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2.
Plant Biotechnol J ; 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38875130

RESUMEN

Epistasis refers to nonallelic interaction between genes that cause bias in estimates of genetic parameters for a phenotype with interactions of two or more genes affecting the same trait. Partitioning of epistatic effects allows true estimation of the genetic parameters affecting phenotypes. Multigenic variation plays a central role in the evolution of complex characteristics, among which pleiotropy, where a single gene affects several phenotypic characters, has a large influence. While pleiotropic interactions provide functional specificity, they increase the challenge of gene discovery and functional analysis. Overcoming pleiotropy-based phenotypic trade-offs offers potential for assisting breeding for complex traits. Modelling higher order nonallelic epistatic interaction, pleiotropy and non-pleiotropy-induced variation, and genotype × environment interaction in genomic selection may provide new paths to increase the productivity and stress tolerance for next generation of crop cultivars. Advances in statistical models, software and algorithm developments, and genomic research have facilitated dissecting the nature and extent of pleiotropy and epistasis. We overview emerging approaches to exploit positive (and avoid negative) epistatic and pleiotropic interactions in a plant breeding context, including developing avenues of artificial intelligence, novel exploitation of large-scale genomics and phenomics data, and involvement of genes with minor effects to analyse epistatic interactions and pleiotropic quantitative trait loci, including missing heritability.

3.
J Neurosci Rural Pract ; 15(2): 169-181, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38746527

RESUMEN

With advances in magnetic resonance imaging (MRI) sequences, there has been increased identification of microbleed/microhemorrhage across different population ages, but more commonly in the older age group. These are defined as focal areas of signal loss on gradient echo MRI sequences (T2* and susceptibility-weighted images), which are usually <5 mm in size representing hemosiderin deposition with wide ranges of etiologies. Susceptibility-weighted imaging (SWI) has become a routine MRI sequence for practices across the globe resulting in better identification of these entities. Over the past decade, there has been a better understanding of the clinical significance of microbleeds including their prognostic value in ischemic and hemorrhagic stroke. Cerebral amyloid angiopathy and hypertension are the two most common causes of microbleeds following peripheral and central pattern, respectively. In the younger age group, microbleeds are more common due to familial conditions or a wide range of hypercoagulable states. This review outlines the pathophysiology, prevalence, and clinical implications of cerebral microhemorrhage along with a brief discussion about the technical considerations of SWI.

4.
Circulation ; 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38695173

RESUMEN

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

5.
Small ; : e2402155, 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38795001

RESUMEN

Two-dimensional (2D) materials exhibit the potential to transform semiconductor technology. Their rich compositional and stacking varieties allow tailoring materials' properties toward device applications. Monolayer to multilayer gallium sulfide (GaS) with its ultraviolet band gap, which can be tuned by varying the layer number, holds promise for solar-blind photodiodes and light-emitting diodes as applications. However, achieving commercial viability requires wafer-scale integration, contrasting with established, limited methods such as mechanical exfoliation. Here the one-step synthesis of 2D GaS is introduced via metal-organic chemical vapor deposition on sapphire substrates. The pulsed-mode deposition of industry-standard precursors promotes 2D growth by inhibiting the vapor phase and on-surface pre-reactions. The interface chemistry with the growth of a Ga adlayer that results in an epitaxial relationship is revealed. Probing structure and composition validate thin-film quality and 2D nature with the possibility to control the thickness by the number of GaS pulses. The results highlight the adaptability of established growth facilities for producing atomically thin to multilayered 2D semiconductor materials, paving the way for practical applications.

7.
Int J Biol Macromol ; 271(Pt 2): 132426, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38820904

RESUMEN

Eye-related diseases, specifically retinal dystrophy (RD) conditions, are the leading cause of blindness worldwide. Gene addition, regulation, or editing could potentially treat such diseases through gene expression regulation. CRISPR/Cas9 gene editing is one of the most prominent and precise gene editing tools which could be employed to edit genes related to the dystrophic condition. However, CRISPR/Cas9 faces in vivo delivery challenges due to its high molecular weight, negative charge, prone to degradation in the presence of nucleases and proteases, poor cellular degradation, etc., which makes it challenging to adopt for therapeutic applications. We developed cRGD-modified lipopolymeric nanoplexes loaded with Cas9 RNPs with a particle size and zeta potential of 175 ±â€¯20 nm and 2.15 ±â€¯0.9 mV, respectively. The cRGD-modified lipopolymeric nanoplexes were stable for 194 h and able to transfect >70 % ARPE-19 and NIH3T3 cells with an Indel frequency of ~40 % for the VEGF-A gene. The cRGD-modified lipopolymeric nanoplexes found good vitreous mobility and could transfection retinal cells in vivo after 48 h of intravitreal injection in Wistar Rats. Moreover, in vivo VEGFA gene editing was ~10 % with minimal toxicities. Collectively, the cRGD-modified lipopolymeric nanoplexes were found to have extreme potential in delivering CRISPR/Cas9 RNPs payload to the retinal tissues for therapeutic applications.

8.
Thromb Res ; 238: 117-128, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38703585

RESUMEN

Previous research has identified intravascular platelet thrombi in regions affected by myocardial ischemia-reperfusion (MI/R) injury and neighbouring areas. However, the occurrence of arterial thrombosis in the context of MI/R injury remains unexplored. This study utilizes intravital microscopy to investigate carotid artery thrombosis during MI/R injury in rats, establishing a connection with the presence of prothrombotic cellular fibronectin containing extra domain A (CFN-EDA) protein. Additionally, the study examines samples from patients with coronary artery disease (CAD) both before and after coronary artery bypass grafting (CABG). Levels of CFN-EDA significantly increase following MI with further elevation observed following reperfusion of the ischemic myocardium. Thrombotic events, such as thrombus formation and growth, show a significant increase, while the time to complete cessation of blood flow in the carotid artery significantly decreases following MI/R injury induced by ferric chloride. The acute infusion of purified CFN-EDA protein accelerates in-vivo thrombotic events in healthy rats and significantly enhances in-vitro adenosine diphosphate and collagen-induced platelet aggregation. Treatment with anti-CFN-EDA antibodies protected the rat against MI/R injury and significantly improved cardiac function as evidenced by increased end-systolic pressure-volume relationship slope and preload recruitable stroke work compared to control. Similarly, in a human study, plasma CFN-EDA levels were notably elevated in CAD patients undergoing CABG. Post-surgery, these levels continued to rise over time, alongside cardiac injury biomarkers such as cardiac troponin and B-type natriuretic peptide. The study highlights that increased CFN-EDA due to CAD or MI initiates a destructive positive feedback loop by amplifying arterial thrombus formation, potentially exacerbating MI/R injury.


Asunto(s)
Fibronectinas , Daño por Reperfusión Miocárdica , Trombosis , Animales , Daño por Reperfusión Miocárdica/patología , Ratas , Humanos , Masculino , Trombosis/etiología , Trombosis/sangre , Trombosis/patología , Fibronectinas/metabolismo , Ratas Sprague-Dawley , Femenino , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/sangre , Anciano
9.
Org Biomol Chem ; 22(21): 4292-4296, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38717327

RESUMEN

Sulfinyls are valuable structural moieties used for developing synthetically new pharmaceuticals and agrochemicals. Herein, we disclose a straightforward synthesis of sulfinylated spiro[5.5]trienones proceeding via an unprecedented BF3·Et2O-promoted spirocyclization of biaryl ynones. The availability of relatively inexpensive BF3·Et2O to carry out transformations on a bulk scale along with its further application towards the synthesis of dibenzocyclohepten-5-ones delivers a unique opportunity to deploy it in various synthetic directions.

10.
Cureus ; 16(4): e57846, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38721161

RESUMEN

AIM AND OBJECTIVE: This questionnaire study aimed to evaluate the impact of a short educational session on the early diagnosis and management of acute kidney injury (AKI) among doctors specializing in fields other than nephrology, assessed through pre- and post-test scores. This educational study included resident doctors from various specialties for assessment. MATERIALS AND METHODS: The study enrolled different specialty resident doctors' departments and assessed them through questionnaires and assessment scores. The pre-test questionnaires were first distributed and collected after 20 minutes. This was followed by a 30-minute short educational lecture on AKI by the nephrology faculty about its early diagnosis and management as per the Kidney Disease Improving Global Outcomes guidelines. Immediately post continuing medical education, the same questionnaires were distributed along with feedback forms and collected after 10 minutes. RESULTS: A total of 110 residents participated in the study. All participants showed significant improvement in the post-lecture questionnaires compared to pre-lecture scores. For medicine and allied branch residents, the pre- and post-lecture scores were significantly higher than those of the surgical and allied branch residents. The lowest score was observed in residents of orthopedics. The improvement scores of all departments also showed significant differences. The highest improvement was seen in the department of gynecology, followed by residents of the critical care unit and the department of anesthesia. The residents of those departments with high pre- and post-test scores had lower improvement scores. CONCLUSION: The study found a significant knowledge gap in different sister specialties in diagnosing and managing AKI. Short educational sessions showed significant improvement in AKI understanding by addressing the knowledge gaps.

11.
Curr Diabetes Rev ; 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38706367

RESUMEN

BACKGROUND: Diabetes Mellitus (DM) is an alarming health concern, affecting approximately 537 million people worldwide. As a leading cause of morbidity and mortality, DM demands a comprehensive understanding of its diverse pathophysiological mechanisms and disease progression. METHODS: This traditional review has consolidated literature on the pathogenesis of hyperglycemia, its progression into complications, and advances in optimal treatment strategies. The literature in the last two decades has been reviewed using several keywords, including "diabetes," "diabetes-associated complications", "novel therapeutic interventions for diabetes-associated diseases", "phyto-extracts as antidiabetic drugs", etc. in prominent databases, such as PubMed, Scopus, Google Scholar, Web of Science, and ClinicalTrials.gov. RESULTS: We have discussed macrovascular and microvascular complications, such as atherosclerosis, cardiovascular disease, Peripheral Arterial Disease (PAD), stroke, diabetic nephropathy, retinopathy, and neuropathy, as well as various pharmacological and non-pharmacological interventions that are currently available for the management of DM. We have also focused on the potential of natural products in targeting molecular mechanisms involved in carbohydrate metabolism, insulin production, repair of pancreatic cells, and reduction of oxidative stress, thereby contributing to their antidiabetic activity. Additionally, novel therapeutic approaches, like genetic, stem cell, and immunomodulatory therapies, have been explored. We have also discussed the benefits and limitations of each intervention, emerging research and technologies, and precision medicine interventions. CONCLUSION: This review has emphasized the need for an improved understanding of these advancements, which is essential to enhance clinicians' ability to identify the most effective therapeutic interventions.

12.
Brain Behav ; 14(2): e3415, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38687552

RESUMEN

INTRODUCTION: Previous studies have reported a decreased risk of dementia with herpes zoster vaccination. Given this background, this systematic review and meta-analysis aimed to investigate the association between herpes zoster vaccination and the risk of dementia. METHODS: We searched five databases until November 2023 for case-control, cross-sectional, or cohort studies investigating the association of herpes zoster vaccination and dementia. Odds ratios and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Meta-regression, subgroup, and sensitivity analysis were also conducted. RESULTS: We evaluated a total of five studies (one cross-sectional, one case-control, and four cohort studies) that included a total number of 103,615 patients who were vaccinated with herpes zoster vaccine. All the studies were of high quality, ranging from 7 to 9. Due to the high heterogeneity (I2 = 100%, p < .00001) observed in our study, a random effect model was used for the analysis. The pooled odds ratio was 0.84 (95% CI: 0.50, 1.43), p (overall effect) = .53), indicating that herpes zoster vaccination reduces the risk of dementia. CONCLUSION: Herpes zoster vaccination is associated with a reduction of the risk of dementia. More epidemiological studies are needed to confirm the association.


Asunto(s)
Demencia , Vacuna contra el Herpes Zóster , Herpes Zóster , Humanos , Demencia/epidemiología , Demencia/prevención & control , Vacuna contra el Herpes Zóster/administración & dosificación , Herpes Zóster/prevención & control , Herpes Zóster/epidemiología , Vacunación/estadística & datos numéricos
13.
Br Dent J ; 236(7): 507, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38609593
15.
Cardiol Rev ; 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38666777

RESUMEN

Iron deficiency is a common comorbidity in heart failure (HF) patients, with up to 50% of ambulatory patients with HF affected. Intravenous (IV) iron therapy has emerged as a promising treatment approach for HF patients with concomitant iron deficiency. This review summarizes the current literature on the use of IV iron therapy in HF patients, focusing on its benefits in improving quality of life, and exercise capacity, and reducing HF hospitalizations. However, concerns about the long-term cardiotoxic effects of IV iron, including the risk of iron overload, are also addressed. The review highlights the importance of a balanced approach to iron replacement and provides an overview of the 2022 American College of Cardiology/American Heart Association guidelines, which recommend IV iron therapy for eligible patients. Additionally, the review underscores the need for further research, particularly in HF patients with preserved ejection fraction and acute HF. While IV iron therapy shows promise, questions about its safety and specific formulations remain to be fully addressed.

16.
Cureus ; 16(3): e56297, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38629013

RESUMEN

Hypoglycemia is common in diabetic populations using insulin or insulin secretagogues, but rare in non-diabetics. A 60-year-old non-diabetic male presented with repeated episodes of abnormal behavior persisting for 10-15 minutes for seven days, associated with sweating, intense hunger, and relief on food intake, with no history of insulin or secretagogue intake, with stable vitals and normal systemic examination. Laboratory tests during attacks revealed low blood sugar, high serum insulin, and normal C-peptide levels, with no evidence of pancreatic or extrapancreatic hyperinsulinism, and serum anti-insulin antibody levels >100 U/ml. Based on these results, he was diagnosed with autoimmune insulin syndrome (AIS). Treatment with low-carb meals, oral prednisolone, and acarbose led to the resolution of symptoms. Hirata syndrome, though rare in India, requires consideration as a differential diagnosis to avoid unnecessary invasive procedures.

17.
Immun Inflamm Dis ; 12(4): e1254, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38639563

RESUMEN

INTRODUCTION: Human leukocyte antigen-G (HLA-G) is a non-classical class I HLA molecule shown to regulate the immunomodulation of maternal immune cells to prevent fetal tissue destruction. Low levels of freely circulating maternal soluble HLA-G (sHLA-G) have been observed in pre-eclampsia, however, no pooled evidence exists. This meta-analysis aimed to generate pooled findings on the association of sHLA-G levels with pre-eclampsia and is the first study to perform a trimester-wise comparison of the levels of sHLA-G in preeclamptic cases and normal pregnant controls. METHODS: The databases PubMed, Emba, Web of Science, and Google Scholar through May 31, 2023. Preeclamptic women were defined as cases and normal pregnancies as controls. Data on the level of sHLA-G in cases and controls was extracted and subjected to a meta-analysis using a random-effects model. The pooled effect was expressed in terms of standardized mean difference (SMD). Sensitivity analysis was performed to investigate the effect of the exclusion of each study on the pooled results. Publication bias was assessed statistically. RESULTS: Nine studies with altogether 567 PE cases and 1132 normal pregnancy controls were included in the meta-analysis. The first and third trimester levels of sHLA-G in PE cases were significantly lower than that of normal pregnant controls: (SMD: -0.84 [-1.29; -0.38]; p = .003; I2 = 54%) and (SMD: -0.39 [-0.71; -0.06]; p = .02; I2 = 79%) respectively. Sensitivity analysis revealed significant fluctuations in the pooled findings when few studies were excluded, raising questions on the consistency of results among studies. CONCLUSION: Although we found that first and third-trimester sHLA-G levels in pre-eclampsia are significantly lower, taking into consideration the inconsistent results from the sensitivity analysis, our findings advocate the demand for more studies with larger sample sizes to generate solid ground pooled evidence on the predictive role of sHLA-G in pre-eclampsia.


Asunto(s)
Preeclampsia , Embarazo , Humanos , Femenino , Antígenos HLA-G , Feto , Biomarcadores
18.
J Nepal Health Res Counc ; 21(4): 689-691, 2024 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-38616605

RESUMEN

Endometrioma is the localization of endometriosis in ovary which often develops as cyst. The condition can be complicated with infection, torsion and rupture leading to significant hemoperitoneum and ascites. We present here a 28-year female P2 L1 presented with the features of acute abdomen and severe anemia referred from other hospital where pain management was done. She had raised Ca-125 level, negative Urine Beta HCG and USG findings of left endometrioma with degenerating subserosal fibroid. The improvement of her general condition with analgesics was misleading however a static hematocrit level despite blood transfusion raised suspicion of ongoing pathology leading to blood loss and diagnostic paracentesis confirmed the hemoperitoneum while awaiting of CT report. She underwent Emergency Laparotomy which revealed hemoperitoneum of 2000ml and right ruptured ovarian endometrioma measuring and left ovarian cyst measuring 6x6 cm was noted. The postoperative period was uneventful. Keywords: Acute abdomen; case report; endometriosis; hemoperitoneum; ruptured endometrioma.


Asunto(s)
Abdomen Agudo , Endometriosis , Femenino , Humanos , Abdomen Agudo/etiología , Abdomen Agudo/cirugía , Endometriosis/complicaciones , Endometriosis/cirugía , Hemoperitoneo/etiología , Hemoperitoneo/cirugía , Laparotomía , Nepal , Adulto
19.
Health Prospect ; 23(1): 1-10, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38645301

RESUMEN

Background: Suicidal thoughts and behaviors (STBs) are prevalent within the Lesbian, Gay, Bisexual, Transgender, and Queers (LGBTQ) community, often exacerbated by challenges in accessing care and the perceived stigma and discrimination tied to disclosing one's identity. Digital health interventions that offer psychosocial self-help present a promising platform to reach individuals at risk of STBs, especially those who may not engage with conventional health services. This review aimed to assess the role of digital-based intervention in reducing STBs among LGBTQ individuals. Methods: We conducted a systematic literature search from three databases, PsycINFO, PubMed, and CINHAL, from 1st Jan 1990 to 31st December 2023. The review encompassed studies investigating the feasibility, acceptability, and impact of digital interventions on STBs, employing randomized control trials (RCTs), pseudo-RCTs, observational pre-posttest designs, and qualitative studies. Potential bias was evaluated using the McGill Mixed Methods Appraisal Tool (MMAT). Results: Five non-overlapping studies were included, reporting data from 777 participants. The studies featured diverse types of digital interventions, including videos, online writing, and mobile applications. The studies included three RCTs, and two qualitative studies. Across most of these studies, notable enhancements or reductions in the proportion of participants reporting STBs were observed post-intervention, alongside improvements in help-seeking intentions. The findings underscored that the applications used in the studies were engaging, acceptable, and deemed feasible in effectively addressing suicide prevention among the LGBTQ community. Conclusion: Overall, digital interventions were found to be feasible and acceptable in suicide prevention among LGBTQ communities, demonstrating preliminary efficacy in increasing help-seeking behavior when experiencing suicidal thoughts and in reducing STBs. Therefore, advocating for widespread promotion and dissemination of digital health interventions is crucial, particularly in low- and middle-income countries (LMICs) with limited access to health services and heightened barriers to obtaining such services. Further research using fully powered RCT is imperative to assess the efficacy of these interventions.

20.
Int J Surg ; 110(4): 2355-2365, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38668663

RESUMEN

BACKGROUND: Sepsis syndromes are a major burden in the ICU with very high mortality. Vasopressin and copeptin are released in response to hypovolemia and have shown potential significance in diagnosing sepsis. OBJECTIVE: To investigate the levels of copeptin in patients with sepsis syndromes and evaluate its relation with patient prognosis and mortality. METHODS: Four databases were searched for literature published from inception to the 8th of November 2022. Original research articles where copeptin was measured in sepsis patients and compared with controls were included. Data extraction and synthesis: study characteristics, levels of copeptin in the participants, and copeptin assay description were extracted. Levels of copeptin in patients were pooled and compared with controls in terms of the standard mean difference (SMD) generated using a random-effects model. RESULTS: Fifteen studies met the selection criteria. Copeptin levels were significantly higher in patients with sepsis, severe sepsis, and septic shock as compared to controls [(SMD: 1.49, 95% CI: 0.81-2.16, P<0.0001), (SMD: 1.94, 95% CI: 0.34-3.54, P=0.02), and (SMD: 2.17, 95% CI: 0.68-3.66, P=0.004), respectively]. The highest copeptin levels were noted in septic shock patients. The admission copeptin levels were significantly lower in survivors as compared to nonsurvivors (SMD: -1.73; 95% CI: -2.41 to -1.06, P<0.001). CONCLUSION AND RELEVANCE: Copeptin was significantly elevated in sepsis, severe sepsis, and septic shock. Survivors had a significantly lower copeptin during admission. Copeptin offered an excellent predictability to predict 1-month mortality. Measuring the copeptin in sepsis patients can aid treating physicians to foresee patients' prognosis.


Asunto(s)
Glicopéptidos , Sepsis , Humanos , Glicopéptidos/sangre , Pronóstico , Sepsis/mortalidad , Sepsis/sangre , Sepsis/diagnóstico , Biomarcadores/sangre
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