neck region at our institute was 80% with 50% achieving a CR. This realworld data demonstrates promising results and suggests T-VEC can be an alternative to systemic therapy in this select, mostly elderly patient population.
Meeting Report: Third International Congress of the International Society of Uterus Transplantation, Tübingen
Authors: Brännström Mats , Tullius Stefan G. , Fronek Jiri , Brucker Sara Y.
Published: November 2022

Uterus transplantation (UTx) is currently the only available treatment for absolute uterine factor infertility. The International Society of Uterus Transplantation (ISUTx) was formally founded in 2017 and joined the Transplantation Society as a formal section in 2021. The Third International Congress of the ISUTx was held in Tübingen, Germany, in October 2021, as a hybrid meeting, attended virtually by about 450 delegates and in person by 35 delegates. This report summarizes the Tübingen meeting and complementary topics of relevance presented at the Second ISUTx state-of-the-art webinar meeting, held in Prague, in October 2020. Main topics covered included surgical considerations, including dissection of veins in living donors and the pros and cons of minimally invasive surgery; managing immune risks; UTx during the COVID-19 pandemic; lessons learnt in the areas of imaging and cytomegalovirus infection; long-term psychological outcomes; opportunities to increase organ availability; and new horizons in UTx, including potential reuse of transplants and the utilization of robotic approaches. Implementation of an International UTx Registry was discussed and considered crucial to assure quality, safety, and further progress in UTx. Attempts made thus far have been promising.
Incidence, Risk Factors, and Outcomes of COVID-19 Infection in a Large Cohort of Solid Organ Transplant Recipients
Authors: Sahota Amandeep , Tien Andy , Yao Janis , Dong Elizabeth , Herald John , Javaherifar Sarah , Neyer Jonathan , Hwang Jennifer , Lee Roland , Fong Tse-Ling
Published: November 2022

Background.

Solid organ transplant recipients (SOTr) are at increased risk for severe disease from coronavirus disease 2019 (COVID-19) compared with non-SOTr.

Methods.

We performed a retrospective cohort study between March 1, 2020, and March, 30, 2021, in an integrated healthcare system with 4.3 million members aged ≥18 y including 5126 SOTr. Comparisons in COVID-19 mortality, hospitalization, and incidence were made between SOTr and non-SOTr, and between different SOTr organs. Multivariate analysis was performed to identify risk factors for COVID-19 mortality and hospitalization.

Results.

There were 600 SOTr (kidney, liver, heart, and lung) with COVID-19. Per person-year incidence of COVID-19 among SOTr was 10.0% versus 7.6% among non-SOTr (P < 0.0001). Compared with uninfected SOTr, infected SOTr were older (57.1 ± 14.0 versus 45.7 ± 17.9 y, P < 0.001), predominantly Hispanic/Latino (58.8% versus 38.6%, P < 0.0001), hypertensive (77.0% versus 23.8%; P < 0.0001), and diabetic (49.6% versus 13.0%; P = 0.0009). Compared with non-SOTr, infected SOTr had higher hospitalization (39.5% versus 6.0%; P < 0.0001), intensive care unit admission (29.1% versus 15.5%; P < 0.0001), and mortality (14.7% versus 1.8%; P < 0.0001) from COVID-19. Older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.05-1.10), male gender (HR, 1.79; 95% CI, 1.11-2.86), and higher body mass index (HR, 1.04; 95% CI, 1.00-1.09; P = 0.047) were associated with increased mortality from COVID-19, whereas race, diabetes, and number/type of immunosuppressive medications were not. Among the different SOTr, COVID-19 mortality risk was lowest in liver recipients (HR, 0.34; 95% CI, 0.16-0.73) and highest in lung recipients (HR, 1.74; 95% CI, 0.68-4.42).

Conclusions.

SOTr have higher rates of hospitalization and mortality from COVID-19 compared with the general population. Among the SOTr, the incidence and outcomes were distinct among different transplantation types.
Optimal implementation of genomic selection in clone breeding programs - exemplified in potato: I. Effect of selection strategy, implementation stage, and selection intensity on short-term genetic gain
Authors: Wu Po-Ya , Stich Benjamin , Renner Juliane , Muders Katja , Prigge Vanessa , van Inghelandt Delphine
Published: November 2022

Genomic selection (GS) is used in many animal and plant breeding programs to enhance genetic gain for complex traits. However, its optimal integration in clone breeding programs that up to now relied on phenotypic selection (PS) requires further research. The objectives of this study were to (i) investigate under a fixed budget how the weight of GS relative to PS, the stage of implementing GS, the correlation between an auxiliary trait assessed in early generations and the target trait, the variance components, and the prediction accuracy affect the genetic gain of the target trait of GS compared to PS, (ii) determine the optimal allocation of resources maximizing the genetic gain of the target trait in each selection strategy and for varying cost scenarios, and (iii) make recommendations to breeders how to implement GS in clone and especially potato breeding programs. In our simulation results, any selection strategy involving GS had a higher short-term genetic gain for the target trait than Standard-PS. In addition, we show that implementing GS in consecutive selection stages can largely enhance short-term genetic gain and recommend the breeders to implement GS at single hills and A clone stages. Furthermore, we observed for selection strategies involving GS that the optimal allocation of resources maximizing the genetic gain of the target trait differed considerably from those typically used in potato breeding programs. Therefore, our study provides new insight for breeders regarding how to optimally implement GS in a commercial potato breeding program to improve the short-term genetic gain for their target trait.
Identifying transcriptomic downstream targets of genes commonly mutated in Hereditary Hemorrhagic Telangiectasia
Authors: Ali Md Khadem , Liu Yu , Schimmel Katharina , Juul Nicholas H. , Stockman Courtney A. , Wu Joseph C. , Spiekerkoetter Edda F.
Published: November 2022

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that causes arteriovenous vascular malformations (AVMs) in different organs, including the lung. Three genes, ENG (endoglin), ACVRL1 (ALK1) and SMAD4, all members of the TGF-β/BMPR2 signaling pathway, are responsible for over 85% of all HHT cases. However, how these loss-of-function gene mutations lead to AVMs formation and what common downstream signaling they target is unknown. Here, using a combination of siRNA-mediated gene silencing, whole transcriptomic RNA sequencing, bioinformatic analysis, transcriptomic-based drug discovery, endothelial cells functional assays and VEGF signaling analysis, andex vivoprecision cut lung slice (PCLS) cultures approach, we uncovered common downstream transcriptomic gene signatures of HHT-casing genes and identified promising drug for HHT. We found the commonly used BMPR2-signaling downstream target ID1 is not a common downstream target of all the three HHT genes knockdown in human pulmonary microvascular endothelial cells (PMVECs). We identified novel common downstream targets of all the three HHT-causing genes that were enriched for HHT-related biological process and signaling pathways. Among those downstream genes, LYVE1, GPNMB, and MC5R were strong downstream targets that could serve as a better common downstream target than ID1. Furthermore, using the common downstream upregulated genes (HHT disease signature) following HHT gene knockdown, we identified a small molecule drug, Brivanib, that reversed the HHT disease signature, and inhibited VEGF-induced ERK1/2 phosphorylation, proliferation, and angiogenesis in PMVECs and inhibited some of the upregulated HHT disease genes in PCLS. Our findings suggest that Brivanib could be an emerging new drug for HHT.
H4K20me3 controls Ash1-mediated H3K36me3 and transcriptional silencing in facultative heterochromatin
Authors: Möller Mareike , Ridenour John B. , Wright Devin F. , Freitag Michael
Published: November 2022

Facultative heterochromatin controls development and differentiation in many eukaryotes. In metazoans, plants, and many filamentous fungi, facultative heterochromatin is characterized by transcriptional repression and enrichment with nucleosomes that are trimethylated at histone H3 lysine 27 (H3K27me3). While loss of H3K27me3 results in derepression of transcriptional gene silencing in many species, additional up- and downstream layers of regulation are necessary to mediate control of transcription in chromosome regions enriched with H3K27me3. Here, we investigated the effects of one histone mark on histone H4, namely H4K20me3, in the fungusZymoseptoria tritici, a globally important pathogen of wheat. Deletion ofkmt5, the gene encoding the sole methyltransferase responsible for H4K20 methylation, resulted in global derepression of transcription, especially in regions of facultative heterochromatin. Reversal of silencing in the absence of H4K20me3 not only affected genes but also a large number of novel, previously undetected, non-coding transcripts generated from regions of facultative heterochromatin on accessory chromosomes. Transcriptional activation inkmt5deletion strains was accompanied by a complete loss of Ash1-mediated H3K36me3 and chromatin reorganization affecting H3K27me3 and H3K4me2 distribution in regions of facultative heterochromatin. Strains with a H4K20M mutation in the single histone H4 gene ofZ. triticirecapitulated these chromatin changes, suggesting that H4K20me3 is essential for Ash1-mediated H3K36me3. The Δkmt5mutants we obtained are more sensitive to genotoxic stressors and both, Δkmt5and Δash1, showed greatly increased rates of accessory chromosome loss. Taken together, our results provide insights into a novel, and unsuspected, mechanism controlling the assembly and maintenance of facultative heterochromatin.

Significance

Facultative heterochromatin contains genes important for specific developmental or life cycle stages. Transcriptional regulation of these genes is influenced by chromatin structure. Here, we report that a little studied histone modification, trimethylation of lysine 20 on histone H4 (H4K20me3), is enriched in facultative heterochromatin and important for transcriptional repression in these regions in an important agricultural pathogen. Furthermore, normal levels of H4K20me3 are essential for deposition of another repressive histone mark, Ash1-mediated H3K36me3, and affect the distribution of other marks including H3K27me3. We conducted the first genome-wide assessment of H4K20 methylation levels in a fungus, and our discoveries reveal that multiple chromatin modifications are required to establish transcriptional silencing, providing the framework to understand epistasis relationships among these histone marks.
The dynamic nature of neurotensin receptor 1 (NTS1) allostery and signaling bias
Authors: Bumbak Fabian , Inoue Asuka , Pons Miquel , Paniagua Juan Carlos , Yan Fei , Wu Hongwei , Robson Scott A. , Bathgate Ross A. D. , Scott Daniel J. , Gooley Paul R. , Ziarek Joshua J.
Published: November 2022

The neurotensin receptor 1 (NTS1) is a G protein-coupled receptor (GPCR) with promise as a drug target for the treatment of pain, schizophrenia, obesity, addiction, and various cancers. A detailed picture of the NTS1structural landscape has been established by X-ray crystallography and cryo-EM and yet, the molecular determinants for why a receptor couples to G protein versus arrestin transducers remain poorly defined. We used13CεH3-methionine NMR spectroscopy to show that phosphatidylinositol-4,5-bisphosphate (PIP2) promotes transducer complexation not by dramatically altering the receptor structure but by strengthening long-range allosteric connections, in the form of correlated conformational kinetics, between the orthosteric pocket and highly-conserved activation motifs. β-arrestin-1 further remodels the receptor ensemble by reducing conformational exchange kinetics for a subset of resonances, whereas G protein coupling has little to no effect on the rate. A β-arrestin biased allosteric modulator transforms the NTS1:G protein complex into a concatenation of substates, without triggering transducer dissociation, suggesting that it may function by stabilizing signaling incompetent G protein conformations such as the non-canonical state. Together, our work demonstrates the importance of kinetic information to a complete picture of the GPCR activation landscape.
Identification of novel natural product inhibitors of BRD4 using high throughput virtual screening and MD simulation
Authors: Barman Soumen , Sahoo Snehasudha Subhadarsini , Padhan Jyotirmayee , Sudhamalla Babu
Published: November 2022

Bromodomains are evolutionarily conserved structural motifs that recognize acetylated lysine residues on histone tails. They play a crucial role in shaping chromatin architecture and regulating gene expression in various biological processes. Mutations in bromodomains containing proteins leads to multiple human diseases, which makes them attractive target for therapeutic intervention. Extensive studies have been done on BRD4 as a target for several cancers, such as Acute Myeloid Leukemia (AML) and Burkitt Lymphoma. Several potential inhibitors have been identified against the BRD4 bromodomain. However, most of these inhibitors have drawbacks such as nonspecificity and toxicity, decreasing their appeal and necessitating the search for novel non-toxic inhibitors. This study aims to address this need by virtually screening natural compounds from the NPASS database against the Kac binding site of BRD4-BD1 using high throughput molecular docking followed by similarity clustering, pharmacokinetic screening, MD simulation, and MM-PBSA binding free energy calculations. Using this approach, we identified five natural product inhibitors having a similar or better binding affinity to the BRD4 bromodomain compared to JQ1 (previously reported inhibitor of BRD4). Further systematic analysis of these inhibitors resulted in the top three hits: NPC268484 (Palodesangren-B), NPC295021 (Candidine), and NPC313112 (Buxifoliadine-D). Collectively, ourin silicoresults identified some promising natural products that have the potential to act as potent BRD4-BD1 inhibitors and can be considered for further validation through futurein vitroandin vivostudies.
A Simplified Model of Motor Control
Authors: Arora K. , Chakrabarty S.
Published: November 2022

In general, control of movement is considered to be either cortical, spinal, or purely biomechanical and is studied separately at these levels. To achieve this separation when studying a particular level, variations that may be introduced by the other levels are generally either ignored or restricted. This restriction misrepresents the way movements occur in realistic scenarios and limits the ability to model movements in a biologically inspired manner. In this work, we propose a heuristic model for motor control that conceptually and mathematically accounts for the entire motor process, from target to endpoint. It simulates human arm motion and is able to represent functionally different motion properties by flexibly choosing more or less complex motion paths without built-in optimization or joint constraints. With a novel implementation of hierarchical control, this model successfully overcomes the problem of degrees of freedom in robotics. It can serve as a template for neurocomputational work that currently uses control architectures that do not mirror the human motor control process. The model itself also suggests a maximum threshold for delays in position feedback for effective movement, and that the primary role of position feedback in movement is to overcome the effects of environmental perturbations at the joint level. These findings can inform future efforts to develop biologically inspired motor control techniques for prosthetic devices.
The cytochromebcarboxyl-terminal region is necessary for mitochondrial Complex III assembly
Authors: Flores-Mireles Daniel , Camacho-Villasana Yolanda , Lutikurti Madhurya , García-Guerrero Aldo E. , Lozano-Rosas Guadalupe , Chagoya Victoria , Gutiérrez-Cirlos Emma Berta , Brandt Ulrich , Cabrera-Orefice Alfredo , Pérez-Martínez Xochitl
Published: November 2022

Mitochondrialbc1complex from yeast has ten subunits, but only Cytochromeb(Cytb) subunit is encoded in the mitochondrial genome. Cytbhas eight transmembrane helices containing two hemesbfor electron transfer. Cbp3 and Cbp6 assist Cytbsynthesis, and together with Cbp4 induce Cytbhemylation. Subunits Qcr7/Qcr8 participate in the first steps of assembly, and lack of Qcr7 reduces Cytbsynthesis through an assembly-feedback mechanism involving Cbp3/Cbp6. Since Qcr7 resides near the Cytbcarboxyl-region, we wondered whether this region is important for Cytbsynthesis/assembly. Although deletion of the CytbC-region did not abrogate Cytbsynthesis, the assembly-feedback regulation was lost, so Cytbsynthesis was normal even if Qcr7 was missing. Mutants lacking the CytbC-terminus were non-respiratory due to absence of fully assembledbc1complex. By performing complexome profiling, we showed the existence of aberrant early-stage subassemblies in the mutant. In this work we demonstrate that the C-terminal region of Cytbis critical for regulation of Cytbsynthesis andbc1complex assembly.
Isolation and characterization of a novel phage ofVibrio parahaemolyticuswith biocontrol potential
Authors: Chen Yubing , Li Wenqing , Shi Keming , Fang Zheng , Yang Yunlan , Zhang Rui
Published: November 2022

Vibrio parahaemolyticusis a major foodborne pathogen that contaminates aquatic products and causes great economic losses to aquaculture. Because of the emergence of multidrug-resistantV. parahaemolyticusstrains, bacteriophages are considered promising agents for their biocontrol as an alternative or supplement to antibiotics. Here, a lytic vibriophage, vB_VpaM_R16F (R16F), was isolated from sewage from a seafood market by infectingV. parahaemolyticus1.1997T. R16F was found to infectV. parahaemolyticus, but not nine otherVibriospp. The phage belongs to the myovirus morphotype and lysed host cells with a short latent period (<10 min) and a small burst size (13 plaque-forming units). R16F has a linear double-stranded DNA with genome size 139,011 bp and a G+C content of 35.21%. Phylogenetic and intergenomic nucleotide sequence similarity analysis revealed that R16F is distinct from currently known vibriophages and belongs to a novel genus. Several genes (e.g., encoding ultraviolet damage endonuclease and endolysin) that may enhance environmental competitiveness were found in the genome of R16F, while no antibiotic resistance- or virulence factor-related gene was detected. In consideration of its biological and genetic properties, R16F is suggested to be a candidate biocontrol agent for use againstV. parahaemolyticus.
Contrasting genomic consequences of anthropogenic reintroduction and natural recolonisation in high-arctic wild reindeer
Authors: Burnett Hamish A. , Bieker Vanessa C. , Moullec Mathilde Le , Peeters Bart , Rosvold Jørgen , Pedersen Åshild Ønvik , Dalén Love , Loe Leif Egil , Jensen Henrik , Hansen Brage B. , Martin Michael D.
Published: November 2022

Anthropogenic reintroduction can supplement natural recolonisation in reestablishing a species’ distribution and abundance. However, both reintroductions and recolonisations can give rise to population bottlenecks that reduce genetic diversity and increase inbreeding, potentially causing accumulation of genetic load and reduced fitness. Most current populations of the endemic high-arctic Svalbard reindeer (Rangifer tarandus platyrhynchus) originate from recent reintroductions or recolonisations following regional extirpations due to past overharvesting. We investigated and compared the genomic consequences of these two paths to reestablishment using whole-genome shotgun sequencing of 100 Svalbard reindeer across their range. We found little admixture between reintroduced and natural populations. Two reintroduced populations, each founded by 12 individuals around four decades (i.e. 8 reindeer generations) ago, formed two distinct genetic clusters. Compared to the source population, these populations showed only small decreases in genome-wide heterozygosity and increases in inbreeding and lengths of runs of homozygosity. In contrast, the two naturally recolonised populations without admixture possessed much lower heterozygosity, higher inbreeding, and longer runs of homozygosity, possibly caused by serial population bottlenecks and/or fewer or more genetically related founders than in the reintroduction events. Naturally recolonised populations can thus be more vulnerable to the accumulation of genetic load than reintroduced populations. This suggests that in some organisms even small-scale reintroduction programs based on genetically diverse source populations can be more effective than natural recolonisation in establishing genetically diverse populations. These findings warrant particular attention in the conservation and management of populations and species threatened by habitat fragmentation and loss.
Free volume theory explains the unusual behavior of viscosity in a non-confluent tissue during morphogenesis
Authors: Das Rajsekhar , Sinha Sumit , Li Xin , Kirkpatrick T. R. , Thirumalai D.
Published: November 2022

A recent experiment on zebrafish blastoderm morphogenesis showed that the viscosity (η) of a non-confluent embryonic tissue grows sharply until a critical cell packing fraction (ϕS). The increase inηup toϕSis similar to the behavior observed in several glass forming materials, which suggests that the cell dynamics is sluggish or glass-like. Surprisingly,ηis a constant aboveϕS. To determine the mechanism of this unusual dependence ofηonϕ, we performed extensive simulations using an agent-based model of a dense non-confluent two-dimensional tissue. We show that polydispersity in the cell size, and the propensity of the cells to deform, results in the saturation of the available free area per cell beyond a critical packing fraction. Saturation in the free space not only explains the viscosity plateau aboveϕSbut also provides a relationship between equilibrium geometrical packing to the dramatic increase in the relaxation dynamics.
Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy
Authors: Cunha Pedro P. , Minogue Eleanor , Krause Lena C. M. , Hess Rita M. , Bargiela David , Wadsworth Brennan J. , Barbieri Laura , Brombach Carolin , Foskolou Iosifina P. , Bogeski Ivan , Veliça Pedro , Johnson Randall S.
Published: November 2022

Oxygenation levels are a determinative factor in T cell function. Here we describe that the oxygen tensions sensed by T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hours of low oxygen levels during initial CD8+T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.
Rapid generation of CD19 CAR-T Cells by minicircle DNA enables anti-tumor activity and prevents fatal CAR-B leukemia
Authors: Ye Xueshuai , Wu Yongqiang , Cai Ziqi , Yuan Qichen , Cai Jianhui
Published: November 2022

Manufacturing CAR (chimeric antigen receptor)-T cell with viral vector is expensive and time-consuming. Besides, during viral transduction, the genes encoding CARs are randomly integrated into the genome, which could cause oncogenesis or produce devastating CAR-tumor cells. Here, using virus-free and non-transgenic minicircle DNA (mcDNA) vector, we enable rapid generation of CD19 CAR-T cells within two days. Further, we demonstrate in vitro and in xenograft models that the anti-tumor effects of CD19 CAR-T cells produced by mcDNA are as effective as those produced by viral vectors. Finally, we show that our manufacturing process can avoid the production of fatal CAR-tumor cells. Taken together, we provide a fast, effective, and therapeutically safe method to generate CD19 CAR-T cells for treating leukemia.
SlideCNA: Spatial copy number alteration detection from Slide-seq-like spatial transcriptomics data
Authors: Zhang Diane , Segerstolpe Asa , Slyper Michal , Waldman Julia , Murray Evan , Cohen Ofir , Ashenberg Orr , Abravanel Daniel , Jané-Valbuena Judit , Mages Simon , Lako Ana , Helvie Karla , Rozenblatt-Rosen Orit , Rodig Scott , Chen Fei , Wagle Nikhil , Regev Aviv , Klughammer Johanna
Published: November 2022

Solid tumors are spatially heterogeneous in their genetic, molecular and cellular composition, and this variation can be meaningful for diagnosis, prognosis and therapy. Recent spatial profiling studies have mostly charted genetic and RNA variation in tumors separately. To leverage the potential of RNA to identify copy number alterations (CNAs), we developed SlideCNA, a computational tool to extract sparse spatial CNA signals from spatial transcriptomics data, using expression-aware spatial binning. We test SlideCNA on simulated and real Slide-seq data of metastatic breast cancer (MBC) and demonstrate its potential for spatial sub-clone detection.