Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Productivity, soil health, and carbon management index of soybean-wheat cropping system under double zero-tillage and natural-farming based organic nutrient management in north-Indian plains.

Conservation-agriculture and organic-farming are two sustainable-agriculture approaches to ensure food security and environmental-sustainability. Hence, a field study assessed the productivity, soil-health and carbon-dynamics of soybean-wheat cropping system (SWCS) under four tillage and residue-management practices (TRMPs) viz., Conventional-tillage without residues (CT-R), conventional-tillage with residue-retention in both crops at 3 t ha-1 each (CT + R), zero-tillage without residues (ZT-R), and zero-tillage with residue-retention in both crops at 3 t ha-1 each (ZT + R); and five organic-nutrient-management-practices (ONMPs) in both crops viz., 100 % RDF (N1), 100 % RDN through FYM (N2), 100 % RDN through VC (N3), 100 % RDN through FYM + Biofertilizers + Cow-urine + Panchgavya + Jeevamrut (N4), and 100 % RDN through VC + Biofertilizers + Cow-urine + Panchgavya + Jeevamrut (N5), in split-plot-design replicated-thrice. Among TRMPs, ZT + R enhanced system-productivity (SEY) by ∼17.2 % over CT-R, besides improved soil available-N, P, K by 6.4, 6.5 and 6.5 %, respectively. SMBC, SMBN and SMBP were higher under ZT + R by 16.2, 21.5 and 10.8 % over CT-R, respectively. ZT + R had higher soil enzyme activities of DHA, Acid-P, ALP, URA, and FDA over CT-R by 19.4, 20.7, 21.5, 20.7 and 15.2 %, respectively. ZT + R also had higher VLC, ACP, LI and CMI over CT-R. Among ONMPs, the natural-farming based ONMP, N5 considerably improved SMBC, SMBN, SMBP, FDA, DHA, Acid-P, URA, and ALP by 12.7-12.9 % over N1 (100 % RDF). ONMP-N5 improved the available-N, P, K content over N1 by 6.6, 5.8 and 6.7 %, respectively. ONMP-N5 had higher (p < 0.05) microbial-count, VLC, APC, LI and CMI; however, system-productivity was ∼4.1 % lower than N1 in this two-years' short-study which further need investigation in multi-location long-term experiments. Overall, the dual-crop basis ZT + R at 6 t ha-1 year-1 + NF-based ONMPs (N5) may harness higher and sustained productivity under SWCS besides advancing soil-health and soil carbon-pools in sandy-loam soils of north-Indian plains and similar soils across south-Asia.

Dissecting chickpea genomic loci associated with the root penetration responsive traits in compacted soil.

MAIN CONCLUSION: Soil compaction reduces root exploration in chickpea. We found genes related to root architectural traits in chickpea that can help understand and improve root growth in compacted soils. Soil compaction is a major concern for modern agriculture, as it constrains plant root growth, leading to reduced resource acquisition. Phenotypic variation for root system architecture (RSA) traits in compacted soils is present for various crops; however, studies on genetic associations with these traits are lacking. Therefore, we investigated RSA traits in different soil compaction levels and identified significant genomic associations in chickpea. We conducted a Genome-Wide Association Study (GWAS) of 210 chickpea accessions for 13 RSA traits under three bulk densities (BD) (1.1BD, 1.6BD, and 1.8BD). Soil compaction decreases root exploration by reducing 12 RSA traits, except average diameter (AD). Further, AD is negatively correlated with lateral root traits, and this correlation increases in 1.8BD, suggesting the negative effect of AD on lateral root traits. Interestingly, we identified probable candidate genes such as GLP3 and LRX for lateral root traits and CRF1-like for total length (TL) in 1.6BD soil. In heavy soil compaction, DGK2 is associated with lateral root traits. Reduction in laterals during soil compaction is mainly due to delayed seedling establishment, thus making lateral root number a critical trait. Interestingly, we also found a higher contribution of the  GxE component of the number of root tips (Tips) to the total variation than the other lateral traits. We also identified a pectin esterase, PPE8B, associated with Tips in high soil compaction and a significantly associated SNP with the relative change in Tips depicting a trade-off between Tips and AD. Identified genes and loci would help develop soil-compaction-resistant chickpea varieties.

Bortezomib-induced neuropathy is in part mediated by the sensitization of TRPV1 channels.

TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30-50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent.

A fourth-order arithmetic average compact finite-difference method for nonlinear singular elliptic PDEs on a 3D smooth quasi-variable grid network.

The analysis of nonlinear elliptic PDEs representing stationary convection-dominated diffusion equation, Sine-Gordon equation, Helmholtz equation, and heat exchange diffusion model in a battery often lacks in closed-form solutions. For the long-term behaviour and to assess the quantitative behaviour of the model, numerical treatment is necessary. A novel numerical approach based on arithmetic average compact discretization employing a quasi-variable grid network is proposed for a wide class of nonlinear three-dimensional elliptic PDEs. The method's key benefit is that it applies to singular models and only needs nineteen-point grids with seven functional approximations. Additionally, the suggested method disseminates the truncation error across the domain, which is unrealistic for finite-difference discretization with a fixed step length of grid points. Often, small diffusion anticipates strong oscillation, and tuning the grid stretching parameter helps error dispersion over the domain. The scheme is examined for maximal error bounds and convergence property with the help of a monotone matrix and its irreducible character. The metrics of solution accuracies, mainly root-mean-squared and absolute errors alongside numerical convergence rate, are inspected by different types of variable coefficients, singular and non-singular 3D elliptic PDEs appearing in a convection-diffusion phenomenon. The performance of the numerical solution corroborates the fourth-order convergence on a quasi-variable grid network.

Reduced-Phenalenyl-Based Molecule as a Super Electron Donor for Radical-Mediated C-N Coupling Catalysis at Room Temperature.

We demonstrate that an in situ generated di-reduced phenalenyl (PLY) species accumulates sufficiently high energy and acts as a super electron donor to generate aryl radicals from aryl halides to accomplish Buchwald-Hartwig-type C-N cross-coupling reactions at room temperature. This catalytic protocol does not require any external stimuli such as heat, light, or cathodic current. This protocol shows a wide variety of substrate scope covering different genres of aryl and heteroaryl halides with various aromatic as well as aliphatic amines and late-stage functionalization of the well-known natural products. The control experiments, along with extensive density functional theory (DFT) calculations, unveil that the aryl radical is generated by a single electron transfer from the di-reduced PLY to the aryl halide substrate. The aryl radical acts as an electrophile and binds with amine, leading to the chemically driven radical-mediated C-N cross-coupling under transition-metal-free conditions.

Corticosteroids: A boon or bane for COVID-19 patients?

Several drugs and antibodies have been repurposed to treat COVID-19. Since the outcome of the drugs and antibodies clinical studies have been mostly inconclusive or with lesser effects, therefore the need for alternative treatments has become unavoidable. However, corticosteroids, which have a history of therapeutic efficacy against coronaviruses (SARS and MERS), might emerge into one of the pandemic's heroic characters. Corticosteroids serve an immunomodulatory function in the post-viral hyper-inflammatory condition (the cytokine storm, or release syndrome), suppressing the excessive immunological response and preventing multi-organ failure and death. Therefore, corticosteroids have been used to treat COVID-19 patients for more than last two years. According to recent clinical trials and the results of observational studies, corticosteroids can be administered to patients with severe and critical COVID-19 symptoms with a favorable risk-benefit ratio. Corticosteroids like Hydrocortisone, dexamethasone, Prednisolone and Methylprednisolone has been reported to be effective against SARS-CoV-2 virus in comparison to that of non-steroid drugs, by using non-genomic and genomic effects to prevent and reduce inflammation in tissues and the circulation. Clinical trials also show that inhaled budesonide (a synthetic corticosteroid) increases time to recovery and has the potential to reduce hospitalizations or fatalities in persons with COVID-19. There is also a brief overview of the industrial preparation of common glucocorticoids.

Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19: A review.

As of August 16, 2021, there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease (COVID-19), and the pandemic remains a global challenge. To date, no effective and approved drugs are available for the treatment of COVID-19. Angiotensin-converting enzyme 2 (ACE2) plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Notably, ACE2 density is influenced by medical conditions, such as hypertension, or by drugs, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which can change the fate of SARS-CoV-2 infectivity. ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells. Different strategies aimed at blocking ACE2 with small molecules, peptides, and antibodies, or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2 (hrsACE2) are currently under investigation. In this article, we review the current state of knowledge that emphasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target. The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease. It has not yet been established whether hypertension and other comorbidities, independent of age, have a direct role in COVID-19. Therefore, the use of renin-angiotensin system inhibitors, ACEIs and ARBs, should not be discontinued during COVID-19 treatment.

Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19:A review / 药物分析学报

As of August 16,2021,there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease(COVID-19),and the pandemic remains a global challenge.To date,no effective and approved drugs are available for the treatment of COVID-19.Angiotensin-converting enzyme 2(ACE2)plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the etiological agent of COVID-19.Notably,ACE2 density is influenced by medical con-ditions,such as hypertension,or by drugs,including angiotensin-converting enzyme inhibitors(ACEIs)and angiotensin receptor blockers(ARBs),which can change the fate of SARS-CoV-2 infectivity.ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells.Different strategies aimed at blocking ACE2 with small molecules,peptides,and antibodies,or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2(hrsACE2)are currently under investigation.In this article,we review the current state of knowledge that em-phasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target.The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease.It has not yet been established whether hypertension and other comorbidities,independent of age,have a direct role in COVID-19.Therefore,the use of renin-angiotensin system inhibitors,ACEls and ARBs,should not be discontinued during COVID-19 treatment.

Randomized trial of high-dose rectal diclofenac suppository and epinephrine spray on duodenal papilla for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND AND AIMS: High-dose rectal diclofenac suppository and epinephrine spray on duodenal papilla during endoscopic retrograde cholangiopancreatography (ERCP) may reduce the incidence of post-ERCP pancreatitis. We performed randomized trial to compare the effect of combination of rectal diclofenac and epinephrine spray on papilla (group A) vs. combination of rectal diclofenac with saline spray (group B) for prevention of post-ERCP pancreatitis. METHODS: We performed a double-blind trial at tertiary care center from April 2018 to May 2020 on 882 patients with naive papilla undergoing ERCP. The patients were randomly assigned to groups, A (n=437) or B (n=445). All patients received a single dose of rectal diclofenac 100 mg within 30 minutes before ERCP; 20 mL of diluted epinephrine 0.02% (group A) or saline (group B) was then sprayed on the duodenal papilla at the end of ERCP. The primary outcome was to compare incidence of post-ERCP pancreatitis (PEP) in two groups. RESULTS: The groups had similar baseline characteristics. PEP developed in 28 patients in group A (6.4%) and 35 patients in group B (7.9%) (relative risk, 1.1; 95% CI, 0.87-1.39; p=0.401). CONCLUSION: Our study showed that addition of epinephrine spray on duodenal papilla did not reduce the risk of post-ERCP pancreatitis. There is need for further studies to evaluate the role of different concentrations of epinephrine spray on papilla for prevention of post-ERCP pancreatitis. TRIAL REGISTRATION: Clinical Trials Registry- India (CTRI/2018/04/013396).

Topoisomerase I inhibition and peripheral nerve injury induce DNA breaks and ATF3-associated axon regeneration in sensory neurons.

Although axonal damage induces rapid changes in gene expression in primary sensory neurons, it remains unclear how this process is initiated. The transcription factor ATF3, one of the earliest genes responding to nerve injury, regulates expression of downstream genes that enable axon regeneration. By exploiting ATF3 reporter systems, we identify topoisomerase inhibitors as ATF3 inducers, including camptothecin. Camptothecin increases ATF3 expression and promotes neurite outgrowth in sensory neurons in vitro and enhances axonal regeneration after sciatic nerve crush in vivo. Given the action of topoisomerases in producing DNA breaks, we determine that they do occur immediately after nerve damage at the ATF3 gene locus in injured sensory neurons and are further increased after camptothecin exposure. Formation of DNA breaks in injured sensory neurons and enhancement of it pharmacologically may contribute to the initiation of those transcriptional changes required for peripheral nerve regeneration.

Reduced Phenalenyl in Catalytic Dehalogenative Deuteration and Hydrodehalogenation of Aryl Halides.

Dehalogenative deuteration reactions are generally performed through metal-mediated processes. This report demonstrates a mild protocol for hydrodehalogenation and dehalogenative deuteration of aryl/heteroaryl halides (39 examples) using a reduced odd alternant hydrocarbon phenalenyl under transition metal-free conditions and has been employed successfully for the incorporation of deuterium in various biologically active compounds. The combined approach of experimental and theoretical studies revealed a single electron transfer-based mechanism.

Deconstructing the origins of sexual dimorphism in sensory modulation of pancreatic ß cells.

The regulation of glucose-stimulated insulin secretion and glucose excursion has a sensory component that operates in a sex-dependent manner. OBJECTIVE: Here, we aim to dissect the basis of the sexually dimorphic interaction between sensory neurons and pancreatic ß cells and its overall impact on insulin release and glucose homeostasis. METHODS: We used viral retrograde tracing techniques, surgical and chemodenervation models, and primary cell-based co-culture systems to uncover the biology underlying sex differences in sensory modulation of pancreatic ß-cell activity. RESULTS: Retrograde transsynaptic labeling revealed a sex difference in the density of sensory innervation in the pancreas. The number of sensory neurons emanating from the dorsal root and nodose ganglia that project in the pancreas is higher in male than in female mice. Immunostaining and confocal laser scanning microscopy confirmed the higher abundance of peri-islet sensory axonal tracts in the male pancreas. Capsaicin-induced sensory chemodenervation concomitantly enhanced glucose-stimulated insulin secretion and glucose clearance in male mice. These metabolic benefits were blunted when mice were orchidectomized prior to the ablation of sensory nerves. Interestingly, orchidectomy also lowered the density of peri-islet sensory neurons. In female mice, capsaicin treatment did not affect glucose-induced insulin secretion nor glucose excursion and ovariectomy did not modify these outcomes. Interestingly, same- and opposite-sex sensory-islet co-culture paradigms unmasked the existence of potential gonadal hormone-independent mechanisms mediating the male-female difference in sensory modulation of islet ß-cell activity. CONCLUSION: Taken together, these data suggest that the sex-biased nature of the sensory control of islet ß-cell activity is a result of a combination of neurodevelopmental inputs, sex hormone-dependent mechanisms and the potential action of somatic molecules encoded by the sex chromosome complement.

Fecaloma presenting as huge abdominal mass.

Fecal impaction is common in elderly, bed ridden, schizoaffective patients on antipsychotics. Intestinal obstruction due to distal colonic fecaliths is rare as it is amenable to digital manual evacuation and enemas. Our patient presented with abdominal distention, with last bowel evacuation reported 3 months ago. Computed tomography (CT) abdomen demonstrated a huge sigmoid fecalith causing bilateral hydronephrosis. He was managed through laparotomy with sigmoid colon resection and end colostomy.

Design and Analysis of Customized Fixation Plate for Femoral Shaft.

BACKGROUND: In the recent years, several techniques have been used to treat femur diaphyseal fracture. Among all the traditional fixation techniques, unstable fixation remains the biggest challenge for orthopedists. Researchers have recommended new approaches to deal with diaphyseal femur fracture. However, solely few had been successful in getting some better results. In the present work, a methodology comprising of design and finite-element analysis of a counter fit customized fixation plate has been suggested to provide a stable fixation. MATERIALS AND METHODS: In the present work, reverse engineering (RE) approach has been invoked to create a 3D model of a fresh fractured femur diaphysis bone using the computed tomography (CT) scan data available in digital imaging and communications in medicine (DICOM) format. To provide stable fixation, a counter fit customized fixation plate at medial side has been designed and simulated under static physiological loading conditions for three different biocompatible materials, viz., titanium alloy (Ti6Al4V), stainless steel (SS-316L), and cobalt-chromium-molybdenum alloy (Co-Cr-Mo). RESULTS: Static stress distribution and deformation analysis of the clinical setup have been performed for the aforementioned materials. It has been observed that the stresses and deformation developed in all the materials are quite low. It implies that customized fixation plates will provide stable fixation resulting in improved fracture union. CONCLUSION: The proposed work will assist the medical practitioners regarding the design and analysis of customized implants. This will reduce the post surgical failures and residual pain due to non-union fractured region.

Impact of Vitamin D Status in Chronic Liver Disease.

BACKGROUND: Vitamin D deficiency is extremely common in chronic liver disease (CLD) patients. Up to 93% of these patients have some degree of vitamin D insufficiency. Liver plays an important role in the metabolism and pleiotropic functions of vitamin D. Vitamin D deficiency has been associated with increased mortality, bacterial infections, portal hypertension complications, and fibrosis severity. We aimed to determine the impact of vitamin D level in CLD. METHODS: One hundred fifty individuals consisting of 75 cirrhotic patients (cases) and 75 respective attendants (controls) were enrolled between July 2015 and July 2017. A detailed clinical and laboratory evaluation was done along with estimation of vitamin D level. Unpaired t-test and analysis of variance was used to compare difference in the level of continuous variables between different groups. Linear regression analysis was performed to analyze the correlation between vitamin D deficiency and severity of liver disease. RESULTS: The age of patients ranged from 18 years to 69 years with mean of 48.85 ± 13.6 years in the case group and 46.57 ± 17.24 years in the control group. Out of 75 CLD patients, vitamin D deficiency (<20 ng/dl) was found in 31 (41.4%) patients, out of which 14(18.7%) suffered from severe vitamin D deficiency (<10 ng/ml). On applying analysis of variance test, there was significant difference in vitamin D level and serum albumin and serum bilirubin (P < 0.05). On linear regression, vitamin D level showed significant negative correlation with Child-Pugh score (r = -0.7379, P < 0.0001) and Model For End-Stage Liver Disease score (r = -0.6671, P < 0.0001). CONCLUSION: Our study concluded that CLD is associated with a significantly low level of vitamin D, which was independent to patient's gender, body mass index, residence, and education level. The findings of our study suggest that awareness of serum vitamin D level in patients with CLD is important. Further studies are required to validate the importance of vitamin D levels and impact of vitamin D supplementation on CLD.

Primary amides to amines or nitriles: a dual role by a single catalyst.

We report a manganese-catalyzed hydrosilylative reduction of various primary amides to amines (25 examples). On simple modification of the reaction conditions such as in the presence of a catalytic amount of secondary amide, the same catalyst can transform the primary amides into intermediate nitrile compounds (16 examples) in excellent yields. This is the first example where such a controlled catalytic transformation of primary amides to amines or nitriles with a single catalyst has been demonstrated.

Catalytic Reduction of Nitriles by Polymethylhydrosiloxane Using a Phenalenyl-Based Iron(III) Complex.

The reduction of nitriles to primary amines using an inexpensive silane such as polymethylhydrosiloxane (PMHS) is an industrially important reaction. Herein we report the synthesis of an earth-abundant Fe(III) complex bearing a phenalenyl-based ligand that was characterized by mass spectroscopy, elemental analysis, cyclic voltammetry, and single-crystal X-ray diffraction. The complex showed excellent catalytic activity toward reduction of aromatic, heteroaromatic, aliphatic, and sterically crowded nitriles to produce primary amines using polymethylhydrosiloxane (PMHS).

Diltiazem Promotes Regenerative Axon Growth.

Axotomy results in permanent loss of function after brain and spinal cord injuries due to the minimal regenerative propensity of the adult central nervous system (CNS). To identify pharmacological enhancers of axon regeneration, 960 compounds were screened for cortical neuron axonal regrowth using an in vitro cortical scrape assay. Diltiazem, verapamil, and bromopride were discovered to facilitate axon regeneration in rat cortical cultures, in the presence of chondroitin sulfate proteoglycans (CSPGs). Diltiazem, an L-type calcium channel blocker (L-CCB), also promotes axon outgrowth in adult primary mouse dorsal root ganglion (DRG) and induced human sensory (iSensory) neurons.

Graphene oxide-phenalenyl composite: transition metal-free recyclable and catalytic C-H functionalization.

An efficient route towards a heterogeneous transition metal-free catalytic C-H functionalization using a covalently linked graphene oxide-phenalenyl conjugate is described herein (28 examples, which include a core of some biologically relevant biaryl and hetero-biaryls). It is an environmentally benign, economical and heterogeneous platform, whose catalytic activity can easily be regenerated through a simple washing-drying technique and the catalytic activity can be retained even after 10 cycles.