Evaluation of the mosquito larvicidal potential and comparative assessment of the juice of Lantana camara Linn and Ocimum gratissimum Linn.

In the present study, the larvicidal efficacy of the juices of the weeds Lantana camara Linn (L. camara) and Ocimum gratissimum Linn (O. gratissimum) was evaluated against the larvae of the malaria vectors Aedes aegypti, Anopheles subpictus and Culex quinquefasciatus. The freshly prepared juices of leaves were prepared by grinding them and diluting them at concentrations of 25, 50, 75, and 100 ppm. Twenty larvae of each species were introduced in different sterile Petri dishes in aqueous media under a controlled environment for the assessment of biological activity. The larvicidal activity of both juices was evaluated at 6, 12 and 24 h post-exposure time points by observing the movement of each larva. The obtained data were subjected to probit analysis to determine the lethal concentrations that kill 50% and 90% (LC50 and LC90) of the treated larvae. The results revealed a noticeable larvicidal activity following 24 h of exposure. The juice of L. camara leaves exhibited an LC50 range of 47.47-52.06 ppm and an LC90 range of 104.33-106.70 ppm. Moreover, for the juice of O. gratissimum leaves, the LC50 range was 42.94-44.91 ppm and the LC90 range was 105.11-108.66 ppm. Taken together, the results indicate that the juices of L. camara and O. gratissimum leaves may be useful as effective, economical and eco-friendly larvicidal agents. However, additional studies are needed to explore the bioactive components of the weeds that exhibit larvicidal activity along with their mode of action.

An appraisal to hydrochemical characterization, source identification, and potential health risks of sulfate and nitrate in groundwater of Bemetara district, Central India.

Gypsum-enriched aquifers (GEA) and intensive agriculture regions (IAR) in semi-arid regions are responsible for very high amounts of sulfate and nitrate in many groundwater systems of the world, respectively. However, in such regions, the problem of nitrate pollution and its associated health risk has been increasing and emerging as a global issue. However, along with nitrate, sulfate contamination and its potential health risks are often neglected worldwide in these regions. Therefore, considering sulfate along with nitrate as a significant threat to water quality in such regions, this study aimed to characterize hydrochemistry, factors controlling groundwater quality, and assessment of risk to human health. To accomplish this objective, 116 groundwater samples were collected over pre-monsoon (PRM) and post-monsoon (POM) (2019) seasons in Bemetara district. As per Bureau of Indian standards (BIS) for drinking, SO42- (28 and 19%) and NO3- (7 and 35%) exceeded the permissible limits in PRM and POM seasons, respectively; thereby, groundwater was not suitable for drinking. SO42- and NO3- pollution sources were identified and mainly attributed to gypsum dissolution and agricultural activities as well as domestic sewage discharge, respectively. In addition, SO42-and NO3- risk assessment results show that total 20% to 46% of all samples surpassed the permissible limit (HQ = 1) of risk to children and adults, over both seasons. To ensure drinking water security in this region, sustainable management of agricultural activities and treatment should be done to reduce the potential health risks due to SO42- and NO3-.

A Retrospective Observational Study of Facial Dog Bite Injuries and Its Management in a Tertiary Care Center.

Background : Facial dog bite injuries result in significant emotional, psychological, and physical trauma to the victims involved and should be considered a significant health issue. The purpose of this study is to share our experience in the management and to add to the existing medical literature regarding the epidemiological patterns of facial dog bite injuries. Materials and Methods : This is a single-center retrospective observational study conducted at Dr. RML Hospital, New Delhi, from January 2021 to January 2022. A total of 105 patients were included. The wounds were managed according to the recommendations made by the national rabies control program and surgical intervention was performed in the form of primary suturing or flap cover. Results : Children of age group 0 to 10 years are most commonly affected. Pet dogs are the cause in 61% of cases and 57.1% of bites were provoked. Midface is most commonly affected and modified Lackmann's class 3A and 3B are the most common wounds. Conclusion : In view of raising incidence of dog bites with pet dogs, the general public needs to be educated regarding the practices to prevent these injuries. Postexposure prophylaxis should be given to all affected individuals irrespective of the vaccination status of the dog. Immediate surgical intervention gives better results.

Analytical Study of the Risk Factors Affecting the Fracture Risk in Rheumatoid arthritis Patients using FRAX Algorithm.

OBJECTIVES: The present study aimed to calculate the risk of osteoporotic fracture in patients of Rheumatoid arthritis (RA) by Fracture Risk Assessment Tool (FRAX) and its relationship with osteoporotic-specific risk factors. METHODS: This was a observational cross-sectional analytical study conducted from January 2019 to September 2020 where 185 patients, aged 40-90 years, who presented to the Rheumatology Clinic meeting the ACR/EULAR (2010) Classification Criteria for Rheumatoid Arthritis were included in the study and matched with 185 healthy individuals. We assessed the severity of the disease by using the DAS28 score. In addition, we evaluated the FRAX algorithm for all patients and controls to determine the 10-year fracture risk of major osteoporotic fracture and hip fracture. RESULTS: RA patients had a significantly higher mean 10-year risk of major osteoporotic fracture (4.77 ± 5.04 vs 2.05 ± 1.84, P<0.05) and significantly higher mean 10-year risk of hip fracture (1.71 ± 2.81 vs 0.5 ± 0.95) (p<0.05).There was a significant positive correlation of duration of disease, previous fracture; parent fractured hip with major osteoporotic fracture (r=0.257, 0.435, 0.169 respectively) and with hip fracture (r=0.26, 0.369, 0.212 respectively). We saw no correlation of fracture risk with ESR (mm/hr), DAS28, CRP (mg/dL), glucocorticoid use, smoking, and alcohol use. CONCLUSION: The risk of hip fracture and major osteoporotic fracture significantly increased in both male and female patients with RA as assessed by the FRAX algorithm. Duration of the disease, previous fracture, and parent fracture hip showed a significant correlation with major osteoporotic fracture and hip fracture. Therefore, the early recognition and treatment of RA hold importance in reducing the fracture risk.

Post-symptomatic detection of COVID-2019 grade based mediative fuzzy projection.

The concept of fuzzy set, intuitionistic set, and mediative fuzzy set as a generalization of a crisp set have been introduced in many real-life applications. The concept of crisp relation between elements of sets can be extended to fuzzy relations. Extended relations will be considered as relations on fuzzy sets. In this work, we developed the concept of mediative fuzzy relation and meditative fuzzy projection in the context of fuzzy relation and fuzzy projection. We extended the basic operations of fuzzy projection into intuitionistic fuzzy projection and then in the mediative fuzzy projection. We have shown the credibility and impact of mediative index factor involves in the mediative fuzzy projection in context of prediction work in relation to the proposed model. Further, we applied the mediative fuzzy projection in the medical diagnosis in post-COVID-19 patients. The obtained results have also been discussed with their geometrical representation.

Single-trait, multi-locus and multi-trait GWAS using four different models for yield traits in bread wheat.

A genome-wide association study (GWAS) for 10 yield and yield component traits was conducted using an association panel comprising 225 diverse spring wheat genotypes. The panel was genotyped using 10,904 SNPs and evaluated for three years (2016-2019), which constituted three environments (E1, E2 and E3). Heritability for different traits ranged from 29.21 to 97.69%. Marker-trait associations (MTAs) were identified for each trait using data from each environment separately and also using BLUP values. Four different models were used, which included three single trait models (CMLM, FarmCPU, SUPER) and one multi-trait model (mvLMM). Hundreds of MTAs were obtained using each model, but after Bonferroni correction, only 6 MTAs for 3 traits were available using CMLM, and 21 MTAs for 4 traits were available using FarmCPU; none of the 525 MTAs obtained using SUPER could qualify after Bonferroni correction. Using BLUP, 20 MTAs were available, five of which also figured among MTAs identified for individual environments. Using mvLMM model, after Bonferroni correction, 38 multi-trait MTAs, for 15 different trait combinations were available. Epistatic interactions involving 28 pairs of MTAs were also available for seven of the 10 traits; no epistatic interactions were available for GNPS, PH, and BYPP. As many as 164 putative candidate genes (CGs) were identified using all the 50 MTAs (CMLM, 3; FarmCPU, 9; mvLMM, 6, epistasis, 21 and BLUP, 11 MTAs), which ranged from 20 (CMLM) to 66 (epistasis) CGs. In-silico expression analysis of CGs was also conducted in different tissues at different developmental stages. The information generated through the present study proved useful for developing a better understanding of the genetics of each of the 10 traits; the study also provided novel markers for marker-assisted selection (MAS) to be utilized for the development of wheat cultivars with improved agronomic traits. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01240-1.

Evaluation of Serum Levels of Procalcitonin and C-Reactive Protein as Prognostic Indicators in Burns.

Background Burn is a leading cause of fatality in a developing country. C-reactive protein levels (CRP) and procalcitonin (PCT) can be prognostic indicators for the burn patients' mortality. Aim To assess serial levels of serum PCT and serum CRP as prognostic indicators in burns. Patient and Methods In patients admitted with burns, alternate-day serum PCT and CRP were measured from the time of admission until the time of discharge or until survival. The change in trends of CRP and PCT serum levels were studied, and it was then correlated with mortality among these burn patients. Results The first-day value of serum PCT > 1772 pg/mL and serum CRP > 71 mg/mL or any value of serum PCT > 2163 pg/mL and of serum CRP > 90 mg/L indicate a poor prognosis in burns. Conclusions The day-1 values of PCT and CRP were significantly higher in nonsurvivors than survivors in burns. The increasing trends of serum PCT and CRP levels are independent predictors of mortality in burns requiring prompt intervention. Rising PCT and CRP level denote poor prognosis in burns with an increased likelihood of death by 4.5 and 23.6 times, respectively.

Use of Preexpanded Forehead and Neck Skin in Case of Giant Facial Hairy Naevus: Planning and Technique.

A congenital nevi is a pigmented patch which requires complete surgical excision for cosmetic reasons. Here, we report a case of a patient with facial hairy pigmented lesion, occupying the right half of her face since birth, who underwent complete surgical excision and staged reconstruction utilizing, preexpanded forehead and neck skin. We used two rectangular tissue expanders with 150 and 300 cubic cm of volumes inserted in the forehead and the neck, respectively. The length of the expanders selected were equal to 1.2 to 1.5 times the length of their respective lesions, whereas the width of the base of the expanders were approximately similar to the width of their defects. It is concluded with this case report that tissue expansion provides a good cosmetic and anatomical correction to cover large defects, with adjacent skin having similar properties.

The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the huntingtin protein (Htt). Transcriptional dysregulation is an early event in the course of HD progression and is thought to contribute to disease pathogenesis, but how mutant Htt causes transcriptional alterations and subsequent cell death in neurons is not well understood. RNA-Seq analysis revealed that expression of a mutant Htt fragment in primary cortical neurons leads to robust gene expression changes before neuronal death. Basic helix-loop-helix transcription factor Twist1, which is essential for embryogenesis and is normally expressed at low levels in mature neurons, was substantially up-regulated in mutant Htt-expressing neurons in culture and in the brains of HD mouse models. Knockdown of Twist1 by RNAi in mutant Htt-expressing primary cortical neurons reversed the altered expression of a subset of genes involved in neuronal function and, importantly, abrogated neurotoxicity. Using brain-derived neurotrophic factor (Bdnf), which is known to be involved in HD pathogenesis, as a model gene, we found that Twist1 knockdown could reverse mutant Htt-induced DNA hypermethylation at the Bdnf regulatory region and reactivate Bdnf expression. Together, these results suggest that Twist1 is an important upstream mediator of mutant Htt-induced neuronal death and may in part operate through epigenetic mechanisms.

Caspase-mediated cleavage of X-ray repair cross-complementing group 4 promotes apoptosis by enhancing nuclear translocation of caspase-activated DNase.

X-ray repair cross-complementing group 4 (XRCC4), a repair protein for DNA double-strand breaks, is cleaved by caspases during apoptosis. In this study, we examined the role of XRCC4 in apoptosis. Cell lines, derived from XRCC4-deficient M10 mouse lymphoma cells and stably expressing wild-type XRCC4 or caspase-resistant XRCC4, were established and treated with staurosporine (STS) to induce apoptosis. In STS-induced apoptosis, expression of wild-type, but not caspase-resistant, XRCC4 in XRCC4-deficient cells enhanced oligonucleosomal DNA fragmentation and the appearance of TUNEL-positive cells by promoting nuclear translocation of caspase-activated DNase (CAD), a major nuclease for oligonucleosomal DNA fragmentation. CAD activity is reportedly regulated by the ratio of two inhibitor of CAD (ICAD) splice variants, ICAD-L and ICAD-S mRNA, which, respectively, produce proteins with and without the ability to transport CAD into the nucleus. The XRCC4-dependent promotion of nuclear import of CAD in STS-treated cells was associated with reduction of ICAD-S mRNA and protein, and enhancement of phosphorylation and nuclear import of serine/arginine-rich splicing factor (SRSF) 1. These XRCC4-dependent, apoptosis-enhancing effects were canceled by depletion of SRSF1 or SR protein kinase (SRPK) 1. In addition, overexpression of SRSF1 in XRCC4-deficient cells restored the normal level of apoptosis, suggesting that SRSF1 functions downstream of XRCC4 in activating CAD. This XRCC4-dependent, SRPK1/SRSF1-mediated regulatory mechanism was conserved in apoptosis in Jurkat human leukemia cells triggered by STS, and by two widely used anti-cancer agents, Paclitaxel and Vincristine. These data imply that the level of XRCC4 expression could be used to predict the effects of apoptosis-inducing drugs in cancer treatment.

DCE-MRI and parametric imaging in monitoring response to neoadjuvant chemotherapy in breast carcinoma: a preliminary report.

PURPOSE: Neoadjuvant chemotherapy is recommended in patients with locally advanced breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) enables evaluation of the tumour neovasculature that occurs prior to any volume change, which helps identify early treatment failures and allows prompt implementation of second-line therapy. MATERIAL AND METHODS: We conducted a prospective study in 14 patients with histopathologically proven breast cancer. DCE-MRI data were acquired using multisection, T1-weighted, 3D vibe sequences with fat suppression before, during, and after IV bolus injection (0.1 mmol/kg body weight, Gadoversetamide, Optimark). Post-processing of dynamic contrast perfusion data was done with the vendor's Tissue 4D software to generate various dynamic contrast parameters, i.e. Ktrans, Kep, Ve, initial area under the time signal curve (IAUC), apparent diffusion coefficient (ADC), and enhancement curve. Patients underwent MRI examinations at baseline, and then after two cycles, and finally at completion of chemotherapy. RESULTS: Based on Sataloff criteria for pathological responses, four patients out of 14 were responders, and 10 were non-responders. At the 2nd MRI examination, IAUC was significantly smaller in responders than in non-responders (p = 0.023). When the results of the first and second MRI examinations were compared, Kep decreased from baseline to the second MRI (p = 0.03) in non-responders and in responders (p = 0.04). This change was statistically significant in both groups. The ADC values increased significantly in responders from baseline to the third MRI (p = 0.012). CONCLUSIONS: In our study, IAUC and ADC were the only parameters that reliably differentiated responders from non-responders after two and three cycles of chemotherapy.

Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy. METHODS: Clinical genomic profiling was performed using 1000 ng of DNA from 7 cases of NF1-MPNST, and bioinformatic analyses were conducted to identify genes with actionable mutations. RESULTS: A total of 3 women and 4 men with NF1-MPNST were identified (median age, 38 years). Nonsynonymous mutations were discovered in 4 genes (neurofibromatosis type 1 [NF1], ROS proto-oncogene 1 [ROS1], tumor protein p53 [TP53], and tyrosine kinase 2 [TYK2]), which in addition were mutated in other MPNST cases in this sample set. Consistent with their occurrence in individuals with NF1, all tumors had at least 1 mutation in the NF1 gene. Whereas TP53 gene mutations are frequently observed in other cancers, ROS1 mutations are common in melanoma (15%-35%), another neural crest-derived malignancy. In contrast, TYK2 mutations are uncommon in other malignancies (<7%). In the current series, recurrent TYK2 mutations were identified in 2 cases of NF1-MPNST (30% of cases), whereas TYK2 protein overexpression was observed in 60% of MPNST cases using an independently generated tissue microarray, regardless of NF1 status. CONCLUSIONS: Clinical genomic analysis of the current series of NF1-MPNST cases found that TYK2 is a new gene mutated in MPNST. Future work will focus on examining the utility of TYK2 expression as a biomarker and therapeutic target for these cancers. Cancer 2017;123:1194-1201. © 2016 American Cancer Society.

Routine use of clinical exome-based next-generation sequencing for evaluation of patients with thrombotic microangiopathies.

Next-generation sequencing is increasingly used for clinical evaluation of patients presenting with thrombotic microangiopathies because it allows for simultaneous interrogation of multiple complement and coagulation pathway genes known to be associated with disease. However, the diagnostic yield is undefined in routine clinical practice. Historic studies relied on case-control cohorts, did not apply current guidelines for variant pathogenicity assessment, and used targeted gene enrichment combined with next-generation sequencing. A clinically enhanced exome, targeting ~54 Mb, was sequenced for 73 patients. Variant analysis and interpretation were performed on genes with biological relevance in thrombotic microangiopathy (C3,CD46, CFB, CFH, CFI, DGKE, and THBD). CFHR3-CFHR1 deletion status was also assessed using multiplex ligation-dependent probe amplification. Variants were classified using American College of Medical Genetics and Genomics guidelines. We identified 5 unique novel and 14 unique rare variants in 25% (18/73) of patients, including a total of 5 pathogenic, 4 likely pathogenic, and 15 variants of uncertain clinical significance. Nine patients had homozygous deletions in CFHR3-CFHR1. The diagnostic yield, defined as the presence of a pathogenic variant, likely pathogenic variant or homozygous deletion of CFHR3-CFHR1, was 25% for all patients tested. Variants of uncertain clinical significance were identified in 21% (15/73) of patients.These results illustrate the expected diagnositic yield in the setting of thrombotic microangiopathies through the application of standardized variant interpretation, and highlight the utility of such an approach. Sequencing a clinically enhanced exome to enable targeted, disease-specific variant analysis is a viable approach. The moderate rate of variants of uncertain clinical significance highlights the paucity of data surrounding the variants in our cohort and illustrates the need for expanded variant curation resources to aid in thrombotic microangiopathy-related disease variant classification.

Influence of solubilizing environments on membrane protein structures.

Membrane protein structures are stabilized by weak interactions and are influenced by additional interactions with the solubilizing environment. Structures of influenza virus A M2 protein, a proven drug target, have been determined in three different environments, thus providing a unique opportunity to assess environmental influences. Structures determined in detergents and detergent micelles can have notable differences from those determined in lipid bilayers. These differences make it imperative to validate membrane protein structures.

Lysine 271 but not lysine 210 of XRCC4 is required for the nuclear localization of XRCC4 and DNA ligase IV.

XRCC4 and DNA Ligase IV (LIG4) cooperate to join two DNA ends at the final step of DNA double-strand break (DSB) repair through non-homologous end-joining (NHEJ). However, it is not fully understood how these proteins are localized to the nucleus. Here we created XRCC4(K271R) mutant, as Lys271 lies within the putative nuclear localization signal (NLS), and XRCC4(K210R) mutant, as Lys210 was reported to undergo SUMOylation, implicated in the nuclear localization of XRCC4. Wild-type and mutated XRCC4 with EGFP tag were introduced into HeLa cell, in which endogenous XRCC4 had been knocked down using siRNA directed to 3'-untranslated region, and tested for the nuclear localization function by fluorescence microscopy. XRCC4(K271R) was defective in the nuclear localization of itself and LIG4, whereas XRCC4(K210R) was competent for the nuclear localization with LIG4. To examine DSB repair function, wild-type and mutated XRCC4 were introduced into XRCC4-deficient M10. M10-XRCC4(K271R), but not M10-XRCC4(K210R), showed significantly reduced surviving fraction after 2 Gy γ-ray irradiation as compared to M10-XRCC4(WT). The number of γ-H2AX foci remaining 2 h after 2 Gy γ-ray irradiation was significantly greater in M10-XRCC4(K271R) than in M10-XRCC4(WT), whereas it was only marginally increased in M10-XRCC4(K210R) as compared to M10-XRCC4(WT). The present results collectively indicated that Lys271, but not Lys210, of XRCC4 is required for the nuclear localization of XRCC4 and LIG4 and that the nuclear localizing ability is essential for DSB repair function of XRCC4.

Asparagine 326 in the extremely C-terminal region of XRCC4 is essential for the cell survival after irradiation.

XRCC4 is one of the crucial proteins in the repair of DNA double-strand break (DSB) through non-homologous end-joining (NHEJ). As XRCC4 consists of 336 amino acids, N-terminal 200 amino acids include domains for dimerization and for association with DNA ligase IV and XLF and shown to be essential for XRCC4 function in DSB repair and V(D)J recombination. On the other hand, the role of the remaining C-terminal region of XRCC4 is not well understood. In the present study, we noticed that a stretch of ∼20 amino acids located at the extreme C-terminus of XRCC4 is highly conserved among vertebrate species. To explore its possible importance, series of mutants in this region were constructed and assessed for the functionality in terms of ability to rescue radiosensitivity of M10 cells lacking XRCC4. Among 13 mutants, M10 transfectant with N326L mutant (M10-XRCC4(N326L)) showed elevated radiosensitivity. N326L protein showed defective nuclear localization. N326L sequence matched the consensus sequence of nuclear export signal. Leptomycin B treatment accumulated XRCC4(N326L) in the nucleus but only partially rescued radiosensitivity of M10-XRCC4(N326L). These results collectively indicated that the functional defects of XRCC4(N326L) might be partially, but not solely, due to its exclusion from nucleus by synthetic nuclear export signal. Further mutation of XRCC4 Asn326 to other amino acids, i.e., alanine, aspartic acid or glutamine did not affect the nuclear localization but still exhibited radiosensitivity. The present results indicated the importance of the extremely C-terminal region of XRCC4 and, especially, Asn326 therein.

Chemoenzymatic routes to enantiomerically enriched and polyoxygenated perhydro-3,5a-methanoindeno[4,5-c]furans related to the tashironin class of sesquiterpenes.

The alcohol 12, which is available in eight steps from the enzymatically derived cis-1,2-dihydrocatechol 8, engages in an intramolecular alkoxy radical-mediated remote functionalization reaction to form the tetrahydrofuran 13, thus establishing the perhydro-3,5a-methanoindeno[4,5-c]furan framework associated with the biologically active tashironins. Various manipulations of compound 13 and certain derivatives allow for the formation of compounds bearing strong structural resemblances to the title natural products.

caTissue Suite to OpenSpecimen: Developing an extensible, open source, web-based biobanking management system.

The National Cancer Institute (NCI) Cancer Biomedical Informatics Grid® (caBIG®) program established standards and best practices for biorepository data management by creating an infrastructure to propagate biospecimen resource sharing while maintaining data integrity and security. caTissue Suite, a biospecimen data management software tool, has evolved from this effort. More recently, the caTissue Suite continues to evolve as an open source initiative known as OpenSpecimen. The essential functionality of OpenSpecimen includes the capture and representation of highly granular, hierarchically-structured data for biospecimen processing, quality assurance, tracking, and annotation. Ideal for multi-user and multi-site biorepository environments, OpenSpecimen permits role-based access to specific sets of data operations through a user-interface designed to accommodate varying workflows and unique user needs. The software is interoperable, both syntactically and semantically, with an array of other bioinformatics tools given its integration of standard vocabularies thus enabling research involving biospecimens. End-users are encouraged to share their day-to-day experiences in working with the application, thus providing to the community board insight into the needs and limitations which need be addressed. Users are also requested to review and validate new features through group testing environments and mock screens. Through this user interaction, application flexibility and interoperability have been recognized as necessary developmental focuses essential for accommodating diverse adoption scenarios and biobanking workflows to catalyze advances in biomedical research and operations. Given the diversity of biobanking practices and workforce roles, efforts have been made consistently to maintain robust data granularity while aiding user accessibility, data discoverability, and security within and across applications by providing a lower learning curve in using OpenSpecimen. Iterative development and testing cycles provide continuous maintenance and up-to-date capabilities for this freely available, open-access, web-based software application that is globally-adopted at over 25 institutions.

Metronomic chemotherapy in anaplastic thyroid carcinoma: a potentially feasible alternative to therapeutic nihilism.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC.

High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion.

While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of (1)H-(15)N dipolar couplings and (15)N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound α-helical peptides. The tilt of the helical axis, τ, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, ρ, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their τ angles (<10°) and significant difference in their ρ angles (~25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt ρ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger ρ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 Å more deeply inserted than p1 in PE/PG. In contrast to the ideal α-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted α-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie ~1.2-3.6 Å below the plane defined by the C2 atoms of the lipid acyl chains.