Miracle-dz/UniFAR-FTUs huggingface dataset:
Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis

Mosaic loss of chromosome Y (mLOY) in blood cells is one of the most frequent chromosome alterations in adult males. It is strongly associated with clonal hematopoiesis, hematopoietic malignancies, and other hematopoietic and nonhematopoietic diseases. However, whether there is a causal relationship between mLOY and human diseases is unknown. Here, we generated mLOY in murine hematopoietic stem and progenitor cells (HSPCs) with CRISPR/Cas9 genome editing. We found that mLOY led to dramatically increased DNA damage in HSPCs. Interestingly, HSPCs with mLOY displayed significantly enhanced reconstitution capacity and gave rise to clonal hematopoiesis in vivo. mLOY, which is associated with AML1-ETO translocation and p53 defects in patients with acute myeloid leukemia (AML), promoted AML in mice. Mechanistically, loss of KDM5D, a chromosome Y–specific histone 3 lysine 4 demethylase in both humans and mice, partially recapitulated mLOY in DNA damage and leukemogenesis. Thus, our study validates mLOY as a functional driver for clonal hematopoiesis and leukemogenesis.
Overcoming Lexical Bias in the Judgment of Emotion in Speech: Role of Executive Function and Usefulness Understanding in Young Children

Abstract Studies have shown that when listening to speech sounds that express different emotions through prosodic and lexical content, adults tend to judge a speaker’s emotion based on prosody, while young children tend to judge a speaker’s emotion based on lexical content. This study examined three factors that can help 3- to 5-year-old children overcome their lexical bias and use prosody to judge a speaker’s emotion. The results showed that an understanding of the usefulness of prosody to infer emotion from speech influenced young children’s tendency to focus on prosody, and that only children with well-developed executive functions could judge a speaker’s emotions by focusing on prosody—to the extent that they could read emotions from it. To achieve this, in addition to understanding, children needed to switch their attention away from lexical content and read emotions from prosody.
Software change management process in the development of embedded software

The goal of the research presented in this thesis is to examine software change management processes in order to identify essential change management problems and improvement requirements, to define processes which would aid in solving these problems, and give an example of how these processes can be implemented in practice. The subjects of the empirical research part of the study have been four Finnish companies which develop embedded software. Therefore, the focus of the study is on the processes which are used in developing embedded software. However, the literature study explores the problems of software change management from a more generic viewpoint, and can also be used as a reference for software development done for other purposes. Three of the four case studies are used in deriving the generic change management problem classes and process descriptions. These three case studies include only analysis of the change processes and problems related to them. The fourth case study is used for illustrating how the proposed problem classification can be used in change process analysis, and how the proposed process models can be instantiated in practice. The change processes were not only analysed, but the study also included the definition of new processes, the planning of their implementation, and the implementation and enactment of the new processes in the organisation.
Regulatory changes of local produced prostaglandins in corpus luteum after experimentally induced luteolysis in the cow

The objective of the study was to evaluate the expression patterns of prostaglandin F2alpha (PGF), prostaglandin E2 (PGE), PGF receptor (FP), PGE receptors (EP2 and EP4), prostaglandin‐endoperoxide synthase 2 (PTGS2) and prostaglandin synthases (PGFS and PGES) in corpora lutea (CL) during experimentally induced luteolysis in cow. The Fleckvieh cows in the mid‐luteal phase (days 8–12, control group) were injected with cloprostenol (PGF analogue), and CL were collected by transvaginal ovariectomy before (days 8–12, control group) and at 0.5, 2, 4, 12, 24, 48 and 64 h after PGF application (n = 5 per group). The mRNA expression was determined by RT‐qPCR, the hormone concentrations by enzyme immunoassay and localization by immunohistochemistry. PTGS2 gene expression increased significantly 2 h after PGF application, followed by continuous and significant downregulation afterwards. The PGF tissue concentration increased significantly just after PGF injection and again during structural luteolysis (after 12 h), whereas PGE concentration significantly decreased during structural luteolysis. The FP receptor mRNA decreased significantly at 2 h and again at 12 h after PGF. In contrast, EP4 receptor mRNA increased significantly just after the PGF application (0.5 h). The immunostaining of PGES and PTGS2 on day 15–17 shows numerous positive luteal cells, followed by lower activity afterwards on day 18 (luteolysis). In conclusion, the changes of examined prostaglandin family members in CL tissue after PGF application may be key components of the local mechanisms regulating the cascade of actions leading to functional and subsequent structural luteolysis in the bovine ovary.
Cost-Effectiveness of a Sublingual Bacterial Vaccine for the Prophylaxis of Recurrent Urinary Tract Infections

Introduction: Recurrent urinary tract infections (rUTIs) affect 5–10% of women, resulting in an enormous healthcare and society burden. Uromune® is a polybacterial sublingual vaccine with an excellent clinical benefit in rUTI prophylaxis. This study assesses the impact of sublingual vaccination on healthcare resource use and expenditures associated with this pathology. Methods: A quasi-experimental, pretest-posttest, single center study including women with rUTI and vaccinated with Uromune® in real-life clinical practice was performed. Variables were the need of healthcare resources, collected prospectively during two follow-up years, and the rUTI-associated expenditure, calculated using the micro-costing methodology; these were compared before and after vaccination. Results: A total of 166 women {mean (standard deviation [SD]) urinary tract infection episodes/year 6.19 (2.15)} were included. After vaccination, annual consultations with a primary care physician (PCP) (43.9%), emergency room visits (71.8%), urinary analysis (90.0%), and ultrasound exams (35.6%) decreased compared to pre-vaccination (all p < 0.001). Per patient consumption in antibiotics, PCP consultations, emergency room visits, and complementary exams significantly decreased (all p < 0.02), resulting in a reduction in healthcare expenditure per patient/year from mean (SD) 1,001.1 (655.0) to 497.1 (444.4) EUR. Conclusion: Sublingual bacterial vaccination with Uromune® decreased healthcare resource use and associated expenditure in women with rUTI, representing an optimal strategy to reduce rUTI-associated healthcare and economic burden.
Strategies for meiotic sex chromosome dynamics and telomeric elongation in Marsupials

During meiotic prophase I, homologous chromosomes pair, synapse and recombine in a tightly regulated process that ensures the generation of genetically variable haploid gametes. Although the mechanisms underlying meiotic cell division have been well studied in model species, our understanding of the dynamics of meiotic prophase I in non-traditional model mammals remains in its infancy. Here, we reveal key meiotic features in previously uncharacterised marsupial species (the tammar wallaby and the fat-tailed dunnart), plus the fat-tailed mouse opossum, with a focus on sex chromosome pairing strategies, recombination and meiotic telomere homeostasis. We uncovered differences between phylogroups with important functional and evolutionary implications. First, sex chromosomes, which lack a pseudo-autosomal region in marsupials, had species specific pairing and silencing strategies, with implications for sex chromosome evolution. Second, we detected two waves of γH2AX accumulation during prophase I. The first wave was accompanied by low γH2AX levels on autosomes, which correlated with the low recombination rates that distinguish marsupials from eutherian mammals. In the second wave, γH2AX was restricted to sex chromosomes in all three species, which correlated with transcription from the X in tammar wallaby. This suggests non-canonical functions of γH2AX on meiotic sex chromosomes. Finally, we uncover evidence for telomere elongation in primary spermatocytes of the fat-tailed dunnart, a unique strategy within mammals. Our results provide new insights into meiotic progression and telomere homeostasis in marsupials, highlighting the importance of capturing the diversity of meiotic strategies within mammals.
Interactomic inhibition of Eomes in the nucleus alleviates EAE via blocking the conversion of Th17 cells into non-classic Th1 cells

Abstract Th17 cells are implicated in the pathogenesis of several autoimmune diseases. During the inflammation, Th17 cells exposed to IL-12 can shift towards the Th1 phenotype. These shifted cells are defined as ‘non-classic Th1 cells’. Th17-derived non-classic Th1 cells play a critical role in late-onset chronic inflammatory diseases and are more pathogenic than the unshifted Th17 cells. Eomes is a transcription factor highly expressed in non-classic Th1 cells. To study the functional role of Eomes without genetic alteration, novel recombinant protein, ntEomes-TMD, was generated by fusing TMD of Eomes and Hph-1-PTD that facilitate intracellular delivery of its cargo molecule. ntEomes-TMD was delivered into the nucleus of the cells without influencing the T cell activation and cytotoxicity. ntEomes-TMD specifically inhibited the Eomes- and ROR-γt-mediated transcription and suppressed the Th1 and Th17 differentiation. Interestingly, ntEomes-TMD blocked the generation of non-classic Th1 cells from Th17 cells, leading to the inhibition of IFN-γ and GM-CSF secretion. In EAE, ntEomes-TMD alleviated the symptoms of EAE, and the combination treatment using ntEomes-TMD and anti-IL-17 mAb together showed better therapeutic efficacy than anti-IL-17 mAb treatment. The results suggest that ntEomes-TMD can be a new therapeutic reagent for treating chronic inflammatory diseases associated with non-classic Th1 cells.
Effects of Blood Flow Restriction Training on Clinical Outcomes for Patients With ACL Reconstruction: A Systematic Review

Context: Knee muscle atrophy and weakness are common impairments after anterior cruciate ligament (ACL) reconstruction. Blood flow restriction (BFR) training represents a new approach to treat such impairments. However, limited evidence currently exists to support this intervention in related patients. Objective: To appraise literature comparing the effects of BFR training with conventional therapy on knee muscle morphological and strength properties in ACL-reconstructed patients. Data Sources: PubMed, SPORTDiscus, CINAHL, and Cochrane Central Register databases were searched for relevant articles from January 1991 through April 2021. Study Selection: Articles were minimum Level 3 evidence focusing on knee muscle morphologic as well as extensor and flexor strength outcomes in ACL-reconstructed patients of all graft types. Study Design: Systematic review. Level of Evidence: Level 2. Data Extraction: Critical appraisal instruments (Downs and Black checklist, Cochrane Collaboration tool, ROBINS-1 tool) were used to evaluate study quality. We independently calculated effect sizes (ESs) (Cohen d) between groups in each study. The Strength of Recommendation Taxonomy grading scale was used for clinical recommendations. Results: Six articles (4 randomized control studies, 1 nonrandomized study, and 1 case-control study) met inclusion criteria. Exercises paired with BFR training included open kinetic chain, closed kinetic chain, and passive applications. Diverse assessments and time of intervention were observed across studies. ESs ranged from trivial to large in favor of BFR training for muscle morphological (d = 0.06 to 0.81) and strength assessments (d = −0.12 to 1.24) with CIs spanning zero. Conclusion: At this time, grade B or inconsistent and limited-quality patient-oriented evidence exists to support using BFR training to improve or maintain thigh muscle size as well as knee extensor and flexor strength in ACL-reconstructed patients. ESs indicated no consistent clinically meaningful differences when compared with conventional therapy. Subsequent analyses should be repeated as new evidence emerges to update practice guidelines.
Unimanual sensorimotor learning—A simultaneous EEG‐fMRI aging study

Sensorimotor coordination requires orchestrated network activity in the brain, mediated by inter‐ and intra‐hemispheric interactions that may be affected by aging‐related changes. We adopted a theoretical model, according to which intra‐hemispheric inhibition from premotor to primary motor cortex is mandatory to compensate for inter‐hemispheric excitation through the corpus callosum. To test this as a function of age we acquired electroencephalography (EEG) simultaneously with functional magnetic resonance imaging (fMRI) in two groups of healthy adults (younger N = 13: 20–25 year and older N = 14: 59–70 year) while learning a unimanual motor task. On average, quality of performance of older participants stayed significantly below that of the younger ones. Accompanying decreases in motor‐event‐related EEG β‐activity were lateralized toward contralateral motor regions, albeit more so in younger participants. In this younger group, the mean β‐power during motor task execution was significantly higher in bilateral premotor areas compared to the older adults. In both groups, fMRI blood oxygen level dependent (BOLD) signals were positively correlated with source‐reconstructed β‐amplitudes: positive in primary motor and negative in premotor cortex. This suggests that β‐amplitude modulation is associated with primary motor cortex “activation” (positive BOLD response) and premotor “deactivation” (negative BOLD response). Although the latter results did not discriminate between age groups, they underscore that enhanced modulation in primary motor cortex may be explained by a β‐associated excitatory crosstalk between hemispheres.
Cut-off values and sub-items of the Berg Balance Scale for walking-aid use in hospitalized older adults with a hip fracture: a retrospective analysis

ABSTRACT Objective To identify the Berg Balance Scale (BBS) values that can be used to discriminate the use of a walking aid and the BBS sub-items that reveal the differences in the use of walking aids among hospitalized older adults with a hip fracture Methods The cases of 77 older adults (age 80.8 ± 7.5 years) with a hip fracture who were able to walk independently in the hospital were retrospectively analyzed. A receiver operating characteristic curve (AUC) analysis was used to identify BBS scores that optimized the identification of subjects with different levels of aids. The BBS sub-items identifying differing among the walking aids were identified by a classification and regression tree analysis Results The BBS scores were highest for no aid, a cane, and a walker, in that order. The ability to walk without an aid and the ability to walk without a walker showed moderate AUCs (0.824 and 0.865) with cutoff values of 51.5 and 45.5 points, respectively. The sub-items identified were Turning 360° (4 vs. < 4 points) as the best discriminator for using/not using a cane and Stool Stepping (≥ 2 vs. < 2 points) for using a cane or walker Conclusion The BBS is useful for determining whether to discontinue the use of a walker in individuals with a hip fracture.
Blood Pressure Monitoring as a Digital Health Tool for Improving Diabetes Clinical Outcomes: Retrospective Real-world Study

Background Remote data capture for blood glucose (BG) or blood pressure (BP) monitoring and the use of a supportive digital app are becoming the model in diabetes and hypertension chronic care. One of the goals in chronic condition management is to increase awareness and generate behavioral change in order to improve outcomes in diabetes and related comorbidities, such as hypertension. In addition, there is a lack of understanding of the association between BG and BP levels when using digital health tools. Objective By applying a rigorous study framework to digital health data, this study investigated the relationship between BP monitoring and BG and BP levels, as well as a lagged association between BP and BG. We hypothesized that during the first 6 months of BP monitoring, BG and BP levels would decrease. Finally, we suggested a positive association between BP levels and the following month’s BG levels. Methods In this retrospective, real-world case-control study, we extracted the data of 269 people with type 2 diabetes (T2D) who tracked their BG levels using the Dario digital platform for a chronic condition. We analyzed the digital data of the users who, in addition to BG, monitored their BP using the same app (BP-monitoring [BPM] group, n=137) 6 months before and after starting their BP monitoring. Propensity score matching established a control group, no blood pressure monitoring (NBPM, n=132), matched on demographic and baseline clinical measures to the BPM group. A piecewise mixed model was used for analyzing the time trajectories of BG, BP, and their lagged association. Results Analysis revealed a significant difference in BG time trajectories associated with BP monitoring in BPM and NBPM groups (t=–2.12, P=.03). The BPM group demonstrated BG reduction improvement in the monthly average BG levels during the first 6 months (t=–3.57, P<.001), while BG did not change for the NBPM group (t=0.39, P=.70). Both groups showed similarly stable BG time trajectories (B=0.98, t=1.16, P=.25) before starting the use of the BP-monitoring system. In addition, the BPM group showed a significant reduction in systolic (t=–6.42, P<.001) and diastolic (t=–4.80, P<.001) BP during the first 6 months of BP monitoring. Finally, BG levels were positively associated with systolic (B=0.24, t=2.77, P=.001) and diastolic (B=0.30, t=2.41, P=.02) BP. Conclusions The results of this study shed light on the association between BG and BP levels and on the role of BP self-monitoring in diabetes management. Our findings also underscore the need and provide a basis for a comprehensive approach to understanding the mechanism of BP regulation associated with BG.
Routine Catheter Lock Solutions in Pediatric Cancer Care

Background Central venous access devices (CVADs) are integral to cancer care provision. Despite the high prevalence of CVAD complications in children with cancer, preventative strategies are understudied. Objective The aim of this study was to assess study feasibility, occlusive events, thrombolytic use, adverse events, and direct costs of catheter lock solutions. Methods A single-center, parallel-group, pilot randomized controlled trial was undertaken at a tertiary-referral pediatric hospital in Australia. Children 18 years or younger with an oncological or malignant hematological condition and a CVAD were eligible. Participants were 1:1 randomized to (1) normal or (2) heparinized (10–100 U/mL; CVAD-type dependent) saline lock solutions. Results Of 217 children assessed for eligibility, 61 were recruited and randomized to normal (n = 30; 3850 CVAD days) or heparinized (n = 31; 4036 CVAD days) saline. Eligibility (52%) and recruitment (54%) feasibility targets were not met. Protocol adherence was high (95% assessments), with no attrition. Parent/clinician satisfaction of interventions was high (median, 10/10 clinicians/parents). Complete CVAD occlusion occurred in heparin only (n = 2, 6.7% CVADs; incidence rate [IR], 0.49/1000 CVAD days [0.06–1.78]). Central venous access device partial occlusion was detected in 23.3% of CVADs in heparin (n = 7; IR, 2.73/1000 CVAD days [1.36–4.87]) and 13.8% of CVADs in normal saline (n = 4; IR, 2.59/1000 CVAD days [1.24–4.77]). Thrombolytic agents were used in 16.7% heparin (5 CVADs) and 3.5% normal saline (1 CVAD). Adverse events did not differ between groups. Conclusion Multisite randomized controlled trials examining CVAD locks are safe, but strategies and resources to increase recruitment and eligibility are required. Implications for Practice Both routine CVAD lock solutions seem safe but may not prevent all forms of CVAD-associated harm.
Chlorogenic acid improves diabetic retinopathy by alleviating blood‐retinal‐barrier dysfunction via inducing Nrf2 activation

As one of the major diabetic microvascular complications, diabetic retinopathy (DR) is mainly initiated by the blood‐retinal barrier (BRB) dysfunction. Chlorogenic acid (CGA) is a natural polyphenolic compound in Lonicerae Japonicae Flos, which traditionally has the beneficial function for eyes and is commonly included in many anti‐diabetic formulas. In this study, the potential protective mechanism of CGA against DR was investigated. Streptozotocin (STZ) was used to induce diabetes in mice. CGA attenuated BRB dysfunction and reversed endothelial‐mesenchymal transition (EndoMT) and epithelial‐mesenchymal transition (EMT) in retinas in vivo. CGA inhibited microglia activation and reduced tumor necrosis factor (TNF)α release both in vivo and in vitro. CGA promoted nuclear factor erythroid 2‐related factor 2 (Nrf2) activation and prevented EndoMT/EMT in TNFα‐treated human retinal endothelial cells (HRECs) or retinal pigment epithelial APRE19 cells. CGA alleviated endothelial/epithelial barrier oxidative injury in HRECs or APRE19 cells stimulated with TNFα, but this effect was disappeared in cells co‐incubated with Nrf2 inhibitor. Additionally, the CGA‐supplied alleviation on BRB damage and EndoMT/EMT was markedly weakened in retinas from STZ‐treated Nrf2 knock‐out mice. All results suggest that CGA improves DR through attenuating BRB injury by reducing microglia‐initiated inflammation and preventing TNFα‐induced EndoMT/EMT and oxidative injury via inducing Nrf2 activation.
First report of collagenase production by Trichosporon sp. strain isolated from pollen of Amazonian bee (Melipona seminigra seminigra)

Abstract Trichosporon yeasts are widely employed to produce lipids, lipases, and aspartic peptidases, but there are no previous studies on collagenase production. This work aimed to select the best collagenase producing Amazonian Trichosporon strains. Moreover, a 23-full factorial design (FFD) and a 22-central composite design combined with Response Surface Methodology were applied to optimize production and find the best conditions for hydrolysis of type I bovine collagen. Most of the studied strains had some collagenolytic activity, but the selected one achieved the highest value (44.02 U) and a biomass concentration of 2.31 g/L. The best collagenase production conditions were 160 rpm of agitation, pH 5.5 and a substrate concentration of 4.0 g/L. The former experimental design showed that substrate concentration was the only statistically significant factor on both biomass concentration and collagenase activity, while the latter showed simultaneous effects of substrate concentration and pH on collagenolytic activity, which peaked at pH 5.5–6.4 and substrate concentration of 3.0–3.4 g/L. An additional 2³-FFD was finally used to optimize the conditions collagen hydrolysis, and pH 6, 25 °C and a substrate concentration of 7.5 (g/L) ensured the highest hydrolysis degree. This study is the first that describes optimized conditions of collagenase production by Trichosporon strains.