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Aims and Objectives: The high cost of LH-RH analogues for patients with advanced prostatic carcinoma raises the need to consider highly cost-effective one-time surgical castration. This study was done to compare the effectiveness of bilateral subepididymal orchiectomy, bilateral total orchiectomy and bilateral subcapsular orchiectomy in terms of androgen ablation (serum testosterone), control of disease progression (serum PSA) and esthetic superiority (patient satisfaction). Materials and Methods: 114 patients of advanced prostatic carcinoma (T3, T4 or any T with bony metastasis) in the age group of 55-92 years were divided in 3 groups- Group A: bilateral total orchiectomy (38 patients), Group B: bilateral subcapsular orchiectomy (38 patients), and Group C: bilateral subepididymal orchiectomy with epididymoplasty (38 patients). Serum PSA and serum testosterone values were done preoperatively and at 3 months follow-up. Patients' esthetic satisfaction was scored on a quality of life scale of 1-5. Results: In Groups A, B and C, at 3 months the post-operative mean serum testosterone values were 33.4, 38.8 and 36.7 ng/ml; and mean serum PSA values were 4.2, 3.9 and 3.4 ng/ml respectively, the difference not being statistically significant in both groups. On satisfaction scale the average scores were 1.81, 2.76 and 4 respectively ( P<0.05), the difference being highly significant. Conclusion: All three procedures are equally effective in reducing the serum testosterone values to post-castration levels (<50 ng/ml) and controlling the disease in terms of reduction in serum PSA values. Bilateral sub-epididymal orchiectomy clearly stands out in terms of highest patient satisfaction score. Bilateral sub-epididymal orchiectomy may be considered procedure of choice to achieve surgical castration in advanced prostatic carcinoma. [ABSTRACT FROM AUTHOR]

Introduction: A significant amount of post-operative pain after PNL is caused by nephrostomy tube. We present our experience with 'nephrostomy-free' PNL, a modification of the standard technique, to reduce duration of hospital stay and minimize postoperative discomfort. Materials and Methods: 202 patients undergoing PNL were randomized in two groups, Group A (standard PNL) with nephrostomy tube placement postoperatively, and Group B ('tubeless' PNL) with antegrade placement of DJ stent without nephrostomy. Inclusion criteria were normal renal functions, single tract procedure with complete clearance of calculi, and minimal bleeding at completion. The two groups were comparable in terms of age/sex/metabolic and anatomical features. Factors evaluated included postoperative analgesia requirement, blood loss, postoperative urinary leak, infection, and the hospital stay. Results: All patients had uneventful postoperative recovery. The mean analgesia requirement for group A (pentazocine 127±34.6 mg) was significantly more as compared to group B (pentazocine 84±21.8 mg) ( P<0.05). The difference in average blood loss and urinary infection for two groups was not statistically significant. The incidence of urinary leak from the nephrostomy site was significantly less for tubeless group (0/101), as compared to standard PNL group (7/101). The average hospital stay in the tubeless group (23±4.7 hours) was significantly shorter than the standard PNL group (54±7.1 hours) ( P<0.05). No long-term sequelae were noticed in follow-up of up to 2 years in any patient. Conclusion: 'Nephrostomy-free' or 'Tubeless' PNL reduces postoperative urinary leak and local pain related to the drainage tube. It also minimizes the hospital stay, allowing many patients to be discharged from hospital in <24 hours. [ABSTRACT FROM AUTHOR]

Introduction: Staghorn / branched renal stones in children pose special challenge in management. This presentation reviews our experience and results of PNL monotherapy for staghorn calculi in children below 12 years of age. Materials and Methods: Out of 412 pediatric renal calculi treated by PNL at our center since 1997, branched / staghorn stones were present in 46 kidney units in 41 patients. The age ranged from 4 to 12 (mean: 9.2±1.7) years. Sex ratio was 1.8:1 (M:F). PNL was performed with standard technique, aiming to clear the stone completely endourologically, reserving SWL for the really inaccessible stones. Results: Complete stone clearance was achieved in 43 out of 46 (93.5%) cases. 31 were completed in single session, 11 required two, and 4 needed three sessions. A single tract was made in 30, two in 13, and three in 3 cases. The average OR time was 72.6±12.8 (44-126) minutes.18 patients required blood transfusion. The overall drop in Hemoglobin and hematocrit were 7.5% and 11.2% respectively. Duration of nephrostomy was 2-5 (mean 3.2±1.0) days. The average hospital stay was 4.6±1.1 (range 3-6) days. There were no major complications. Residual nonobstructive calculi in 3 cases were treated by SWL subsequently. Conclusions: Aggressive PNL is our treatment of choice in pediatric staghorn calculi, which can achieve complete clearance of stones in majority of cases. This approach shortens the overall treatment duration and saves costs as compared to sandwich therapy. [ABSTRACT FROM AUTHOR]

Objective: Intravesical bacillus Calmette-Guéin (BCG) is an established treatment in superficial bladder cancer, however its local and systemic toxicity continues to be a cause for concern. This trial was conducted using three different doses of BCG to determine whether lowering the dose of BCG could reduce toxicity without compromising its efficacy. Materials and Methods: From July 2002 to June 2006, 152 patients with superficial bladder cancer entered the trial. The patients were randomized to receive three different doses of BCG: 40, 80 and 120 mg respectively. There were no significant differences in clinical and pathological characteristics among the three groups. 24 patients could not be followed till the end of the study due to poor compliance. At completion of the study, 40 patients could be evaluated in group A (40 mg), 48 in group B (80 mg) and 40 in group C (120 mg). Results: Following treatment, patients were evaluated for a mean follow-up of 36 (range 18 to 52) months. No significant difference in recurrence rate (20 vs. 25 vs. 20% respectively; P >0.05) was observed among the groups and no progression of the disease was seen. Significant differences were observed among groups A, B and C in local toxicity (30 vs. 41.7 vs. 70% respectively; P <0.01). Systemic toxicity was more common in group C as compared to groups B and A ( P <0.01). Conclusion: Reduction in the dose of intravesical BCG can reduce the toxicity associated with the treatment without affecting the effificacy of therapy. [ABSTRACT FROM AUTHOR]

One of the fundamental mechanisms developed by the host to contain the highly infectious and rapidly proliferating SARS-coronavirus is elevation of body temperature, a natural fallout of which is heat shock proteins over-expression. Here, for the first time, we demonstrate that the SARS-CoV-2 exploits the host Heat shock protein 70 (Hsp70) chaperone for its entry and propagation, and blocking it can combat the infection. SARS-CoV-2 infection as well as febrile temperature enhanced Hsp70 expression in host Vero E6 cells. Furthermore, heat shock or viral infection elevated the host cell autophagic response which is a prerequisite for viral propagation. In addition, Hsp70 protein demonstrated strong interaction with host Angiotensin-converting enzyme 2 (ACE2) as well as the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, indicating that interaction of Hsp70 with ACE2 and Spike protein may serve to protect them during febrile conditions. Suppressive and prophylactic treatment of Vero E6 cells with Hsp70 inhibitor PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), abrogated viral infection more potently than the currently used drug Remdesivir. In conclusion, our study not only provides a fundamental insight into the role of host Hsp70 in SARS-CoV-2 pathogenesis, it paves the way for development of potent and irresistible anti-viral therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: An ambitious plan was set into motion with the aim of TB elimination from India in 2025. To achieve this, it is high time to give emphasis on other prevalent forms of TB, such as extra pulmonary TB (EPTB)., Objectives: The study aims to discern the differences in patient characteristics and management practices between pulmonary TB and EPTB using data from district Ambala., Methods: This retrospective study used data of 12,985 TB patients from district Ambala, India. The differences in patient characteristics and management practices between pulmonary TB and EPTB were analyzed using the NIKSHAY database., Results: In the studied population, extra pulmonary TB (EPTB) formed 29.7% of all TB cases. Among all EPTB cases, pleural TB was found to be the most common form, accounting for 27%. The study also revealed that female gender, young age, non-diabetic status, and high BMI were associated with an increased propensity to have EPTB. Interestingly, unlike pulmonary TB, which had increased odds for contracting the disease in diabetic individuals (OR - 2.02), there were no increased odds for contracting EPTB in diabetic individuals. However, HIV infection significantly increased the odds for both pulmonary TB and EPTB. The results also showed diagnostic discrepancies between the private and public sectors, along with a low microbiological confirmation rate of 7.1% in EPTB cases., Conclusion: The study highlights the importance of focusing on EPTB in addition to pulmonary TB for effective TB elimination in India. The differences in patient characteristics and management practices warrant further investigation and targeted interventions for both forms of the disease. Efforts should be made to improve diagnostic accuracy and reduce discrepancies between the private and public sectors., Competing Interests: Conflict of interest The authors have none to declare., (Copyright © 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Eighty-five percent of infants with congenital nephrotic syndrome (CNS) and 66% with infantile NS (INS) are likely to have a monogenic etiology. There exists a significant genetic variability between different regions and ethnic groups. This study aimed to determine the genetic defects in children with CNS and INS by establishing a registry in western India., Methods: In this cross-sectional study, pediatric nephrologists from 13 private and government institutions shared relevant clinical data and details of the genetic evaluation of children presenting with NS within the first year of life., Results: The median age at presentation was 9 months (range 1-23, IQR 3-13 months), history of consanguinity between parents existed in 14 patients (34%), family history of similar illness in 6 (15%), and extra-renal manifestations in 17 (41%). Twenty-five (61%) were confirmed to have a monogenic etiology. NPHS1 gene was the most implicated (9/25) followed by PLCE1 (5/25). There were 12 variants of uncertain significance (VUS) involving 10 genes (10/25, 40%), and no definite genetic abnormality was found in 4 (25%). A re-analysis of these VUS attempted 2-3 years later facilitated reclassification of 7/12 (58%); increasing the diagnostic yield from 61 to 68.2%., Conclusions: Consistent with worldwide data, variants in NPHS1 gene were the most common cause of NS in infancy; however, PLCE1 was implicated more frequently in our cohort. NUP93 and COL4A3 were reported in early onset NS for the first time. Reclassification of VUS should be attempted, if feasible, since it may lead to a useful revision of diagnosis., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Palmitoylation is an essential post-translational modification in Leishmania donovani , catalyzed by enzymes called palmitoyl acyl transferases (PATs) and has an essential role in virulence. Due to the toxicity and promiscuity of known PAT inhibitors, identification of new molecules is needed. Herein, we identified a specific novel de novo peptide inhibitor, PS1, against the PAT6 Leishmania donovani palmitoyl acyl transferase ( Ld PAT6). To demonstrate specific inhibition of Ld PAT6 by PS1, we employed a bacterial orthologue system and metabolic labeling-coupled click chemistry where both Ld PAT6 and PS1 were coexpressed and displayed palmitoylation suppression. Furthermore, strong binding of the Ld PAT6-DHHC domain with PS1 was observed through analysis using microscale thermophoresis, ELISA, and dot blot assay. PS1 specific to Ld PAT6 showed significant growth inhibition in promastigotes and amastigotes by expressing low cytokines levels and invasion. This study reveals discovery of a novel de novo peptide against Ld PAT6-DHHC which has potential to block survivability and infectivity of L. donovani .

Metabolic reprogramming is a hallmark of T-cell activation, and metabolic fitness is fundamental for T-cell-mediated antitumor immunity. Insights into the metabolic plasticity of chimeric antigen receptor (CAR) T cells in patients could help identify approaches to improve their efficacy in treating cancer. Here, we investigated the spatiotemporal immunometabolic adaptation of CD19-targeted CAR T cells using clinical samples from CAR T-cell-treated patients. Context-dependent immunometabolic adaptation of CAR T cells demonstrated the link between their metabolism, activation, differentiation, function, and local microenvironment. Specifically, compared with the peripheral blood, low lipid availability, high IL15, and low TGFβ in the central nervous system microenvironment promoted immunometabolic adaptation of CAR T cells, including upregulation of a lipolytic signature and memory properties. Pharmacologic inhibition of lipolysis in cerebrospinal fluid led to decreased CAR T-cell survival. Furthermore, manufacturing CAR T cells in cerebrospinal fluid enhanced their metabolic fitness and antileukemic activity. Overall, this study elucidates spatiotemporal immunometabolic rewiring of CAR T cells in patients and demonstrates that these adaptations can be exploited to maximize the therapeutic efficacy of CAR T cells., Significance: The spatiotemporal immunometabolic landscape of CD19-targeted CAR T cells from patients reveals metabolic adaptations in specific microenvironments that can be exploited to maximize the therapeutic efficacy of CAR T cells., (©2024 American Association for Cancer Research.)

Objectives: Wolfram syndrome is characterised by insulin-dependent diabetes (IDDM), diabetes insipidus (DI), optic atrophy, sensorineural deafness and neurocognitive disorders. The DIDMOAD acronym has been recently modified to DIDMOAUD suggesting the rising awareness of the prevalence of urinary tract dysfunction (UD). End stage renal disease is the commonest cause of mortality in Wolfram syndrome. We present a case series with main objective of long term follow up in four children having Wolfram syndrome with evaluation of their urodynamic profile., Methods: A prospective follow up of four genetically proven children with Wolfram syndrome presenting to a tertiary care pediatric diabetes clinic in Pune, India was conducted. Their clinical, and urodynamic parameters were reviewed., Results: IDDM, in the first decade, was the initial presentation in all the four children (three male and one female). Three children had persistent polyuria and polydipsia despite having optimum glycemic control; hence were diagnosed to have DI and treated with desmopressin. All four patients entered spontaneous puberty. All patients had homozygous mutation in WFS1 gene; three with exon 8 and one with exon 6 novel mutations. These children with symptoms of lower urinary tract malfunction were further evaluated with urodynamic studies; two of them had hypocontractile detrusor and another had sphincter-detrusor dyssynergia. Patients with hypocontractile bladder were taught clean intermittent catheterization and the use of overnight drain., Conclusions: We report a novel homozygous deletion in exon 6 of WFS-1 gene. The importance of evaluation of lower urinary tract malfunction is highlighted by our case series. The final bladder outcome in our cases was a poorly contractile bladder in three patients., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Available anti-leishmanial drugs are associated with toxic side effects, necessitating the search for safe and effective alternatives. This study is focused on identifying traditional medicinal plant natural products for anti-leishmanial potential and possible mechanism of action. Compounds S and T. cordifolia residual fraction (TC-5) presented the best anti-leishmanial activity (IC 50 : 0.446 and 1.028 mg/ml) against promastigotes at 48 h and less cytotoxicity to THP-1 macrophages. These test agents elicited increased expression of pro-inflammatory cytokines; TNFα and IL-12. In infected untreated macrophages, NO release was suppressed but was significantly ( p  < 0.05) increased in infected cells treated with compound S. Importantly, Compound S was found to interact with Ld TopoII dimer in silico , resulting in a likely reduced ability of nucleic acid (dsDNA)-remodelling and, as a result, parasite proliferation in vitro . Thereby, Compound S possesses anti-leishmanial activity and this effect occurs via a Th1-mediated pro-inflammatory response. An increase in NO release and its inhibitory effect on Ld TopoII may also contribute to the anti-leishmanial effect of compound S. These results show the potential of this compound as a potential starting point for the discovery of novel anti-leishmanial leads.Communicated by Ramaswamy H. Sarma.

Background: The effect of different dosing regimens of cholecalciferol supplementation on bone biomarkers has not been studied in children with chronic kidney disease (CKD)., Methods: This is a post hoc analysis of a multi-center randomized controlled trial which included children with CKD stages 2-4 with vitamin D deficiency (25-hydroxy vitamin D (25OHD) < 30 ng/ml) randomized 1:1:1 to receive an equivalent dose of oral cholecalciferol as daily, weekly or monthly treatment. Markers of bone formation (bone alkaline phosphatase (BAP), procollagen I N terminal peptide (PINP)), bone resorption (tartarate-resistant acid phosphatase 5b (TRAP), C terminal telopeptide (CTX)), and osteocyte markers (intact fibroblast growth factor 23 (iFGF23), sclerostin) and soluble klotho were measured at baseline and after 3 months of intensive replacement therapy. The change in biomarkers and ratio of markers of bone formation to resorption were compared between treatment arms. BAP and TRAP were expressed as age- and sex-specific z-scores., Results: 25OHD levels increased with cholecalciferol supplementation, with 85% achieving normal levels. There was a significant increase in the BAP/TRAP ratio (p = 0.04), iFGF23 (p = 0.004), and klotho (p = 0.002) with cholecalciferol therapy, but this was comparable across all three therapy arms. The BAPz was significantly higher in the weekly arm (p = 0.01). The change in 25OHD (Δ25OHD) inversely correlated with ΔPTH (r =  - 0.4, p < 0.001)., Conclusions: Although cholecalciferol supplementation was associated with a significant increase in bone formation, the three dosing regimens of cholecalciferol supplementation have a comparable effect on the bone biomarker profile, suggesting that they can be used interchangeably to suit the patient's needs and optimize adherence to therapy. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Aims and Objective: This study aimed to compare hormone receptor (HR) status before and after neoadjuvant chemotherapy that is discordance in locally advanced breast cancer patients, which are amenable for surgery. The secondary objective was to study the correlation between tumor response and HR expression., Materials and Methods: The duration of the study was from August 2018 to December 2020. A total of 23 patients were selected as per certain inclusion criteria. American Society of Clinical Oncologys methodology was used to analyze estrogen receptor (ER) and progesterone receptor (PR) status of histopathology specimen. For study purposes, patients were classified into four groups after core biopsy of breast lump and after definitive surgery (post-NACT (neoadjuvant chemotherapy)) - Group A (ER+, PR+), Group B (ER+, PR-), Group C (ER-, PR+), and Group D (ER-, PR-)., Results: ER discordance was found to be (2/23) 8.69% (P value 0.76). PR discordance was (4/23) 17.39%. PR discordance was found to be higher than ER discordance. Changes in staining patterns in ERs were seen in 14 patients (93.33%). Changes in staining percentage in PRs were seen in eight patients (80%). It was found that both receptor-positive and negative diseases had an equal proportion of stable disease., Conclusion: From the study, it is noted that performing ER PR study twice (before and after chemotherapy) is necessary as discordance is noted and this may impact the further treatment strategy., Competing Interests: None

Background: Atypical hemolytic uremic syndrome (aHUS) is hemolytic uremic syndrome (HUS) without a coexisting disease or specific infection. Eculizumab is the standard of care for children with aHUS. However, since it is not yet available in India, plasma therapy remains the treatment of choice in these patients. We studied the clinical profile of children with aHUS and the determinants associated with low estimated glomerular filtration rate (eGFR) on follow-up., Materials and Methods: A retrospective chart review of children (1-18 years) with aHUS managed at a tertiary care center was done. Demographic details, clinical features, and investigations at presentation and on subsequent visits were noted. Details of treatment and duration of hospital stay were recorded., Results: Of 26 children, boys outnumbered girls (2:1). The mean age at presentation was 80 ± 37.6 months. All children were hypertensive during the early phase of illness. Anti-factor H antibodies were elevated in 84% (22/26). Plasma therapy was initiated for 25 patients, and in 17 children, additionally immunosuppression was given. The median duration to achieve hematological remission was 17 days. As compared to children with normal eGFR, those with CKD stage 2 or more had significant delay in initiation of plasma therapy (4 vs. 14 days) and also took a longer time to achieve hematological remission (15 vs. 28 days). The prevalence of hypertension and proteinuria at the last follow-up was 63% and 27%, respectively., Conclusion: Delayed initiation of plasma therapy and longer time to achieve hematological remission are associated with lower eGFR on follow-up. Long-term monitoring of hypertension and proteinuria is needed in these children., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Nephrology.)

The emergence of Plasmodium falciparum resistance raises an urgent need to find new antimalarial drugs. Here, we report the rational repurposing of the anti-hepatitis C virus drug, alisporivir, a nonimmunosuppressive analog of cyclosporin A, against artemisinin-resistant strains of P. falciparum. In silico docking studies and molecular dynamic simulation predicted strong interaction of alisporivir with Pf Cyclophilin 19B, confirmed through biophysical assays with a K d value of 354.3 nM. Alisporivir showed potent antimalarial activity against chloroquine-resistant ( Pf RKL-9 with resistance index [Ri] 2.14 ± 0.23) and artemisinin-resistant ( Pf Kelch13 R539T with Ri 1.15 ± 0.04) parasites. The Ri is defined as the ratio between the IC 50 values of the resistant line to that of the sensitive line. To further investigate the mechanism involved, we analyzed the expression level of Pf Cyclophilin 19B in artemisinin-resistant P. falciparum ( Pf Kelch13 R539T ). Semiquantitative real-time transcript, Western blot, and immunofluorescence analyses confirmed the overexpression of Pf Cyclophilin 19B in Pf Kelch13 R539T . A 50% inhibitory concentration in the nanomolar range, together with the targeting of Pf Cyclophilin 19B, suggests that alisporivir can be used in combination with artemisinin. Since artemisinin resistance slows the clearance of ring-stage parasites, we performed a ring survival assay on artemisinin-resistant strain Pf Kelch13 R539T and found significant decrease in parasite survival with alisporivir. Alisporivir was found to act synergistically with dihydroartemisinin and increase its efficacy. Furthermore, alisporivir exhibited antimalarial activity in vivo . Altogether, with the rational target-based Repurposing of alisporivir against malaria, our results support the hypothesis that targeting resistance mechanisms is a viable approach toward dealing with drug-resistant parasite.

Background: Extensive vaccination drives undertaken globally helped in the fight against the coronavirus disease 2019 (COVID-19) pandemic, but different nations adopted different vaccination policies to tackle the disease. The vaccination drive in India began with the administration of two different vaccines: Covishield and Covaxin. We assessed the effect of vaccination status on imaging severity in patients with positive COVID-19 reverse transcription-polymerase chain reaction (RT-PCR)/antigen tests., Method: This was a single-center retrospective observation analysis carried out over three months between March 1, 2021, to May 31, 2021. Data access was provided by the District Hospital Review Board (DHRB) and the Department of Health (DOH), District Ambala, Haryana. Appropriate statistical tools were used to analyze the data. Statistical Package for Social Sciences (SPSS) 26.0 and Python 3.9 were used for statistical analysis and visualization, and a p-value of less than 0.05 was considered statistically significant., Results: The total sample size of the study was 1,316, out of which 371 (28.2%) were vaccinated and 945 (71.8%) were not vaccinated. The mean age of the study participants was 49.6 ± 15.7 years. Seven hundred ninety-seven (60.6%) participants were male, while 519 (39.4%) participants were female. A statistically significant reduction was observed in the computed tomography severity score (CTSS) of the vaccinated population compared to the non-vaccinated group (χ 2 = 74.3, p < 0.001). Vaccination led to a statistically significant decrease in mean CTSS across all lung lobes., Conclusion: Emerging COVID-19 variants challenge the effect of available vaccines, with different nations adopting different vaccination strategies to deal with the ongoing health problem. CTSS was employed as an objective marker to study the disease severity and effect of vaccination. Vaccination resulted in a significant reduction in CTSS seen on high-resolution computed tomography (HRCT) chest scans. There was a significant decrease in the incidence of severe COVID-19 pneumonia among vaccinated individuals. We need more observational data to corroborate the efficacy of vaccines presented in the randomized trials. Sharing such data between different nations can help us adopt a unifying vaccination strategy and decrease the impact of COVID-19 in subsequent disease waves., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Singhal et al.)

Post-translational modifications (PTMs) including phosphorylation and palmitoylation have emerged as crucial biomolecular events that govern many cellular processes including functioning of motility- and invasion-associated proteins during Plasmodium falciparum invasion. However, no study has ever focused on understanding the possibility of a crosstalk between these two molecular events and its direct impact on preinvasion- and invasion-associated protein-protein interaction (PPI) network-based molecular machinery. Here, we used an integrated in silico analysis to enrich two different catalogues of proteins: (i) the first group defines the cumulative pool of phosphorylated and palmitoylated proteins, and (ii) the second group represents a common set of proteins predicted to have both phosphorylation and palmitoylation. Subsequent PPI analysis identified an important protein cluster comprising myosin A tail interacting protein (MTIP) as one of the hub proteins of the glideosome motor complex in P. falciparum , predicted to have dual modification with the possibility of a crosstalk between the same. Our findings suggested that blocking palmitoylation led to reduced phosphorylation and blocking phosphorylation led to abrogated palmitoylation of MTIP. As a result of the crosstalk between these biomolecular events, MTIP's interaction with myosin A was found to be abrogated. Next, the crosstalk between phosphorylation and palmitoylation was confirmed at a global proteome level by click chemistry and the phenotypic effect of this crosstalk was observed via synergistic inhibition in P. falciparum invasion using checkerboard assay and isobologram method. Overall, our findings revealed, for the first time, an interdependence between two PTM types, their possible crosstalk, and its direct impact on MTIP-mediated invasion via glideosome assembly protein myosin A in P. falciparum . These insights can be exploited for futuristic drug discovery platforms targeting parasite molecular machinery for developing novel antimalarial therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Anam, Kumari, Mukherjee, Rex, Biswas, Maurya, Ravikumar, Gupta, Kushawaha, Sah, Chaurasiya, Singhal, Singh, Kaushik, Prasad, Pati, Ranganathan and Singh.)

N-polar aluminum nitride (AlN) is an important building block for next-generation high-power radio frequency electronics. We report successful homoepitaxial growth of N-polar AlN by molecular beam epitaxy (MBE) on large-area, cost-effective N-polar AlN templates. Direct growth without any in situ surface cleaning leads to films with inverted Al polarity. It is found that Al-assisted cleaning before growth enables the epitaxial film to maintain N-polarity. The grown N-polar AlN epilayer with its smooth, pit-free surface duplicates the structural quality of the substrate, as evidenced by a clean and smooth growth interface with no noticeable extended defects generation. Near band-edge photoluminescence peaks are observed at room temperature on samples with MBE-grown layers but not on the bare AlN templates, implying the suppression of nonradiative recombination centers in the epitaxial N-polar AlN.

Global hunger and nutritional deficiency demand the advancement of existing and conventional approaches to food production. The application of nanoenabled strategies in agriculture has opened up new avenues for enhancing crop yield and productivity. Recently, two-dimensional (2D) nanomaterials (NMs) have manifested new possibilities for increasing food production and nutrition. Graphene nanosheets, the 2D form of graphene has been exemplary in enhancing the loading capacity of agro-active ingredients, their target-specific delivery, bioavailability, and controlled release with slow degradation, resulting in the increased shelf-life/active time of the agro-active components. Also, the development of novel formulations/composites of MXenes and Transition Metal Dichalcogenides (TMDs) can foster plant growth, metabolism, crop production, protection and improvement of soil quality. Additionally, the 2D NM-based biosensors can monitor the nutrient levels and other parameters affecting agronomical traits in plants. This review provides an insight into the details of 2D NM synthesis and functionalization methods. Notably, the review highlights the broad-range of 2D NM applications and their suitability in the development of nanotechnology-based agriformulations. The 2D NM-based derivatives have shown immense potential in enhancing the pedologic parameters, crop productivity, pest-protection and nutritional value. Thus, assisting in achieving food and environmental sustainability goals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

SUMOylation is one of the post-translational modifications that have recently been described as a key regulator of various cellular, nuclear, metabolic, and immunological processes. The process of SUMOylation involves the modification of one or more lysine residues of target proteins by conjugation of a ubiquitin-like, small polypeptide known as SUMO for their degradation, stability, transcriptional regulation, cellular localization, and transport. Herein, for the first time, we report the involvement of the host SUMOylation pathway in the process of infection of Leishmania donovani , a causative agent of visceral leishmaniasis. Our data revealed that infection of L. donovani to the host macrophages leads to upregulation of SUMOylation pathway genes and downregulation of a deSUMOylating gene, SENP1. Further, to confirm the effect of the host SUMOylation on the growth of Leishmania , the genes associated with the SUMOylation pathway were silenced and parasite load was analyzed. The knockdown of the SUMOylation pathway led to a reduction in parasitic load, suggesting the role of the host SUMOylation pathway in the disease progression and parasite survival. Owing to the effect of the SUMOylation pathway in autophagy, we further investigated the status of host autophagy to gain mechanistic insights into how SUMOylation mediates the regulation of growth of L. donovani . Knockdown of genes of host SUMOylation pathway led to the reduction of the expression levels of host autophagy markers while promoting autophagosome-lysosome fusion, suggesting SUMOylation-mediated autophagy in terms of autophagy initiation and autophagy maturation during parasite survival. The levels of reactive oxygen species (ROS) generation, nitric oxide (NO) production, and pro-inflammatory cytokines were also elevated upon the knockdown of genes of the host SUMOylation pathway during L. donovani infection. This indicates the involvement of the SUMOylation pathway in the modulation of protective immune responses and thus favoring parasite survival. Taken together, the results of this study indicate the hijacking of the host SUMOylation pathway by L. donovani toward the suppression of host immune responses and facilitation of host autophagy to potentially facilitate its survival. Targeting of SUMOylation pathway can provide a starting point for the design and development of novel therapeutic interventions to combat leishmaniasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Singhal, Madan, Chaurasiya, Srivastava, Singh, Kaushik, Kahlon, Maurya, Marothia, Joshi, Ranganathan and Singh.)

We asked if transfer RNA (tRNA) ever got an opportunity of translating its own sequence during evolution, what would have been the function of such tRNA-encoded peptides (tREPs)? If not, could one artificially synthesize tREPs to study the corresponding functional outcomes? Here, we report a novel, first-in-the-class, chemically synthesized tREP-18 molecule originating from the Escherichia coli tRNA sequence showing potent antileishmanial property. As a first step, E. coli tRNAs were computationally translated into peptide sequence equivalents and a database of full-length hypothetical tREPs was created. The tREP sequences were sent into sequence, structure, and energy filters to narrow down potential peptides for experimental validation. Based on the functional predictions, tREPs were screened against antiparasitic targets, leading to the identification of tREP-18 as a potential antiparasitic peptide. The in vitro assay of chemically synthesized tREP-18 on the Ag83 strain of Leishmania donovani showed its potent antileishmanial property (IC50 value of 22.13 nM). The atomic force microscopy and scanning electron microscopy images indicated significant alteration in the cytoskeletal architecture of tREP-18-treated parasites. Also, tREP-18 seems to destabilize the mitochondrial membrane potential of parasites, disrupting their cellular integrity and leading to parasitic death. The cellular assays of the tREP-18 peptide on the BS12 strain, a clinical isolate of post-kala azar dermal leishmaniasis, demonstrated its significant efficacy at an IC50 value of 15 nM. The tREP-18 peptide showed a toxic effect on the amastigote stage of the parasite, showing macrophage pathogen clearance at a concentration of 22.5 nM. This study provides the proof of the concept of making a new class of functional peptides from tRNA sequences. It also opens a huge untapped tRNA-peptide space toward novel discoveries and applications. In the future, it would be interesting to perform tREP edits and redesign tREPs toward specific applications., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: There is increasing research focus on prediction and prevention of rheumatoid arthritis (RA). Information about risk of RA is increasingly available via direct-to-consumer testing. However, there is limited understanding of public perceptions around predictive testing for RA. This study explores public perceptions of predictive testing for RA in comparison to breast cancer (BC) and early-onset Alzheimer's disease (AD)., Methods: Four focus groups with 21 members of the public were conducted using hypothetical vignettes about predictive testing for each disease. Transcripts of focus group proceedings were analysed inductively using thematic analysis., Results: Thematic analysis of the data produced three key themes: decision-making factors, consequences, and consumer needs. Factors suggested that might influence decision-making about predictive testing included family history, fear, and perceived severity and treatability of the illness. RA was perceived to be less severe and more treatable than BC/AD. Potential consequences of predictive testing across all diseases included lifestyle modification, planning for the future and discrimination by employers or insurers. Predictive testing for RA was perceived to have less potential for negative psychological consequences than other diseases. Participants highlighted that individuals undertaking predictive testing should be signposted to appropriate support services and receive information on the accuracy of predictive testing. It was suggested that strategies to mitigate concerns regarding communication and confidentiality of risk results are required., Conclusions: The findings of this study reflect public misunderstandings regarding RA that may impact the uptake of and responses to predictive testing, and key informational needs of individuals considering a predictive test. Predictive strategies should be accompanied by awareness-raising initiatives and informational resources., (© 2022. The Author(s).)

Aims: The prevalence of vitamin D deficiency is high in children with chronic kidney disease (CKD). However, current dosing recommendations are based on limited pharmacokinetic (PK) data. This study aimed to develop a population PK model of colecalciferol that can be used to optimise colecalciferol dosing in this population., Methods: Data from 83 children with CKD were used to develop a population PK model using a nonlinear mixed effects modelling approach. Serum creatinine and type of kidney disease (glomerular vs. nonglomerular disease) were investigated as covariates, and optimal dosing was determined based on achieving and maintaining 25-hydroxyvitamin D (25(OH)D) concentration of 30-48 ng/mL., Results: The time course of 25(OH)D concentrations was best described by a 1-compartment model with the addition of a basal concentration parameter to reflect endogenous 25(OH)D production from diet and sun exposure. Colecalciferol showed wide between-subject variability in its PK, with total body weight scaled allometrically the only covariate included in the model. Model-based simulations showed that current dosing recommendations for colecalciferol can be optimised using a weight-based dosing strategy., Conclusion: This is the first study to describe the population PK of colecalciferol in children with CKD. PK model informed dosing is expected to improve the attainment of target 25(OH)D concentrations, while minimising the risk of overdosing., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30 ng/mL in children with CKD stages 2-4., Methods: An open-label, multicentre randomized controlled trial randomized children with 25OHD concentrations <30 ng/mL in 1:1:1 to oral cholecalciferol 3000 IU daily, 25 000 IU weekly or 100 000 IU monthly for 3 months (maximum three intensive courses). In those with 25OHD ≥30 ng/mL, 1000 IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD ≥30 ng/mL at the end of intensive phase treatment., Results: Ninety children were randomized to daily (n = 30), weekly (n = 29) or monthly (n = 31) treatment groups. At the end of intensive phase, 70/90 (77.8%) achieved 25OHD ≥30 ng/mL; 25OHD concentrations were comparable between groups (median 44.3, 39.4 and 39.3 ng/mL for daily, weekly and monthly groups, respectively; P = 0.24) with no difference between groups for time to achieve 25OHD ≥30 ng/mL (P = 0.28). There was no change in calcium, phosphorus and parathyroid hormone, but fibroblast growth factor 23 (P = 0.002) and klotho (P = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 versus 41.8 ng/mL; P = 0.007). One child had a 25OHD concentration of 134 ng/mL, and 5.5% had hypercalcemia without symptoms of toxicity., Conclusion: Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups, without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared with those with non-glomerular disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of the ERA.)

We report a further case of spondylometaphyseal dysplasia - corner fracture type due to the fibronectin-1 gene (SMD-FN1) in a child originally thought to have metaphyseal chondrodysplasia-Brussels type (MCD Brussels). We highlight phenotypic differences with the SMD-FN1 published reports. This case is unique in terms of the method of molecular confirmation. Findings from the 100 000 Genomes Project were originally negative (in both tier 1 and 2); however, subsequent reanalysis, initiated by an automated search for new gene-disease associations in PanelApp, highlighted a candidate diagnostic variant. Our child had short stature, facial dysmorphism, spondylometaphyseal dysplasia and corner fractures and a heterozygous de novo missense variant in FN1 (c.675C>G p.(Cys225Trp), which was likely pathogenic. The variant matched the clinical and radiological features and a diagnosis of SMD-FN1 was confirmed. We explore the diagnostic journey of this patient, compare her findings with the previous 15 patients reported with SMD-FN1 and discuss the diagnostic utility of automated reanalysis. We consider differences and similarities between MCD Brussels and SMD-FN1, by reviewing literature on both conditions and assess whether they are in fact the same disorder., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Nanotechnology-based miniaturized devices have been a breakthrough in the pre-clinical and clinical research areas, e.g. drug delivery, personalized medicine. They have revolutionized the discovery and development of biomarker-based diagnostic devices for detection of various diseases such as tuberculosis, malaria and cancer. Nanomaterials (NMs) hold tremendous diagnostic potential due to their high surface-to-volume ratio and quantum confinement phenomenon, improving the detection limit of clinically relevant biomolecules in bio-fluids. Thus, they are helpful in the translation of bench-on platform to point-of-care (POC) screening device. The nanomaterial-based biosensor fabrication technology has also simplified and improved oral cancer (OC) or oral squamous cell carcinomas (OSCC) diagnosis. The fabrication of nano-bio sensors involves application specific modifications of NMs. The unique properties functionalized NMs have augmented their application on the nano-biosensing platform for the detection of clinically relevant biomolecules in bio-fluids. Therefore, this article summarizes the recent advancements in the process of fabrication of nano-biosensors for detection of OC.

Aberrations in RLIP, p53, and PKCα represent essentially the entire spectrum of all human neoplasms. Elevated PKCα expression, failure of the cell cycle checkpoint (p53 dysfunction), and abnormal glutathione (GSH) metabolism are fundamental hallmarks of carcinogenesis and drug/radiation resistance. However, a lack of investigations into the interactions between these important regulatory nodes has fundamentally limited our understanding of carcinogenesis and the development of effective interventions for cancer prevention and therapy. Loss of p53, perhaps the most powerful tumor suppressor gene, predisposes rodents to spontaneous cancer and humans to familial, as well as acquired, cancers. Until recently, no genetic manipulation of any oncogene had been reported to abrogate spontaneous carcinogenesis in p53 -/- rodent models. However, the overexpression of RLIP, a GSH-electrophile conjugate (GS-E) transporter, has been found to enhance cancer cell proliferation and confer drug/radiation resistance, whereas its depletion causes tumor regression, suggesting its importance in cancer and drug/radiation resistance. Indeed, RLIP is an essential effector of p53 that is necessary for broad cancer-promoting epigenetic remodeling. Interestingly, through a haploinsufficiency mechanism, the partial depletion of RLIP in p53 -/- mice provides complete protection from neoplasia. Furthermore, RLIP -/- mice exhibit altered p53 and PKCα function, marked deficiency in clathrin-dependent endocytosis (CDE), and almost total resistance to chemical carcinogenesis. Based on these findings, in this review, we present a novel and radical hypothesis that expands our understanding of the highly significant cross-talk between p53, PKCα, and GSH signaling by RLIP in multiple tumor models., (Copyright © 2021 Elsevier B.V. All rights reserved.)