Miracle-dz/UniFAR-FTUs huggingface dataset:
Induction of p21 WAF1/CIP1 and Inhibition of Cdk2 Mediated by the Tumor Suppressor p16 INK4a

The tumor suppressor p16 INK4a inhibits cyclin-dependent kinases 4 and 6. This activates the retinoblastoma protein (pRB) and, through incompletely understood events, arrests the cell division cycle. To permit bio- chemical analysis of the arrest, we generated U2-OS osteogenic sarcoma cell clones in which p16 transcription could be induced. In these clones, binding of p16 to cdk4 and cdk6 abrogated binding of cyclin D1, p27 KIP1 , and p21 WAF1/CIP1 . Concomitantly, the total cellular level of p21 increased severalfold via a posttranscriptional mechanism. Most cyclin E-cdk2 complexes associated with p21 and became inactive, expression of cyclin A was curtailed, and DNA synthesis was strongly inhibited. Induction of p21 alone, in a sibling clone, to the level observed during p16 induction substantially reproduced these effects. Overexpression of either cyclin E or A prevented p16 from mediating arrest. We then extended these studies to HCT 116 colorectal carcinoma cells and a p21-null clone derived by homologous recombination. In the parental cells, p16
Human Leukocyte Antigen (HLA) Haplotype Does Not Inﬂuence the Inﬂammatory Pattern of Duodenal Lymphocytosis Linked to Irritable Bowel Syndrome

: Background and objectives: Duodenal lymphocytosis (DL) is a condition characterized by enhanced inﬁltration of intraepithelial lymphocytes (IELs) in the duodenal mucosa, and it can be linked to both gluten- and non-gluten-related diseases, such as irritable bowel syndrome (IBS). Materials and methods: We retrospectively selected patients with DL linked to IBS. Formalin-embedded biopsy samples of the duodenum were collected. CD3 lymphocyte immunohistochemistry was used for IELs. The real-time polymerase chain reaction was used to quantify the amount of mRNA coding for tissue transglutaminase 2 (tTG2), interferon-gamma (IFN γ ), toll-like receptor 2 (TLR2), and myeloid di ﬀ erentiation primary response 88 (MyD88). All subjects underwent DQ2-8 haplotype analysis. Controls were represented by subjects with IBS without DL. Results: Thirty-two patients with IBS-DL were retrospectively recruited. Fourteen subjects (43.8%) had a DQ2-8 haplotype. DQ2-8 positive subjects had similar levels compared to negative ones for tTG2, IFN γ , TLR2, and MyD88. Cigarette smoke did not inﬂuence molecular expression in our study. Smokers had a statistically higher IELs count than non-smokers (54.2 ± 7.7 vs. 36.0 ± 8.8, p < 0.001). A signiﬁcant, direct correlation between IELs and duodenal expression of IFN γ was found (r = 0.36, p = 0.04). Conclusions: IBS with DL showed higher expression of inﬂammatory markers than controls, but DQ2-8 haplotype did not seem to a ﬀ ect their expression. Smoking might increase IELs inﬁltration.
3 Generation Self-Inactivating gp91 Lentivector Corrects the Oxidase Defect in NOD/SCID Mouse Repopulating Peripheral Blood Mobilized CD34 Cells from Patients with X-linked Chronic Granulomatous Disease Running head: Lentivector correction of X-linked CGD Scientific section heading: Gene Therapy

HIV-1 derived lentivectors are promising for gene transfer into hematopoietic stem cells, but require pre-clinical in vivo evaluation relevant to specific human diseases. Non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice accept human hematopoietic stem cell grafts providing a unique opportunity for in vivo evaluation of therapies targeting human hematopoietic diseases. We demonstrate for the first time that hematopoietic stem cells from X-linked chronic granulomatous disease (X-CGD) patients give rise to X-CGD phenotype neutrophils in the NOD/SCID model that can be corrected using VSV-G pseudotyped 3 generation self-inactivating (SIN) lentivector encoding gp91. We transduced X-CGD patient mobilized CD34 peripheral blood stem cells (CD34PBSC) with lentivector-gp91 or amphotropic onco-retrovirus MFGS-gp91 and evaluated correction ex vivo and in vivo in NOD/SCID mice. Only lentivector transduced CD34PBSC under ex vivo conditions non-permissive for cell division, but both vectors performed best under conditions permissive for proliferation (multiple growth factors). Under the latter conditions both lentivector and MFGS achieved significant ex vivo correction of X-CGD CD34PBSC (18% and 54% of cells expressing gp91, associated with 53% and 163% of normal superoxide production, respectively). However, lentivector, but not MFGS, achieved significant correction of human X-CGD neutrophils arising in vivo in transplanted NOD/SCID mice (20% and 2.4%, respectively). Thus, 3 generation SIN lentivector-gp91 performs well as assessed in human X-CGD neutrophils differentiating in vivo, and our studies suggest that the NOD/SCID model is generally applicable for in vivo study of therapies evaluated in human blood cells expressing a specific disease phenotype. email: hmalech@nih.gov For personal use only. on August 21, 2017. by guest www.bloodjournal. org From
Deterministic Factors Determine the Comammox Community Composition in the Pearl River Estuary Ecosystem

Microbial communities are shaped by stochastic (emigration, immigration, birth, death, and genetic drift of species) and deterministic (e.g., environmental factors) processes. However, it remains unknown as to which type of process is more important in influencing the comammox community assembly from freshwater to marine environments. ABSTRACT Complete ammonia oxidizers (comammox) have been widely detected in riverine and estuarine ecosystems. However, knowledge about the process of comammox community assembly from freshwater to marine environments is still limited. Here, based on deep sequencing, we investigated the community composition of comammox along a salinity gradient in the Pearl River Estuary (PRE), South China. Our results showed that comammox microorganisms in the PRE sediments were extremely diverse and displayed distinct distributional patterns between upstream and downstream habitats. Quantitative PCR demonstrated that comammox was the dominant ammonia-oxidizing microorganism (AOM) in the PRE upstream sediments, and ammonia-oxidizing archaea (AOA) dominated the PRE downstream sediments, while ammonia-oxidizing bacteria (AOB) were not dominant in any section of the PRE. Neutral modeling revealed that stochastic processes explained a limited part of the variation in the comammox community. The majority of beta nearest-taxon index values were higher than 2, indicating that comammox community assembly in the PRE sediments was better explained through a deterministic process than through a stochastic process. Salinity and total nitrogen were the most important contributing factors that shaped the comammox community. This study expanded the current knowledge of the diversity and niche preference of comammox in the estuarine ecosystem, and further enhances our understanding of the assembly of comammox community from freshwater to marine environments. IMPORTANCE Microbial communities are shaped by stochastic (emigration, immigration, birth, death, and genetic drift of species) and deterministic (e.g., environmental factors) processes. However, it remains unknown as to which type of process is more important in influencing the comammox community assembly from freshwater to marine environments. In this study, we compared the relative importance of stochastic and deterministic processes in shaping the assembly of the comammox community, which demonstrated that the deterministic process was more important in determining the community assembly patterns in the PRE ecosystem.
Fostering cognitive performance in older adults with a process- and a strategy-based cognitive training

ABSTRACT The present study investigates the impact of process-based and strategy-based cognitive training to boost performance in healthy older adults. Three groups trained with either a dichotic listening training (process-based training, n = 25), an implementation intention strategy training (strategy-based training, n = 23), or served as a non-contact control group (n = 30). Our results demonstrated that training participants improved their performance in the trained tasks (process-based training: d = 3.01, strategy-based training: d = 2.6). For untrained tasks, the process-based training group showed significant working memory (d = .58) as well as episodic memory task improvement (d = 1.19) compared to the strategy-based training and to the non-contact control group (all d < .03). In contrast, in the strategy-based training group there was a tendency towards some performance gain in a fluid intelligence test (d = .92). These results indicate that cognitive training can be tailored to improve specific cognitive abilities.
OPERATOR MEANS AS UNIQUE SOLUTIONS OF OPERATOR EQUATIONS (幾何学及び確率論的手法による作用素の構造解析の研究 : RIMS研究集会報告集)

In this article we consider means of positive bounded linear operators on a Hilbert space and announce the new results of [31]. We extend the theory of matrix power means to arbitrary operator means in the sense of Kubo-Ando. We consider generalized Karcher equations for positive operators and show that such equations admit unique positive solutions that can be obtained as a limit of one-parameter families of operator means called induced operator means. These means are themselves unique fixed points of one parameter families of strict contractions induced, through Kubo-Ando theory of operator means, by semigroups of holomorphic functions mapping the upper half-plane into itself. These semigroups of holomorphic functions are considered with Koenigs function corresponding to Schroeder’s functional equation. Koenigs function in this setting provides us with a logarithm map corresponding to every 2-variable operator mean. The unique solutions of these generalized Karcher equations are called lambda extensions and have numerous desirable properties which are inherited from the induced operator means themselves.
Mental health and periodontal and peri‐implant diseases

Abstract Mental health disorders, particularly depression and anxiety, affect a significant number of the global population. Several pathophysiological pathways for these disorders have been identified, including the hypothalamic‐pituitary‐adrenal axis, autonomic nervous system, and the immune system. In addition, life events, environmental factors, and lifestyle affect the onset, progression, and recurrence of mental health disorders. These may all overlap with periodontal and/or peri‐implant disease. Mental health disorders are associated with more severe periodontal disease and, in some cases, poorer healing outcomes to nonsurgical periodontal therapy. They can result in behavior modification, such as poor oral hygiene practices, tobacco smoking, and alcohol abuse, which are also risk factors for periodontal disease and, therefore, may have a contributory effect. Stress has immunomodulatory effects regulating immune cell numbers and function, as well as proinflammatory cytokine production. Stress markers such as cortisol and catecholamines may modulate periodontal bacterial growth and the expression of virulence factors. Stress and some mental health disorders are accompanied by a low‐grade chronic inflammation that may be involved in their relationship with periodontal disease and vice versa. Although the gut microbiome interacting with the central nervous system (gut‐brain axis) is thought to play a significant role in mental illness, less is understood about the role of the oral microbiome. The evidence for mental health disorders on implant outcomes is lacking, but may mainly be through behaviourial changes. Through lack of compliance withoral hygiene and maintenance visits, peri‐implant health can be affected. Increased smoking and risk of periodontal disease may also affect implant outcomes. Selective serotonin reuptake inhibitors have been linked with higher implant failure. They have an anabolic effect on bone, reducing turnover, which could account for the increased loss.
The survival of esophageal cancer by subtype in China with comparison to the United States

Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the main subtypes of esophageal cancer (EC), but nationwide survival of both EC subtypes has never been reported in China. Our study aimed to estimate the survival trends of EC by subtype in China and compare them with those in the United States for the same period. We used data from 64 Chinese cancer registries, which included EC patients diagnosed during 2008 and 2015 and followed up until 31st December 2017. The 5‐year age‐standardized relative survival by subtype, sex, age group and urban or rural area between 2008 and 2017 were analyzed. We stratified survival estimates by calendar period (2008‐2009, 2010‐2011, 2012‐2014 and 2015‐2017). Data from the SEER 18 program were calculated to estimate the survival of EC in the United States. A further comparison between the survivals in areas covered and not covered by population‐based endoscopic screening programs in China was conducted. A total of 129 962 records were included in the survival analyses. Results revealed that age‐standardized 5‐year relative survivals for AC and SCC increased in both China and the United States from 2008 to 2017. In 2015 to 2017, 5‐year survival from both subtypes in China was better than the United States (SCC: 36.9% vs 18.5%, AC: 34.8% vs 22.3%). The survival for both subtypes was significantly higher in screening areas than in nonscreening areas in China (SCC: 40.6% vs 32.8%; AC: 43.0% vs 31.3%). A survival gap in EC by subtype exists between China and the United States. Our results may support the beneficial effect of population‐based endoscopic screening for survival, and may be poised to inform national policy‐making in both countries.
Effectiveness of a community-driven, asthma intervention: project asthma in-home response

Abstract Objectives: Project Asthma In-home Response (AIR) is a multilevel, home-based intervention to address childhood asthma. This study aims to assess the effectiveness of the community-driven, multilevel Project AIR intervention. We hypothesize that children participating in the Project AIR intervention will have reduced asthma-related emergency room visits, hospitalizations, and asthma exacerbations. Methods: Seventy-Five participants of an in-home asthma intervention were surveyed at the onset of intervention and six months after the intervention. Results: The mean age of clients in the sample population was ten years. Most clients in the sample population were 11–15 years old (34.7%), followed by 6–10 years old (29.3%) and 3–5 years (26.0%). Participation in the Project AIR intervention resulted in significant reductions in asthma attacks (p-value 0.0003), asthma-related emergency room visits (p-value > 0.0001), and asthma-related hospitalizations (p-value 0.008). Conclusion: The results of this study support that in-home environmental asthma programs are an efficient method of treating asthma in a smaller metro area. Our findings reinforce prior studies in larger metropolitan areas such as New York and Boston.
Healthcare workers’ knowledge and attitudes towards sterilization and reuse of medical devices in primary and secondary care public hospitals in Nepal: A multi-centre cross-sectional survey

Background Healthcare facilities reprocess and sterilize reusable medical devices before each invasive clinical procedure, such as surgery, to prevent person-to-person or environmental transmission of pathogens through medical devices. We conducted a nationwide multi-centre cross-sectional survey in primary and secondary-care public hospitals in Nepal to assess the knowledge and attitudes of healthcare workers towards sterilization and reuse of medical devices. Methods We carried out a multi-centre cross-sectional survey comprising eleven primary-care (two district-level and nine district hospitals) and two secondary-care (zonal hospitals) public hospitals which covered all seven provinces of Nepal. Survey questionnaires were distributed to 234 healthcare workers including doctors, nurses, paramedics, and office assistants (involved in medical device reprocessing); 219 (93.6%) returned the completed questionnaire. Descriptive analyses of demographic information, knowledge and attitude responses of survey participants were performed. Logistic regression and ordinal regression models for complex samples were used to investigate associations between responses and independent variables. Results Except for a few areas, more than 70% of healthcare workers had proper knowledge about different aspects of sterilization and reuse of medical devices. Paramedics and office assistants were less likely to have the correct knowledge in different aspects compared to nurses. Permanent staff were more likely to give correct answers to some knowledge questions compared to temporary staff. Previous infection control training was positively associated with correct responses to some knowledge items. Most of the healthcare workers had positive attitudes towards different aspects of sterilization and reuse of medical devices, and nurses were more likely to have positive attitudes compared with other staff categories. Conclusions Most of the healthcare workers had correct knowledge and positive attitudes towards most areas of sterilization and reuse of medical devices. However, they need proper education and training in some areas such as sterilization procedures, storage of sterilized devices, prion decontamination and standard precautions.
The fibro‐ and cyto‐architecture demarcating the border between the dentate gyrus and CA3 in sheep (Ovis aries) and domestic pig (Sus scrofa domesticus)

The hippocampal formation is essential for spatial navigation and episodic memory. The anatomical structure is largely similar across mammalian species, apart from the deep polymorphic layer of the dentate gyrus and the adjacent part of cornu ammonis 3 (CA3) which feature substantial variations. In rodents, the polymorphic layer has a triangular cross‐section abutting on the end of the CA3 pyramidal layer, while in primates it is long and band‐shaped capping the expanded CA3 end, which here lacks a distinct pyramidal layer. This structural variation has resulted in a confusing nomenclature and unclear anatomical criteria for the definition of the dentate‐ammonic border. Seeking to clarify the border, we present here a light microscopic investigation based on Golgi‐impregnated and Timm–thionin‐stained sections of the Artiodactyla sheep and domestic pig, in which the dentate gyrus and CA3 end have some topographical features in common with primates. In short, the band‐shaped polymorphic layer coincides with the Timm‐positive mossy fiber collateral plexus and the Timm‐negative subgranular zone. While the soma and excrescence‐covered proximal dendrites of the mossy cells are localized within the plexus, the peripheral mossy cell dendrites extend outside the plexus, both into the granular and molecular layers, and the CA3. The main mossy fibers leave the collateral plexus in a scattered formation to converge gradually through the CA3 end in between the dispersed pyramidal cells, which are of three subtypes, as in monkey, with the classical apical subtype dominating near the hidden blade, the nonapical subtype near the exposed blade, and the dentate subtype being the only pyramidal cells that extend dendrites into the dentate gyrus. In agreement with our previous study in mink, the findings show that the border between the dentate gyrus and the CA3 end can be more accurately localized by the mossy fiber system than by cyto‐architecture alone.
Understanding perspectives on health-promoting behaviours among older adults with hypertension

ABSTRACT Purpose Health-promoting behaviours (HPBs) are considered the key to determining health among older adults with hypertension. Increasing our understanding of older adults’ views on HPBs could facilitate the development of interventions aimed at improving their quality of life. This study aims to describe the perceptions of older adults with high blood pressure concerning their HPBs and associated factors. Methods Semi-structured interviews with 40 individuals in Thailand were used to collect the data, which were analysed using thematic analysis. Results The results were categorized into five main themes related to personal, social, and environmental factors. Older adults explained that their experiences with HPBs involve taking responsibility for controlling blood pressure by following a doctor’s prescription, modifying their lifestyles to be healthier, sustaining social relationships, and experiencing spiritual growth through religious practices for inner peace. Older adults also identified environmental factors that influenced their engagement in HPBs depending on their residential areas. Conclusions The findings of this study highlight the importance of practices in which professionals support and encourage older adults to perform HPBs to maintain health and improve their well-being.
Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds

Mitochondria play a central role in metabolic homeostasis, and dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Tetrapeptides with alternating cationic and aromatic residues such as SS-31 (elamipretide) show promise as therapeutic compounds for mitochondrial disorders. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs, benchmarked against SS-31, that differ with respect to aromatic side chain composition and sequence register. We present the first structural models for this class of compounds, obtained with Nuclear Magnetic Resonance (NMR) and molecular dynamics approaches, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. The peptides had no strict requirement for side chain composition or sequence register to permeate cells and target mitochondria in mammalian cell culture assays. All four peptides were pharmacologically active in serum withdrawal cell stress models yet showed significant differences in their abilities to restore mitochondrial membrane potential, preserve ATP content, and promote cell survival. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register influence the activity of these mitochondria-targeted peptides, helping provide a framework for the rational design of next-generation therapeutics with enhanced potency.