Design and Development of Stable Nanocrystalline High-Entropy Alloy: Coupling Self-Stabilization and Solute Grain Boundary Segregation Effects.

Grain growth is prevalent in nanocrystalline (NC) materials at low homologous temperatures. Solute element addition is used to offset excess energy that drives coarsening at grain boundaries (GBs), albeit mostly for simple binary alloys. This thermodynamic approach is considered complicated in multi-component alloy systems due to complex pairwise interactions among alloying elements. Guided by empirical and GB-segregation enthalpy considerations for binary-alloy systems, a novel alloy design strategy, the "pseudo-binary thermodynamic" approach, for stabilizing NC-high entropy alloys (HEAs) and other multi-component-alloy variants is proposed. Using Al25Co25Cr25Fe25 as a model-HEA to validate this approach, Zr, Sc, and Hf, are identified as the preferred solutes that would segregate to HEA-GBs to stabilize it against growth. Using Zr, NC-Al25Co25Cr25Fe25 HEAs with minor additions of Zr are synthesized, followed by annealing up to 1123 K. Using advanced characterization techniques- in situ X-ray diffraction (XRD), scanning/transmission electron microscopy (S/TEM), and atom probe tomography, nanograin stability due to coupling self-stabilization and solute-GB segregation effects is reported in HEAs up to substantially high temperatures. The self-stabilization effect originates from the preferential GB-segregation of constituent HEA-elements that stabilizes NC-Al25Co25Cr25Fe25 up to 0.5Tm (Tm-melting temperature). Meanwhile, solute-GB segregation originates from Zr segregation to NC-Al25Co25Cr25Fe25 GBs; this results in further stabilization of the phase and grain-size (≈14 nm) up to ≈0.58 and ≈0.64Tm, respectively.

Potent competitive inhibition of human ribonucleotide reductase by a nonnucleoside small molecule.

Human ribonucleotide reductase (hRR) is crucial for DNA replication and maintenance of a balanced dNTP pool, and is an established cancer target. Nucleoside analogs such as gemcitabine diphosphate and clofarabine nucleotides target the large subunit (hRRM1) of hRR. These drugs have a poor therapeutic index due to toxicity caused by additional effects, including DNA chain termination. The discovery of nonnucleoside, reversible, small-molecule inhibitors with greater specificity against hRRM1 is a key step in the development of more effective treatments for cancer. Here, we report the identification and characterization of a unique nonnucleoside small-molecule hRR inhibitor, naphthyl salicylic acyl hydrazone (NSAH), using virtual screening, binding affinity, inhibition, and cell toxicity assays. NSAH binds to hRRM1 with an apparent dissociation constant of 37 µM, and steady-state kinetics reveal a competitive mode of inhibition. A 2.66-Å resolution crystal structure of NSAH in complex with hRRM1 demonstrates that NSAH functions by binding at the catalytic site (C-site) where it makes both common and unique contacts with the enzyme compared with NDP substrates. Importantly, the IC50 for NSAH is within twofold of gemcitabine for growth inhibition of multiple cancer cell lines, while demonstrating little cytotoxicity against normal mobilized peripheral blood progenitor cells. NSAH depresses dGTP and dATP levels in the dNTP pool causing S-phase arrest, providing evidence for RR inhibition in cells. This report of a nonnucleoside reversible inhibitor binding at the catalytic site of hRRM1 provides a starting point for the design of a unique class of hRR inhibitors.

Beyond Traditional Training: Exploring the Benefits of Virtual Reality Simulator in Lumbar Pedicle Screw Insertion - A Randomized Controlled Trial.

INTRODUCTION: This study compares the effectiveness of virtual reality simulators (VRS) and a saw bone model for learning lumbar pedicle screw insertion (LPSI) in neurosurgery. METHODS: A single-center, cross-sectional, randomized controlled laboratory investigation was conducted involving residents and fellows from a tertiary care referral hospital. Participants were divided into two groups (A and B). Group A performed 3 LPSI tasks: the first on a saw bone model, the second on VRS, and the third on another saw bone model. Group B completed 2 LPSI tasks: the first on a saw bone model and the second on another saw bone model. The accuracy of LPSI was evaluated through noncontrast computed tomography scans for the saw bone models, while the in-built application of VRS was utilized to check for accuracy of screw placement using the simulator. RESULTS: The study included 38 participants (19 in each group). Group A participants showed reduced mean entry point error (0.11 mm, P 0.024), increased mean purchase length (4.66 cm, P 0.007), and no cortical breaches (P 0.031) when placing the second saw bone model screw. Similar improvements were observed among group A participants in PGY 1-3 while placing the second saw bone model screws. CONCLUSIONS: Virtual reality simulators (VRS) prove to be an invaluable tool for teaching complex neurosurgical skills, such as LPSI, to trainees. This technology investment can enhance the learning curve while maintaining patient safety.

Polidocanol sclerotherapy for the treatment of aneurysmal bone cyst, with or without pathological fractures: A prospective, comparative study.

Introduction: Polidocanol sclerotherapy in the treatment of aneurysmal bone cysts (ABCs) with or without pathological fractures has been a topic of debate. While some studies recommend intralesional curettage as the preferred treatment, others suggest intralesional sclerosants as an effective alternative. Material and methods: This study evaluates the use of polidocanol-based percutaneous sclerosant therapy in 28 patients with ABCs, of which 8 patients had pathological fracture. The patients received injections every four weeks based on clinical and radiological evaluation of the cyst, and the study assessed the results and complications of the treatment. Results: In group A (without pathological fractures), 14 out of 17 (82.4 %) lesions healed without any significant residual lesion. Three out of 17 (17.6 %) patients required further surgical intervention and were treated by curettage and bone grafting, definitively. Minor local inflammatory reaction was observed in 3 patients, which resolved without intervention within 3-4 days. In group B, all the 8 patients (100 %) with pathological fracture in their lesions healed as Grade 1 healing, without any significant residual lesion. One patient developed an episode of anesthesia related complication (delayed recovery) which resolved within an hour, without any residual effect. At final follow up, no recurrence was seen in any patient. Conclusion: The study concludes that polidocanol sclerotherapy is an effective treatment option for patients with ABCs, with or without pathological fractures, and has the potential to become the new treatment of choice for pathological fractures due to its low invasiveness, low morbidity, and affordability. However, further research is needed to confirm the efficacy of polidocanol sclerotherapy in larger patient populations and to compare its effectiveness with other treatment options.

Analysis of Distance of Frontal Sinus Ostium from Columella by CT PNS: Our Experience.

Introduction: Knowledge of variable anatomy, narrow frontal sinus ostium and vital anatomical structures near outflow tract, is very important during preoperative planning for exposure of the frontal sinus recess during endoscopic sinus surgery. Preoperative knowledge of distance of nasofrontal beak and anterior skull base from columella is very helpful in avoiding intraoperative complication by deeper penetration into cranial cavity. Aim: To analyse distance from columella to the anterior and posterior border of the Frontal sinus ostium in males and females by CT PNS. Materials and methods: This retrospective observational study carried out in katihar medical college, Katihar during the period of 01 July 2021 to 31 December 2021 including 31 patients. Result and Conclusion: A distance approx 60.9 mm in men and 57.34 mm in women from the columella to frontal sinus ostium is safe during endoscopic sinus surgery.

Short- and Long-Term Effects of Drought on Selected Causes of Mortality in Northern Bangladesh.

Drought has exacerbated morbidity and mortality worldwide. Here, a time series study was conducted in northern Bangladesh to evaluate the impact of drought on selected causes of mortality during 2007-2017. Rainfall and temperature data from six meteorological stations were used to analyze drought and non-drought periods and to categorize mild, moderate, severe, and extreme drought based on the 3-month and 12-month Standardized Precipitation Index (SPI) and Standardized Precipitation Evaporation Index (SPEI). A generalized linear model with Poisson regression with log link, a negative binomial with log link, and a zero-inflated Poisson model were used to determine associations between drought severity and mortality. The SPI and SPEI produced slightly different analysis results. Compared with the SPEI, the SPI showed a stronger and more sensitive correlation with mortality. The relative risk for respiratory disease mortality was high, and Saidpur was the most vulnerable area. Health care expenditure was negatively associated with mortality. High temperatures during the drought period were associated with suicide-related mortality in Rajshahi. The impact of drought on mortality differed with small changes in climate. The findings of this study improve our understanding of the differences between the two most used drought indicators and the impact of drought on mortality.

Effect of Various Electron and Hole Transport Layers on the Performance of CsPbI3-Based Perovskite Solar Cells: A Numerical Investigation in DFT, SCAPS-1D, and wxAMPS Frameworks.

CsPbI3 has recently received tremendous attention as a possible absorber of perovskite solar cells (PSCs). However, CsPbI3-based PSCs have yet to achieve the high performance of the hybrid PSCs. In this work, we performed a density functional theory (DFT) study using the Cambridge Serial Total Energy Package (CASTEP) code for the cubic CsPbI3 absorber to compare and evaluate its structural, electronic, and optical properties. The calculated electronic band gap (E g) using the GGA-PBE approach of CASTEP was 1.483 eV for this CsPbI3 absorber. Moreover, the computed density of states (DOS) exhibited the dominant contribution from the Pb-5d orbital, and most charges also accumulated for the Pb atom as seen from the electronic charge density map. Fermi surface calculation showed multiband character, and optical properties were computed to investigate the optical response of CsPbI3. Furthermore, we used IGZO, SnO2, WS2, CeO2, PCBM, TiO2, ZnO, and C60 as the electron transport layers (ETLs) and Cu2O, CuSCN, CuSbS2, Spiro-MeOTAD, V2O5, CBTS, CFTS, P3HT, PEDOT:PSS, NiO, CuO, and CuI as the hole transport layers (HTLs) to identify the best HTL/CsPbI3/ETL combinations using the SCAPS-1D solar cell simulation software. Among 96 device structures, the best-optimized device structure, ITO/TiO2/CsPbI3/CBTS/Au, was identified, which exhibited an efficiency of 17.9%. The effect of the absorber and ETL thickness, series resistance, shunt resistance, and operating temperature was also evaluated for the six best devices along with their corresponding generation rate, recombination rate, capacitance-voltage, current density-voltage, and quantum efficiency characteristics. The obtained results from SCAPS-1D were also compared with wxAMPS simulation results.

Managing Traumatic Brain Injury During the Coronavirus Disease 2019 Pandemic-A Case-Matched Controlled Analysis of Immediate Outcomes.

OBJECTIVE: The primary objective of this study was to evaluate the outcome of patients with traumatic brain injury (TBI) during the coronavirus disease 2019 (COVID-19) pandemic and to compare their outcome with case-matched controls from the prepandemic phase. METHODS: This is a retrospective case-control study in which all patients with TBI admitted during COVID-19 pandemic phase (Arm A) from March 24, 2020 to November 30, 2020 were matched with age and Glasgow Coma Scale score-matched controls from the patients admitted before March 2020 (Arm B). RESULTS: The total number of patients matched in each arm was 118. The length of hospital stay (8 days vs. 5 days; P < 0.001), transit time from emergency room to operation room (150 minutes vs. 97 minutes; P = 0.271), anesthesia induction time (75 minutes vs. 45 minutes; P = 0.002), and operative duration (275 minutes vs. 180 minutes; P = 0.002) were longer in arm A. Although the incidence of fever and pneumonia was significantly higher in arm A than in arm B (50% vs. 26.3%, P < 0.001 and 27.1% vs. 1.7%, P < 0.001, respectively), outcome (Glasgow Outcome Scale-Extended) and mortality (18.6% vs. 14.4% respectively; P = 0.42) were similar in both the groups. CONCLUSIONS: The outcome of the patients managed for TBI during the COVID-19 pandemic was similar to matched patients with TBI managed at our center before the onset of the COVID-19 pandemic. This finding suggests that the guidelines followed during the COVID-19 pandemic were effective in dealing with patients with TBI. This model can serve as a guide for any future pandemic waves for effective management of patients with TBI without compromising their outcome.

Crystal structures of murine norovirus-1 RNA-dependent RNA polymerase.

Norovirus is one of the leading agents of gastroenteritis and is a major public health concern. In this study, the crystal structures of recombinant RNA-dependent RNA polymerase (RdRp) from murine norovirus-1 (MNV-1) and its complex with 5-fluorouracil (5FU) were determined at 2.5 Å resolution. Crystals with C2 symmetry revealed a dimer with half a dimer in the asymmetrical unit, and the protein exists predominantly as a monomer in solution, in equilibrium with a smaller population of dimers, trimers and hexamers. MNV-1 RdRp exhibited polymerization activity with a right-hand fold typical of polynucleotide polymerases. The metal ion modelled in close proximity to the active site was found to be coordinated tetrahedrally to the carboxyl groups of aspartate clusters. The orientation of 5FU observed in three molecules in the asymmetrical unit was found to be slightly different, but it was stabilized by a network of favourable interactions with the conserved active-site residues Arg185, Asp245, Asp346, Asp347 and Arg395. The information gained on the structural and functional features of MNV-1 RdRp will be helpful in understanding replication of norovirus and in designing novel therapeutic agents against this important pathogen.

The Effects of Drought Severity and Its Aftereffects on Mortality in Bangladesh.

BACKGROUND: Drought has been a considerable problem for many years in northern Bangladesh. However, the health impacts of drought in this region are not well understood. METHODS: This study analyzed the impact of drought duration and severity on select causes of mortality in northern Bangladesh. Rainfall data from three meteorological stations (Rangpur, Dinajpur and Nilphamari) in northern Bangladesh were used to assess drought and non-drought periods, and the Standardized Precipitation Index was used to categorize mild, moderate, severe, and extreme drought. Mortality data from 2007 to 2017 for the three areas were collected from the Sample Vital Registration System, which is a survey of 1 million people. The generalized linear model with Poisson regression link was used to identify associations between mortality and the drought severity and 1-month preceding SPI. RESULTS: Only severe and extreme drought in the short-term drought periods affected mortality. Long-term drought was not associated with natural cause mortality in Rangpur and Nilphamari. In Dinajpur, mild and moderate drought was associated with circulatory- and respiratory-related mortality. CONCLUSION: The impact of drought on mortality varied by region. This study improves our understanding of how droughts affect specific causes of mortality and will help policy makers to take appropriate measures against drought impacts on selected cause of mortality. Future research will be critical to reduce drought-related risks of health.

Analysis of Neurosurgical Cases Before and During the Coronavirus Disease 2019 Pandemic from a Tertiary-Care Centre in India.

OBJECTIVE: We present the unique administrative issues as well as specific patient-related and surgeon-related challenges and solutions implemented while treating neurosurgical patients during the coronavirus disease 2019 (COVID-19) pandemic vis-à-vis pre-COVID-19 times at our tertiary-care center. METHODS: This is a retrospective study comparing the outcome of the neurosurgical patients treated from the beginning of lockdown in India on March 25, 2020 to November 30, 2020 with that of same period in the previous year, 2019. RESULTS: There were 687 neurosurgery admissions during the study period compared with 2550 admissions in 2019. The total number of surgeries performed in neurosurgery also showed a similar trend, with only 654 surgeries in 2020 compared with 3165 surgeries in 2019. During COVID-19 times, 474 patients were operated on including both trauma and nontrauma cases. Of the 50 patients with suspected/indeterminate COVID-19 who were operated on, 5 turned out to be positive for COVID-19. Significant differences were seen in the mortality (P < 0.01) and morbidity (P < 0.01) among patients with trauma on comparing COVID and pre-COVID periods. Similarly, a significant difference was observed in the mortality (P < 0.001) and morbidity (P < 0.001) in patients who did not have trauma. CONCLUSIONS: The higher mortality and morbidity during the COVID pandemic is primarily attributable to poorer baseline clinical status. Our experience from this COVID period might not only help us in tackling subsequent waves but also help other institutions in the developing world to be better prepared for similar circumstances.

Factors predicting loss of cervical lordosis following cervical laminoplasty: A critical review.

BACKGROUND: Laminoplasty is a method of posterior cervical decompression which indirectly decompresses the spinal column. Unfortunately, many patients undergoing laminoplasty develops postoperative loss of cervical lordosis (LCL) or kyphotic alignment of cervical spine even though they have sufficient preoperative lordosis which results in poor surgical outcome. OBJECTIVE: We would like to highlight the relationship between various radiological parameters of cervical alignment and postoperative LCL in patients undergoing laminoplasty. METHODS: We performed extensive literature search using PubMed, Google Scholar, and Web of Science for relevant articles that report factors affecting cervical alignment following laminoplasty. RESULTS: On reviewing the literature, patients with high T1 slope have more lordotic alignment of cervical spine preoperatively. They also have more chances of LCL following laminoplasty. C2-C7 sagittal vertical axis (SVA) has no role in predicting LCL following laminoplasty though patients with low T1 slope (≤20°) and high C2-C7 SVA (>22 mm) had correction of kyphotic deformity following laminoplasty. C2-C7 lordosis, Neck Tilt, cervical range of motion, and thoracic kyphosis has no predictive value for LCL. Lower value of T1 slope (T1S-CL) and CL/T1S has more incidence of developing LCL following laminoplasty. The role of C2-C3 disc angle has not yet been evaluated in patients undergoing laminoplasty. Dynamic extension reserve determines the contraction reserve of SPMLC and lower dynamic extension reserve is associated with higher chances of LCL following laminoplasty. CONCLUSIONS: Cervical lordotic alignment is important in maintaining cervical sagittal balance which ultimately is responsible for global spinal sagittal balance and horizontal gaze. Among various radiological parameters, T1 Slope has been reported to be the most important factor affecting cervical alignment following laminoplasty.

The Influence of Income and Livelihood Diversification on Health-Related Quality of Life in Rural Ethiopia.

Examining health-related quality of life (HRQOL) in a rural setting can be beneficial for improving rural household policies and fostering public health promotion. The objective of this study was to measure the HRQOL and associated socioeconomic characteristics as well as test the reliability of the Amharic version of SF-8 (eight-item short form of HRQOL survey). A cross-sectional study was employed in three agroecologically different sites in rural Ethiopia, involving 270 household heads (218 male and 52 female) with a mean age ± standard deviation of 49 ± 12.88 years. The survey material consisted of a structured questionnaire for socioeconomic characteristics and SF-8 for HRQOL. The mean physical and mental component summary score of the whole sample was 30.50 ± 12.18 and 34.40 ± 7.26, respectively, well underneath the instrument average of 50. The SF-8 items showed excellent internal consistency in terms of both Cronbach's α coefficients and item-total correlation. In stepwise multiple linear regression, the low-income group had worse self-perceived physical health than the higher-income groups. Likewise, a diversified livelihood had a profound influence on positive self-perceived physical health. These findings imply that developing and distributing wide-ranging socioeconomic and public health policies is crucial for effective health promotion in rural communities.

The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells.

Breast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In meiosis, BRCA2 binds to MEILB2 to localize to DNA double-strand breaks (DSBs). Here, we identify BRCA2 and MEILB2-associating protein 1 (BRME1), which functions as a stabilizer of MEILB2 by binding to an α-helical N-terminus of MEILB2 and preventing MEILB2 self-association. BRCA2 binds to the C-terminus of MEILB2, resulting in the formation of the BRCA2-MEILB2-BRME1 ternary complex. In Brme1 knockout (Brme1-/-) mice, the BRCA2-MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. Persistent DSBs in Brme1-/- reactivate the somatic-like DNA-damage response, which repairs DSBs but cannot complement the crossover formation defects. Further, MEILB2-BRME1 is activated in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic HR. Thus, the meiotic BRCA2 complex is central in meiotic HR, and its misregulation is implicated in cancer development.

Corrigendum: Insight Into the Interaction Between RNA Polymerase and VPg for Murine Norovirus Replication.

[This corrects the article DOI: 10.3389/fmicb.2018.01466.].

Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition.

New anti-inflammatory agents possessing dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition were discovered by computer-aided prediction of biological activity for 573 virtually designed chemical compounds. Prediction of biological activity was performed by PASS, and prediction results were analyzed with PharmaExpert software. Nine 2-(thiazole-2-ylamino)-5-phenylidene-4-thiazolidinone derivatives differing by the phenyl group substitution were selected for synthesis and experimental testing as potential COX/LOX inhibitors. Eight tested compounds exhibited anti-inflammatory activity in the carrageenin-induced paw edema. It was shown that seven tested compounds (77.8%) were LOX inhibitors, seven compounds were COX inhibitors (77.8%), and six tested compounds (66.7%) were dual COX/LOX inhibitors. Analysis of lipophilicity of the compounds showed a negative correlation with inhibition of edema formation. The binding modes of the most active compounds of this series (2-(thiazole-2-ylamino)-5-( m-chlorophenylidene)-4-thiazolidinone for COX-1 and COX-2, and 2-(thiazole-2-ylamino)-5-( m-nitrophenylidene)-4-thiazolidinone for 15-LOX) were proposed on the basis of docking studies.

Insight Into the Interaction Between RNA Polymerase and VPg for Murine Norovirus Replication.

Norovirus (NoV) is a leading cause of epidemic acute non-bacterial gastroenteritis, and replicates through virion protein genome-linked (VPg)-primed or de novo RNA synthesis by RNA-dependent RNA polymerase (RdRp). VPg is a multifunctional protein that plays crucial roles in viral protein translation and genome replication. However, the interaction between the RdRp and this multifunctional VPg in NoV replication has been unknown. In this study, VPg derived from murine NoV (MNV) was found to mediate the formation of higher-order multimers or tubular fibrils of MNV RdRp, which led to significantly enhanced polymerase activity in vitro. The replication of MNV mutants containing a VPg-binding defective RdRp, based on the crystal structure of an RdRp-VPg(1-73) complex, was completely blocked in a cell culture system. Our data suggest that the interaction between RdRp and VPg plays a crucial role in the multimerization-mediated RdRp activity in vivo and consequently in MNV replication, which can provide a new target of therapeutic intervention for NoV outbreaks.

Modified blalock-taussig shunt and levosimendan for left ventricular preparation in a child with transposition of great arteries and regressed ventricle undergoing rapid 2 stage arterial switch operation.

Rapid two-stage arterial switch operation (ASO) is very relevant as many patients of transposition of great arteries (TGA) present late to the hospital when primary switch either is not possible or carries a high risk of morbidity and mortality. Hence, other means apart from the traditional methods of left ventricle preparedness should be tried to help this category of patients, who are to undergo rapid two-stage ASO. We successfully used levosimendan and continuous positive airway pressure after 1st stage operation in a patient with dTGA and regressed ventricle, which helped in left ventricular preparedness, and the child underwent rapid two-stage ASO uneventfully.