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1.
Nat Commun ; 15(1): 6712, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39112489

ABSTRACT

Development of a vaccine against gonorrhoea is a global priority, driven by the rise in antibiotic resistance. Although Neisseria gonorrhoeae (Ng) infection does not induce substantial protective immunity, highly exposed individuals may develop immunity against re-infection with the same strain. Retrospective epidemiological studies have shown that vaccines containing Neisseria meningitidis (Nm) outer membrane vesicles (OMVs) provide a degree of cross-protection against Ng infection. We conducted a clinical trial (NCT04297436) of 4CMenB (Bexsero, GSK), a licensed Nm vaccine containing OMVs and recombinant antigens, comprising a single arm, open label study of two doses with 50 adults in coastal Kenya who have high exposure to Ng. Data from a Ng antigen microarray established that serum IgG and IgA reactivities against the gonococcal homologs of the recombinant antigens in the vaccine peaked at 10 but had declined by 24 weeks. For most reactive OMV-derived antigens, the reverse was the case. A cohort of similar individuals with laboratory-confirmed gonococcal infection were compared before, during, and after infection: their reactivities were weaker and differed from the vaccinated cohort. We conclude that the cross-protection of the 4CMenB vaccine against gonorrhoea could be explained by cross-reaction against a diverse selection of antigens derived from the OMV component.


Subject(s)
Antibodies, Bacterial , Gonorrhea , Immunoglobulin A , Immunoglobulin G , Neisseria gonorrhoeae , Vaccination , Humans , Gonorrhea/immunology , Gonorrhea/prevention & control , Neisseria gonorrhoeae/immunology , Adult , Immunoglobulin A/immunology , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin G/immunology , Male , Female , Antibodies, Bacterial/immunology , Antibodies, Bacterial/blood , Kenya/epidemiology , Meningococcal Vaccines/immunology , Meningococcal Vaccines/administration & dosage , Young Adult , Antigens, Bacterial/immunology , Neisseria meningitidis/immunology , Antibody Formation/immunology , Cross Protection/immunology , Middle Aged
2.
Article in English | MEDLINE | ID: mdl-39112763

ABSTRACT

PURPOSE: The role of transobturator-cable-fixation (TOCF) in traumatic symphyseal rupture of the pelvic ring remains unclear. This case series aims to evaluate TOCF in complex and revision cases in pelvic surgery. METHODS: A retrospective analysis of a chronological case series was conducted, studying pelvic fractures stabilized using TOCF between January 2006 and December 2022. The variables considered included age, gender, fracture classification, Injury Severity Score (ISS), Body Mass Index (BMI), trauma mechanism, time to surgery, fixation technique, hospital duration, complications, status on discharge (Glasgow Outcome Scale; GOS), follow-up time and indication for the use of TOCF. RESULTS: All patients (N = 7) were male with a mean age of 64 years and a mean BMI of 29. The mean ISS was 45, with the lowest ISS of 25, indicating that only polytraumatized patients were included. Two anterior-posterior-compression-, four lateral-compression-, and one vertical-shear-pelvic-injury were identified. TOCF was added in six cases to support symphyseal plating and in one case to external fixation. The mean hospital stay was 49 days and the mean follow-up duration was 8.5 months. No complications associated with TOCF were observed during the surgical procedure or follow-up. CONCLUSION: TOCF showed no procedure-associated complications and effectively supported symphyseal healing in all cases. The main indications were obesity, poor bone quality in elderly patients, and revision cases. TOCF could be considered as a last treatment option in open-book pelvic injuries where plating or external fixation is at risk to fail.

3.
HardwareX ; 19: e00548, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39092421

ABSTRACT

In optical experiments, shutters are devices that open or close a path of light. They are often used to limit the duration of light exposure onto a target or onto a detector to reduce possible light-induced damage. Many commercial shutters are available for different applications - some provide very fast opening and closing times, some can handle large optical powers, and others allow for fail-safe operation. Many of these devices are costly and offer limited control options. Here we provide an open-source design for a low-cost, general purpose shutter system based on ubiquitous actuators (servo motors or solenoids) that are connected to an Arduino-based controller. Several shutters can be controlled by one controller, further reducing system cost. The state of the shutters can be controlled via a display built into the controller, by serial commands via USB, or by electrical control lines. The use of a microcontroller makes the shutter controller adaptable - only control options that are used need to be included, and the design accommodates a selection of display and actuator options. We provide designs for all required components, including 3D print files for the actuator holders and cases, the Arduino code, libraries for serial communication (C and python), and example graphical user interfaces for testing.

4.
Small ; : e2403461, 2024 Aug 03.
Article in English | MEDLINE | ID: mdl-39096104

ABSTRACT

Luminescent coupling (LC) is a key phenomenon in monolithic tandem solar cells. This study presents a nondestructive technique to quantitatively evaluate the LC effect, addressing a gap in the existing predictions made by optical modeling. The method involves measuring the ratio of photons emitted from the high bandgap top cell that escape through the rear, contributing additional current to the bottom cell, and to those escaping from the front side of top cell. The findings indicate that in the analyzed monolithic perovskite/silicon tandem solar cells, more than 85% of the emitted photons escaping from the perovskite top cell are used to generate additional current in the bottom cell. This process notably reduces the mismatch in the generated current between each subcell, particularly when the current is limited by the low bandgap subcell. The presented method is applicable to a variety of monolithic tandem structures, providing vital information for subcell characterization, providing vital information for predicting energy output and optimization for outdoor applications.

5.
EFORT Open Rev ; 9(8): 827-836, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39087500

ABSTRACT

Purpose: To compare anterior plate fixation (SP fixation) both alone and in combination with an additional posterior sacroiliac screw (SP+SIS fixation) as a treatment for pelvic ring injuries with widening of the pubic symphysis and disruption to the anterior sacroiliac ligaments. Methods: To find studies with pelvic ring injuries (APC II; B2.3d) and SP or SP+SIS fixation, a systematic literature review was conducted by searching four databases. A protocol was published a priori at Open Science Framework (https://doi.org/10.17605/OSF.IO/3YHAV). Exclusion criteria included perineal injuries, chronic instability of the symphysis, complete sacroiliac separation, and pediatric patients (age <18 years). Primary outcomes of interest were defined as implant failure, health-related quality of life, and revision rate. Results: Altogether, 1861 studies were screened, and 40 studies qualified for full-text analysis. In total, 14 studies (two surveys, six biomechanical studies, and six retrospective clinical studies) were included. The surveys revealed that surgeons who had more recently begun practicing were more likely to use posterior fixation (SP+ISS). The biomechanical studies were heterogenous and did not yield a uniform pattern. In clinical studies, 117 patients (45%) received SP fixation, and 142 patients (55%) received SP+SIS fixation. Complications occurred in 31 SP patients (30%) and in five SP+SIS patients (3.5%). Conclusion: A high risk of bias was uncovered, and reporting was found to be incomplete. SP+SIS may have the potential to improve outcomes, but the evidence remains too inconclusive to draw reliable recommendations.

6.
J Dig Dis ; 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39081006

ABSTRACT

OBJECTIVE: To determine a risk scoring system for predicting advanced colorectal neoplasia (ACN) within subcentimetric polyps in a large Asian population. METHODS: A retrospective study was conducted in Hong Kong SAR, China involving participants who underwent colonoscopy between 2008 and 2015. A random sample of 20 072 subjects were included as the derivation cohort to assess ACN-associated independent factors using logistic regression modeling. Another 8603 subjects formed a validation cohort. A risk scoring system was developed and its performance was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: The risk scores were assigned based on the following criteria: (a) patients who were admitted from inpatient colonoscopy (2.2) or not (1); (b) with three or more chronic diseases (hypertension, diabetes mellitus, hyperlipidemia, heart disease, or cancer) (1.7) or not (1); (c) anemia (1.3) or without anemia (1); (d) receiving aspirin (0.5) or not (1); (e) receiving other nonsteroidal anti-inflammatory drugs (0.3) or not (1); (f) male (1.2) or female gender (1); (g) age <55 (1), 55-64 (1.4), 65-69 (2), 70 years or above (2.2). ACN was more common in those with scores of 2.192 or higher, and they were classified as high risk (HR). The prevalence of ACN in the validation cohort was 13.28% and 3.56% in the HR and low-risk groups, respectively. In both the derivation and validation cohorts, AUROC of the risk-scoring model was 0.7138. CONCLUSION: Physicians are recommended to utilize this validated score for risk-stratification of patients having subcentimetric polyps.

8.
medRxiv ; 2024 Jul 07.
Article in English | MEDLINE | ID: mdl-39006446

ABSTRACT

Post-acute sequelae of SARS-CoV-2 (SARS2) infection (PASC) is a heterogeneous condition, but the main viral drivers are unknown. Here, we use MENSA, Media Enriched with Newly Synthesized Antibodies, secreted exclusively from circulating human plasmablasts, to provide an immune snapshot that defines the underlying viral triggers. We provide proof-of-concept testing that the MENSA technology can capture the new host immune response to accurately diagnose acute primary and breakthrough infections when known SARS2 virus or proteins are present. It is also positive after vaccination when spike proteins elicit an acute immune response. Applying the same principles for long-COVID patients, MENSA is positive for SARS2 in 40% of PASC vs none of the COVID recovered (CR) patients without any sequelae demonstrating ongoing SARS2 viral inflammation only in PASC. Additionally, in PASC patients, MENSAs are also positive for Epstein-Barr Virus (EBV) in 37%, Human Cytomegalovirus (CMV) in 23%, and herpes simplex virus 2 (HSV2) in 15% compared to 17%, 4%, and 4% in CR controls respectively. Combined, a total of 60% of PASC patients have a positive MENSA for SARS2, EBV, CMV, and/or HSV2. MENSA offers a unique antibody snapshot to reveal the underlying viral drivers in long-COVID thus demonstrating the persistence of SARS2 and reactivation of viral herpes in 60% of PASC patients.

9.
Nat Commun ; 15(1): 5988, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39013881

ABSTRACT

Maintenance of water homeostasis is a fundamental cellular process required by all living organisms. Here, we use the single-celled green alga Chlamydomonas reinhardtii to establish a foundational understanding of osmotic-stress signaling pathways through transcriptomics, phosphoproteomics, and functional genomics approaches. Comparison of pathways identified through these analyses with yeast and Arabidopsis allows us to infer their evolutionary conservation and divergence across these lineages. 76 genes, acting across diverse cellular compartments, were found to be important for osmotic-stress tolerance in Chlamydomonas through their functions in cytoskeletal organization, potassium transport, vesicle trafficking, mitogen-activated protein kinase and chloroplast signaling. We show that homologs for five of these genes have conserved functions in stress tolerance in Arabidopsis and reveal a novel PROFILIN-dependent stage of acclimation affecting the actin cytoskeleton that ensures tissue integrity upon osmotic stress. This study highlights the conservation of the stress response in algae and land plants, and establishes Chlamydomonas as a unicellular plant model system to dissect the osmotic stress signaling pathway.


Subject(s)
Arabidopsis , Chlamydomonas reinhardtii , Osmotic Pressure , Signal Transduction , Chlamydomonas reinhardtii/metabolism , Chlamydomonas reinhardtii/genetics , Arabidopsis/metabolism , Arabidopsis/genetics , Proteomics , Gene Expression Regulation, Plant , Genomics , Stress, Physiological , Plant Proteins/metabolism , Plant Proteins/genetics , Transcriptome , Cell Compartmentation , Chloroplasts/metabolism , Multiomics
10.
Proteins ; 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39031927

ABSTRACT

Amyloidosis are a group of diseases in which soluble proteins aggregate and deposit in fibrillar conformation extracellularly in tissues. The effectiveness of therapeutic strategies depends on the specific protein involved, being crucial to accurately determine its nature. Moreover, following the diagnosis, the search for the mutation within relatives allows the clinical advice. Here we report the precise diagnosis and explored the possible reasons of the structural pathogenicity for a renal amyloidosis related to a fibrinogen Aα-chain variant. Whole-exome sequencing and GATK calling pipeline were leveraged to characterize the protein variant present in a patient with kidney failure. Bioinformatics strategies were applied to suggest potential explanations of the variants aggregation. Our pipeline allowed the identification of a single-point variant of fibrinogen Aα-chain, which opened the possibility of curative transplantation. In silico structural analysis suggested that the pathogenicity of the variant may be attributed to a heightened susceptibility to yield a peptide prone to deposit as an oligomer with a ß-sheet structure. Exploiting the comprehensive coverage of whole-genome sequencing, we managed to fill a vacant stage in the diagnosis of hereditary amyloidosis and to stimulate the advancement in biomedicine.

11.
J Invest Dermatol ; 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38960086

ABSTRACT

Exudates of non-healing wounds contain drivers of pathogenicity. We utilized >800 exudates from non-healing and healing wounds of diverse etiologies, collected by three different methods, to develop a wound-specific, cell-based functional biomarker assay. Human dermal fibroblast proliferation served as readout to a) to differentiate between healing and non-healing wounds, b) follow the healing process of individual patients, and c) assess the effects of therapeutics for chronic wounds ex vivo. We observed a strong correlation between wound chronicity and inhibitory effects of individual exudates on fibroblast proliferation, with good diagnostic sensitivity (76-90%, depending on the sample collection method). Transition of a clinically non-healing to a healing phenotype restored fibroblast proliferation and extracellular matrix formation while reducing inflammatory cytokine production. Transcriptional analysis of fibroblasts exposed to ex vivo non-healing wound exudates revealed an induction of inflammatory cytokine- and chemokine pathways and the unfolded protein response, indicating that these changes may contribute to the pathology of non-healing wounds. Testing the wound therapeutics platelet derived growth factor and silver sulfadiazine yielded responses in line with clinical experience and indicate the usefulness of the assay to search for and profile new therapeutics.

12.
Front Public Health ; 12: 1367818, 2024.
Article in English | MEDLINE | ID: mdl-38966706

ABSTRACT

Background: The incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019. Methods: Data on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0-4, 5-9, 10-14 and 15-19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC. Results: The global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0-4, 5-9, 10-14 and 15-19 years were also associated with the incidences, particularly for the exposures at ages 15-19 years. Conclusion: The global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.


Subject(s)
Colorectal Neoplasms , Global Health , Humans , Incidence , Colorectal Neoplasms/epidemiology , Adolescent , Child , Infant , Child, Preschool , Young Adult , Global Health/statistics & numerical data , Risk Factors , Infant, Newborn , Female , Male , Global Burden of Disease/trends , Age of Onset , Adult
13.
Mil Med ; 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38970432

ABSTRACT

Ethical practice within military health care is a significant topic of professional and academic debate. The term "military health care ethics" enfranchises the entire health care team. Military health care professionals are subject to tension between their duties as military personnel, and their ethical duties as health care professionals, so-called "Dual Loyalty." Some military health care practitioners have suffered moral injury because of the psychological stress associated with ethical challenges on military operations. It is important to define military health care ethics and also to consider how it should be taught. The essence of ethical practice is ethical decision-making. It has become self-evident from our experience of teaching military health care ethics that a simple and agreed framework for analyzing an ethical problem is required. This paper describes the development of the King's Military Healthcare Ethics Framework in support of a military health care ethics policy on behalf of the NATO Military Healthcare Working Group. There is logic to using a stepped approach to analyze an ethical problem in military health care. These steps are: "Identify" the problem, "Analyze" the problem including consideration of perspectives, "Fuse" the analysis, and "Decide". Step 1-Identify-is intended to orientate the decision-making group, and to articulate the problem specifically and clearly in order to determine the exact ethical issue and the secondary issues that arise. Step 2-Analyse-considers the problem from 4 perspectives: patient, clinical, legal, and societal/military. These reflect the breadth of perspectives that impact on health care practice within a military context. Step 3-Fuse-is the culminating step. The conclusions from the analysis of perspectives should be summarized and key references cited. This will determine the exact decision(s) to be made. Step 4-Decide-clearly articulates the decision made and provides the record of the key reasons for making that decision. This may include areas of enduring uncertainly and any planned review of the decision. The King's Military Healthcare Ethics Analytical Framework has been evaluated for content validity through iterative discussion at 4 meetings of the NATO MHCWG and a specific workshop on military health care ethics over 2022/2023. It is included within the draft NATO Standardization Agreement on Military Healthcare Ethics.

14.
Sports Med ; 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38970765

ABSTRACT

BACKGROUND: The proximity to failure in which sets are terminated has gained attention in the scientific literature as a potentially key resistance training variable. Multiple meta-analyses have directly (i.e., failure versus not to failure) or indirectly (e.g., velocity loss, alternative set structures) evaluated the effect of proximity to failure on strength and muscle hypertrophy outcomes categorically; however, the dose-response effects of proximity to failure have not been analyzed collectively in a continuous manner. OBJECTIVE: To meta-analyze the aforementioned areas of relevant research, proximity to failure was quantified as the number of repetitions in reserve (RIR). Importantly, the RIR associated with each effect in the analysis was estimated on the basis of the available descriptions of the training interventions in each study. Data were extracted and a series of exploratory multilevel meta-regressions were performed for outcomes related to both strength and muscle hypertrophy. A range of sensitivity analyses were also performed. All models were adjusted for the effects of load, method of volume equating, duration of intervention, and training status. RESULTS: The best fit models for both strength and muscle hypertrophy outcomes demonstrated modest quality of overall fit. In all of the best-fit models for strength, the confidence intervals of the marginal slopes for estimated RIR contained a null point estimate, indicating a negligible relationship with strength gains. However, in all of the best-fit models for muscle hypertrophy, the marginal slopes for estimated RIR were negative and their confidence intervals did not contain a null point estimate, indicating that changes in muscle size increased as sets were terminated closer to failure. CONCLUSIONS: The dose-response relationship between proximity to failure and strength gain appears to differ from the relationship with muscle hypertrophy, with only the latter being meaningfully influenced by RIR. Strength gains were similar across a wide range of RIR, while muscle hypertrophy improves as sets are terminated closer to failure. Considering the RIR estimation procedures used, however, the exact relationship between RIR and muscle hypertrophy and strength remains unclear. Researchers and practitioners should be aware that optimal proximity to failure may differ between strength and muscle hypertrophy outcomes, but caution is warranted when interpreting the present analysis due to its exploratory nature. Future studies deliberately designed to explore the continuous nature of the dose-response effects of proximity to failure in large samples should be considered.

15.
Pediatr Crit Care Med ; 25(7): 643-675, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38959353

ABSTRACT

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.


Subject(s)
Anticoagulants , Critical Illness , Extracorporeal Membrane Oxygenation , Extracorporeal Membrane Oxygenation/methods , Humans , Anticoagulants/therapeutic use , Anticoagulants/administration & dosage , Child , Critical Illness/therapy , Infant, Newborn , Infant , Child, Preschool
16.
Pediatr Crit Care Med ; 25(7 Suppl 1): e25-e34, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38959357

ABSTRACT

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding prophylactic transfusions in neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021. STUDY SELECTION: Included studies assessed use of prophylactic blood product transfusion in pediatric ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Thirty-three references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. MEASUREMENTS AND MAIN RESULTS: The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for prophylactic transfusion strategies for children supported with ECMO. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. We developed two good practice statements, 4 weak recommendations, and three expert consensus statements. CONCLUSIONS: Despite the frequency with which pediatric ECMO patients are transfused, there is insufficient evidence to formulate evidence-based prophylactic transfusion strategies.


Subject(s)
Blood Transfusion , Delphi Technique , Extracorporeal Membrane Oxygenation , Humans , Extracorporeal Membrane Oxygenation/methods , Child , Blood Transfusion/standards , Blood Transfusion/methods , Infant, Newborn , Infant , Consensus , Child, Preschool
17.
Cell Death Dis ; 15(7): 513, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39025852

ABSTRACT

Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.


Subject(s)
Prostatic Neoplasms , Valine , Male , Humans , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Valine/pharmacology , Valine/metabolism , Cell Line, Tumor , Cell Proliferation , Mitochondria/metabolism , Amino Acids, Branched-Chain/metabolism , Lipid Metabolism/drug effects , Succinic Acid/metabolism , Metabolic Reprogramming
18.
Trop Med Infect Dis ; 9(7)2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39058203

ABSTRACT

Rabies persists as a longstanding issue in Zambia, despite being preventable. The current control measures, including dog vaccination, population control, and movement restriction, guided by 'The Control of Dogs Act Chapter 247 of the Laws of Zambia', have not yielded the desired impact in many areas of the country including Manyinga and Mwansabombwe districts. These two districts continue to report low dog vaccination rates, unrestricted dog movements, and escalating cases of animal and human rabies, along with dog bites. Aligned with global aspirations to achieve zero human rabies cases by 2030, this study scrutinizes the determinants and obstacles hampering the execution of rabies control initiatives in Manyinga and Mwansabombwe. Spanning approximately 11 months, this cross-sectional study gathered pre- and post-vaccination data from 301 households in Manyinga and 100 households in Mwansabombwe. Questionnaires probed knowledge, attitudes, and practices related to rabies prevention and control. A transect survey, key informant interviews, and assessment of rabies vaccination and dog bite records complemented the data collection. Findings revealed that 88.0% of respondents from both districts possessed knowledge about rabies, confirming affected species and transmission. Moreover, 76.8% in Manyinga and 88.6% in Mwansabombwe were acquainted with rabies prevention and control methods. Concerning dog owners, 89.0% were aware of rabies, 66.0% understood its prevention and control, and the majority identified bites as the primary mode of transmission. Despite the high level of knowledge recorded during the survey, the implementation of preventive measures was low, which was attributed to low levels of law enforcement by the local government authority, inadequate staffing in the veterinary department, unwillingness to pay for dog vaccinations, and unavailability of rabies vaccine at the veterinary office in both districts. Vaccination coverage stood at 64.0% in Manyinga and 21.0% in Mwansabombwe. Notably, education and occupation exhibited a positive significant association with rabies knowledge. In terms of dog bite cases, Manyinga recorded 538 dog bite cases from 2017 to June 2022, while Mwansabombwe recorded 81 dog bite and 23 jackal bite cases from 2021 to June 2022. The study underscores critical knowledge gaps in rural areas and emphasizes the imperative for enhanced public education and awareness programs, improved rabies surveillance, free mass vaccination campaigns, and community engagement to augment vaccination coverage and knowledge about rabies.

19.
Sci Adv ; 10(30): eado0373, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39047103

ABSTRACT

Parahydrogen-induced polarization (PHIP) is a potent technique for generating target molecules with high nuclear spin polarization. The PHIP process involves a chemical reaction between parahydrogen and a target molecule, followed by the transformation of nuclear singlet spin order into magnetization of a designated target nucleus through magnetic field manipulations. Although the singlet-to-magnetization polarization transfer process works effectively at moderate concentrations, it is observed to become much less efficient at high molar polarization, defined as the product of polarization and concentration. This strong dependence on the molar polarization is attributed to interference due to the field produced by the sample magnetization during polarization transfer, which leads to complex dynamics and can severely affect the scalability of the technique. We address this challenge with a pulse sequence that suppresses the influence of the distant dipolar field, while simultaneously achieving singlet-to-magnetization polarization transfer to the desired target spins, free from restrictions on the molar polarization.

20.
Sci Rep ; 14(1): 16944, 2024 07 23.
Article in English | MEDLINE | ID: mdl-39043761

ABSTRACT

The present study aimed to assess mosquito species diversity, distribution, and ecological preferences in the Covè, Ouinhi, and Zangnanado communes, Southern Benin. Such information is critical to understand mosquito bio-ecology and to focus control efforts in high-risk areas for vector-borne diseases. Mosquito collections occurred quarterly in 60 clusters between June 2020 and April 2021, using human landing catches. In addition to the seasonal mosquito abundance, Shannon's diversity, Simpson, and Pielou's equitability indices were also evaluated to assess mosquito diversity. Ecological niche models were developed with MaxEnt using environmental variables to assess species distribution. Overall, mosquito density was higher in the wet season than in the dry season in all communes. A significantly higher Shannon's diversity index was also observed in the wet season than in the dry seasons in all communes (p < 0.05). Habitat suitability of An. gambiae s.s., An. coluzzii, Cx. quinquefasciatus and Ma. africana was highly influenced by slope, isothermality, site aspect, elevation, and precipitation seasonality in both wet and dry seasons. Overall, depending on the season, the ecological preferences of the four main mosquito species were variable across study communes. This emphasizes the impact of environmental conditions on mosquito species distribution. Moreover, mosquito populations were found to be more diverse in the wet season compared to the dry season.


Subject(s)
Biodiversity , Ecosystem , Malaria , Mosquito Vectors , Seasons , Animals , Benin , Mosquito Vectors/physiology , Malaria/transmission , Culicidae/classification , Culicidae/physiology , Humans , Anopheles/physiology , Anopheles/classification
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