Robust superconductivity and the suppression of charge-density wave in the quasi-skutteruditesCa3(Ir1-xRhx)4Sn13single crystals at ambient pressure.

Single crystals of the quasi-skutterudite compounds Ca3(Ir1-xRhx)4Sn13(3-4-13) were synthesized by flux growth and characterized by x-ray diffraction, energy dispersive x-ray spectroscopy, magnetization, resistivity, and radio frequency magnetic susceptibility techniques. The coexistence and competition between the charge density wave (CDW) and superconductivity was studied by varying the Rh/Ir ratio. The superconducting transition temperature,Tc, varies from 7 K in pure Ir (x = 0) to 8.3 K in pure Rh (x = 1). Temperature-dependent electrical resistivity reveals monotonic suppression of the CDW transition temperature,TCDW(x). The CDW starts in pure Ir,x = 0, atTCDW≈ 40 K and extrapolates roughly linearly to zero atxc≈0.53-0.58 under the superconducting dome. Magnetization and transport measurements show a significant influence of CDW on superconducting and normal states. Meissner expulsion is substantially reduced in the CDW region, indicating competition between the CDW and superconductivity. The low-temperature resistivity is higher in the CDW part of the phase diagram, consistent with the reduced density of states due to CDW gapping. Its temperature dependence just aboveTcshows signs of non-Fermi liquid behavior in a cone-like composition pattern. We conclude that the Ca3(Ir1-xRhx)4Sn13alloy is a good candidate for a composition-driven quantum critical point at ambient pressure.

Transitional Hemodynamics in Neonates Born Through Meconium-Stained Amniotic Fluid: A Prospective Observational Study.

Neonates born through meconium-stained amniotic fluid (MSAF) are at increased risk of altered cardiopulmonary transition at birth. There is a paucity of literature evaluating the transitional hemodynamics in these neonates. We aimed to evaluate transitional hemodynamics via echocardiography in neonates born through MSAF, compared to healthy neonates. The primary objective was to assess pulmonary vascular resistance using left pulmonary artery-velocity time integral (LPA-VTI). The secondary objectives were to assess other pulmonary vascular parameters and myocardial function. We enrolled 35 MSAF-born and 35 healthy neonates. Echocardiography was performed at 24 and 48 h of life by a pediatric cardiologist. Echocardiographic parameters were compared between MSAF-born and healthy neonates, and between MSAF-born neonates who developed meconium aspiration syndrome (MAS) and who did not (non-MAS). Among 35 MSAF-born neonates, 14 (40%) were non-vigorous, 18 (51%) required admission to neonatal intensive care unit, 8 (23%) developed MAS, 3 (9%) pulmonary hypertension and 1 (3%) air leak. On echocardiography, LPA-VTI (cm; mean ± SD) was significantly decreased at 24 and 48 h in MSAF-born neonates (14.38 ± 2.48; 15.55 ± 2.48), compared to healthy neonates (16.60 ± 2.14; 17.66 ± 2.71), respectively. Further, LPA-VTI was significantly reduced at 24 and 48 h among MAS (11.81 ± 3.0; 12.43 ± 2.5), compared to non-MAS neonates (15.15 ± 1.72; 16.48 ± 1.55), respectively. Other pulmonary vascular and myocardial function parameters were comparable between the two groups. Pulmonary adaptation was significantly delayed in neonates with MSAF, which was more pronounced in MAS neonates. Further studies should explore the utility of these parameters for early prediction of cardiorespiratory morbidities in this population.

Birds and environment: a multidisciplinary approach to ecological, behavioural and conservation issues.

Birds perform significant ecosystem services in the environment. Nevertheless, they have been facing threats to their survival globally. This special collection assembles diverse articles on various aspects of birds' life, their interactions with the environment, their adaptations, and threats they have been facing along with conservation measures.

A Case of Fibrinous Pericardial Effusion: Masquerading Presentation of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with varied presentations varying from nonspecific features like fever, malaise, and arthralgia to serious manifestations like serositis (pleural, pericardial effusions), neurological manifestations, and renal involvement (lupus nephritis). SLE is a great mimicker, especially for infections like tuberculosis (TB) which is rampant in low- and middle-income countries (LMIC). We report a case of massive pericardial effusion, which was initially diagnosed as TB on clinico-radiological basis, but the diagnosis was later revised owing to new findings.

Fetal Hydantoin Syndrome: A Case Report.

Epilepsy is not a common cause of morbidity in pregnancy. It has widespread effects on maternal and fetal health necessitating adequate control of seizures. Many anti-seizure medications (ASM) have teratogenic effects on the fetus. We report a case of severe fetal hydantoin syndrome resulting in life-threatening major congenital anomalies. The mother was on phenytoin for the last three years and the pregnancy was not registered. We discuss various features of fetal hydantoin syndrome and the ideal management of epilepsy in pregnancy in brief.

Suspect the Unexpected: A Rare Association of Autoimmune Hemolytic Anemia and Hemophagocytic Lymphohistiocytosis with Visceral Leishmaniasis: A Case Report and Review of Literature.

Visceral leishmaniasis is a common tropical infection presenting with a myriad of hematological abnormalities. We report an unusual case of an 11-year-old girl suffering from a febrile illness with hepatosplenomegaly and anemia. Laboratory findings included pancytopenia and hyperbilirubinemia. The leishmania antigen rK39 was positive and bone marrow examination revealed hemophagocytosis and amastigote forms of Leishmania donovani. Direct Coombs' test was positive (warm type, IgG) and LDH was elevated. Tests for other infections were negative. A diagnosis of visceral leishmaniasis with autoimmune hemolytic anemia (warm antibody type, IgG) with hemophagocytic lymphohistiocytosis was made. Patient showed response with anti-leishmanial treatment with improvement in clinical condition.

Systemic Pseudohypoaldosteronism Type 1 Due to a Novel Mutation in SCNN1B Gene: A Case Report.

Pseudo hypoaldosteronism (PHA) is a type of channelopathy leading to life-threatening hyperkalemia, hyponatremia and metabolic acidosis in neonates. Type I PHA (PHAI) is characterized by either mutation in NR3C2 (MLR) gene or genes related to subunit of ENaC channel, whereas Type II (A to E) PHA is due to mutations in other genes. Type I PHA is further divided into systemic and renal forms based on the gene and organ involved. Systemic PHAI is a rare, multisystem disease presenting as severe salt wasting in neonates. In this article, we report a case of systemic pseudohypoaldosteronism type 1 in a 2 days old neonate with a novel mutation involving SCNN1B gene. Our patient appears to be the first reported case of systemic PHAI due to SCNN1B mutation from India.

Ethnomedicinal Use, Phytochemistry, and Other Potential Application of Aquatic and Semiaquatic Medicinal Plants.

Medicinal plants have been treating various ailments and diseases since ancient times. Aquatic and semiaquatic medicinal plants play an essential role in human welfare to fulfill their daily needs. They have shown biological, pharmacological, nutraceutical, and commercial applications. This review aims to collect and update all recent information on ethnomedicinal, phytochemistry, pharmacological activities, and nanoparticle synthesis and their uses in aquatic and semiaquatic medicinal plants. Original research papers, review papers, short communications, and book chapters on aquatic and semiaquatic plants have been retrieved from PubMed, Web of Science, Scopus, and Google Scholar. Keywords, ethnomedicinal studies, phytochemistry, pharmacological activities, and nanoparticle synthesis from aquatic and semiaquatic medicinal plants are used for the search. Different aquatic and semiaquatic medicinal plants belonging to the families Acanthaceae, Alismataceae, Amaranthaceae, Apiaceae, Araceae, Asteraceae, Boraginaceae, Ceratophyllaceae, Cyperaceae, Fabaceae, Hydrocharitaceae, Lythraceae, Marsileaceae, Menyanthaceae, Nelumbonaceae, Nymphaeaceae, Onagraceae, Plantaginaceae, Poaceae, Polygonaceae, Pontederiaceae, Primulaceae, Scrophulariaceae, and Zingiberaceae have been studied. They are rich in alkaloids, flavonoids, terpenoids, phenolics, saponins, tannins, dietary fiber, glycosidic derivatives, carbohydrates, and proteins. These phytochemicals have been used for their antimicrobial, antioxidant, hepatoprotective, sedative, anticonvulsant, cytotoxic, antiparasitic, and antidiabetic activities. Besides this, various parts of the plants are used as dietary supplements and green nanoparticle synthesis. These plants are also known for their commercial value and are used as an ingredient in some pharmaceutical industries.

Submandibular gland in squamous cell carcinoma of the tongue: Can preservation during neck dissection be a pragmatic option?

Context: The submandibular glands (SMGs) excision during head-and-neck oncosurgeries lead to significant morbidity and degradation of quality of life (QOL). The preservation of SMGs during head-and-neck oncosurgeries, without affecting oncological safety, will improve QOL by preventing xerostomia in these patients. Aims: The aim of this retrospective study was to assess the involvement of SMG by malignancy during neck dissection being done for the squamous cell carcinoma (SCC) of tongue and to evaluate oncological safety of SMG preservation in SCC of the tongue. Settings and Design: The study design was a retrospective analytical study. Subjects and Methods: The study included 391 patients of SCC of tongue operated at Quaternary oncological center from January 2016 to February 2020. The treatment records of 371 patients were reviewed for demographical data, nodal metastasis, and histopathological involvement of SMG by SCC. The statistical analysis was done using SPSS 22. Results: A total of 555 necks dissected were assessed, out of which 95 necks dissected were positive for nodal metastasis at level Ib. The SMG was involved by SCC in only two cases, both of which were poorly differentiated SCC. No intraglandular lymph nodes were detected in any of the SMG dissected. Conclusions: The study showed that involvement of the SMG by SCC of the tongue is not very common, and it may be possible to preserve the SMG during neck dissection in selected cases in SCC of the tongue. The preservation will definitely improve QOL of the patients, as excision of the SMG is one of the prominent factors, resulting in xerostomia.

Surgical Management of Parapharyngeal Tumors: Our Experience.

Context Tumors of parapharyngeal space (PPS) are rare and histologically diverse. The management of these tumors requires diligent assessment and planning with due consideration of various anatomical and pathological aspects of the lesion. Aims This retrospective study aims to present our experiences in the clinical and pathological aspects of PPS tumors with a critical evaluation of management. Settings and Design Retrospective analytical study. Methods and Material The electronic medical records of 60 cases of PPS tumors, managed surgically from 2007 to 2017, were reviewed and analyzed using SPSS 22 software. The mean follow-up duration was 44 months. Results The mean age was 45 years with a male-to-female ratio of 1.7 (38:22). The majority of the tumors were benign (71.7%) and the most common presentation being upper neck mass or oropharyngeal mass. Histologically, neurogenic tumors were most common (43.3%) PPS tumors, followed by tumors of salivary gland origin. Magnetic resonance imaging was used as a diagnostic modality in 70% of cases, and computed tomography scan and positron emission tomography/CT were used in 26.7 and 3.3% of cases, respectively. In our study, the diagnostic accuracy of fine-needle aspiration cytology was 71% for benign and 47% for malignant lesions. The most common approach for surgery used was transcervical (72%). Conclusion The study reveals that cranial nerve palsy is the most common complication associated with PPS tumors. Completely resected, malignant tumors originating within PPS have a good prognosis, as compared with tumors extending or metastasized to PPS.

Avian diversity in forest, agriculture and water stream habitats of Dehradun Valley, Uttarakhand, India.

The Western Himalaya is recognised for its biological diversity and ecological values. An attempt was made to understand the avian diversity distribution in Forest, Agriculture and Water stream habitats of Dehradun (Western Himalaya) Uttarakhand. A total of two hundred and thirty one species belonging to 54 families were encountered during the survey. Out of these, one endangered species (Egyptian Vulture, Neophron percnopterus) and three near-threatened species Alexandrine Parakeet (Psittacula eupatria), Black-necked Stork (Ephippiorhynchus asiaticu) and River Lapwing (Vanellus duvaucelii) and one vulnerable species Woolly-necked Stork (Ciconia episcopus) were sighted. Three avian species, Mistle Thrush, Sulphur-bellied Warbler and White-rumped Munia. have been recorded as isolates in the study area. The presence of these species indicates the habitats extension in Dehradun District of Uttarakhand. The present study provides significant records in the study site and provides a baseline data for future study with reference to conservation in Dehradun Region.

Can BMI be a predictor of perioperative complications in Head and Neck cancer surgery?

<b>Introduction:</b> The effect of BMI on development of perioperative complications in head and neck cancer surgeries is not welldefined. </br></br> <b> Aim:</b> This study aims to evaluate the effect of body mass index (BMI) on the development of surgical complications during the perioperative period in head and neck carcinoma (HNC) patients. </br></br> <b>Materials and methods:</b> This study was conducted from 2019 to 2020. Electronic medical records of 210 patients undergoing major (clean-contaminated) surgeries were analysed. Chi-square test or Fisher exact test for determining association in categorical data and independent T-test or Mann-Whitney U test for comparison between the presence of complications and relation with continuous clinical parameters were used. </br></br> <b>Results:</b> The majority of patients were within normal-weight range (68.57%). Only 12.85% of patients had BMI under 18.5 kg/m2 and 18.57% of patients had BMI equal to or more than 25 kg/m2. Coexisting comorbidities were present in 48.7% of patients with BMI of more than 25 kg/m2. Major and minor complications were present in 10.5% and 16.7% of all patients, respectively. Surgical site infections were present in 18.1% of patients. There was no statistical difference in the rate of complications (major, minor and SSI) in underweight, normal weight and overweight categories. The complications were significantly associated with the extent of surgery (P = 0.00413) and blood loss of more than 775 mL (P-value 0.005). </br></br> <b> Conclusions:</b> In conclusion, the rate of surgical complications in head and neck onco-surgeries is not related to BMI of the patients. The perioperative management of these patients might require some modification due to co-existing comorbidities, but the overall impact on the development of complications could not be proven in this study.

Polyherbal Medicine Divya Sarva-Kalp-Kwath Ameliorates Persistent Carbon Tetrachloride Induced Biochemical and Pathological Liver Impairments in Wistar Rats and in HepG2 Cells.

Divya Sarva-Kalp-Kwath (SKK) is a poly-herbal ayurvedic medicine formulated using plant extracts of Boerhavia diffusa L. (Nyctaginaceae), Phyllanthus niruri L. (Euphorbiaceae), and Solanum nigrum L. (Solanaceae), described to improve liver function and general health. In the present study, we have explored the hepatoprotective effects of SKK in ameliorating carbon tetrachloride (CCl4) induced liver toxicity using in-vitro and in-vivo test systems. Chemical analysis of SKK using Liquid Chromatography-Mass Spectroscopy (LC-MS-QToF) and High-Performance Liquid Chromatography (HPLC) revealed the presence of different bioactive plant metabolites, known to impart hepatoprotective effects. In human hepatocarcinoma (HepG2) cells, co-treatment of SKK with CCl4 effectively reduced the hepatotoxicity induced by the latter. These effects were confirmed by studying parameters such as loss of cell viability; release of hepatic injury enzymatic biomarkers- aspartate aminotransferase (AST), and alkaline phosphatase (ALP); and changes in reactive oxygen species and in mitochondrial membrane potentials. In-vivo safety analysis in Wistar rats showed no loss in animal body weight, or change in feeding habits after repeated oral dosing of SKK up to 1,000 mg/kg/day for 28 days. Also, no injury-related histopathological changes were observed in the animal's blood, liver, kidney, heart, brain, and lung. Pharmacologically, SKK played a significant role in modulating CCl4 induced hepatic injuries in the Wistar rats at a higher dose. In the 9 weeks' study, SKK (200 mg/kg) reduced the CCl4 stimulated increase in the release of enzymes (ALT, AST, and ALP), bilirubin, total cholesterol, and uric acid levels in the Wistar rats. It also reduced the CCl4 stimulated inflammatory lesions such as liver fibrosis, lymphocytic infiltration, and hyper-plasticity. In conclusion, SKK showed pharmacological effects in improving the CCl4 stimulated liver injuries in HepG2 cells and in Wistar rats. Furthermore, no adverse effects were observed up to 10× higher human equivalent dose of SKK during 28-days repeated dose exposure in Wistar rats. Based on the literature search on the identified plant metabolites, SKK was found to act in multiple ways to ameliorate CCl4 induced hepatotoxicity. Therefore, polyherbal SKK medicine has shown remarkable potentials as a possible alternative therapeutics for reducing liver toxicity induced by drugs, and other toxins.

The impact of mechanical oesophageal deviation on posterior wall pulmonary vein reconnection.

AIMS: During atrial fibrillation ablation, oesophageal heating typically prompts reduction or termination of radiofrequency energy delivery. We previously demonstrated oesophageal temperature rises are associated with posterior left atrial pulmonary vein reconnection (PVR) during redo procedures. In this study, we assessed whether mechanical oesophageal deviation (MED) during an index procedure minimizes posterior wall PVRs during redo procedures. METHODS AND RESULTS: Patients in whom we performed a first-ever procedure followed by a clinically driven redo procedure were divided based on both the use of MED for oesophageal protection and the ablation catheter employed (force or non-force sensing) in the first procedure. The PVR sites were compared between MED using a force-sensing catheter (MEDForce), or no MED with a non-force (ControlNoForce) or force (ControlForce) sensing catheter. Despite similar clinical characteristics, the MEDForce redo procedure rate (9.2%, 26/282 patients) was significantly less than the ControlNoForce (17.2%, 126/734 patients; P = 0.002) and ControlForce (17.5%, 20/114 patients; P = 0.024) groups. During the redo procedure, the posterior PVR rate with MEDForce (2%, 1/50 PV pairs) was significantly less than with either ControlNoForce (17.7%, 44/249 PV pairs; P = 0.004) or ControlForce (22.5%, 9/40 PV pairs; P = 0.003), or aggregate Controls (18.3%, 53/289 PV pairs; P = 0.006). However, the anterior PVR rate with MEDForce (8%, 4/50 PV pairs) was not significantly different than Controls (aggregate Controls-3.5%, 10/289 PV pairs, P = 0.136; ControlNoForce-2.4%, 6/249 PV pairs, P = 0.067; ControlForce-10%, 4/40 PV pairs, P = 1.0). CONCLUSION: Oesophageal deviation improves the durability of the posterior wall ablation lesion set during AF ablation.

Cytokines Driven Anti-Inflammatory and Anti-Psoriasis Like Efficacies of Nutraceutical Sea Buckthorn (Hippophae rhamnoides) Oil.

Psoriasis is a chronic inflammatory skin disease characterized by circumscribed, red, thickened plaques with overlying silvery white scales. It is associated with the release of pro-inflammatory mediators that lead to the development of edema and distress. Here we show the anti-inflammatory and anti-psoriatic efficacies of a neutraceutical sea buckthorn oil (SBKT) derived from the fruit pulp of Hippophae rhamnoides. Chemical analysis of the SBKT showed the presence of 16 major saturated, mono-, and polyunsaturated fatty acids components, imparting significant nutritional values. Efficacy of the SBKT in modulating psoriasis and associated inflammation was first tested in vitro using human monocytic (THP-1) cells. SBKT induced cytotoxicity at a dose of ≥25 µl/ml. Treatment of the lipopolysaccharide-stimulated THP-1 cells with SBKT subdued the enhanced release of intracellular reactive nitrogen species and expression of NF-κB protein, in a concentration-dependent manner. This was accompanied by a reduction in the release of downstream pro-inflammatory cytokines: Interleukin-1ß and interleukin-6. Tumor necrosis factor-α released in the stimulated THP-1 cells were also inhibited by SBKT dose of 5 µl/ml. In vivo oral and topical treatment with SBKT in the Carrageenan-stimulated paw edema model, showed a significant decrease in paw volume and edema. In the 12-O tetradecanoyl phorbol 13-acetate (TPA) stimulated CD-1 mice psoriasis-like model, concurrent oral and tropical SBKT treatments substantially reduced ear edema and ear biopsy weights. Histopathologically, significant reduction in ear epidermal thickness and skin lesion scores was observed in the SBKT-treated animals. In conclusion, SBKT showed anti-inflammatory and anti-psoriasis-like efficacies in healing chemical-induced inflammation and psoriasis. The possible mode of action of SBKT was found through inhibition of reactive nitrogen species, and downregulation of NF-κB protein and pro-inflammatory cytokines. Thus, the present data suggest that Sea buckthorn oil can be used as an anti-inflammatory and anti-psoriatic nutraceutical.

Anti-Inflammatory and Anti-Arthritic Efficacies of an Indian Traditional Herbo-Mineral Medicine "Divya Amvatari Ras" in Collagen Antibody-Induced Arthritis (CAIA) Mouse Model Through Modulation of IL-6/IL-1ß/TNF-α/NFκB Signaling.

Rheumatoid arthritis (RA) is defined as a chronic autoimmune inflammatory disorder that causes damage to limb joints and progressive injuries to secondary organs. Medical practitioners prescribe Methotrexate (MTX) as standard care medicine for treating RA. However, the long-term application of MTX has shown to have adverse health-related effects. Divya Amvatari Ras (DAR), an Indian Ayurvedic herbo-mineral formulation, has been described in ancient texts to provide relief from RA inflammation associated distress. Therefore, in the present study, we explored the biocompatibility, anti-inflammatory, and anti-arthritic efficacy of DAR using in vivo and in vitro disease models. Using carrageenan (CA)-stimulated Wistar rat paw edema model, we showed a reduction in inflammation-induced paw edema at human equivalent dose of DAR. Anti-rheumatic efficacy of DAR was studied using collagen-antibody cocktail (C-Ab) Induced Arthritis (CAIA) mouse model. The onset of RA in the CAIA mice was determined using parameters such as the increase in arthritis score, and induction of disease associated lesions in the ankle and knee joints, and increase in mechanical and thermal hyperalgesia. Treatment of CAIA animals with a human equivalent dose of DAR significantly reversed the RA-associated pathogenesis. These effects were comparable with the standard of care RA drug, MTX. DAR acted at multiple levels of inflammation associated with RA to reduce progressive pathogenesis. Animal serum biochemistry showed DAR was capable of ameliorating RA induced increase in liver enzyme Alanine Aminotransferase (ALT) and pro-inflammatory cytokine interleukin 6 (IL-6). In the lipopolysaccharide stimulated THP-1 cells, DAR was found to inhibit the release of IL-6, IL-1ß, TNF-α, and upstream inflammatory gene regulatory protein, NFκB. The study endorsed the anti-arthritic and anti-inflammatory activity of the Indian Traditional herbo-mineral medicine, DAR. These results also confirm that DAR was highly biocompatible and would show minimal health-related side effects than those associated with standard of care MTX. Taken together, we show that the DAR could be utilized as a promising alternative or complementary therapy for treating rheumatoid arthritis.

Elucidating heavy/light chain pairing preferences to facilitate the assembly of bispecific IgG in single cells.

Multiple strategies have been developed to facilitate the efficient production of bispecific IgG (BsIgG) in single host cells. For example, we previously demonstrated near quantitative (≥90%) formation of BsIgG of different species and isotypes by combining 'knob-into-hole' mutations for heavy chain heterodimerization with engineered antigen-binding fragments (Fabs) for preferential cognate heavy/light chain pairing. Surprisingly, in this study we found high yield (>65%) of BsIgG1without Fab engineering to be a common occurrence, i.e., observed for 33 of the 99 different antibody pairs evaluated. Installing charge mutations at both CH1/CL interfaces was sufficient for near quantitative yield (>90%) of BsIgG1 for most (9 of 11) antibody pairs tested with this inherent cognate chain pairing preference. Mechanistically, we demonstrate that a strong cognate pairing preference in one Fab arm can be sufficient for high BsIgG1 yield. These observed chain pairing preferences are apparently driven by variable domain sequences and can result from a few specific residues in the complementarity-determining region (CDR) L3 and H3. Transfer of these CDR residues into other antibodies increased BsIgG1 yield in most cases. Mutational analysis revealed that the disulfide bond between heavy and light chains did not affect the yield of BsIgG1. This study provides some mechanistic understanding of factors contributing to antibody heavy/light chain pairing preference and subsequently contributes to the efficient production of BsIgG in single host cells.

Herbo-mineral formulation 'Ashwashila' attenuates rheumatoid arthritis symptoms in collagen-antibody-induced arthritis (CAIA) mice model.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that affects joints of hands and feet and introduces injury in secondary organs such as cardiac tissue. In the present study, we induced RA in male Balb/c mice (CAIA) using collagen-antibody cocktail (C-Ab) and lipopolysaccharide intraperitoneal injections. Induction of RA in the animals was detected through the loss of body weight, food, and water consumption, pedal edema, increased arthritis score of the paw and ankle, increase in radiological and histological lesion score of ankle and knee joints and enhanced pain perception in the C-Ab induced RA animals. Ashwashila is a herbo-mineral medicine from Indian Ayurvedic system. Human equivalent doses of Ashwashila (ASHW) and standard of care, Methotrexate were given to the CAIA animals for two weeks. ASHW treatment significantly reversed the effect of C-Ab with reduced pedal edema, arthritis score, radiological and histological lesion scores in ankle-joint, knee-joint and articular cartilage, reduced pain perception. These effects were comparable with the Methotrexate treatment. In human monocytic (THP-1) cells, ASHW was found to be biocompatible at in-vitro test doses. The anti-arthritis mechanism of action for ASHW was established through the suppression of pro-inflammatory cytokines such as IL-1ß, IL-6, TNF-α; and upstream regulator, NF-κB. Taken together, we show the pre-clinical efficacy of ASHW in reducing RA associated symptoms by controlling inflammation and suggest it as a potential therapeutic candidate for rheumatoid arthritis.

Polar Localization Hub Protein PopZ Restrains Adaptor-Dependent ClpXP Proteolysis in Caulobacter crescentus.

In Caulobacter crescentus, timely degradation of several proteins by the ClpXP protease is critical for proper cell cycle progression. During the cell cycle, the ClpXP protease, the substrate CtrA, and many other proteins are localized to the stalked pole dependent on a polar interaction hub composed of PopZ protein oligomers. Prior work suggests that the localization of ClpXP, protease substrates, and cofactors is needed for recognition of substrates, such as CtrA, by ClpXP. Here, we formally test this hypothesis by examining the role of PopZ in ClpXP activity and find, surprisingly, that CtrA degradation is enhanced in cells lacking polar localization due to loss of PopZ. The ClpXP adaptor CpdR is required for this enhanced degradation of CtrA and other adaptor-dependent substrates, but adaptor-independent substrate degradation is not affected upon loss of PopZ. We find that overexpression of PopZ also leads to faster degradation of CtrA but is likely due to nonphysiologically relevant recognition of CtrA by ClpXP alone, as loss of CpdR does not affect this enhancement. Our main conclusion is that loss of PopZ, and therefore loss of polar localization, does not result in the loss of ClpXP-regulated proteolysis, as would be predicted from a model which requires polar localization of ClpXP for its activation. Rather, our data point to a model where PopZ normally restrains ClpXP proteolysis by promoting the inactivation of the CpdR adaptor, perhaps through the activity and localization of the CckA kinase.IMPORTANCE Regulated proteolysis is critical for the cell cycle progression of bacteria, such as Caulobacter crescentus According to one model, this regulated proteolysis requires localization of the ClpXP protease at the stalked pole for its subsequent degradation of substrates, such as CtrA. This study offers evidence that supports an alternative model to explain how localization might influence protein degradation. Using a delocalized in vivo system created by the deletion of a polar organizing protein, PopZ, we show that activation of the ClpXP protease is independent of its polar localization. The data point to a role for PopZ in restraining ClpXP activity, likely by controlling the activity of upstream regulators of protease activity, such as CckA, though changes in its localization.