bluuebunny/crossref_metadata_2025 huggingface dataset:
Synggen: fast and data-driven generation of synthetic heterogeneous NGS cancer data
Authors: Scandino Riccardo , Calabrese Federico , Romanel Alessandro
Published: December 2022

Whole-exome and targeted sequencing are widely utilized both in translational cancer genomics and in the setting of precision medicine. The benchmarking of computational methods and tools that are in continuous development is fundamental for the correct interpretation of somatic genomic profiling results. To this aim we developed synggen, a tool for the fast generation of large-scale realistic and heterogeneous cancer whole-exome and targeted sequencing synthetic datasets, which enables the incorporation of phased germline single nucleotide polymorphisms and complex allele-specific somatic genomic events. Synggen performances and effectiveness in generating synthetic cancer data are shown across different scenarios and considering different platforms with distinct characteristics.

Availability and implementation

synggen is freely available at https://bitbucket.org/CibioBCG/synggen/.

Supplementary information

Supplementary data are available at Bioinformatics online.
DockNet: high-throughput protein–protein interface contact prediction
Authors: Williams Nathan P , Rodrigues Carlos H M , Truong Jia , Ascher David B , Holien Jessica K
Published: December 2022

Motivation

Over 300 000 protein–protein interaction (PPI) pairs have been identified in the human proteome and targeting these is fast becoming the next frontier in drug design. Predicting PPI sites, however, is a challenging task that traditionally requires computationally expensive and time-consuming docking simulations. A major weakness of modern protein docking algorithms is the inability to account for protein flexibility, which ultimately leads to relatively poor results.

Results

Here, we propose DockNet, an efficient Siamese graph-based neural network method which predicts contact residues between two interacting proteins. Unlike other methods that only utilize a protein’s surface or treat the protein structure as a rigid body, DockNet incorporates the entire protein structure and places no limits on protein flexibility during an interaction. Predictions are modeled at the residue level, based on a diverse set of input node features including residue type, surface accessibility, residue depth, secondary structure, pharmacophore and torsional angles. DockNet is comparable to current state-of-the-art methods, achieving an area under the curve (AUC) value of up to 0.84 on an independent test set (DB5), can be applied to a variety of different protein structures and can be utilized in situations where accurate unbound protein structures cannot be obtained.

Availability and implementation

DockNet is available at https://github.com/npwilliams09/docknet and an easy-to-use webserver at https://biosig.lab.uq.edu.au/docknet. All other data underlying this article are available in the article and in its online supplementary material.

Supplementary information

Supplementary data are available at Bioinformatics online.
Medial temporal tau predicts memory decline in cognitively unimpaired elderly
Authors: Kwan Angela T H , Arfaie Saman , Therriault Joseph , Azizi Zahra , Lussier Firoza Z , Tissot Cecile , Chamoun Mira , Bezgin Gleb , Servaes Stijn , Stevenon Jenna , Rahmouni Nesrine , Pallen Vanessa , Gauthier Serge , Rosa-Neto Pedro
Published: December 2022

Alzheimer’s disease can be detected in living people using in vivo biomarkers of amyloid-β and tau, even in the absence of cognitive impairment during the preclinical phase. [18F]-MK-6420 is a high-affinity PET tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early Alzheimer’s disease symptoms, such as memory decline, is unclear. Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau-PET for predicting longitudinal memory decline in asymptomatic elderly individuals. In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants (n = 111) from the translational biomarkers in ageing and dementia study (data collected between October 2017 and July 2020, with a follow-up period of 12 months). All participants underwent tau-PET with [18F]-MK-6420 and amyloid-β PET with [18F]-AZD-4694. The exclusion criteria included the presence of head trauma, stroke or other neurological disorders. There were 111 eligible participants selected based on the availability of amyloid-β PET, tau-PET, MRI and APOEɛ4 genotyping. Among these participants, the mean standard deviation age was 70.1 (8.6) years; 20 (18%) were tau-PET-positive and 71 of 111 (63.9%) were women. A significant association between the baseline Braak Stages I–II [18F]-MK-6240 standardized uptake value ratio positivity and change in composite memory score were observed at the 12-month follow-up, after correcting for age, sex and years of education [logical memory and Rey Auditory Verbal Learning Test, standardized beta = −0.52 (−0.82–0.21), P < 0.001, for dichotomized tau-PET and −1.22 (−1.84−(−0.61)], P < 0.0001, for continuous tau-PET]. Moderate cognitive decline was observed for A + T + over the follow-up period, whereas no significant change was observed for A−T+, A + T- and A-T-, although it should be noted that the A−T + group was small. Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function, supporting the use of [18F]-MK-6420 PET to predict the likelihood of asymptomatic elderly individuals experiencing future memory decline. Overall, [18F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. This is of critical relevance as the field is shifting towards a biological model of Alzheimer’s disease defined by the aggregation of pathologic tau. Therefore, early detection of tau pathology using [18F]-MK-6420 PET provides us with hope that living patients with Alzheimer’s disease may be diagnosed during the preclinical phase before it is too late.
Electoral Politics of Disaster: how earthquake and pandemic relief was used to earn votes
Authors: Imami Drini , Pojani Dorina , Merkaj Elvina
Published: December 2022

Disasters can be good for incumbent governments. Amidst an emergency, budgets can be revised and reallocated in a hurry, framing the government as a ‘saviour,’ issuing contracts to the government’s business clientele and/or prioritising the electoral base more than the victims. Thus elected officials can curry favour with voters and increase their chances of retaining their seats. We examine this claim in the context of Albania, a middle-income country with weak public institutions. We show that the relief for two calamities, a destructive earthquake in 2019 and the Covid-19 pandemic, was used by the government to mobilise votes, thereby increasing the likelihood of electoral success in 2021. Both earthquake relief funding and Covid-19 vaccination rates spiked right before the elections only to drop soon afterwards. This phenomenon, known as the Electoral Politics of Disaster (EPD), poses a risk for the national economy, public health, spatial planning and democracy.
Emati: a recommender system for biomedical literature based on supervised learning
Authors: Kart Özge , Mestiashvili Alexandre , Lachmann Kurt , Kwasnicki Richard , Schroeder Michael
Published: December 2022

The scientific literature continues to grow at an ever-increasing rate. Considering that thousands of new articles are published every week, it is obvious how challenging it is to keep up with newly published literature on a regular basis. Using a recommender system that improves the user experience in the online environment can be a solution to this problem. In the present study, we aimed to develop a web-based article recommender service, called Emati. Since the data are text-based by nature and we wanted our system to be independent of the number of users, a content-based approach has been adopted in this study. A supervised machine learning model has been proposed to generate article recommendations. Two different supervised learning approaches, namely the naïve Bayes model with Term Frequency-Inverse Document Frequency (TF-IDF) vectorizer and the state-of-the-art language model bidirectional encoder representations from transformers (BERT), have been implemented. In the first one, a list of documents is converted into TF-IDF–weighted features and fed into a classifier to distinguish relevant articles from irrelevant ones. Multinomial naïve Bayes algorithm is used as a classifier since, along with the class label, it also gives the probability that the input belongs to this class. The second approach is based on fine-tuning the pretrained state-of-the-art language model BERT for the text classification task. Emati provides a weekly updated list of article recommendations and presents it to the user, sorted by probability scores. New article recommendations are also sent to users’ email addresses on a weekly basis. Additionally, Emati has a personalized search feature to search online services’ (such as PubMed and arXiv) content and have the results sorted by the user’s classifier.

Database URL: https://emati.biotec.tu-dresden.de
Identification of birch lncRNAs and mRNAs responding to salt stress and characterization of functions of lncRNA
Authors: Jia Yaqi , Zhao Huimin , Niu Yani , Wang Yucheng
Published: December 2022

Long noncoding RNAs (lncRNAs) are important in abiotic stress tolerance. Here, we identified salt-responsive genes and lncRNAs in the roots and leaves of Betula platyphylla Suk. (birch), and characterized their lncRNAs functions. In total, 2660 mRNAs and 539 lncRNAs responding to salt treatment were identified using RNA-seq. The salt-responsive genes were substantially enriched in ‘cell wall biogenesis’ and ‘wood development’ in the roots and were enriched in ‘photosynthesis’ and ‘response to stimulus’ in the leaves. Meanwhile, the potential target genes of the salt-responsive lncRNAs in roots and leaves were both enriched in ‘nitrogen compound metabolic process’ and ‘response to stimulus’. We further built a method for quickly identifying abiotic stress tolerance of lncRNAs, which employed transient transformation for overexpression and knock-down of the lncRNA, enabling gain- and loss-of-function analysis. Using this method, 11 randomly selected salt-responsive lncRNAs were characterized. Among them, six lncRNAs confer salt tolerance, two lncRNAs confer salt sensitivity, and the other three lncRNAs are not involved in salt tolerance. In addition, a lncRNA, LncY1, was further characterized, which improves salt tolerance by regulating two transcription factors, BpMYB96 and BpCDF3. Taken together, our results suggested that lncRNAs play important roles in the salt response of birch plants.
An Intrinsic Characterization of Moment Functionals in the Compact Case
Authors: Infusino Maria , Kuhlmann Salma , Kuna Tobias , Michalski Patrick
Published: December 2022

We consider the class of all linear functionals $L$ on a unital commutative real algebra $A$ that can be represented as an integral w.r.t. to a Radon measure with compact support in the character space of $A$. Exploiting a recent generalization of the classical Nussbaum theorem, we establish a new characterization of this class of moment functionals solely in terms of a growth condition intrinsic to the given linear functional. To the best of our knowledge, our result is the first to exactly identify the compact support of the representing Radon measure. We also describe the compact support in terms of the largest Archimedean quadratic module on which $L$ is nonnegative and in terms of the smallest submultiplicative seminorm w.r.t. which $L$ is continuous. Moreover, we derive a formula for computing the measure of each singleton in the compact support, which in turn gives a necessary and sufficient condition for the support to be a finite set. Finally, some aspects related to our growth condition for topological algebras are also investigated.
Mpox Evolution: Has the Current Outbreak Revealed a Pox on “U”?
Authors: Kohli Rahul M , Isaacs Stuart N
Published: December 2022

The recent mpox (monkeypox) outbreak has prompted genomic studies to track global spread of the disease. These studies have also revealed unexpected patterns of mutations that implicate the action of the immune defense APOBEC3 family of enzymes, which catalyze conversion of cytosine (C) to uracil (U) in DNA, in viral evolution. As poxviruses have conventionally been regarded as slow-evolving viruses, the rapid emergence of APOBEC3 mutational signatures begs a series of important and open questions regarding how host-pathogen interactions may have changed and whether these mutations are bystanders or have roles in pathogenesis.
Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection
Authors: Acosta Camilo J , Diaz Clemente , Nordio Francesco , Han Htay-Htay , Moss Kelley J , Bohning Kelly , Kumar Pradeep , Liu Mengya , Patel Hetal , Pacciarini Filippo , Mwangi Vincent , Walter Elke , Powell Tim D , El Sahly Hana M , Baldwin Whitney R , Santangelo Joseph , Anderson Evan J , Dubin Gary
Published: December 2022

Background

We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection.

Methods

A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18–49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)–naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-μg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection.

Results

TAK-426 at 10-μg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection.

Conclusions

These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations.

Clinical Trials Registration

NCT03343626
We Can Manage: Experimental Evidence From Savings Groups in Uganda
Authors: Bjorvatn Kjetil , Tungodden Bertil
Published: December 2022

Village savings and loans associations (VSLAs) are promoted as an important tool for economic and social empowerment, primarily targeting women. However, there is relatively limited evidence on the impact of VSLAs, and no evidence on whether such programs work better for some groups than for others. Using a large-scale field experiment on a VSLA targeting people with disabilities in Uganda, we document positive effects of the program on economic empowerment, social empowerment and general well-being. The effects are overall somewhat stronger for the male participants, and in particular we find no evidence of social empowerment for women. Our findings suggest that VSLAs can be an important tool for improving the situation also for economically active persons with disabilities, but that additional measures need to be implemented to achieve a more comprehensive empowerment of women.
Stable Isotopes Indicate Seasonal Changes in Natal Geographic Origins and Host Plants of Ostrinia furnacalis (Guenée) Migrants Across the Bohai Strait in China
Authors: Shen Xiujing , Guo Jianglong , Yang Xianming , Wei Shujun , Wu Kongming
Published: December 2022

The Asian corn borer, Ostrinia furnacalis (Guenée), is a notorious pest of maize that migrates seasonally in Asia. Two migration peaks were found on Beihuang island in the Bohai Strait of China by observing the number of migrants. However, the origins and host plants of the migrants in the two migration periods remain unclear. Here, stable hydrogen (δ2H) and carbon (δ13C) isotope levels were measured to infer the origin and host plants of the O. furnacalis captured on Beihuang island in 2017–2019. δ2H in wings of spring-summer O. furnacalis captured from May to June ranged from −99 to −56‰, while that of autumn migrants from August to September ranged from −127 to −81‰. Based on the linear relationship between δ2H in the wing of migrants (δ2Hw) and δ2H in precipitation (δ2Hp), the spring-summer O. furnacalis likely originated from the summer maize area in the Huang-Huai-Hai Plain in China. In contrast, the autumn migrants came from the northern spring maize area in Liaoning, Jilin and Inner Mongolia. Based on δ13C, the spring-summer migrants fed on both C3 plants such as wheat (47.76%) and C4 weeds or belonged to the over winter individuals in maize field (52.24%), while the autumn migrants mainly fed on maize (C4, 91.21%). The results point to a northward migration in spring-summer and southward migration in autumn of O. furnacalis. Our study gives an important knowledge for improving the forecasting and management level of this pest.
Retrospective study on the effectiveness of medroxyprogesterone acetate in the treatment of ER-positive/HER2-negative post-menopausal advanced breast cancer: an additional analysis of the JBCRG-C06 Safari study
Authors: Kawaguchi Hidetoshi , Yamamoto Yutaka , Saji Shigehira , Masuda Norikazu , Nakayama Takahiro , Aogi Kenjiro , Anan Keisei , Ohtani Shoichiro , Sato Nobuaki , Takano Toshimi , Tokunaga Eriko , Nakamura Seigo , Hasegawa Yoshie , Hattori Masaya , Fujisawa Tomomi , Morita Satoshi , Yamaguchi Miki , Yamashita Toshinari , Yotsumoto Daisuke , Toi Masakazu , Ohno Shinji
Published: December 2022

Background

Only old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment.

Methods

This was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan–Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate.

Results

From the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer.

Conclusion

In actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents.
Switch-maintenance avelumab immunotherapy following first-line chemotherapy for patients with advanced, unresectable or metastatic urothelial carcinoma: the first Japanese real-world evidence from a multicenter study
Authors: Miyake Makito , Shimizu Takuto , Oda Yuki , Tachibana Akira , Ohmori Chihiro , Itami Yoshitaka , Kiba Keisuke , Tomioka Atsushi , Yamamoto Hiroaki , Ohnishi Kenta , Nishimura Nobutaka , Hori Shunta , Morizawa Yosuke , Gotoh Daisuke , Nakai Yasushi , Torimoto Kazumasa , Fujii Tomomi , Tanaka Nobumichi , Fujimoto Kiyohide
Published: December 2022

Objective

To develop the first Japanese real-world evidence of switch-maintenance avelumab in advanced, unresectable or metastatic urothelial carcinoma (aUC).

Methods

A multicenter-derived database registered 505 patients diagnosed with aUC between 2008 and 2021. Of these, 204 patients (40%) were selected and stratified according to the type of therapy used: maintenance avelumab group (27 [5.3%]), second-line (2 L) pembrolizumab group (103 [20%]) and 2 L cytotoxic chemotherapy group (74 [15%]). The progression-free survival and overall survival from the initiation of following therapy were compared. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors guideline v1.1 during the treatment period. A detailed analysis was performed in the maintenance avelumab group to investigate possible factors associated with response to avelumab therapy.

Results

The maintenance avelumab group had a longer overall survival, not progression-free survival, compared with the other two treatment groups. The median treatment-free interval between the last dose of first-line (1 L) chemotherapy and the initiation of avelumab therapy was 6 weeks (range, 3–22). Disease control rate of maintenance avelumab therapy in patients with a treatment-free interval of ≤6 weeks was higher than that in patients with a treatment-free interval of >6 weeks (77 vs 40%, P = 0.029). The patients showing objective response to 1 L chemotherapy were less likely to experience tumor relapse (4 of 19) after the initiation of avelumab therapy compared with those showing stable disease (7 of 8).

Conclusions

Objective response to 1 L chemotherapy and early induction of maintenance avelumab therapy may be associated with increased benefit from maintenance avelumab therapy.
Rich Hairdressers and Fancy Car Repairmen: The Rise of a Service Worker Elite in the USSR and the Evolution of Soviet Society in the 1970s
Authors: Ivanova Anna
Published: December 2022

In the Soviet Union during the 1970s, many service workers, such as salespeople, hairdressers, and car mechanics who worked in the state-owned retail sector, rose to prominent financial positions. They achieved this mobility because they had access to coveted goods and services that were in short supply. Soviet citizens’ disposable incomes were growing, producing a desire to consume in a more sophisticated way. However, shortages of the planned economy meant that people often could not satisfy their growing demands for consumption. Service providers illegally sold goods and services on the side for higher prices and became wealthy by collecting a huge portion of the money that the populace could not spend in the state retail system. The Soviet state was reluctant to prosecute these dealers because it needed their services to provide for consumers and to avoid pursuing large-scale economic reform. However, the enrichment of service workers caused resentment among the broader population. The newly rich, as opposed to members of an older Soviet upper class including party and state officials and the cultural and academic elite, flaunted their wealth and created a new mass culture of luxurious lifestyle. They not only became role models for some Soviet youth, but also created a sense among many Soviet citizens that socialism was in crisis. The prominent status of this new elite and its conspicuous consumption contradicted traditional socialist values of modesty, collectivism, and the priority of spiritual over material concerns.
The legal determinants of health (in)justice
Authors: Coggon John , Kamunge-Kpodo Beth
Published: December 2022

The mutual influences of social epidemiology and ideas of justice, each on the other, have been seminal in the development of public health ethics and law over the past two decades, and to the prominence that these fields give to health inequalities and the social—including commercial, political, and legal—determinants of health. General and political recognition of injustices in systematised health inequalities have further increased given the crushingly unequal impacts of the COVID-19 pandemic; including impacts of the legal and policy responses to it. However, despite apparent attention from successive UK governments to injustices concerning avoidable inequalities in health opportunities and outcomes, significant challenges impede the creation of health laws and policy that are both effective and ethically rigorous. This article critically explores these points. It addresses deficiencies in a UK health law landscape where health care contexts and medico-ethical assumptions predominate, to the great exclusion of broader social and governmental influences on health. The article explains how a public health framing better serves analysis, and engages with a framework of justice-oriented questions that must be asked if we are to understand the proper place and roles of law and regulation for the public’s health.
Distraction arthroplasty combined with autologous bone grafting for diffuse-type tenosynovial giant cell tumour with articular cartilage defect and subchondral bone cysts: A case report
Authors: Ikuta Yasunari , Nakasa Tomoyuki , Sumii Junichi , Nekomoto Akinori , Kawabata Shingo , Adachi Nobuo
Published: December 2022

Tenosynovial giant cell tumour (TGCT) encompasses a group of lesions that present with synovial differentiation and most commonly occur in the joint synovium, bursae, and tendon sheaths. Diffuse-type TGCT (Dt-TGCT), previously known as pigmented villonodular synovitis, is one of the most common benign soft-tissue tumours of the foot and ankle and usually affects young adults. The differential diagnosis of Dt-TGCTs remains a clinical problem because their clinical symptoms are similar to those of inflammatory arthritis, including rheumatoid arthritis. Moreover, persistent Dt-TGCTs can lead to articular deterioration, including osseous erosions and subchondral bone cysts. Joint-preserving procedures are considered optimal for treating younger patients with ankle osteoarthritis because the indication of ankle arthrodesis and total ankle arthroplasty is limited. Thus, ankle distraction arthroplasty could be an alternative for treating Dt-TGCT with articular deterioration in young patients. Here, we report about a woman in her early 30s who presented with ankle pain owing to a Dt-TGCT with an articular cartilage defect and subchondral bone cysts. We performed ankle distraction arthroplasty combined with an autologous bone graft. A follow-up examination at 2 years revealed preservation of physical function and pain alleviation. These findings suggest that distraction arthroplasty is a viable treatment option for remedying the destruction of the articular cartilage and subchondral bone owing to Dt-TGCTs in young adults.
Computationally-guided design and selection of high performing ribosomal active site mutants
Authors: Kofman Camila , Watkins Andrew M , Kim Do Soon , Willi Jessica A , Wooldredge Alexandra C , Karim Ashty S , Das Rhiju , Jewett Michael C
Published: December 2022

Understanding how modifications to the ribosome affect function has implications for studying ribosome biogenesis, building minimal cells, and repurposing ribosomes for synthetic biology. However, efforts to design sequence-modified ribosomes have been limited because point mutations in the ribosomal RNA (rRNA), especially in the catalytic active site (peptidyl transferase center; PTC), are often functionally detrimental. Moreover, methods for directed evolution of rRNA are constrained by practical considerations (e.g. library size). Here, to address these limitations, we developed a computational rRNA design approach for screening guided libraries of mutant ribosomes. Our method includes in silico library design and selection using a Rosetta stepwise Monte Carlo method (SWM), library construction and in vitro testing of combined ribosomal assembly and translation activity, and functional characterization in vivo. As a model, we apply our method to making modified ribosomes with mutant PTCs. We engineer ribosomes with as many as 30 mutations in their PTCs, highlighting previously unidentified epistatic interactions, and show that SWM helps identify sequences with beneficial phenotypes as compared to random library sequences. We further demonstrate that some variants improve cell growth in vivo, relative to wild type ribosomes. We anticipate that SWM design and selection may serve as a powerful tool for rRNA engineering.
DrugCentral 2023 extends human clinical data and integrates veterinary drugs
Authors: Avram Sorin , Wilson Thomas B , Curpan Ramona , Halip Liliana , Borota Ana , Bora Alina , Bologa Cristian G , Holmes Jayme , Knockel Jeffrey , Yang Jeremy J , Oprea Tudor I
Published: December 2022

DrugCentral monitors new drug approvals and standardizes drug information. The current update contains 285 drugs (131 for human use). New additions include: (i) the integration of veterinary drugs (154 for animal use only), (ii) the addition of 66 documented off-label uses and iii) the identification of adverse drug events from pharmacovigilance data for pediatric and geriatric patients. Additional enhancements include chemical substructure searching using SMILES and ‘Target Cards’ based on UniProt accession codes. Statistics of interests include the following: (i) 60% of the covered drugs are on-market drugs with expired patent and exclusivity coverage, 17% are off-market, and 23% are on-market drugs with active patents and exclusivity coverage; (ii) 59% of the drugs are oral, 33% are parenteral and 18% topical, at the level of the active ingredients; (iii) only 3% of all drugs are for animal use only; however, 61% of the veterinary drugs are also approved for human use; (iv) dogs, cats and horses are by far the most represented target species for veterinary drugs; (v) the physicochemical property profile of animal drugs is very similar to that of human drugs. Use cases include azaperone, the only sedative approved for swine, and ruxolitinib, a Janus kinase inhibitor.
The Caulobacter crescentus DciA promotes chromosome replication through topological loading of the DnaB replicative helicase at replication forks
Authors: Ozaki Shogo , Wang Dengyu , Wakasugi Yasutaka , Itani Naoto , Katayama Tsutomu
Published: December 2022

The replicative DNA helicase translocates on single-stranded DNA to drive replication forks during chromosome replication. In most bacteria the ubiquitous replicative helicase, DnaB, co-evolved with the accessory subunit DciA, but how they function remains incompletely understood. Here, using the model bacterium Caulobacter crescentus, we demonstrate that DciA plays a prominent role in DNA replication fork maintenance. Cell cycle analyses using a synchronized Caulobacter cell population showed that cells devoid of DciA exhibit a severe delay in fork progression. Biochemical characterization revealed that the DnaB helicase in its default state forms a hexamer that inhibits self-loading onto single-stranded DNA. We found that upon binding to DciA, the DnaB hexamer undergoes conformational changes required for encircling single-stranded DNA, thereby establishing the replication fork. Further investigation of the functional structure of DciA revealed that the C-terminus of DciA includes conserved leucine residues responsible for DnaB binding and is essential for DciA in vivo functions. We propose that DciA stimulates loading of DnaB onto single strands through topological isomerization of the DnaB structure, thereby ensuring fork progression. Given that the DnaB-DciA modules are widespread among eubacterial species, our findings suggest that a common mechanism underlies chromosome replication.
Heterogeneous nuclear ribonucleoprotein K is overexpressed in acute myeloid leukemia and causes myeloproliferation in mice via altered Runx1 splicing
Authors: Aitken Marisa J L , Malaney Prerna , Zhang Xiaorui , Herbrich Shelley M , Chan Lauren , Benitez Oscar , Rodriguez Ashley G , Ma Huaxian , Jacamo Rodrigo , Duan Ruizhi , Link Todd M , Kornblau Steven M , Kanagal-Shamanna Rashmi , Bueso-Ramos Carlos E , Post Sean M
Published: December 2022

Acute myeloid leukemia (AML) is driven by numerous molecular events that contribute to disease progression. Herein, we identify hnRNP K overexpression as a recurrent abnormality in AML that negatively correlates with patient survival. Overexpression of hnRNP K in murine fetal liver cells results in altered self-renewal and differentiation potential. Further, murine transplantation models reveal that hnRNP K overexpression results in myeloproliferation in vivo. Mechanistic studies expose a direct functional relationship between hnRNP K and RUNX1—a master transcriptional regulator of hematopoiesis often dysregulated in leukemia. Molecular analyses show that overexpression of hnRNP K results in an enrichment of an alternatively spliced isoform of RUNX1 lacking exon 4. Our work establishes hnRNP K’s oncogenic potential in influencing myelogenesis through its regulation of RUNX1 splicing and subsequent transcriptional activity.
Prediction of all-cause mortality for chronic kidney disease patients using four models of machine learning
Authors: Tran Nu Thuy Dung , Balezeaux Margaux , Granal Maelys , Fouque Denis , Ducher Michel , Fauvel Jean-Pierre
Published: December 2022

Background

The prediction tools developed from general population data to predict all-cause mortality are not adapted to chronic kidney disease (CKD) patients, because this population displays a higher mortality risk. This study aimed to create a clinical prediction tool with good predictive performance to predict the 2-year all-cause mortality of stage 4 or stage 5 CKD patients.

Methods

The performance of four different models (deep learning, random forest, Bayesian network, logistic regression) to create four prediction tools was compared using a 10-fold cross validation. The model that offered the best performance for predicting mortality in the Photo-Graphe 3 cohort was selected and then optimized using synthetic data and a selected number of explanatory variables. The performance of the optimized prediction tool to correctly predict the 2-year mortality of the patients included in the Photo-Graphe 3 database were then assessed.

Results

Prediction tools developed using the Bayesian network and logistic regression tended to have the best performances. Although not significantly different from logistic regression, the prediction tool developed using the Bayesian network was chosen because of its advantages and then optimized. The optimized prediction tool that was developed using synthetic data and the seven variables with the best predictive value (age, erythropoietin-stimulating agent, cardiovascular history, smoking status, 25-hydroxy vitamin D, parathyroid hormone and ferritin levels) had satisfactory internal performance.

Conclusions

A Bayesian network was used to create a seven-variable prediction tool to predict the 2-year all-cause mortality in patients with stage 4–5 CKD. Prior to external validation, the proposed prediction tool can be used at: https://dev.hed.cc/?a=jpfauvel&n=2022-05%20Modele%20Bayesien%2020000%20Mortalite%207%20variables%20Naif%20Zou%20online(1).neta for research purposes.
DROUGHT-INDUCED BRANCHED-CHAIN AMINO ACID AMINOTRANSFERASE enhances drought tolerance in rice
Authors: Shim Jae Sung , Jeong Hye In , Bang Seung Woon , Jung Se Eun , Kim Goeun , Kim Youn Shic , Redillas Mark Christian Felipe R , Oh Se-Jun , Seo Jun Sung , Kim Ju-Kon
Published: December 2022

Plants accumulate several metabolites in response to drought stress, including branched-chain amino acids (BCAAs). However, the roles of BCAAs in plant drought responses and the underlying molecular mechanisms for BCAA accumulation remain elusive. Here, we demonstrate that rice (Oryza sativa) DROUGHT-INDUCED BRANCHED-CHAIN AMINO ACID AMINOTRANSFERASE (OsDIAT) mediates the accumulation of BCAAs in rice in response to drought stress. An in vitro enzyme activity assay indicated that OsDIAT is a branched-chain amino acid aminotransferase, and subcellular localization analysis revealed that OsDIAT localizes to the cytoplasm. The expression of OsDIAT was induced in plants upon exposure to abiotic stress. OsDIAT-overexpressing (OsDIATOX) plants were more tolerant to drought stress, whereas osdiat plants were more susceptible to drought stress compared with nontransgenic (NT) plants. Amino acid analysis revealed that BCAA levels were higher in OsDIATOX but lower in osdiat compared with in NT plants. Finally, the exogenous application of BCAAs improved plant tolerance to osmotic stress compared with that in control plants. Collectively, these findings suggest that OsDIAT mediates drought tolerance by promoting the accumulation of BCAAs.
Neurological complications of COVID-19
Authors: Dai X , Cao X , Jiang Q , Wu B , Lou T , Shao Y , Hu Y , Lan Q
Published: December 2022

Corona Virus Disease 2019 (COVID-19) has caused several pandemic peaks worldwide due to its high variability and infectiousness, and COVID-19 has become a long-standing global public health problem. There is growing evidence that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) frequently causes multi-organ injuries and more severe neurological manifestations. Therefore, increased awareness of possible neurological complications is beneficial in preventing and mitigating the impact of long-term sequelae and improving the prognostic outcome of critically ill patients with COVID-19. Here, we review the main pathways of SARS-CoV-2 neuroinvasion and the potential mechanisms causing neurological damage. We also discuss in detail neurological complications, aiming to provide cutting-edge basis for subsequent related basic research and clinical studies of diagnosis and treatment.
Brain-Derived Neurotrophic Factor Val66Met Genotype Modulates Latent Inhibition: Relevance for Schizophrenia
Authors: Buhusi Mona , Griffin Daniel , Buhusi Catalin V
Published: December 2022

Background and Hypothesis

Latent inhibition (LI) is a measure of selective attention and learning relevant to Schizophrenia (SZ), with 2 abnormality poles: Disrupted LI in acute SZ, thought to underlie positive symptoms, and persistent LI (PLI) in schizotypy and chronic SZ under conditions where normal participants fail to show LI. We hypothesized that Brain-Derived Neurotrophic Factor (BDNF)-Met genotype shifts LI toward the PLI pole.

Study Design

We investigated the role of BDNF-Val66Met polymorphism and neural activation in regions involved in LI in mice, and the interaction between the BDNF and CHL1, a gene associated with SZ.

Study Results

No LI differences occurred between BDNF-wild-type (WT) (Val/Val) and knock-in (KI) (Met/Met) mice after weak conditioning. Chronic stress or stronger conditioning disrupted LI in WT but not KI mice. Behavior correlated with activation in infralimbic and orbitofrontal cortices, and nucleus accumbens. Examination of LI in CHL1-KO mice revealed no LI with no Met alleles (BDNF-WTs), PLI in CHL1-WT mice with 1 Met allele (BDNF-HETs), and PLI in both CHL1-WTs and CHL1-KOs with 2 Met alleles (BDNF-KIs), suggesting a shift to LI persistence with the number of BDNF-Met alleles in the CHL1 model of acute SZ.

Conclusions

Results support a role for BDNF polymorphisms in gene-gene and gene-environment interactions relevant to SZ. BDNF-Met allele may reduce expression of some acute SZ symptoms, and may increase expression of negative symptoms in individuals with chronic SZ. Evaluation of (screening for) SZ phenotypes associated with mutations at a particular locus (eg, CHL1), may be masked by strong effects at different loci (eg, BDNF).
The use of residual serum samples to perform serological surveillance of severe acute respiratory syndrome coronavirus 2 in Dili and regional areas of Timor-Leste
Authors: Sarmento Nevio , Ico Lourenço C , Sheridan Sarah L , Tanesi Maria Y , Santos Celia G , Barreto Ismael , Gomes Nelia , Oakley Tessa , Draper Anthony D K , Fancourt Nicholas S S , Yan Jennifer , Macartney Kristine , Francis Joshua R , Arkell Paul
Published: December 2022

Background

Lack of access to diagnostic testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can limit disease surveillance in remote areas. Serological surveillance can indicate the true extent and distribution of infections in such settings.

Methods

This study monitored SARS-CoV-2 seroprevalence in residual serum samples salvaged from laboratories at five healthcare facilities across Timor-Leste from March to October 2021.

Results

Seroprevalence increased from 8.3% to 87.0% during the study period. Potential immunity gaps were identified among children aged 0–15 y (who had not been eligible for vaccination) and individuals aged >60 y.

Conclusions

Efforts to vaccinate vulnerable individuals including older people should be maintained. Residual serum samples can be analysed to give local, contemporary information about the extent and distribution of antibodies to infections, especially SARS-CoV-2, in areas where epidemiological information is limited.
Bullying in Academic Medicine: Experiences of Women Physician Leaders
Authors: Iyer Maya S. , Way David P. , MacDowell Doug J. , Overholser Barbara M. , Spector Nancy D. , Jagsi Reshma
Published: December 2022

Purpose

Bullying is defined as offenders abusing positions of authority and intentionally targeting individuals through persistent negative behaviors to impede education or career growth. This study sought to estimate the prevalence and nature of bullying experienced by women physician leaders in academic medicine.

Method

In this survey-based study, 547 physician graduates of an executive women’s leadership training program were invited to complete a survey that measured workplace bullying in 2021. Participants were asked whether and when they had been bullied, how it impacted their careers, and remedies for bullying. Descriptive statistics were used to profile mistreatment and bullying experienced by the respondents during their professional careers and the nature of bullying. Content analysis of open-ended comments was used to describe how bullying impacted women physicians and outline recommendations for bullying prevention and mitigation.

Results

The survey response rate was 64.7% (354/547). Most women (302/354 [85.3%]) had experienced mistreatment during their careers, with more than half experiencing bullying while an attending physician (198/302 [65.6%]). Many women (187/302 [61.9%]) who screened positive for mistreatment also reported that they had been bullied at work. Of these 187 respondents, 173 (92.5%) experienced bullying from men and 121 (64.7%) reporting bullying from women (effect size = 0.34, P ≤ .001), and 115 (61.5%) reported that bullies were their immediate supervisors. Qualitative findings suggested that bullying harmed individuals’ career advancement, mental health, reputation, and relationships with others. Many had to change roles or leave jobs. Participants proposed that initiatives by top-level leaders, clear definitions of bullying behavior, reporting mechanisms, and upstander training for faculty and staff could mitigate bullying.

Conclusions

Most women physician leaders have experienced bullying. These results highlight the need to address bullying in academic medicine so that women can reach their full career potential.
The influence of low-level viremia on CD4+ cell count in human immunodeficiency virus–infected patients
Authors: Lee Cheng-Te , Chen Hsin-Pai , Lin Hsi-Hsun , Ke Meng-Yu , Wu Ping-Feng
Published: December 2022

Background:

Following initiation of combined antiretroviral therapy, the majority of human immunodeficiency virus–infected patients experience immune reconstitution indicated by virologic suppression and an increase in peripheral CD4+ T-cell counts. Some patients may suffer from low-level viremia, which was reported to be significantly associated with acquired immunodeficiency syndrome cases, virologic failure, and death. We aimed to further investigate the influence of low-level viremia on CD4+ T-cell count.

Methods:

In our study, we included human immunodeficiency virus-seropositive patients on combined antiretroviral therapy, for at least 6 months, who received at least one assessment of human immunodeficiency virus plasma viral load and CD4+ cell count every 6 months, from January 2009 to January 2019. The copy-year viremia was determined by calculating the area under the curve of the plasma human immunodeficiency virus viral load.

Results:

When comparing patients with a mean CD4+ cell count <200 cells/μL, there was no significant difference between patients with a mean viral load <1000 copies/mL and patients with a mean viral load ≥1000 copies/mL (p = 0.219). Among those with a mean viral load <1000 copies/mL, a higher proportion of patients had a mean CD4+ cell count ≥500 cells/µL (p < 0.001). The mean CD4+ cell count of patients with copy-years viremia (log10) <4 (577.7, interquartile range 429.2-736.7) was significantly higher than that of patients with copy-years viremia (log10) ≥4 (443.3, interquartile range 319.0-558.4) (p < 0.001). In multivariate logistic regression analysis, we observed that malignancy without history, lower copy-years viremia, and high nadir CD4+ cell count were independent predictors of mean CD4+ cell count ≥500 cells/µL.

Conclusion:

Human immunodeficiency virus–infected patients with a history of malignancy, high copy-year viremia, and lower nadir CD4+ cell counts should be monitored carefully in clinical settings.
Anti-thrombotic Therapy With Cangrelor and Bivalirudin in Venoarterial Extracorporeal Membrane Oxygenation Patients Undergoing Percutaneous Coronary Intervention: A Single-Center Experience
Authors: Baldetti Luca , Nardelli Pasquale , Ajello Silvia , Melisurgo Giulio , Calabrò Maria Grazia , Pieri Marina , Scandroglio Anna Mara
Published: December 2022

VA-ECMO is commonly used for patients in cardiogenic shock (CS) or refractory cardiac arrest (CA) undergoing PCI for ACS. In this setting at high risk of both thrombotic and hemorrhagic complications, optimal anti-thrombotic therapy remains ill-defined. We hypothesized that an anti-thrombotic therapy comprising a parenteral anticoagulant (bivalirudin) and a parenteral anti-platelet agent (cangrelor) may prove safe and effective in this scenario. From November 2019 to December 2021, 14 patients received at least one dose of cangrelor (starting dose: 0.125 μg/kg/min) plus bivalirudin, without background aspirin, in the context of PCI and VA-ECMO for ACS-related CS/CA, and were included in this study. Efficacy endpoint was occurrence of thrombotic events and safety endpoint was major bleeding occurrence. Median age was 58 years. The majority (64%) presented with refractory CA. A thrombotic event occurred in 14%, while major bleeding occurred in 21% patients. One patient experienced arterial thrombosis after VA-ECMO arterial cannula removal, another experienced ischemic cerebellar stroke without functional sequelae. Bleeding events were: 29% BARC 3a, 14% BARC 3b, and 7% BARC 5b. Overall in-hospital mortality was 50%. Cangrelor was continued for 5 (4–10) days; temporary discontinuation was necessary in 36%, either for VA-ECMO cannula removal or for bleeding events. A low dose of cangrelor, associated with standard-intensity anticoagulation with bivalirudin was a feasible anti-thrombotic strategy in patients undergoing PCI during VA-ECMO support for ACS-related CS/CA. Bleeding events rates outweighed thrombotic events rates in this critically-ill population, although the observed rates were lowest among available studies.