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Mapping of the mutational landscape of juvenile myelomonocytic leukemia patients by whole exome sequencing
No full textBackground and Aim - Juvenile Myelomonocytic Leukemia(JMML) is a rare myelodysplastic/myeloproliferative neoplasm. The RAS-pathway related genes are most commonly mutated in JMML. Other secondary mutations/alternative pathways are also thought to be involved in the pathogenesis. This study was prospectively done to map the mutational landscape of newly diagnosed and treatment naive JMML patients.
Method - The mutational profile of 38 JMML patients was analysed by whole-exome-sequencing. The DNA from the blood/bone-marrow sample (for somatic mutations) and the buccal swab (for germline mutations) was isolated and sequenced on the Illumina platform at 250x and 100x respectively.
Results - Out of the 38 patients, somatic mutations were found in 34 (89%). These were as follows: PTPN11(n=12) was the most altered gene, followed by NRAS(n=9), KRAS(n=6), NF1(n=4) and CBL(n=3). The germline mutations were detected in 11 patients out of 36 patients (31%) ((NF1=3, KRAS=1, NRAS=2, PTPN11=1, CBL=3, SETBP1=1). Thirteen patients had more than one co-existing somatic mutation in genes known to play a role in hematopoiesis or known to be associated with malignancies. The patients with PTPN11 somatic mutations most commonly had another mutation: PTPN11-SETBP1 (n=4); PTPN11-TP53 (n=1); PTPN11-JAK3 (n=1); PTPN11-ASXL1-EZH2(n=1), PTPN11-SETBP1-ETV-6 (n=1). Other co-existing mutation combinations were NF1-NOTCH1(n=1), NF1-ZRSR2 (n=1), NRAS-CBL (n=1), NRAS-FLT3-ITD-EP300 (n=1) and KRAS-SUSD2 (n=1)
Piezo1 mechanosensing regulates integrin-dependent chemotactic migration in human T cells.
No full textT cells are crucial for efficient antigen-specific immune responses and thus their migration within the body, to inflamed tissues from circulating blood or to secondary lymphoid organs, plays a very critical role. T cell extravasation in inflamed tissues depends on chemotactic cues and interaction between endothelial adhesion molecules and cellular integrins. A migrating T cell is expected to sense diverse external and membrane-intrinsic mechano-physical cues, but molecular mechanisms of such mechanosensing in cell migration are not established. We explored if the professional mechanosensor Piezo1 plays any role during integrin-dependent chemotaxis of human T cells. We found that deficiency of Piezo1 in human T cells interfered with integrin-dependent cellular motility on ICAM-1-coated surface. Piezo1 recruitment at the leading edge of moving T cells is dependent on and follows focal adhesion formation at the leading edge and local increase in membrane tension upon chemokine receptor activation. Piezo1 recruitment and activation, followed by calcium influx and calpain activation, in turn, are crucial for the integrin LFA1 (CD11a/CD18) recruitment at the leading edge of the chemotactic human T cells. Thus, we find that Piezo1 activation in response to local mechanical cues constitutes a membrane-intrinsic component of the ‘outside-in’ signaling in human T cells, migrating in response to chemokines, that mediates integrin recruitment to the leading edge
Carbothermal reduction-induced oxygen vacancies in spinel cathodes for high-performance aqueous zinc-ion batteries
No full textAdvancement of aqueous zinc-ion batteries (AZIBs) for practical application is limited due to the inferior performance of the existing cathode. Herein, we demonstrate rational design and synthesis of an oxygen vacancy-rich low-valent vanadium-based spinel cathode (OV-ZnV2O4) for the fabrication of high-performance AZIBs. ZnV2O4 having an urchin-like morphology with nanorods ∼19 nm in diameter is synthesized carbothermally. The carbothermal reduction induces oxygen vacancies and makes ZnV2O4 ideal for Zn2+ storage. Theoretical studies show the enhancement of electrical conductivity and facile diffusion of charge carriers due to oxygen vacancies. The urchin-like OV-ZnV2O4 delivers a high discharge capacity (599.6 mA h g−1 at 100 mA g−1) and high energy density (371.8 W h kg−1). The device has a decent cycle life of over 2000 cycles at 4000 mA g−1. A series of ex situ characterization studies and operando X-ray characterization reveal that the charge storage mechanism involves the co-intercalation of Zn2+/H+ onto the cathode
In situ metal vacancy filling in stable Pd‐Sn intermetallic catalyst for enhanced C—C bond cleavage in ethanol oxidation
No full textA common challenge in electrochemical processes is developing high performance, stable catalysts for specific chemical reactions. In this work, a Pd-Sn intermetallic compound with Pd site deficiency (Pd1.9-xSn) (x = 0.06) and trace amount of SnOx was synthesised by controlled process. Under the electrochemical conditions, the deficient Pd site is filled by metallic Sn, which generates a highly active and stable (Pd1.84Sn0.06)Sn catalyst for ethanol oxidation reaction (EOR). The crystal structure and atomic arrangements for synthesized and in situ generated compound are comprehensively characterized by various spectroscopic techniques. The in situ generated catalyst exhibits excellent performance toward EOR (anodic reaction in fuel cell), which outperforms the state-of-the-art Pd/C catalyst by three times in terms of activity. Furthermore, it is observed that the catalyst preferentially cleaves the C—C bond in ethanol, which is a crucial process that enhances the efficiency of the fuel cells. The catalyst retains its superlative activity even after 1500 cycles of continuous operation. The mechanism for EOR and C—C bond cleavage is evidenced by operando Infra Red spectroscopy and Differential Electrochemical Mass Spectroscopy (DEMS), and the driving force toward excellent performance has been proposed via theoretical calculations
Neurosurgery residency match for international medical graduates in the United States
No full textOBJECTIVE
Training of international medical graduates (IMGs) offers opportunities for the US neurosurgery community to engage the global talent pool and impact national and international healthcare. Here, the authors analyzed the time trend of IMGs matching into US neurosurgery programs and identified potential opportunities for enhancing IMG engagement.
METHODS
The authors analyzed the National Resident Matching Program (NRMP) match results, NRMP program director (PD) surveys, and applicant surveys from 2013 to 2022. Regression methods were used to analyze time trends.
RESULTS
Between 2013 and 2022, the number of US neurosurgery residency positions increased by 17.6% (from 204 to 240). During this period, the percentage of IMGs matching into neurosurgery increased from 3.5% to 7%, translating into a 6.8% increase in the likelihood of a successful IMG match per year (95% CI 0.3%–13.8%, p = 0.042). The likelihoods of a successful match for US MDs and IMGs scoring > 260 on the USMLE Step 1 were > 90% and approximately 55%, respectively. In PD surveys, approximately 90% of PDs indicated that they seldom/never interview or rank IMGs. In terms of factors that influenced the PD decision for interviewing/ranking, IMGs are disadvantaged in several categories, including the ability to secure an audition elective/rotation, and proper letters of recommendation, as well as the influence of the culture on the preconceived perception of poor interpersonal skills.
CONCLUSIONS
The number of IMGs matching successfully in neurosurgery has increased marginally during the past decade. The authors outline the challenges that IMGs encounter in this process and suggest strategies for considerations of IMG training in NRMP-associated institutions
Clinicoradiological Parameters and Biochemical and Molecular Alterations Predicting Remission and Recurrence After Surgical Treatment of Corticotroph Adenomas—Cushing Disease
No full textObjective
Endonasal endoscopic transsphenoidal surgery (TSS) and resection of pituitary adenomas are considered the gold standard treatment for Cushing disease (CD). Even with various recent advances in management, disease persistence and recurrence are common in these patients. The remission rate in the global population after surgery has been reported to vary widely from 64% to 93%. This study aims to determine the various clinical, biochemical, radiological, and histological factors that correlate with persistence and recurrence in patients with CD. This study also aims to understand the clinicopathological significance of EGFR-MAPK, NF-κB, and SHH pathway activation and to study the protein expression of activation markers of these pathways (i.e., c-Fos, c-Jun, GLI-1, pMEK, NR4A1, and p44) in functioning corticotroph pituitary adenomas.
Methods
From January 2009 to September 2022, the clinical data of 167 patients who underwent surgical treatment (n = 174 surgeries) for CD with a median follow-up of 8.1 years (range, 1–13.29 years) were ambispectively analyzed. The preoperative clinical, biochemical, and radiological features, operative findings, postoperative clinical and biochemical data, and histopathological and molecular profiles were retrieved from the electronic medical records. The patients were followed up to assess their remission status.
Results
Among the 174 surgeries performed, 140 were primary surgeries, 22 were revision surgeries, 24 surgeries were for pediatric patients, and 12 surgeries were for patients with Nelson syndrome. In the primary surgery cohort, 74.3% were female, and the average age was 28.73 ± 10.15 years. Of the primary surgery cohort, 75% of the patients experienced remission compared with 47.4% after revision surgery. The remission rate for the pediatric patients was 55.5%. The postoperative day 1 plasma cortisol (P < 0.001; area under the curve, 0.8894; range, 0.8087–0.9701) and adrenocorticotropic hormone (P < 0.001; area under the curve, 0.9; range, 0.7386–1) levels were seen to be strong independent predictors of remission in the primary surgery cohort. The remission rate after endoscopic TSS was greater than that after microscopic TSS in patients undergoing primary surgery (81.08% vs. 57.14%; P = 0.008). The presence of adenoma on histopathological examination (HPE) was also a strong predictor of disease remission (P = 0.020). On stratifying by surgical approach and HPE, microscopically operated patients without histopathological evidence of adenoma had significantly higher odds of nonremission (odds ratio, 38.1; 95% confidence interval, 4.2–348.3) compared with endoscopically operated patients with adenoma found on HPE. A lower immunoreactivity score for NR4A1 was found to correlate with higher remission rates (P = 0.074). However, none of the molecular markers studied (i.e., c-Fos, c-Jun, GLI-1, pMEK, and p44) showed a significant correlation with the preoperative cortisol values.
Conclusions
The remission rate after primary surgery is higher than that after revision surgery and is lower for pediatric patients than for adults. The postoperative day 1 plasma cortisol and adrenocorticotropic hormone levels are strong independent predictors of remission in the primary surgery cohort. An endoscopic approach with histopathological evidence of adenoma is associated with a higher remission rate; thus, endoscopy should be the approach of choice for these patients with the goal of identification of an adenoma on HPE
A Comparison of Gradient-Based Optimization Techniques in Magnetic Resonance Elastography
No full textMagnetic Resonance Elastography (MRE) involves the solution of an inverse problem as a PDE-constrained optimization problem to determine the unknown material model parameters by utilizing the full-field displacement data. Levenberg–Marquardt (LM) within the Gauss–Newton’s methods and Broyden–Fletcher–Goldfarb–Shanno (BFGS) algorithm within the Quasi-Newton methods are the two most commonly used gradient-based optimization techniques for solving the inverse problem of MRE. A comparison between their performance and efficiency is lacking in the literature. The present study demonstrates the application of these two techniques for solving the inverse problem. A two-dimensional linear elastic boundary value problem under plane strain condition was considered for generating the synthetic displacement field data for the MRE. The performance of both LM and BFGS algorithms has been compared based on metrics such as accuracy, convergence, and computation cost. It has been observed that LM converges faster than the BFGS method with higher reconstruction accuracy. However, as the number of model parameters increases, the computational cost associated with the LM method significantly outweighs that of the BFGS method. An alternative strategy based on the sub-domain approach coupled with the LM method demonstrated high efficacy, even for a large number of model parameters. The proposed approach can also be deployed to large-scale optimization problems in other engineering domains
Drought Atlas of India, 1901–2020
No full textIndia has been considerably affected by droughts in the recent past. Despite the considerable impacts of droughts on agriculture and water resources, long-term datasets to examine droughts and their consequences at appropriate spatial and temporal scales have been lacking in India. Datasets that provide drought information are mostly available for a short period and at coarser resolutions, therefore, these do not comprehend the information regarding the major droughts that occurred in the distant past at administrative scales of decision-making. To fill this critical gap, we developed the high-resolution (0.05°) and long-term monthly precipitation and temperature datasets for the 1901–2021 period. We used long-term high-resolution precipitation and temperature to estimate droughts using standardized precipitation and evapotranspiration index (SPEI). As SPEI considers the role of air temperature in drought estimation, it can be used to examine meteorological, agricultural, and hydrological droughts. Using high-resolution SPEI, we developed drought atlas for India (1901–2020) that can provide comprehensive information on drought occurrence, impacts, and risks in India
Flood risk assessment for Indian sub-continental river basins
No full textFloods are among India's most frequently occurring natural disasters, which disrupt all aspects of socio-economic well-being. A large population is affected by floods, which leave their footprints through human mortality, migration, and damage to agriculture and infrastructure, during almost every summer monsoon season in India. Despite the massive imprints of floods, sub-basin level flood risk assessment is still in its infancy and requires advancements. Using hydrological and hydrodynamic models, we reconstructed sub-basin level observed floods for the 1901–2020 period. Our modeling framework includes the influence of 51 major reservoirs that affect flow variability and flood inundation. Sub-basins in the Ganga and Brahmaputra river basins witnessed substantial flood inundation extent during the worst flood in the observational record. Major floods in the sub-basins of the Ganga and Brahmaputra occur during the late summer monsoon season (August–September). While the Beas, Brahmani, upper Satluj, upper Godavari, middle and lower Krishna, and Vashishti are among the sub-basins influenced by the presence of dams on downstream flood dynamics, the Beas, Brahmani, Ravi, and lower Satluj sub-basins are the most impacted by floods and the presence of dams. Bhagirathi, Gandak, Kosi, lower Brahmaputra, and Ghaghara are India's sub-basins with the highest flood risk. Our findings have implications for flood risk assessment and mitigation in India