A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression.

The diverse roles of the dynein motor in shaping microtubule networks and cargo transport complicate in vivo analysis of its functions significantly. To address this issue, we have generated a series of missense mutations in Drosophila Dynein heavy chain. We show that mutations associated with human neurological disease cause a range of defects, including impaired cargo trafficking in neurons. We also describe a novel microtubule-binding domain mutation that specifically blocks the metaphase-anaphase transition during mitosis in the embryo. This effect is independent from dynein's canonical role in silencing the spindle assembly checkpoint. Optical trapping of purified dynein complexes reveals that this mutation only compromises motor performance under load, a finding rationalized by the results of all-atom molecular dynamics simulations. We propose that dynein has a novel function in anaphase progression that depends on it operating in a specific load regime. More broadly, our work illustrates how in vivo functions of motors can be dissected by manipulating their mechanical properties.

Case study: Evaluating deep-water start techniques and training demands in seated slalom waterskiing for an athlete with paraplegia.

Purpose: Recreational and competitive slalom waterskiing is increasingly popular among individuals with spinal cord injuries (SCI), particularly for those with paraplegia using sit-skis. A key component of slalom skiing is the deep-water start (DWS), yet little is known about the physiological and physical demands of this activity when the athlete is seated. This study aims to fill this gap by focusing on the training requirements for a seated slalom athlete. Materials and methods: Focusing on a young male athlete with paraplegia, this case study evaluates the effectiveness and efficiency of traditional (TDWS) and alternative (ADWS) DWS techniques during seated slalom waterskiing sessions. It assesses internal training load (TL) through heart rate (HR) zones and session rating of perceived exertion (sRPE), alongside pre- and post-session handgrip strength measurements to gauge peripheral muscle fatigue. Results and conclusions: Performing the ADWS, achieving a full success rate, proved more effective but slightly more time-consuming than TDWS, which had limited success. HR during DWS maneuvers ranged from 63.2 to 81.3% of maximal HR, with most sessions occurring below the ventilatory threshold, thus perceived as hard effort. A moderate yet non-significant correlation was found between HR and sRPE-based TL. A significant reduction in handgrip strength post-session underscores the activity's demands. These insights illuminate the technical, physiological, and physical challenges in mastering DWS for seated slalom athletes with SCI, providing valuable guidance for the development of tailored training programs and techniques in this sport.

Automatic semantic segmentation of EHG recordings by deep learning: An approach to a screening tool for use in clinical practice.

BACKGROUND AND OBJECTIVE: Preterm delivery is an important factor in the disease burden of the newborn and infants worldwide. Electrohysterography (EHG) has become a promising technique for predicting this condition, thanks to its high degree of sensitivity. Despite the technological progress made in predicting preterm labor, its use in clinical practice is still limited, one of the main barriers being the lack of tools for automatic signal processing without expert supervision, i.e. automatic screening of motion and respiratory artifacts in EHG records. Our main objective was thus to design and validate an automatic system of segmenting and screening the physiological segments of uterine origin in EHG records for robust characterization of uterine myoelectric activity, predicting preterm labor and help to promote the transferability of the EHG technique to clinical practice. METHODS: For this, we combined 300 EHG recordings from the TPEHG DS database and 69 EHG recordings from our own database (Ci2B-La Fe) of women with singleton gestations. This dataset was used to train and evaluate U-Net, U-Net++, and U-Net 3+ for semantic segmentation of the physiological and artifacted segments of EHG signals. The model's predictions were then fine-tuned by post-processing. RESULTS: U-Net 3+ outperformed the other models, achieving an area under the ROC curve of 91.4 % and an average precision of 96.4 % in detecting physiological activity. Thresholds from 0.6 to 0.8 achieved precision from 93.7 % to 97.4 % and specificity from 81.7 % to 94.5 %, detecting high-quality physiological segments while maintaining a trade-off between recall and specificity. Post-processing improved the model's adaptability by fine-tuning both the physiological and corrupted segments, ensuring accurate artifact detection while maintaining physiological segment integrity in EHG signals. CONCLUSIONS: As automatic segmentation proved to be as effective as double-blind manual segmentation in predicting preterm labor, this automatic segmentation tool fills a crucial gap in the existing preterm delivery prediction system workflow by eliminating the need for double-blind segmentation by experts and facilitates the practical clinical use of EHG. This work potentially contributes to the early detection of authentic preterm labor women and will allow clinicians to design individual patient strategies for maternal health surveillance systems and predict adverse pregnancy outcomes.

Assessment of corrected JT-peak (JTpc) and Tpeak-to-Tend (TpTec) as proarrhythmia biomarkers in non-human primates: Outcome from a HESI consortium.

INTRODUCTION: Corrected QT interval (QTc)is an established biomarker for drug-induced Torsade de Pointe (TdP), but with concerns for a false positive signal. Clinically, JTpc and TpTec have emerged as ECG sub-intervals to differentiate predominant hERG vs. mixed ion channel blocking drugs that prolong QTc. METHODS: In a multicentric, prospective, controlled study, different proarrhythmic drug effects on QTc, JTpc and TpTec were characterized with cynomolgus monkeys using telemetry in a Lead II configuration for internal and external telemetry.Drugs and vehicle were administered orally (PO) to group size of 4 to 8 animals, in 4 laboratories. RESULTS: In monkeys, dofetilide (0.03-0.3 mg/kg) was associated with exposure dependent QTc and JTpc increase, but no significant TpTec effect. Similarly, quinidine (2-50 mg/kg) increased QTc and JTpc but did not change TpTec. Mexiletine (1-15 mg/kg) and verapamil (50 mg/kg) did not induce any significant effect on QTc, JTpc or TpTec. DISCUSSION: Clinically, predominant hERG blockers (dofetilide and quinidine) prolong QTc, JTpc and TpTec and are associated with increased risk for TdP. Results from this study demonstrate that ECG changes after dofetilide and quinidine administration to telemetered monkeys differ from the clinical response, lacking the expected effects on TpTec. Potential explanations for the lack of translation include physio-pharmacology species differences or ECG recording and analysis methodology variations. Mixed ion channel blockers verapamil and mexiletine administered to monkeys showed no significant QTc, JTpc or TpTec prolongation as expected based on the similar clinical response for these agents.

TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents.

Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist Giardia lamblia, which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Giardia lamblia. Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.

Exploring research on competitive Para-cyclists and its related factors: A scoping review.

ABSTRACT: This scoping review aimed to explore the characteristics and performance factors of competitive Para-cyclists. A systematic search for studies on competitive Para-cycling on WOS, PubMed, SPORTDiscus and Scopus was performed until December 2023. Five methodological phases were followed: (i) identifying the research question, (ii) identifying relevant studies, (iii) study selection, (iv) charting the data, and (v) collating, summarizing, and reporting the results. A systematic search across multiple databases was performed until March 2024. Five methodological phases were employed: identifying the research question, relevant studies, study selection, charting data, and summarizing results. A total of 36 relevant studies were selected. Three main research themes emerged: Sport performance (n = 15), Biomechanics (n = 12), and Physical and mental health (n = 9). Despite progress, gaps were identified, particularly in physiological response to exercise, fitness, and training. Biomechanics studies focused on prosthetic use and aerodynamics, mostly involving lower-limb amputees and simulated tandem competition. Injury risk in Para-cycling appeared comparable to able-bodied cycling, but comprehensive studies considering confounding variables are needed. Overall, while research on Para-cycling is growing, more studies with larger and diverse samples across all sport classes are essential to advance scientific understanding in this field.

Collaborative science in action: A 20 year perspective from the Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee.

The Health and Environmental Sciences Institute (HESI) is a nonprofit organization dedicated to resolving global health challenges through collaborative scientific efforts across academia, regulatory authorities and the private sector. Collaborative science across non-clinical disciplines offers an important keystone to accelerate the development of safer and more effective medicines. HESI works to address complex challenges by leveraging diverse subject-matter expertise across sectors offering access to resources, data and shared knowledge. In 2008, the HESI Cardiac Safety Committee (CSC) was established to improve public health by reducing unanticipated cardiovascular (CV)-related adverse effects from pharmaceuticals or chemicals. The committee continues to significantly impact the field of CV safety by bringing together experts from across sectors to address challenges of detecting and predicting adverse cardiac outcomes. Committee members have collaborated on the organization, management and publication of prospective studies, retrospective analyses, workshops, and symposia resulting in 38 peer reviewed manuscripts. Without this collaboration these manuscripts would not have been published. Through their work, the CSC is actively addressing challenges and opportunities in detecting potential cardiac failure modes using in vivo, in vitro and in silico models, with the aim of facilitating drug development and improving study design. By examining past successes and future prospects of the CSC, this manuscript sheds light on how the consortium's multifaceted approach not only addresses current challenges in detecting potential cardiac failure modes but also paves the way for enhanced drug development and study design methodologies. Further, exploring future opportunities and challenges will focus on improving the translational predictability of nonclinical evaluations and reducing reliance on animal research in CV safety assessments.

Anatomical outcomes and complications of sacrocolpopexy using Surelift Uplift mesh: A multicentric observational study.

OBJECTIVE: The study evaluated the anatomical and functional outcomes, as well as the safety data of laparoscopic sacrocolpopexy (LSC) for pelvic organ prolapse (POP) using a lightweight macroporous mesh. METHODS: A multicentric observational study was developed including five expert centers between March 2011 and December 2019. Inclusion criteria were female patients with symptomatic ≥stage II POP (POP-Q classification), who underwent a LSC. A lightweight and macroporous mesh device (Surelift Uplift) was used. Baseline anatomical positions were evaluated using POP-Q stage. The anatomical outcomes and procedural complications were assessed during the postoperative period. Primary outcomes were anatomical success, defined as POP-Q stage ≤I, and subjective success, defined as no bothersome bulge symptoms, and no repeat surgery or pessary use for recurrent prolapse. RESULTS: A total of 325 LSCs were analyzed with a median patient age of 66 (interquartile range [IQR] 61-73). After a median follow-up of 68 months (IQR 46.5-89), anatomical success was found in 88.9%, whereas subjective success was seen in 98.5% of the patients. Recurrent prolapse presented as cystocele (1.5%). Reported complications were bladder (4.6%) or rectum lesions (0.6%), de novo urinary incontinence (12.9%), and mesh extrusion (1.2%). CONCLUSIONS: LSC provides significant clinical improvement and excellent anatomical results, with a low risk of serious complications for women with ≥2 grade POP in a real clinical practice setting.

Cost-effectiveness of active tuberculosis screening among high-risk populations in low tuberculosis incidence countries: a systematic review, 2008 to 2023.

BackgroundIn countries with a low TB incidence (≤ 10 cases/100,000 population), active pulmonary tuberculosis (PTB) mostly affects vulnerable populations with limited access to healthcare. Thus, passive case-finding systems may not be successful in detecting and treating cases and preventing further transmission. Active and cost-effective search strategies can overcome this problem.AimWe aimed to review the evidence on the cost-effectiveness (C-E) of active PTB screening programmes among high-risk populations in low TB incidence countries.MethodsWe performed a systematic literature search covering 2008-2023 on PubMed, Embase, Center for Reviews and Dissemination, including Database of Abstracts of Reviews of Effects (DARE), National Health Services Economic Evaluation Database (NHS EED), Global Index Medicus and Cochrane Central Register of Controlled Trials (CENTRAL).ResultsWe retrieved 6,318 articles and included nine in this review. All included studies had an active case-finding approach and used chest X-ray, tuberculin skin test, interferon-gamma release assay and a symptoms questionnaire for screening. The results indicate that screening immigrants from countries with a TB incidence > 40 cases per 100,000 population and other vulnerable populations as individuals from isolated communities, people experiencing homelessness, those accessing drug treatment services and contacts, is cost-effective in low-incidence countries.ConclusionIn low-incidence countries, targeting high-risk groups is C-E. However, due to the data heterogenicity, we were unable to compare C-E. Harmonisation of the methods for C-E analysis is needed and would facilitate comparisons. To outline comprehensive screening and its subsequent C-E analysis, researchers should consider multiple factors influencing screening methods and outcomes.

Ecoepidemiology of Chagas Disease in a Biological Corridor in Southeastern Mexico: A Promising Approach to Understand the Risk of Chagas Disease.

Ecoepidemiology is an emerging field that attempts to explain how biotic, environmental, and even social factors influence the dynamics of infectious diseases. Particularly in vector-borne diseases, the study under this approach offers us an overview of the pathogens, vectors, and hosts that coexist in a given region and their ecological determinants. As a result of this, risk predictions can be established in a changing environment and how it may impact human populations. This paper is aimed at evaluating some ecoepidemiological characteristics of Chagas disease in a natural reserve in southeastern Mexico that borders human settlements. We carry out a cross-sectional study in 2022 where we search insects manually and with light traps. We set traps for small mammals and bats and conducted interviews with the inhabitants living around the study site. We identified the presence of Triatoma dimidiata and T. huehuetenanguensis species with a percentage of TcI T. cruzi infection of 68.4% (95% CI: 66.9-69.9). Temperature and humidity were not determining factors for the probability of insect capture. Of the 108 wild mammals (Chiroptera, Rodentia, and Didelphimorphia), none was infected with T. cruzi. Knowledge about Chagas disease in nearby inhabitants is poor, and some characteristics were found on the periphery of dwellings that could offer a refuge for insect vectors. With this information, surveillance strategies can be generated in the study area that reduce the risk of transmission of T. cruzi parasite to humans, and it is expected to motivate the use of this field in future research.

First report of mixed Trypanosoma cruzi discrete typing units infection in Triatoma phyllosoma in the peri-urban environment of Oaxaca, Mexico.

BACKGROUND: Chagas disease, a zoonosis transmitted mainly by hematophagous insects of the subfamily Triatominae, is caused by Trypanosoma cruzi, classified into six discrete typing units (DTUs: TcI-TcVI and Tcbat). METHODS: Insect vectors were collected from 84 human dwellings in the municipality of Santo Domingo Tehuantepec, Oaxaca, Mexico; 4.76% were infested. DTUs were determined using conventional and nested PCR. RESULTS: The infection rate was 43.6%. All insects were infected with TcI while one specimen showed mixed infection with TcII. CONCLUSIONS: This is the first report of T. cruzi mixed infection in Triatoma phyllosoma, its main vector in the study region.

Oocyte competence and gene expression in parthenogenetic produced embryos from repeat breeder and normally fertile buffaloes (Bubalus bubalis) raised in sub-humid tropical climate.

The reproductive management of the buffalo species still faces several unresolved problems, which directly affect the productivity of the herd, one of them being the presence of repeat breeder females. Given this scenario, this study aimed to verify the developmental competence of oocytes obtained from repeat breeder females and submitted to parthenogenetic activation. In addition, embryo gene expression was compared to normally fertile females. Murrah buffaloes were divided into two groups: repeat breeder (RB, n = 8) and normally fertile or control (CR, n = 7). Cumulus-oocyte complexes (COCs) were aspirated by transvaginal ovum pick-up from estrus synchronized females. The COCs were submitted to IVM for 24 h, and subsequently, the oocytes were activated using ionomycin, followed by 6-DMAP. Afterwards, the presumptive parthenotes were cultured for six or seven days in a microenvironment of 5 % CO2, 5 % O2, and 90 % N2 at 38.5 °C. The expression of OCT4, GLUT1, BCL2 and TFAM genes from blastocysts was evaluated. The overall COCs recovery rate was 70.9 % (190/268). The maturation (57.8 vs 71.1), cleavage (45.2 vs 62.2) and blastocyst (30.1 vs 45.9) rates did not differ (P > 0.05) between RB and CR females, respectively. Similarly, no significant difference (P > 0.05) was observed for the expression of studied genes in both RB and CR females. In conclusion, oocytes obtained from RB were as developmentally competent as those collected from CR females, with similar energy metabolism and in vitro development capacity. Thus, the low fertility rate of repeat breeder buffaloes, when compared to normal cyclic females, must be due to subsequent events to the blastocyst stage.

Comparative Effects of Two High-Intensity Intermittent Training Programs on Sub-Elite Male Basketball Referees' Fitness Levels.

This study aimed to compare the effects of an 8-week short-term training program, comprising repeated sprints or running-based high-intensity intermittent training (HIIT), on the aerobic fitness and repeated sprint ability (RSA) performance of sub-elite basketball referees. Twenty male referees participated in supervised training sessions twice a week. They were randomly assigned to either the RSA-based group (RSAG) or the running-based HIIT group (HIITG). The RSAG conducted 3-4 sets of 8 × 20-m all-out sprints, while the HIITG performed 2-3 sets of 6 × 20-s runs at 90% of their maximal velocity achieved in the 30-15 intermittent fitness test (30-15IFT). Referees underwent a graded exercise test on a treadmill, the 30-15IFT, and an RSA test before and after the training program. Both groups showed significant improvement (~3%) in the fastest (22.6 ± 1.4 vs. 23.4 ± 1.7 and 22.0 ±1.9 vs. 22.4 ± 1.7 km·h-1 in RSAG and HIITG, respectively) and mean (21.5 ± 1.2 vs. 22.4 ± 1.4 and 21.3 ± 1.8 vs. 21.7 ± 1.6 km·h-1 in RSAG and HIITG, respectively) sprint velocity of the RSA test (p < 0.05). Moreover, positive changes (p < 0.05) were observed in the 30-15IFT maximal velocity (18.6 ± 1.1 vs. 19.3 ± 1.0 and 19.4 ± 0.9 vs. 20.5 ± 0.9 km·h-1 in RSAG and HIITG, respectively). In conclusion, an 8-week training intervention using either RSA or running-based HIIT led to similar improvements in referees' RSA performance and specific aerobic fitness measures. These findings could assist in devising tailored training programs for basketball referees.

Revised New World bioregions and environmental correlates for vectors of Chagas disease (Hemiptera, Triatominae).

The subfamily Triatominae includes a group of hematophagous insects, vectors of the parasite Trypanosoma cruzi, which is the etiological agent of Chagas disease, also known as American trypanosomiasis. Triatomines occur in the Old and New World and occupy diverse habitats including tropical and temperate areas. Some studies suggest the distributions of triatomines group into three or four regions. This study objectively determined bioregions focused specifically on New World Triatominae, using clustering and ordination analysis. We also identified indicator species by bioregion and investigated relationships among bioregions and environmental variables using redundancy analysis and multivariate regression trees. We delineated seven bioregions specific to Triatominae and linked each with indicator species. This result suggests more biogeographical structure exists than was revealed in earlier studies that were more general, subjective, and based on older taxonomic and distributional information. Precipitation, elevation, and vegetation were important variables in the delimitating bioregions. This implies that more detailed study of how these factors influence triatomine distributions could benefit understanding of how Chagas disease is spread.

First report of mixed Trypanosoma cruzi discrete typing units infection in Triatoma phyllosoma in the peri-urban environment of Oaxaca, Mexico

ABSTRACT Background: Chagas disease, a zoonosis transmitted mainly by hematophagous insects of the subfamily Triatominae, is caused by Trypanosoma cruzi, classified into six discrete typing units (DTUs: TcI-TcVI and Tcbat). Methods: Insect vectors were collected from 84 human dwellings in the municipality of Santo Domingo Tehuantepec, Oaxaca, Mexico; 4.76% were infested. DTUs were determined using conventional and nested PCR. Results: The infection rate was 43.6%. All insects were infected with TcI while one specimen showed mixed infection with TcII. Conclusions: This is the first report of T. cruzi mixed infection in Triatoma phyllosoma, its main vector in the study region.

Identification of Discrete Typing Units of Trypanosoma cruzi Isolated from Domestic Environments in Southeastern Mexico.

Background: The Trypanosoma cruzi parasite is the causal agent of Chagas disease, recognized by the World Health Organization as a neglected tropical disease. Currently there are seven discrete typing units (DTUs) of T. cruzi distributed in America, but there are still gaps about its distribution in some endemic regions. Materials and Methods: Seventeen units isolated from Chiapas and Oaxaca in Mexico were identified by amplification of the C-5 sterol desaturase gene. Results: Three DTUs of T. cruzi, TcI (6), TcII (10), and TcIV (1) were detected by comparing polymorphic sites in specific regions. Conclusions: New DTUs are reported for both states, where TcII was the most common DTU. The genetic characterization of the isolates can help to understand the epidemiology of Chagas disease.

In vitro embryo production in small ruminants: what is still missing?

In vitro embryo production (IVEP) is an extremely important tool for genetic improvement in livestock and it is the biotechnology that has grown the most recently. However, multiple ovulation followed by embryo transfer is still considered the leading biotechnology for embryo production in small ruminants. This review aimed to identify what is still missing for more efficient diffusion of IVEP in small ruminants, going through the IVEP steps and highlighting the main factors affecting the outcomes. Oocyte quality is essential for the success of IVEP and an aspect to be considered in small ruminants is their reproductive seasonality and strategies to mitigate the effect of season. The logistics for oocyte collection from live females is more complex than in cattle, and tools to simplify this collection system and/or to promote an alternative way of recovering oocytes may be an important point in this scenario. The heterogeneity of oocytes collected from growing follicles in live females or from ovaries collected from abattoirs remains a challenge, and there is a demand to standardize/homogenize the hormonal stimulatory protocols and IVM protocols for each source of oocytes. The use of sexed semen is technically possible, however the low market demand associated with the high costs of the sexing process prevents the routine use of this technique, but its higher availability is an important aspect aiming for greater dissemination of IVEP. New noninvasive approaches for embryo selection are key factors since the selection for transfer or cryopreservation is another difficulty faced among laboratories. Embryo selection is based on morphological traits, although these are not necessarily reliable in predicting pregnancy. Several issues described in this review must be considered by researchers in other to promote the diffusion of IVEP in small ruminants.