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1.
Proc Natl Acad Sci U S A ; 121(28): e2317833121, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38968112

RESUMEN

Parkinson's disease (PD) is a multifactorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal-based cognitive function are common, appear early, and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation in Lrrk2 also exhibit deficits in fronto-striatal-based cognitive tasks. In mice and humans, cognitive functions require dynamic adjustments in glutamatergic synapse strength through cell-surface trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs), but it is unknown how LRRK2 mutation impacts dynamic features of AMPAR trafficking in striatal projection neurons (SPNs). Here, we used Lrrk2G2019S knockin mice to show that surface AMPAR subunit stoichiometry is altered biochemically and functionally in mutant SPNs in dorsomedial striatum to favor the incorporation of GluA1 over GluA2. GluA1-containing AMPARs were resistant to internalization from the cell surface, leaving an excessive accumulation of GluA1 on the surface within and outside synapses. This negatively impacted trafficking dynamics that normally support synapse strengthening, as GluA1-containing AMPARs failed to increase at synapses in response to a potentiating stimulus and showed significantly reduced surface mobility. Surface GluA2-containing AMPARs were expressed at normal levels in synapses, indicating subunit-selective impairment. Abnormal surface accumulation of GluA1 was independent of PKA activity and was limited to D1R SPNs. Since LRRK2 mutation is thought to be part of a common PD pathogenic pathway, our data suggest that sustained, striatal cell-type specific changes in AMPAR composition and trafficking contribute to cognitive or other impairments associated with PD.


Asunto(s)
Cuerpo Estriado , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Transporte de Proteínas , Receptores AMPA , Animales , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Receptores AMPA/metabolismo , Receptores AMPA/genética , Ratones , Cuerpo Estriado/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Mutación Missense , Humanos , Sinapsis/metabolismo
2.
Lancet Infect Dis ; 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38964363

RESUMEN

In 2016, WHO designated Lassa fever a priority disease for epidemic preparedness as part of the WHO Blueprint for Action to Prevent Epidemics. One aspect of preparedness is to promote development of effective medical countermeasures (ie, diagnostics, therapeutics, and vaccines) against Lassa fever. Diagnostic testing for Lassa fever has important limitations and key advancements are needed to ensure rapid and accurate diagnosis. Additionally, the only treatment available for Lassa fever is ribavirin, but controversy exists regarding its effectiveness. Finally, no licensed vaccines are available for the prevention and control of Lassa fever. Ongoing epidemiological and behavioural studies are also crucial in providing actionable information for medical countermeasure development, use, and effectiveness in preventing and treating Lassa fever. This Personal View provides current research priorities for development of Lassa fever medical countermeasures based on literature published primarily in the last 5 years and consensus opinion of 20 subject matter experts with broad experience in public health or the development of diagnostics, therapeutics, and vaccines for Lassa fever. These priorities provide an important framework to ensure that Lassa fever medical countermeasures are developed and readily available for use in endemic and at-risk areas by the end of the decade.

3.
bioRxiv ; 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38895277

RESUMEN

Anxiety is a psychiatric non-motor symptom of Parkinson's that can appear in the prodromal period, prior to significant loss of brainstem dopamine neurons and motor symptoms. Parkinson's-related anxiety affects females more than males, despite the greater prevalence of Parkinson's in males. How stress, anxiety and Parkinson's are related and the basis for a sex-specific impact of stress in Parkinson's are not clear. We addressed this using young adult male and female mice carrying a G2019S knockin mutation of leucine-rich repeat kinase 2 ( Lrrk2 G2019S ) and Lrrk2 WT control mice. In humans, LRRK2 G2019S significantly elevates the risk of late-onset Parkinson's. To assess within-sex differences between Lrrk2 G2019S and control mice in stress-induced anxiety-like behaviors in young adulthood, we used a within-subject design whereby Lrrk2 G2019S and Lrrk2 WT control mice underwent tests of anxiety-like behaviors before (baseline) and following a 28 day (d) variable stress paradigm. There were no differences in behavioral measures between genotypes in males or females at baseline, indicating that the mutation alone does not produce anxiety-like responses. Following chronic stress, male Lrrk2 G2019S mice were affected similarly to male wildtypes except for novelty-suppressed feeding, where stress had no impact on Lrrk2 G2019S mice while significantly increasing latency to feed in Lrrk2 WT control mice. Female Lrrk2 G2019S mice were impacted by chronic stress similarly to wildtype females across all behavioral measures. Subsequent post-stress analyses compared cFos immunolabeling-based cellular activity patterns across several stress-relevant brain regions. The density of cFos-activated neurons across brain regions in both male and female Lrrk2 G2019S mice was generally lower compared to stressed Lrrk2 WT mice, except for the nucleus accumbens of male Lrrk2 G2019S mice, where cFos-labeled cell density was significantly higher than all other groups. Together, these data suggest that the Lrrk2 G2019S mutation differentially impacts anxiety-like behavioral responses to chronic stress in males and females that may reflect sex-specific adaptations observed in circuit activation patterns in stress-related brain regions.

5.
J Biomol Struct Dyn ; : 1-11, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38605579

RESUMEN

We compare the WebGeSTer and INtrinsic transcription TERmination hairPIN (INTERPIN) databases used for intrinsic transcription termination (ITT) site prediction in bacteria. The former deploys inverted nucleotide repeat detection for identification of RNA hairpin, while the latter a pair-potential function - the hairpin energy score evaluation being identical for both. We find INTERPIN more sensitive than WebGeSTer with about 6% and 51% additional predictions for ITTs in chromosomal and plasmid operons, respectively. INTERPIN hairpins are relatively shorter in length with ungapped stem, and even located in AT-rich segments, compared to GC-rich longer hairpins with a gapped stem in WebGeSTer. The GC%, length, and energy score from INTERPIN transcription units (TUs) are best inter-correlated while the lowest energy single hairpins from WebGeSTer, considered suitable for ITT, being the worst. Around 72% TUs from the two databases overlap, and ∼60% of all alternate ITT sites downstream of TUs overlap, of which 65% are cluster hairpins. This helps highlight hairpin features that can be used to identify termination sites in bacteria across different prediction methods. Overall, the pair-potential-function-based hairpins screened appear to be more consistent with the kinetic and thermodynamics processes of ITT known to date.Communicated by Ramaswamy H. Sarma.

6.
Sci Prog ; 107(2): 368504241244657, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38614470

RESUMEN

METHODOLOGY: An electronic search was done in PUBMED, SCOPUS, and a hand search was done in radiology, periodontology, and oral surgery journals. The search yielded 428 results, from which only 6 articles were selected for this literature review. Both prospective and retrospective studies were included. Clinical studies with information on the pre-implant condition of the site, detailed implant procedure, and follow-up after implant placement of more than 6 months were only considered for this review. RESULTS AND CONCLUSION: Limited clinical studies, shorter follow-up periods were the shortcomings of this review. However, it can be summarized that dental implants should not be placed at the site of FCOD, however can be placed at adjacent sites. Variations in implant type or the implant length had no bearing on the survival of implants at the sites of FCOD.


Asunto(s)
Displasia Fibrosa Ósea , Osteomielitis , Humanos , Estudios Prospectivos , Estudios Retrospectivos
8.
Bioanalysis ; 16(7): 77-119, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38389403

RESUMEN

The 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on June 19-23, 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with these NEW Regulations" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity. Part 1A (Mass Spectrometry Assays and Regulated Bioanalysis/BMV), P1B (Regulatory Inputs) and Part 2 (Biomarkers, IVD/CDx, LBA and Cell-Based Assays) are published in volume 16 of Bioanalysis, issues 8 and 9 (2024), respectively.


Asunto(s)
Bioensayo , Tecnología , Bioensayo/métodos , Biomarcadores/análisis , Tratamiento Basado en Trasplante de Células y Tejidos , Inmunoterapia Activa
9.
Angew Chem Int Ed Engl ; 63(13): e202315726, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38329885

RESUMEN

We have developed a photochemical protecting group that enables wavelength selective uncaging using green versus violet light. Change of the exocyclic oxygen of the laser dye coumarin-102 to sulfur, gave thio-coumarin-102, a new chromophore with an absorption ratio at 503/402 nm of 37. Photolysis of thio-coumarin-102 caged γ-aminobutyric acid was found to be highly wavelength selective on neurons, with normalized electrical responses >100-fold higher in the green versus violet channel. When partnered with coumarin-102 caged glutamate, we could use whole cell violet and green irradiation to fire and block neuronal action potentials with complete orthogonality. Localized irradiation of different dendritic segments, each connected to a neuronal cell body, in concert with 3-dimenional Ca2+ imaging, revealed that such inputs could function independently. Chemical signaling in living cells always involves a complex balance of multiple pathways, use of (thio)-coumarin-102 caged compounds will enable arbitrarily timed flashes of green and violet light to interrogate two independent pathways simultaneously.


Asunto(s)
Luz Verde , Neuronas , Neuronas/metabolismo , Fotólisis , Cumarinas/química , Ácido Glutámico/metabolismo
10.
Indian J Med Microbiol ; 48: 100548, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38403268

RESUMEN

BACKGROUND: Emerging infectious diseases, often zoonotic, demand a collaborative "One-Health" surveillance approach due to human activities. The need for standardized diagnostic and surveillance algorithms is emphasized to address the difficulty in clinical differentiation and curb antimicrobial resistance. OBJECTIVE: The present recommendations are comprehensive diagnostic and surveillance algorithm for ARIs, developed by the Indian Council of Medical Research (ICMR), which aims to enhance early detection and treatment with improved surveillance. This algorithm shall be serving as a blueprint for respiratory infections landscape in the country and early detection of surge of respiratory infections in the country. CONTENT: The ICMR has risen up to the threat of emerging and re-emerging infections. Here, we seek to recommend a structured approach for diagnosing respiratory illnesses. The recommendations emphasize the significance of prioritizing respiratory pathogens based on factors such as the frequency of occurrence (seasonal or geographical), disease severity, ease of diagnosis and public health importance. The proposed surveillance-based diagnostic algorithm for ARI relies on a combination of gold-standard conventional methods, innovative serological and molecular techniques, as well as radiological approaches, which collectively contribute to the detection of various causative agents. The diagnostic part of the integrated algorithm can be dealt at the local microbiology laboratory of the healthcare facility with the few positive and negative specimens shipped to linked viral disease research laboratories (VRDLs) and other ICMR designated laboratories for genome characterisation, cluster identification and identification of novel agents.


Asunto(s)
Infecciones del Sistema Respiratorio , Humanos , India/epidemiología , Infecciones del Sistema Respiratorio/diagnóstico , Algoritmos , Monitoreo Epidemiológico , Enfermedades Transmisibles Emergentes/diagnóstico , Enfermedades Transmisibles Emergentes/epidemiología
11.
J Invest Dermatol ; 144(1): 106-115.e4, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37562584

RESUMEN

Tumors evade immunity through the overexpression of immune inhibitory molecules in the tumor microenvironment such as PD-L1/B7-H1. An immune inhibitory molecule named PD-1 homolog (also known as V-domain Ig-containing suppressor of T cell activation [VISTA]) functions to control both T cells and myeloid cells. Current clinical trials using anti-VISTA-blocking agents for treatment of cancer are ongoing. We sought to determine the extent of VISTA expression in primary cutaneous melanomas (n = 190), identify the critical cell types expressing VISTA, and correlate its expression with PD-L1 expression using multiplexed quantitative immunofluorescence. Within the tumor subcompartments, VISTA is most highly expressed on CD11b myeloid cells, and PD-L1 is most highly expressed on CD68 myeloid cells in our melanoma cohort. There is little correlation between VISTA and PD-L1 expression intensity, suggesting that individual tumors have distinct immunosuppressive tumor microenvironments. High levels of VISTA expression on CD11b myeloid cells but not PD-L1 expression were associated with greater melanoma recurrence and greater all-cause mortality. Our findings suggest that cell-specific VISTA expression may be a negative prognostic biomarker for melanoma and a future potential therapeutic target.


Asunto(s)
Antígeno B7-H1 , Melanoma , Humanos , Antígenos B7 , Antígeno B7-H1/metabolismo , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T , Microambiente Tumoral
12.
Clin Pharmacol Ther ; 115(2): 188-200, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37983584

RESUMEN

CAR-T therapies have shown remarkable efficacy against hematological malignancies in the clinic over the last decade and new studies indicate that progress is being made to use these novel therapies to target solid tumors as well as treat autoimmune disease. Innovation in the field, including TCR-T, allogeneic or "off the shelf" CAR-T, and autoantigen/armored CAR-Ts are likely to increase the efficacy and applications of these therapies. The unique aspects of these cell-based therapeutics; patient-derived cells, intracellular expression, in vivo expansion, and phenotypic changes provide unique bioanalytical challenges to develop pharmacokinetic and immunogenicity assessments. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Translational and ADME Sciences Leadership Group (TALG) has brought together a group of industry experts to discuss and consider these challenges. In this white paper, we present the IQ consortium perspective on the best practices and considerations for bioanalytical and immunogenicity aspects toward the optimal development of CAR-T and TCR-T cell therapies.


Asunto(s)
Neoplasias Hematológicas , Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Linfocitos T , Neoplasias/metabolismo , Inmunoterapia Adoptiva
13.
Environ Sci Pollut Res Int ; 30(57): 120749-120762, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37943434

RESUMEN

Diaphorobacter strain DS2 degrades 3-nitrotoluene and 2-nitrotoluene via ring oxidation with 3-nitrotoluene dioxygenase (3NTDO). In the current study, we hypothesized that 3NTDO might also be involved in the degradation of 2,4,6-trinitrotoluene (TNT), a major nitroaromatic explosive contaminant in soil and groundwater. Strain DS2 transforms TNT as a sole carbon and nitrogen source when grown on it. Ammonium chloride and succinate in the medium accelerated the TNT degradation rate. A resting cell experiment suggested that TNT does not compete with 3NT degradation (no negative impact of TNT on the reaction velocity for 3NT). Enzyme assay with 3NTDO did not exhibit TNT transformation activity. The above results confirmed that 3NTDO of DS2 is not responsible for TNT degradation. In the resting cell experiment, within 10 h, 4ADNT completely degraded. The degradation of 2ADNT was 97% at the same time. We hypothesized that 3NTDO involve in this reaction. Based on the DS2 genome, we proposed that the N-ethylmaleimide reductases (nemA) were involved in the initial reduction of the nitro group and aromatic ring of TNT. Our findings suggest that strain DS2 could be helpful for the removal of TNT from contaminated sites with or without any additional carbon and nitrogen source and with minimal accumulation of undesirable intermediates.


Asunto(s)
Trinitrotolueno , Trinitrotolueno/metabolismo , Biotransformación , Carbono , Nitrógeno/metabolismo , Biodegradación Ambiental
14.
Cureus ; 15(10): e47549, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38022080

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder caused due to decreased dopamine, a neurotransmitter, advancing to a range of motor and non-motor attributes. There is a death of dopamine-producing neurons (dopaminergic neurons) in the Substantia Nigra. Bradykinesia, postural instability, resting tremor, and rigidity are four main symptoms in this patient. A variety of other symptoms, like hypomimia, micrographia, freezing gait, decreased movement amplitude, constipation, cognitive impairments, etc., can be seen in this patient. In this paper, we report a 62-year-old female with stage 5 PD with chief complaints of uncoordinated movements, weakness, and difficulty in daily activities. She was treated with strengthening, stretching, Lee Silverman Voice Treatment (LSVT) BIG, bed mobility, gait training with auditory cueing, balance training, etc. LSVT-BIG enhances motor function by incorporating high amplitude motions of high intensity, consisting of numerous repetitions and progressive complexity. At the end of three weeks, the patient had improved strength, static and dynamic balance, gait, and quality of life.

15.
bioRxiv ; 2023 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-37905106

RESUMEN

Parkinson's (PD) is a multi-factorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal based cognitive function are common, appear early and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation in Lrrk2 also exhibit deficits in fronto-striatal-based cognitive tasks. In mice and humans, cognitive functions require dynamic adjustments in glutamatergic synapse strength through cell-surface trafficking of AMPA-type glutamate receptors (AMPARs), but it is unknown how LRRK2 mutation impacts dynamic features of AMPAR trafficking in striatal projection neurons (SPNs). Here, we used Lrrk2 G2019S knockin mice to show that surface AMPAR subunit stoichiometry is altered biochemically and functionally in mutant SPNs to favor incorporation of GluA1 over GluA2. GluA1-containing AMPARs were resistant to internalization from the cell surface, leaving an excessive accumulation of GluA1 on the surface within and outside synapses. This negatively impacted trafficking dynamics that normally support synapse strengthening, as GluA1-containing AMPARs failed to increase at synapses in response to a potentiating stimulus and showed significantly reduced surface mobility. Surface GluA2-containing AMPARs were expressed at normal levels in synapses, indicating subunit-selective impairment. Abnormal surface accumulation of GluA1 was independent of PKA activity and was limited to D 1 R SPNs. Since LRRK2 mutation is thought to be part of a common PD pathogenic pathway, our data suggest that sustained, striatal cell-type specific changes in AMPAR composition and trafficking contribute to cognitive or other impairments associated with PD. SIGNIFICANCE STATEMENT: Mutations in LRRK2 are common genetic risks for PD. Lrrk2 G2019S mice fail to exhibit long-term potentiation at corticostriatal synapses and show significant deficits in frontal-striatal based cognitive tasks. While LRRK2 has been implicated generally in protein trafficking, whether G2019S derails AMPAR trafficking at synapses on striatal neurons (SPNs) is unknown. We show that surface GluA1-AMPARs fail to internalize and instead accumulate excessively within and outside synapses. This effect is selective to D 1 R SPNs and negatively impacts synapse strengthening as GluA1-AMPARs fail to increase at the surface in response to potentiation and show limited surface mobility. Thus, LRRK2-G2019S narrows the effective range of plasticity mechanisms, supporting the idea that cognitive symptoms reflect an imbalance in AMPAR trafficking mechanisms within cell-type specific projections.

16.
BMJ Open ; 13(9): e067722, 2023 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-37714672

RESUMEN

INTRODUCTION: Tobacco smoking is associated with a substantially increased risk of perioperative complications. The perioperative period is an opportunity to introduce tobacco-cessation strategies. A previous systematic review provided evidence that perioperative interventions increase short-term abstinence and may reduce postoperative complications. The evidence base has since expanded, with the subsequent publication of numerous randomised studies. This protocol outlines a systematic review examining the impact of perioperative tobacco-cessation interventions on successful abstinence from tobacco smoking, and on the incidence of perioperative complications. METHODS AND ANALYSIS: A systematic search of the literature will be run across EMBASE (Ovid), MEDLINE (Ovid), CINAHL (Ebsco) and PsycInfo (ProQuest), from inception to present, using text words and subject headings. Randomised controlled trials published in English, examining adults in the perioperative period and reporting the outcomes from tobacco-cessation interventions will be included.Abstract screening and data extraction will be performed by five reviewers. Each abstract will be screened by two blinded reviewers, with discrepancies resolved by group consensus. The primary outcome will be point prevalence abstinence from tobacco-use at the time of surgery. Secondary outcomes are prolonged abstinence from tobacco use at 6 months and 12 months, and postoperative complications. Any other reported outcomes will be documented in the descriptive analysis. The review will also describe details of the investigated perioperative tobacco-cessation interventions. If sufficient studies report relevant data, meta-analysis of the primary and secondary outcomes will be undertaken. Results will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: No ethical approval is required. Results will be disseminated by open-access, peer-reviewed journal publication and conference presentations. Results will underpin future work to modify perioperative tobacco-cessation interventions to enhance engagement and accessibility, and to develop trials aiming to facilitate abstinence from tobacco-use in patients presenting for surgery.


Asunto(s)
Fumar Tabaco , Adulto , Humanos , Revisiones Sistemáticas como Asunto , Metaanálisis como Asunto , Complicaciones Posoperatorias/prevención & control
17.
bioRxiv ; 2023 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-37662400

RESUMEN

Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.

18.
Indian J Orthop ; 57(9): 1510-1518, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37609023

RESUMEN

Summary of Background Data: There is a paucity of the literature that aims to improve sagittal plane balance of femoral stem in hip arthroplasty. We have comparatively evaluated the effect of trimming the posterior cortex left in situ after femoral neck osteotomy and counter-clockwise rotation of starting awl with respect to their ability to achieve neutral alignment of femoral stem in sagittal plane. Questions/Purposes: (1) Which of the two techniques under reference is more reliable in achieving a sagittal plane balance of the femoral stem in the femoral canal? (2) Does either of the two techniques have the potential to adversely affect other parameters for the optimum placement of femoral stem? Patients and Methods: This prospective study involved a total of 60 patients (age group of 18 to 60 years) who underwent primary total hip arthroplasty (THA) through a standard posterolateral approach. They were randomized into groups (1) PNCT (n = 30): femoral canal preparation was done by posterior neck cortex trimming method; (2) CCRA (n = 30): femoral canal preparation was done by counter-clockwise rotation of starting awl. Postoperatively, radiographs and computed tomography were obtained and angle of femoral stem with the femoral canal in coronal and sagittal plane, femoral stem tip deviation in coronal and sagittal plane, anteversion of the femoral stem, duration of canal preparation and blood loss were analyzed between the two groups. Results: Based on our results, there is a significantly better sagittal alignment of the femoral stem within the femoral canal, both in terms of angle of the femoral stem with the femoral canal (p < 0.001) and the deviation of the femoral stem tip from the center of the medullary canal (p < 0.001) when the posterior neck cortex was trimmed. Canal preparation by trimming the posterior neck cortex took a mean of 11.93 min (range 8-15 min) against the mean duration of 6.87 min (range; 5 min to 9 min) in the other group (p < 0.001). Conclusion: Trimming the posterior femoral neck cortex after neck osteotomy results in better sagittal plane balance of uncemented straight femoral stem. Level of Evidence: III.

19.
J Glob Antimicrob Resist ; 35: 67-75, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37633420

RESUMEN

OBJECTIVES: Artemisinin (ART) resistance in Plasmodium is threatening the artemisinin combination therapies-the first line of defence against malaria. ART resistance has been established to be mediated by the Plasmodium Kelch13 (PfK13) protein. For the crucial role of PfK13 in multiple pathways of the Plasmodium life cycle and ART resistance, it is imperative that we investigate its interacting partners. METHODS: We recombinantly expressed PfK13-p (Bric a brac/Poxvirus and zinc finger and propeller domains), generating anti-PfK13-p antibodies to perform co-immunoprecipitation assays and probed PfK13 interacting partners. Surface plasmon resonance and pull-down assays were performed to establish physical interactions of representative proteins with PfK13-p. RESULTS: The co-immunoprecipitation assays identified 17 proteins with distinct functions in the parasite life cycle- protein folding, cellular metabolism, and protein binding and invasion. In addition to the overlap with previously identified proteins, our study identified 10 unique proteins. Fructose-biphosphate aldolase and heat shock protein 70 demonstrated strong biophysical interaction with PfK13-p, with KD values of 6.6 µM and 7.6 µM, respectively. Additionally, Plasmodium merozoite surface protein 1 formed a complex with PfK13-p, which is evident from the pull-down assay. CONCLUSION: This study adds to our knowledge of the PfK13 protein in mediating ART resistance by identifying new PfK13 interacting partners. Three representative proteins-fructose-biphosphate aldolase, heat shock protein 70, and merozoite surface protein 1-demonstrated clear evidence of biophysical interactions with PfK13-p. However, elucidation of the functional relevance of these physical interactions are crucial in context of PfK13 role in ART resistance.


Asunto(s)
Antimaláricos , Artemisininas , Malaria Falciparum , Parásitos , Animales , Plasmodium falciparum/genética , Antimaláricos/farmacología , Proteína 1 de Superficie de Merozoito/uso terapéutico , Resistencia a Medicamentos , Proteínas Protozoarias/genética , Mutación , Malaria Falciparum/tratamiento farmacológico , Artemisininas/farmacología , Proteínas HSP70 de Choque Térmico/uso terapéutico , Aldehído-Liasas/uso terapéutico , Fructosa/uso terapéutico
20.
Bioanalysis ; 15(14): 773-814, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37526071

RESUMEN

The 2022 16th Workshop on Recent Issues in Bioanalysis (WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity. Part 1 (Mass Spectrometry and ICH M10) and Part 2 (LBA, Biomarkers/CDx and Cytometry) are published in volume 15 of Bioanalysis, issues 16 and 15 (2023), respectively.


Asunto(s)
Medicamentos bajo Prescripción , Tecnología , Bioensayo/métodos , Biomarcadores/análisis , Tratamiento Basado en Trasplante de Células y Tejidos
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