bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing reinforcement learning for de novo molecular design applying self-attention mechanisms
Authors: Pereira Tiago O , Abbasi Maryam , Arrais Joel P 
Published: October 2023

Abstract
The drug discovery process can be significantly improved by applying deep reinforcement learning (RL) methods that learn to generate compounds with desired pharmacological properties. Nevertheless, RL-based methods typically condense the evaluation of sampled compounds into a single scalar value, making it difficult for the generative agent to learn the optimal policy. This work combines self-attention mechanisms and RL to generate promising molecules. The idea is to evaluate the relative significance of each atom and functional group in their interaction with the target, and to utilize this information for optimizing the Generator. Therefore, the framework for de novo drug design is composed of a Generator that samples new compounds combined with a Transformer-encoder and a biological affinity Predictor that evaluate the generated structures. Moreover, it takes the advantage of the knowledge encapsulated in the Transformer’s attention weights to evaluate each token individually. We compared the performance of two output prediction strategies for the Transformer: standard and masked language model (MLM). The results show that the MLM Transformer is more effective in optimizing the Generator compared with the state-of-the-art works. Additionally, the evaluation models identified the most important regions of each molecule for the biological interaction with the target. As a case study, we generated synthesizable hit compounds that can be putative inhibitors of the enzyme ubiquitin-specific protein 7 (USP7).
Group B streptococcus induces cellular senescence in human amnion epithelial cells through a partial interleukin-1-mediated mechanism
Authors: Park Hae-Ryung , Hogan Kelly A , Harris Sean M , Chames Mark C , Loch-Caruso Rita 
Published: October 2023

Abstract
Group B streptococcus (GBS) infection is a significant public health concern associated with adverse pregnancy complications and increased neonatal mortality and morbidity. However, the mechanisms underlying the impact of GBS on the fetal membrane, the first line of defense against pathogens, are not fully understood. Here, we propose that GBS induces senescence and inflammatory factors (IL-6 and IL-8) in the fetal membrane through interleukin-1 (IL-1). Utilizing the existing transcriptomic data on GBS-exposed human fetal membrane, we showed that GBS affects senescence-related pathways and genes. Next, we treated primary amnion epithelial cells with conditioned medium from the choriodecidual layer of human fetal membrane exposed to GBS (GBS collected choriodecidual [CD] conditioned medium) in the absence or presence of an IL-1 receptor antagonist (IL-1Ra). GBS CD conditioned medium significantly increased β-galactosidase activity, IL-6 and IL-8 release from the amnion epithelial cells. Cotreatment with IL1Ra reduced GBS-induced β-galactosidase activity and IL-6 and IL-8 secretion. Direct treatment with IL-1α or IL-1β confirmed the role of IL-1 signaling in the regulation of senescence in the fetal membrane. We further showed that GBS CD conditioned medium and IL-1 decreased cell proliferation in amnion epithelial cells. In summary, for the first time, we demonstrate GBS-induced senescence in the fetal membrane and present evidence of IL-1 pathway signaling between the choriodecidua and amnion layer of fetal membrane in a paracrine manner. Further studies will be warranted to understand the pathogenesis of adverse pregnancy outcomes associated with GBS infection and develop therapeutic interventions to mitigate these complications.
Dysregulation of MTFR2, ATP5IF1 and BAK1 in Sertoli cells relates to idiopathic non-obstructive azoospermia via inhibiting mitochondrial fission and inducing mitochondrial dysfunction
Authors: Wei Lei , Feng Zonggang , Dou Qian , Tan Li , Zhao Xinghua , Hao Bin 
Published: October 2023

Abstract
Non-obstructive azoospermia affects more than 10% of infertile men with over 70% patients are idiopathic with uncharacterized molecular mechanisms, which is referred as idiopathic non-obstructive azoospermia. In this study, we checked the morphology of Sertoli cell mitochondria in testis biopsies from patients with idiopathic non-obstructive azoospermia and patients with obstructive azoospermia who have normal spermiogenesis. The expression of 104 genes controlling mitochondria fission and fusion were analyzed in three gene expression datasets including a total of 60 patients with non-obstructive azoospermia. The levels of 7 candidate genes were detected in testis biopsies from 38 patients with idiopathic non-obstructive azoospermia and 24 patients with obstructive azoospermia who have normal spermatogenesis by RT-qPCR. Cell viability, apoptosis, mitochondria membrane potential, adenosine triphosphate production, oxygen consumption, and mitochondria morphology were examined in primary human Sertoli cells. Mouse spermatogonial stem cells were used to detect the cell supporting capacity of Sertoli cells. We observed that patients with idiopathic non-obstructive azoospermia had elongated mitochondria. MTFR2 and ATP5IF1 were downregulated, whereas BAK1 was upregulated in idiopathic non-obstructive azoospermia testis and Sertoli cells. Sertoli cells from patients with idiopathic non-obstructive azoospermia had reduced viability, mitochondria membrane potential, adenosine triphosphate production, oxygen consumption rate, glycolysis and increased apoptosis. Knockdown MTFR2 in Sertoli cells increased the mitochondria size. Knockdown ATP5IF1 did not change mitochondrial morphology but increased adenosine triphosphate hydrolysis. Overexpression of BAK1 reduced membrane potential and upregulated cell apoptosis. The dysregulation of all these three genes contributed to the dysfunction of Sertoli cells, which provides a clue for idiopathic non-obstructive azoospermia treatment.
Marx, Keynes and the future of working time
Authors: Spencer David A 
Published: October 2023

Abstract
This paper re-examines the different visions of the future of working time offered by Marx and Keynes. While Marx and Keynes differed radically on some fundamental matters, they agreed that society would benefit from reducing work time. The idea of society using technology to curtail work hours was a central aspect of their respective visions of a better future. The paper compares Marx’s and Keynes’s visions. It also considers the fate of their visions as well as their relevance for modern debates on the future of work. The conclusion is that a critical political economy can learn from the different ideas of Marx and Keynes in supporting the case for reducing work hours in the present.
Changes to the understory vegetation community of the Acadian Forest a decade after herbicide use
Authors: Xiao Jennifer , Yakimowski Sarah , Brown Marika , Heartz Shane , Parachnowitsch Amy L , Edge Christopher B 
Published: October 2023

Abstract
Herbicides are commonly used in forestry to enhance conifer tree growth by reducing the abundance of competitive, undesired, early successional species. Reducing the abundance of understory species could also lead to changes in community composition that need to be documented to aid the understanding of any downstream ecosystem changes. We examined the effects of glyphosate-based herbicides on the abundance, diversity, and community composition of the understory vegetation community of forests located in the temperate-boreal transition zone. We sampled 37 blocks in two ecoregions of the Acadian Forest in eastern Canada that were harvested over the last 15 years. Species richness, Shannon’s diversity, or evenness did not differ among blocks with different herbicide history. However, community composition differed between the non-herbicide and herbicide blocks in both ecoregions. Overall, 26.5% of the plant community variation was explained by the factors herbicide use (10.6%), Biomass Growth Index/site quality (8.6%), time since harvest (3.6%), and ecoregion (1.7%). We found 16 indicator species that differentiated the non-herbicide (9 species) and herbicide blocks (7 species). Indicator species for non-herbicide blocks included two blueberry species, three shrubs (two flowering), and two ferns, whereas indicator species for herbicide blocks were largely perennial forbs. Together, our results indicate that herbicide use does not alter species richness but does reduce shrub abundance, a change that persists throughout the 10 years post-herbicide application captured in our study. The reduced shrub layer likely leads to other changes in the plant community. Herbicide use is associated with subtle changes to the understory plant community, and these changes are missed when only alpha diversity is used to examine the effects of herbicides use on community composition.
Epigenetic Age Acceleration and Chronological Age: Associations With Cognitive Performance in Daily Life
Authors: Zavala Daisy V , Dzikowski Natalie , Gopalan Shyamalika , Harrington Karra D , Pasquini Giancarlo , Mogle Jacqueline , Reid Kerry , Sliwinski Martin , Graham-Engeland Jennifer E , Engeland Christopher G , Bernard Kristin , Veeramah Krishna , Scott Stacey B 
Published: October 2023

Abstract
DNA methylation-derived epigenetic clocks offer the opportunity to examine aspects of age acceleration (ie, the difference between an individual’s biological age and chronological age), which vary among individuals and may better account for age-related changes in cognitive function than chronological age. Leveraging existing ambulatory cognitive assessments in daily life from a genetically diverse sample of 142 adults in midlife, we examined associations between 5 measures of epigenetic age acceleration and performance on tasks of processing speed and working memory. Covarying for chronological age, we used multilevel models to examine associations of epigenetic age acceleration (Horvath 1, Horvath 2, Hannum, PhenoAge, and GrimAge clocks) with both average level and variability of cognitive performance. Positive age acceleration (ie, epigenetic age greater than chronological age) was associated with poorer mean processing speed (Horvath 1 and 2) and working memory (GrimAge). Higher chronological age was also associated with poorer mean processing speed and working memory performance. Further, positive age acceleration was generally associated with greater intraindividual variability in working memory and processing speed tasks, whereas being chronologically older was associated with less intraindividual variability. Although further work is needed, our results indicate age acceleration effects have comparable or greater size as those for chronological age differences, suggesting that epigenetic age acceleration may account for additional risk and interindividual variation in cognitive performance above chronological age.
Colchicine-resistant sacroiliitis in a Japanese patient with familial Mediterranean fever
Authors: Matsumoto Haruki , Sumichika Yuya , Saito Kenji , Yoshida Shuhei , Temmoku Jumpei , Fujita Yuya , Matsuoka Naoki , Asano Tomoyuki , Sato Shuzo , Migita Kiyoshi 
Published: October 2023

ABSTRACT
The articular involvement in patients with familial Mediterranean fever (FMF) represents a clinical characteristic of acute monoarthritis with pain and hydrarthrosis, which always resolves spontaneously. Colchicine prevents painful arthritis attacks in most FMF cases. Spondyloarthritis is rarely associated with Japanese patients with FMF. Here, we report a Japanese male patient with FMF-related axial joint involvement. A 43-year-old male Japanese patient who presented with recurrent febrile episodes with hip joint and back pain was referred to our hospital. He carried heterozygous variants in exon 2 (L110P/E148Q) of the MEFV gene. FMF was suspected, and oral administration of colchicine (1 mg/day) was initiated. Colchicine treatment improved his febrile attack with hip joint pain. He was diagnosed as having FMF based on the Tel-Hashomer diagnostic criteria for FMF since he fulfilled one major criterion (repeated febrile attack accompanied by hip joint pain) and one minor criterion (improvement with colchicine treatment). Although the human leucocyte antigen-B27 allele was not detected, sacroiliitis-related symptoms progressed despite the ongoing colchicine treatment. Salazosulphapyridine and methotrexate were administered in addition to colchicine; however, these treatments were not effective. Canakinumab treatment successfully resolved this unique aspect of sacroiliitis, and the patient was finally diagnosed with FMF-associated axial joint involvement.
Eosinophilic granulomatous with polyangiitis complicated by swelling of the oral cavity floor and cervical soft tissue as initial manifestation mimicking IgG4-related disease: A case report
Authors: Suzuki Tomoko , Moriyama Mayuko , Takano Ikuko , Miyajima Nobue , Yoshioka Yuki , Honda Manabu , Kondo Masahiro , Shokei Sachiko , Araki Asuka , Kadota Kyuichi , Ichinose Kunihiro 
Published: October 2023

ABSTRACT
Eosinophilic granulomatous polyangiitis is a systemic vasculitis associated with bronchial asthma and eosinophilic sinusitis. Here, we describe an unusual presentation of eosinophilic granulomatous polyangiitis that initially manifested as swelling of the oral cavity floor and cervical soft tissue. A 58 year-old Japanese man was diagnosed with bronchial asthma during childhood but did not receive regular medication. Prior to this presentation, he had a persistent cough for over 1 month, and a local physician diagnosed him with bronchial asthma. However, 6 months later, his cough worsened, and a blood test revealed elevated eosinophil levels. Immediately afterward, swelling of the floor of the oral cavity and cervical soft tissue developed. Cellulitis was suspected and antimicrobial treatment was initiated; however, the symptoms persisted and abdominal pain developed. An endoscopic examination revealed duodenitis and a duodenal ulcer. The patient was diagnosed with eosinophilic granulomatous polyangiitis based on three items of the 2022 American College of Rheumatology/European College of Rheumatology classification criteria: obstructive airway disease, blood eosinophil count ≥1 × 109 cells/L, and extravascular eosinophilic infiltration with a score of 10. Oral prednisolone (70 mg/day), intravenous cyclophosphamide (500 mg/m2), and subcutaneous mepolizumab (300 mg every 4 weeks) were administered. The patient’s symptoms improved after these treatments, and the eosinophil count and inflammatory marker levels declined. When swelling of the oral cavity floor and cervical soft tissue following an increase in eosinophilia and allergic symptoms occurs, it is crucial to consider the likelihood of eosinophilic granulomatous polyangiitis and collaborate with otolaryngologists and dentists to ensure its prompt identification.
Increased lethality of respiratory infection by Streptococcus pneumoniae in the Dp16 mouse model of Down syndrome
Authors: Colvin Kelley L. , Elliott Robert J. , Goodman Desiree M. , Harral Julie , Barrett Edward G. , Yeager Michael E. 
Published: October 2023

AbstractObjectivesWe sought to investigate whether the Dp16 mouse model of Down syndrome (DS) is more susceptible to severe and lethal respiratory tract infection by Streptococcus pneumoniae.Study DesignWe infected controls and Dp16 mice with Streptococcus pneumoniae and measured survival rates. We compared cytokine production by primary lung cell cultures exposed to Streptococcus pneumoniae. We examined lung protein expression for interferon signaling related pathways. We characterized the histopathology and quantified the extent of bronchus‐associated lymphoid tissue. Finally, we examined mouse tissues for the presence of oligomeric tau protein.ResultsWe found that the Dp16 mouse model of DS displayed significantly higher susceptibility to lethal respiratory infection with Streptococcus pneumoniae compared to control mice. Lung cells cultured from Dp16 mice displayed unique secreted cytokine profiles compared to control mice. The Dp16 mouse lungs were characterized by profound lobar pneumonia with massive diffuse consolidation involving nearly the entire lobe. Marked red hepatization was noted, and Dp16 mice lungs contained numerous bronchus‐associated lymphoid tissues that were highly follicularized. Compared to uninfected mice, both control mice and Dp16 mice infected with Streptococcus pneumoniae showed evidence of oligomeric tau aggregates.ConclusionsIncreased susceptibility to severe respiratory tract infection with Streptococcus pneumoniae in Dp16 mice closely phenocopies infection in individuals with DS. The increase does not appear to be linked to overexpression of mouse interferon genes syntenic to human chromosome 21.
Loss of function of ribosomal protein L13a blocks blastocyst formation and reveals a potential nuclear role in gene expression
Authors: Kour Ravinder , Kim Jaehwan , Roy Antara , Richardson Brian , Cameron Mark J. , Knott Jason G. , Mazumder Barsanjit 
Published: October 2023

AbstractRibosomal proteins play diverse roles in development and disease. Most ribosomal proteins have canonical roles in protein synthesis, while some exhibit extra‐ribosomal functions. Previous studies in our laboratory revealed that ribosomal protein L13a (RPL13a) is involved in the translational silencing of a cohort of inflammatory proteins in myeloid cells. This prompted us to investigate the role of RPL13a in embryonic development. Here we report that RPL13a is required for early development in mice. Crosses between Rpl13a+/− mice resulted in no Rpl13a−/− offspring. Closer examination revealed that Rpl13a−/− embryos were arrested at the morula stage during preimplantation development. RNA sequencing analysis of Rpl13a−/− morulae revealed widespread alterations in gene expression, including but not limited to several genes encoding proteins involved in the inflammatory response, embryogenesis, oocyte maturation, stemness, and pluripotency. Ex vivo analysis revealed that RPL13a was localized to the cytoplasm and nucleus between the two‐cell and morula stages. RNAi‐mediated depletion of RPL13a phenocopied Rpl13a−/− embryos and knockdown embryos exhibited increased expression of IL‐7 and IL‐17 and decreased expression of the lineage specifier genes Sox2, Pou5f1, and Cdx2. Lastly, a protein–protein interaction assay revealed that RPL13a is associated with chromatin, suggesting an extra ribosomal function in transcription. In summary, our data demonstrate that RPL13a is essential for the completion of preimplantation embryo development. The mechanistic basis of the absence of RPL13a‐mediated embryonic lethality will be addressed in the future through follow‐up studies on ribosome biogenesis, global protein synthesis, and identification of RPL13a target genes using chromatin immunoprecipitation and RNA‐immunoprecipitation‐based sequencing.
Adverse Events and Infectious Complications in the Critically Ill Treated by Plasma Exchange: A Five-Year Multicenter Cohort Study
Authors: François Mickael , Daubin Delphine , Menouche Dehbia , Gaillet Antoine , Provoost Judith , Trusson Remi , Arrestier Romain , Hequet Olivier , Richard Jean‑Christophe , Moranne Olivier , Larcher Romaric , Klouche Kada 
Published: October 2023

OBJECTIVES:
The aim of this study was to determine, in critically ill patients treated with therapeutic plasma exchange (TPE), the incidence of adverse events as well as the incidence of secondary infections and its predictive factors.

DESIGN:
A multicenter retrospective cohort study of an intensive care population treated with TPE to collect adverse events and infectious complications. The characteristics of patients who developed an infection after plasma exchange were compared with those of patients who did not.

SETTING:
Four ICUs of French university hospitals.

PATIENTS:
All adults admitted between January 1, 2015, and December 31, 2019, who received at least one plasma exchange session were included.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
A total of 711 TPE sessions were performed on 124 patients. The most frequent TPE indications were thrombotic microangiopathies (n = 32, 26%), myasthenia gravis (n = 25, 20%), and acute polyradiculoneuropathy (n = 12, 10%). Among the 124 patients, 22 (21%) developed arterial hypotension, 12 (12%) fever, and 9 (9%) electrolyte disturbance during TPE. Moreover, 60 (48%) presented at least one infectious complication: ventilator-associated pneumonia 42, pneumonia 13, bacteremia 18 (of which 6 catheter-related infections) viral reactivation 14. Independent risk factors for ICU-acquired infection were the ICU length of stay (24 vs. 7 d; hazard ratio [HR]: 1.09 [1.04–1.15], p < 0.001) and invasive mechanical ventilation (92% vs. 35%; HR: 16.2 [5.0–53.0], p < 0.001).

CONCLUSIONS:
In critically ill patients treated with TPE, adverse events occurring during the procedure remain moderately frequent and are mostly not life-threatening. Infectious complications, mainly ventilation-associated pneumonia, are frequent in this population. The need of mechanical ventilation and longer ICU stay is associated with an increased risk of infection.
The role of botulinum toxin in the management of nonneurogenic overactive bladder in children: Highlights for clinical practice. A systematic review
Authors: Câncio Martins Bissaia Barreto José A. , Táboas Simões Maria I. , Gomes Engenheiro Gonçalo , Ferreira Matos Joana I. , Rodrigues Leal Joana A. 
Published: October 2023

Abstract
Overactive bladder (OAB) is the most common voiding dysfunction in children; however, nonneurogenic or idiopathic OAB remains poorly studied. First-line treatment includes conservative measures; however, as many patients are refractory, have adverse effects, or are contraindicated for anticholinergics, new options must be explored. This review covers the use of intravesical botulinum toxin (BoNT) for idiopathic OAB treatment in children, emphasizing its efficacy, safety, differences between toxins, doses, and injection techniques. Clinical results were promising, with all 8 studies reporting good results. All authors used BoNT type A, either onabotulinum or abobotulinum toxin A. Response rates were variable, with full-response percentages of 32%–60%. As proven by the full-response rates of 50%, repeated injections are as safe and effective as first injections. Only a few cases of urinary tract infection, transient urinary retention, and hematuria have been reported, with no major local or systemic adverse effects. Despite these limitations, evidence encourages and supports BoNT type A use as a safe and effective treatment modality for refractory idiopathic OAB in pediatric settings, regardless of dosage and target toxin. To the best of our knowledge, this is the first systematic review of the use of intravesical botulinum toxin type A for idiopathic OAB treatment in children.