Miracle-dz/UniFAR-FTUs huggingface dataset:
Education-Based Cutoffs for Cognitive Screening of Alzheimer’s Disease

Introduction: The educational background and size of the elderly population are undergoing significant changes in Finland during the 2020s. A similar process is likely to occur also in several European countries. For cognitive screening of early Alzheimer’s disease (AD), using outdated norms and cutoff scores may negatively affect clinical accuracy. The aim of the present study was to examine the effects of education, age, and gender on the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery (CERAD-nb) in a large register-based, clinical sample of patients with mild AD and nondemented at-risk persons from the general population (controls) and to examine whether corrected cutoff scores would increase the accuracy of differentiation between the 2 groups. Methods: CERAD-nb scores were obtained from AD patients (n = 389, 58% women, mean age 74.0 years) and from controls (n = 1,980, 52% women, mean age 68.5 years). The differences in CERAD-nb performance were evaluated by univariate GLM. Differentiation between the 2 groups was evaluated using a receiver operating characteristic (ROC) curve, where a larger area under the ROC curve represents better discrimination. Youden’s J was calculated for the overall performance and accuracy of each of the measures. Results: Of the demographic factors, education was the strongest predictor of CERAD-nb performance, explaining more variation than age or gender in both the AD patients and the controls. Education corrected cutoff scores had better diagnostic accuracy in discriminating between the AD patients and controls than existing uncorrected scores. The highest level of discrimination between the 2 groups overall was found for two CERAD-nb total scores. Conclusions: Education-corrected cutoff scores were superior to uncorrected scores in differentiating between controls and AD patients especially for the highest level of education and should therefore be used in clinical cognitive screening, also as the proportion of the educated elderly is increasing substantially during the 2020s. Our results also indicate that total scores of the CERAD-nb are better at discriminating AD patients from controls than any single subtest score. A digital tool for calculating the total scores and comparing education-based cutoffs would increase the efficiency and usability of the test.
From Steroid and Drug Metabolism to Glycobiology, Using Sulfotransferase Structures to Understand and Tailor Function

Sulfotransferases are ubiquitous enzymes that transfer a sulfo group from the universal cofactor donor 3′-phosphoadenosine 5′-phosphosulfate to a broad range of acceptor substrates. In humans, the cytosolic sulfotransferases are involved in the sulfation of endogenous compounds such as steroids, neurotransmitters, hormones, and bile acids as well as xenobiotics including drugs, toxins, and environmental chemicals. The Golgi associated membrane-bound sulfotransferases are involved in post-translational modification of macromolecules from glycosaminoglycans to proteins. The sulfation of small molecules can have profound biologic effects on the functionality of the acceptor, including activation, deactivation, or enhanced metabolism and elimination. Sulfation of macromolecules has been shown to regulate a number of physiologic and pathophysiological pathways by enhancing binding affinity to regulatory proteins or binding partners. Over the last 25 years, crystal structures of these enzymes have provided a wealth of information on the mechanisms of this process and the specificity of these enzymes. This review will focus on the general commonalities of the sulfotransferases, from enzyme structure to catalytic mechanism as well as providing examples into how structural information is being used to either design drugs that inhibit sulfotransferases or to modify the enzymes to improve drug synthesis. SIGNIFICANCE STATEMENT This manuscript honors Dr. Masahiko Negishi’s contribution to the understanding of sulfotransferase mechanism, specificity, and roles in biology by analyzing the crystal structures that have been solved over the last 25 years.
Bcl-2 interacting protein 3 (BNIP3) promotes tumor growth in breast cancer under hypoxic conditions through an autophagy-dependent pathway

ABSTRACT Hypoxia-induced autophagy has been implicated in many cancers. Bcl-2 interacting protein 3 (BNIP3) has been associated with hypoxia, whose aberrant expression is involved in the carcinogenesis of breast cancer (BC). Here, we aim to investigate the role of hypoxia-induced autophagy and the mechanistic actions of the bioinformatically identified BNIP3 in BC. The expression pattern of BNIP3 in BC tissues and cell lines was examined using RT-qPCR and Western blot analyses. The binding affinity among BNIP3, BECN1 and BCL-2 was characterized by co-immunoprecipitation. BNIP3 expression was manipulated to assess its effects on BC cell malignant phenotypes, evaluated by cell counting kit-8, Transwell and wound healing assays, and on BC autophagy under hypoxic conditions. A BC tumor xenografts mouse model was further established to substantiate in vitro findings. Up-regulated expression of BNIP3 was found in BC tissues and cell lines, and BNIP3 expression was positively correlated with hypoxia exposure duration. BNIP3 knockdown restricted BC cell proliferation, invasion, and migration under hypoxic conditions. BNIP3 activated BC cell autophagy by inhibiting the binding between BCL-2 and BECN1 under hypoxic conditions. BNIP3-induced autophagy activation enhanced malignant phenotypes of BC cells, thus accelerating the tumorigenesis of BC cells in vivo. These data collectively supported the tumor-promoting role of BNIP3 in autophagy activation of BC under hypoxic conditions, highlighting a potential therapeutic target against BC. Graphical abstract
Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/day]; oral venetoclax [5-week ramp-up to 400 mg/day]). Primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. 159 patients were enrolled and treated, including 136 patients without del(17p). Median time on study was 27.9 months and 92% of patients completed all planned treatment. Primary endpoint was met, with CR rate of 56% (95% CI, 48-64) in patients without del(17p), significantly higher than prespecified 37% minimum rate (P<.0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood) and 60% (bone marrow); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome risk; after ibrutinib lead-in, only 1% remained in this category. Most common grade ≥3 adverse events were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free, fixed-duration regimen for patients with CLL. Fixed-duration ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.
Validity of chronic restraint stress for modeling anhedonic-like behavior in rodents: a systematic review and meta-analysis

Background Chronic restraint stress (CRS) is widely used to recapitulate depression phenotypes in rodents but is frequently criticized for a perceived lack of efficacy. The aim of this study was to evaluate anhedonic-like behavior in the CRS model in rodents by performing a meta-analysis of studies that included sucrose preference tests. Methods This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. We comprehensively searched for eligible studies published before June 2021 in the PubMed, Embase, Medline, and Web of Science databases. We chose sucrose preference ratio as the indicative measure of anhedonia because it is a core symptom of depression in humans. Results Our pooled analysis included 34 articles with 57 studies and seven rodent species/strains and demonstrated decreased sucrose preference in the stress group compared with controls. The duration of CRS differentially affected the validity of anhedonic-like behavior in the models. Rats exhibited greater susceptibility to restraint stress than mice, demonstrating inter-species variability. Conclusions Our meta-analysis of studies that used the CRS paradigm to evaluate anhedonic-like behavior in rodents was focused on a core symptom of depression (anhedonia) as the main endpoint of the model and identified species-dependent susceptibility to restraint stress.
Activation of PDGFRA signaling contributes to filamin C–related arrhythmogenic cardiomyopathy

FLNC truncating mutations (FLNCtv) are prevalent causes of inherited dilated cardiomyopathy (DCM), with a high risk of developing arrhythmogenic cardiomyopathy. We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). We demonstrated that iPSC-CMs from two patients with different FLNCtv mutations displayed arrhythmias and impaired contraction. FLNC ablation induced a similar phenotype, suggesting that FLNCtv are loss-of-function mutations. Coimmunoprecipitation and proteomic analysis identified β-catenin (CTNNB1) as a downstream target. FLNC deficiency induced nuclear translocation of CTNNB1 and subsequently activated the platelet-derived growth factor receptor alpha (PDGFRA) pathway, which were also observed in human hearts with a-DCM and FLNCtv. Treatment with the PDGFRA inhibitor, crenolanib, improved contractile function of patient iPSC-CMs. Collectively, our findings suggest that PDGFRA signaling is implicated in the pathogenesis, and inhibition of this pathway is a potential therapeutic strategy in FLNC-related cardiomyopathies.
Adaptive Robust Formation Control of Connected and Autonomous Vehicle Swarm System Based on Constraint Following

This article proposes an adaptive robust formation control scheme for the connected and autonomous vehicle (CAV) swarm system by utilizing swarm property, diffeomorphism transformation, and constraint following. The control design is processed by starting from a 2-D dynamics model with (possibly fast) time varying but bounded uncertainty. The uncertainty bounds are unknown. For compact formation, the CAV system is treated as an artificial swarm system, for which the ideal swarm performance is taken as a desired constraint. By this, formation control is converted into a problem of constraint following and then a performance measure $\beta $ is defined as the control object to evaluate the constraint following error. For collision avoidance, a diffeomorphism transformation on space measure between two vehicles is creatively performed, by which the space measure is positive restricted. For uncertainty handling, an adaptive robust control scheme is proposed to render the $\beta $ -measure to be uniformly bounded and uniformly ultimately bounded, that is, drive the controlled (CAV) swarm system to follow the desired constraint approximatively. As a result, the system can achieve the ideal swarm performance; thereout, compact formation is realized, regardless of the uncertainty. The main contribution of this article is exploring a 2-D formation control scheme for (CAV) swarm system under the consideration of collision avoidance and time-varying uncertainty.
Chemical composition and antimicrobial activity of Boswellia serrata oleo-gum-resin essential oil extracted by superheated steam

Abstract Oleo-gum-resin is a complex mixture of essential oils, polysaccharides, and resin acids. The objectives of the present study were to evaluate the variation in chemical components and antimicrobial activity of essential oils extracted by superheated steam at various temperatures. The optimum essential oil yield was obtained at the highest superheated steam temperature (210 °C). In total, twenty-one compounds were quantified by GC-MS with α-pinene as the major compound, followed by α-thujene, trans-verbenol, β-thujone, p-cymene, m-cymene, and sabinene. Antimicrobial activity was performed by disc diffusion, resazurin microtitre-plate and micro-dilution broth susceptibility assays in which essential oil extracted at 150 °C and 180 °C revealed the highest antibacterial and antifungal activity, respectively. It is concluded that superheated steam is an effective method for the isolation of essential oil from oleo-gum-resin that improves the recovery of essential oil as well as antimicrobial activity. Graphical Abstract
Surface haptic rendering of virtual shapes through change in surface temperature

Compared to relatively mature audio and video human-machine interfaces, providing accurate and immersive touch sensation remains a challenge owing to the substantial mechanical and neurophysical complexity of touch. Touch sensations during relative lateral motion between a skin-screen interface are largely dictated by interfacial friction, so controlling interfacial friction has the potential for realistic mimicry of surface texture, shape, and material composition. In this work, we show a large modulation of finger friction by locally changing surface temperature. Experiments showed that finger friction can be increased by ~50% with a surface temperature increase from 23° to 42°C, which was attributed to the temperature dependence of the viscoelasticity and the moisture level of human skin. Rendering virtual features, including zoning and bump(s), without thermal perception was further demonstrated with surface temperature modulation. This method of modulating finger friction has potential applications in gaming, virtual and augmented reality, and touchscreen human-machine interaction. Description This study introduces a method to modulate finger friction force using different surface temperatures.
Circular RNA circSHPRH inhibits the malignant behaviors of bladder cancer by regulating the miR-942/BARX2 pathway

Bladder cancer (BCa) is one of the most common tumors of the genitourinary system. However, the detailed molecular mechanism of BCa progression is still unclear. Recently, an increasing number of studies have demonstrated that circular RNAs (circRNAs) play a critical role in the tumorigenesis and progression of BCa. In this article, we showed that circSHPRH expression was obviously decreased in BCa tissues, compared with adjacent normal tissues. Moreover, a low circSHPRH level was positively correlated with a high grade, a high pathological stage, lymphatic metastasis and an unfavorable prognosis for BCa patients. Cell function studies indicated that silencing circSHPRH dramatically increased the proliferation, migration and invasion of BCa cells. Animal experiments revealed that circSHPRH overexpression repressed tumor growth. Mechanistic studies demonstrated that circSHPRH could combine with miR-942 and serve as a sponge of miR-942, which targets BARX2 in BCa cells. Rescue experiments showed that suppression of miR-942 or BARX2 overexpression could significantly abrogate the promoting effects of circSHPRH silencing on BCa cell proliferation and invasion. Furthermore, circSHPRH overexpression partly eliminated the suppressive effects of miR-942 on BARX2 expression. In addition, circSHPRH knockdown promoted activation of the Wnt/β-catenin signaling pathway by regulating BARX2. Taken together, our findings indicate that circSHPRH serves as a sponge of miR-942 to inhibit BCa progression by upregulating BARX2 expression, thereby inhibiting the Wnt/β-catenin signaling pathway.
Reach of a Fully Digital Diabetes Prevention Program in Health Professional Shortage Areas

The National Diabetes Prevention Program (NDPP) offers lifestyle change education to adults at risk for diabetes across the United States, but its reach is curbed due, in part, to limitations of traditional in-person programs. Diabetes Prevention Programs (DPPs) that are fully digital may increase reach by overcoming these barriers. The aim of this research was to examine the reach of Lark's DPP, a fully digital artificial-intelligence-powered DPP. This study assessed geographic features and demographic characteristics of a sample of Lark DPP commercial health plan members with complete data (N = 16,327) and compared several demographic features with a large composite sample of members from DPPs across the nation (NDPP; N = 143,489) and a National Health Interview Survey (NHIS) sample of prediabetic adults in the United States (NHIS; N = 2118). Examination of the Lark DPP sample revealed that 24.4% of members lived in rural areas, 30.8% lived in whole county health professional shortage areas, and only 7.6% of members lived in a zip code with an in-person DPP. When comparing the Lark sample with the NDPP and NHIS samples, Lark DPP enrollees tended to be younger and have a higher body mass index (BMI) (p's < 0.001). Lark provides convenient access to a DPP for individuals living in hard-to-reach areas who may face barriers to participating in in-person or telephonic DPPs or who prefer a digital program. Compared with the NDPP sample, Lark is also reaching younger and higher BMI users, who are traditionally difficult to enroll and have a high need for intervention.
Role of spreader flaps in primary rhinoplasty, functional and aesthetic outcomes: a systematic review.

BACKGROUND The standard treatment for reconstructing the middle vault of the nose is to use spreader grafts. Recently, an alternative technique using spreader flaps has become widely accepted. METHODOLOGY A literature search was performed in ΜEDLINE, Science Direct, the Cochrane Library and multiple trial registries. The systematic review included studies evaluating the effectiveness of spreader flaps, with or without comparison to the spreader graft technique, in patients who had undergone primary rhinoplasty. RESULTS Thirteen studies with a total of 500 patients met the inclusion criteria and were reviewed systematically. All studies measured breathing function improvement. Additionally, aesthetic improvement/satisfaction was evaluated in seven studies. The use of spreader flaps seems to improve breathing function, as seen in twelve out of thirteen studies. Furthermore, the studies assessing the aesthetic aspect of a primary rhinoplasty showed that spreader flaps can provide satisfactory results. The comparison between spreader flaps and spreader grafts showed similar results in most studies dealing with this topic in both the breathing function improvement and aesthetic improvement/satisfaction domains. CONCLUSIONS This study is the first systematic review assessing the functional and aesthetic outcomes of spreader flaps in primary rhinoplasty, and it shows encouraging results comparable to those of spreader grafts.
Type 1 interferon status in systemic lupus erythematosus: a longitudinal analysis

Objectives Type 1 interferon (IFN) is key to the pathogenesis of SLE, evidenced by the expression of IFN-stimulated genes (ISGs) in most patients, but the clinical utility of serial ISG assessment remains unknown. With the emergence of IFN-blocking drugs, we aimed to examine IFN status in relation to clinical findings longitudinally to provide insights into the value of testing ISG levels over time. Methods Clinical data and whole blood were collected prospectively on adult patients with SLE from a single tertiary lupus centre. IFN status was measured using a panel of ISGs. Findings 729 samples were analysed from 205 patients. At baseline, 62.9% of patients were IFN high, 30.2% IFN low and 6.8% borderline. 142 patients had multiple samples collected, and 87.3% of these demonstrated stable ISG status over time. In longitudinal follow-up, IFN high patients had higher activity in multiple organ domains and spent less time in Lupus Low Disease Activity State, but IFN score did not correlate with SLE Disease Activity Index in individual patients. In the small subset of patients who had large fluctuations in ISG across the observation period, most had high-dose glucocorticoids that correlated with ISG suppression. However, low-moderate-dose glucocorticoids did not suppress ISG expression. Conclusion Although IFN high status is associated with indicators of more severe SLE, in the majority of patients, ISGs are stable across time and do not correlate with disease activity. Changes in ISG expression may be seen with high-dose, but not routine dose, glucocorticoid exposure. These findings suggest baseline but not serial ISG measurement may be of value in the management of SLE.
Preschool children’s consistency of word production

ABSTRACT Consistency of word production contributes to carers’ ability to understand children’s speech. Reports of the proportion of words produced consistently by typically developing preschool children, however, vary widely from 17% to 87%. This paper examines the quantitative (consistency count) and qualitative (e.g. phonemic analysis) characteristics of word consistency in 96 children aged 36–60 months. Children named 15 pictures twice, in separate trials, in the same assessment session. The mean consistency of the production for the whole group was 82%. Older children were more consistent than younger children. Girls were more consistent than boys. Words produced correctly in one trial and in error in another may indicate resolving error patterns. Words produced in error in two different ways provided useful evidence about the nature of inconsistent word production in typically developing children. The clinical and theoretical implications are discussed.
Household air pollution and COPD: cause and effect or confounding by other aspects of poverty?

SETTING : Household air pollution (HAP) and chronic obstructive pulmonary disease (COPD) are both major public health problems, reported to cause around 4 million and 3 million deaths every year, respectively. The great majority of these deaths, as well as the burden of disease during life is felt by people in low- and middle-income countries (LMICs). OBJECTIVE AND DESIGN : The extent to which HAP causes COPD is controversial; we therefore undertook this review to offer a viewpoint on this from the Global Initiative for COPD (GOLD). RESULTS : We find that while COPD is well-defined in many studies on COPD and HAP, there are major limitations to the definition and measurement of HAP. It is thus difficult to disentangle HAP from other features of poverty that are themselves associated with COPD. We identify other limitations to primary research studies, including the use of cross-sectional designs that limit causal inference. CONCLUSION : There is substantial preventable morbidity and mortality associated with HAP, COPD and poverty, separately and together. Although it may not be possible to define clear causal links between HAP and COPD, there is a clear urgency to reduce the avoidable burden of disease these inflict on the world’s poor.