PEDF promotes nuclear degradation of ATGL through COP1.

Adipose triglyceride lipase (ATGL) plays a compelling role in hepatic lipid turnover and in the pathophysiology of non-alcoholic fatty liver disease. Hepatic ATGL is post-transcriptionally regulated by E3 ubiquitin ligase constitutive photomorphogenic1 (COP1) through polyubiquitylation and proteasomal degradation. However the physiological cue for COP1-mediated hepatocellular degradation of ATGL remained unknown. Here we checked for the role of pigment epithelium-derived factor (PEDF), a moonlighting hepatokine and the so-called ligand of ATGL for its stability in hepatocytes. We show that PEDF diminishes ATGL protein stability by promoting its proteasomal degradation in COP1-dependent manner. Despite being a secretory glycoprotein, PEDF is also sequestered in the nuclear compartment so as COP1. Interestingly, PEDF enhances nuclear import of predominantly cytosolic ATGL protein for its subsequent proteasomal degradation in the nucleus. PEDF also controls cell autonomous hepatocyte lipid accumulation and mobilization through COP1-ATGL axis, thereby unraveling a novel pathway for hepatic lipid metabolism.

PPARα-ATGL pathway improves muscle mitochondrial metabolism: implication in aging.

Adipose triglyceride lipase (ATGL) maintains an optimum mitochondrial function putatively by generating cognate ligands for peroxisome proliferator-activated receptor α (PPARα), which, together with PPARγ coactivator-1α (PGC1α), regulate muscle mitochondrial biogenesis. However, the cross-talk between ATGL and PPARα in skeletal muscle mitochondrial metabolism and its implication in chronological aging is poorly understood. The role of ATGL in muscle mitochondrial metabolism was studied by overexpressing and depleting the gene and studying its downstream effect in cultured myotubes and in murine skeletal muscle. We found that PPARα directly induces ATGL expression during myogenesis. Overexpression of ATGL significantly enhanced while depletion of ATGL attenuated mitochondrial oxidative phosphorylation and fatty acid oxidation without alteration in mitochondrial content, and it rendered PPARα and PGC1α redundant in promoting mitochondrial oxidative function. However, ATGL did not alter PPARα-dependent lipid accumulation and insulin sensitivity. In middle-aged rats, ATGL expression was higher and correlated with PPARα expression and sustained fatty acid oxidation in oxidative soleus muscle. Fenofibrate feeding further induced ATGL expression selectively in this muscle compartment. These findings illustrate that PPARα and ATGL constitute a regulatory pathway in skeletal muscle, suggesting their role as a mitochondrial metabolic reserve.-Biswas, D., Ghosh, M., Kumar, S., Chakrabarti, P. PPARα-ATGL pathway improves muscle mitochondrial metabolism: implication in aging.

Diabetes mellitus and abnormalities in semen analysis.

AIM: The aim of this study was to compare the semen parameters of diabetic husbands of infertile couples with those of non-diabetic husbands of proven fertility. MATERIAL AND METHODS: Assuming a 5% fall in DNA integrity of sperms would affect fertility, the required sample size calculated was 103, with 80% power and 5% level of significance. During the study period (January 2010 to May 2012), 52 husbands were found to have diabetes mellitus, by 2-h/post 75 g of glucose load (≥ 200 mg %). Glycosylated hemoglobin level in each case was found to be more than 6.5% (study group). During the same period, six couples with infertility conceived spontaneously while undergoing evaluations, 60 couples conceived following treatment of ovulatory disorders in wives and all had ongoing pregnancies (more than 12 weeks). Husbands of these 66 couples were found to be non-diabetic (control group). Conventional semen analysis (World Health Organization criteria), hypo-osmotic swelling test and DNA integrity test (Acridine Orange test) were done in all cases. Body mass index was measured in each case. RESULTS: There were no differences in the mean age and body mass index between the two groups but significant differences were found in the following parameters: volume of the ejaculate (P = 0.004); total cells per ejaculate (P = 0.01); percent motility (P = 0.0001); total motile cells per ejaculate (P = 0.0001); percent of rapid progressive motility (P = 0.0001); percent normal morphology (P = 0.02); percent hypo-osmotic swelling test (0.0001); and percent normal DNA integrity (P = 0.0001). CONCLUSION: Diabetes mellitus can affect spermatogenesis at various levels, which can cause male-factor infertility.

P-glycoprotein inhibitors as an adjunct therapy for TB.

The primary challenge in TB treatment is the emergence of multidrug-resistant TB (MDR-TB). One of the major factors responsible for MDR is the upregulation of efflux pumps. Permeation-glycoprotein (P-gp), an efflux pump, hinders the bioavailability of the administered drugs inside the infected cells. Simultaneously, angiogenesis, the formation of new blood vessels, contributes to drug delivery complexities. TB infection triggers a cascade of events that upregulates the expression of angiogenic factors and P-gp. The combined action of P-gp and angiogenesis foster the emergence of MDR-TB. Understanding these mechanisms is pivotal for developing targeted interventions to overcome MDR in TB. P-gp inhibitors, such as verapamil, and anti-angiogenic drugs, including bevacizumab, have shown improvement in TB drug delivery to granuloma. In this review, we discuss the potential of P-gp inhibitors as an adjunct therapy to shorten TB treatment.

A Surgical Experience of Oral Squamous Cell Carcinoma Co-Existing with Post Burn Contractures of Neck.

A female patient in her early 60s was diagnosed with squamous cell carcinoma of right buccal mucosa. Interestingly, the patient also presented with post-burn contractures of face, neck and chest which posed significant anaesthetic and surgical challenges, thus making this case report unique. Through this case report, we highlight the reflections in management of such a case.

Role of Perifacial Lymph Node in Nodal Metastasis in Oral Squamous Cell Carcinoma: A Prospective Study.

Nodal involvement in oral squamous cell carcinoma is common due to its lymphatic spread. First echelon group of lymph nodes are to be removed in such scenarios. Perifacial lymph nodes are one of the suspected groups to be affected in metastasis and also missed in dissection due to position. So separate evaluation of this group is important surgically.

Clinicopathologic Predictive Factors of Extranodal Extension in Oral Squamous Cell Carcinoma - A Retrospective Analysis.

The implications of extranodal extension (ENE) in oral carcinoma have been often related to prognosis and survival rates. The clinicopathologic predictive factors of this established prognostic factor were analyzed in this retrospective study. A total of 358 medical records of a single institution were screened. Primary outcome variable was ENE. Predictor variables were clinical tumour (cT) and nodal (cN) staging, tumour subsite, and pathologically tumour size, depth of invasion (DOI), lymph node ratio (LNR), presence, or absence of perineural invasion (PNI), lymphovascular invasion (LVI) and mandibular involvement. After scrutinization, 216 records met the inclusion and exclusion criteria. Presence of ENE was noted in 42.1% (91/216) of patients. In cN0 necks ENE was 34.7% which was statistically significant. The cut-off value for tumour size, DOI and LNR were, 7.28 cm, 9 mm and 0.05 with accuracy rates of 68%, 79% and 94% respectively. The odds of presence ENE were highest with bone involvement (2.91) followed by PNI (2.34) and lastly LVI (2.17). In conclusion, these predictive factors can be used to fortify the pathologic diagnostic criteria of ENE. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-024-04886-3.

C 3 N based heterobilayers: a potential platform to explore optoelectronic and thermoelectric properties.

We theoretically investigate the full thermal transport and optoelectronic features of two estab- lished van der Waals (vdW) heterostructures based on the recently synthesized monolayer of C 3 N using the machinery of the Boltzmann transport and GW+BSE calculations. Among the structures, C 3 N/hBN tends to exhibit a small indirect gap semiconducting nature with an admixture of com- paratively higher 'flat-and-dispersiveness' and band degeneracy in the conduction band minima. A nearly comparable high thermoelectric power factor is observed for both the charge carriers at 300 K and 900 K at specific concentrations. The other material, C 3 N/graphene however maintains a low Seebeck coefficient with large electrical conductivity which correctly manifests its metallic character. A combination of low atomic mass, higher anharmonicity and longer lifetime of acous- tic phonons in C 3 N/hBN results in an intermediate lattice thermal conductivity (196 Wm -1 K -1 ) at room temperature as compared to its constituent monolayers. Under heavy n-type doping, C 3 N/hBN hetero-bilayer displays a figure of merit value of 0.13 (and 0.36) at room temperature (and at 900 K). As per the optical signatures are concerned, C 3 N/hBN reveals two distinct absorp- tion peaks with a high electron-hole quasiparticle interaction energy correction. Besides both the structures display a much better absorption throughout the spectrum compared to graphene. We expect these findings will motivate future research in designing thermoelectric and optoelectronic materials made of light mass, earth-abundant and non-toxic elements.

Transverse Cervical Artery Based Free Flap in Reconstruction of a Tongue Defect: A Case Report.

In the era of reconstructive surgery, new and revolutionary options are being explored in oro-facial defect reconstruction. As free flaps are presently front runners for reconstruction of defects resulting from resection of benign and malignant lesions, there is a need for devising newer options to serve the need of covering defects following oncological resection. The availability of promising pedicles in the supraclavicular region makes it a potential donor site for harvesting regional flaps, and going forward, free flaps. Transverse cervical artery flap has been a useful regional flap for head and neck reconstruction but there are limited literature pertaining to transverse cervical artery free flap. We report a case of successful reconstruction of tongue defect with transverse cervical artery free flap.

Theoretical studies on electronic, magnetic and optical properties of two dimensional transition metal trihalides.

Two dimensional transition metal trihalides have drawn attention over the years due to their intrinsic ferromagnetism and associated large anisotropy at nanoscale. The interactions involved in these layered structures are of van der Waals types which are important for exfoliation to different thin samples. This enables one to compare the journey of physical properties from bulk structures to monolayer counterpart. In this topical review, the modulation of electronic, magnetic and optical properties by strain engineering, alloying, doping, defect engineering etc have been discussed extensively. The results obtained by first principle density functional theory calculations are verified by recent experimental observations. The relevant experimental synthesis of different morphological transition metal trihalides are highlighted. The feasibility of such routes may indicate other possible heterostructures. Apart from spintronics based applications, transition metal trihalides are potential candidates in sensing and data storage. Moreover, high thermoelectric figure of merit of chromium trihalides at higher temperatures leads to the possibility of multi-purpose applications. We hope this review will give important directions to further research in transition metal trihalide systems having tunable band gap with reduced dimensionalities.

Effects of ethinyl estradiol and desogestrel on clinical and metabolic parameters in Indian patients with polycystic ovary syndrome.

AIM: The aim of this study was to examine the therapeutic effects of an ethinyl estradiol (EE) and desogestrel (DSG) combination pill in polycystic ovary syndrome (PCOS). METHODS: A total of 42 women with PCOS were treated with an EE 30 mcg and DSG 150 mcg (EE/DSG) combination pill for 12 cycles. The following parameters were studied at 0, 6, and 12months: body mass index, abdominal circumference, Ferriman-Gallwey score, presence of acne and acanthosis nigricans, serum testosterone and sex-hormone-binding globulin levels, fasting glucose and fasting insulin levels. Free androgen index and glucose:insulin ratio were calculated. RESULTS: There were significant improvements in Ferriman-Gallwey score, incidence of acne, serum testosterone and sex-hormone-binding globulin levels and free androgen index values at the 6-month follow up. But there were no further beneficial changes in the above parameters at the 12-month follow up. There were no significant changes in body mass index, abdominal circumference, incidence of acanthosis nigricans, fasting glucose and insulin levels and glucose:insulin ratio during treatment. CONCLUSION: Significant improvements in hyperandrogenic parameters were seen only in the first 6months of treatment with EE/DSG in PCOS. Further continuation with this pill did not produce any significant improvement. There were no adverse effects on insulin sensitivity.

Determination of safe limit for arsenic contaminated irrigation water using solubility free ion activity model (FIAM) and Tobit Regression Model.

Irrigation water contaminated with arsenic acts as a potent source of contamination to humans through water-soil-crop-food transfer so quantification of safe limit for irrigation water is also critical. A pot experiment was conducted to determine the safe limit for As contaminated irrigation water with two soil types (alluvial and red) using ten levels of contaminated irrigation water (0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.50, 1.75, 2.0, 2.25 mg L-1), applied 5 times in rice (Variety: Sushak Samrat),used as a test crop. The results reveal that the different fractions of arsenic in terms of its profusion followed the order F4 > F2 > F5 > F3 > F1 and F4 > F3 > F2 > F5 > F1 across all the doses of As for alluvial soil and red soil respectively. The safe limit of irrigation water in terms of risk assessment expressed as Hazard Quotient (HQ) was at 0.75 mg L-1 and the solubility FIAM can effectively predict the As content in rice grain in both the soils. The Tobit Regression Model in alluvial soil quantified the safe limit for As in irrigation water from 1.20 to 0.10 mg L-1 for available soil As 0.25-3.0 mg kg-1 and in red soil, the range was from 0.10 to 0.40 mg L-1 for soil As 1.0 to 0.25 mg kg-1 provided that the As content in rice grain is < 0.4 mg kg-1. This proved to be an effective protocol for estimation of safe limits after proper validation and calibration.

Origami based ultraviolet C device for low cost portable disinfection- using a parametric approach to design.

Microorganisms can be present in common equipment of practice, which spread Healthcare-associated infections (HALs), generating major health issues, not only in the hospital environment but outside as well. Especially in this impending crisis due to SARS CoV-19 virus, disinfection (in general) turns out to be of paramount importance and portable disinfection in particular. The rampant spread of the COVID 19 virus, has pushed thinkers to come up with unique disinfection solutions that can help curb the spread of the virus in other places other than the medical facilities. The article aims to establish a design of a portable ultraviolet c disinfectant device that is based on the core principles of origami- the ancient Japanese art of paper folding. Resorting to origami has helped to make the device ultra-portable, robust and can be easily manufactured in order to be commercially produced as an inexpensive alternative to the cost portable disinfection devices in the market.

Ubiquitin Ligase COP1 Controls Hepatic Fat Metabolism by Targeting ATGL for Degradation.

Optimal control of hepatic lipid metabolism is critical for organismal metabolic fitness. In liver, adipose triglyceride lipase (ATGL) serves as a major triacylglycerol (TAG) lipase and controls the bulk of intracellular lipid turnover. However, regulation of ATGL expression and its functional implications in hepatic lipid metabolism, particularly in the context of fatty liver disease, is unclear. We show that E3 ubiquitin ligase COP1 (also known as RFWD2) binds to the consensus VP motif of ATGL and targets it for proteasomal degradation by K-48 linked polyubiquitination, predominantly at the lysine 100 residue. COP1 thus serves as a critical regulator of hepatocyte TAG content, fatty acid mobilization, and oxidation. Moreover, COP1-mediated regulation of hepatic lipid metabolism requires optimum ATGL expression for its metabolic outcome. In vivo, adenovirus-mediated depletion of COP1 ameliorates high-fat diet-induced steatosis in mouse liver and improves liver function. Our study thus provides new insights into the regulation of hepatic lipid metabolism by the ubiquitin-proteasome system and suggests COP1 as a potential therapeutic target for nonalcoholic fatty liver disease.

Changes in serum calcium and vitamin D3 levels after tibolone treatment and their correlations with health-related quality of life.

OBJECTIVE: To assess the effects of tibolone on serum calcium and vitamin D3 levels, the effects on health-related quality of life (HRQOL), and the relationship between these variables. METHODS: An open-label, prospective, parallel-arm study was conducted at S.C. Das Memorial Medical and Research Center, Kolkata, India, between July 2012, and June 2013. Women aged 34-55 years were eligible when they were experiencing surgical menopause and were symptomatic. Group A comprised patients who chose to receive tibolone (2.5mg daily for 6 months) and group B comprised those who refused treatment. At baseline and 6 months, body mass index (BMI), serum calcium and vitamin D3 levels and HRQOL were assessed. RESULTS: Of 79 participants, 53 were in group A and 26 in group B. After 6 months, BMI had increased significantly in both groups. The vitamin D3 level had increased significantly from baseline in group A (P=0.02), and was higher than that in group B (P=0.01). HRQOL had also improved significantly from baseline in group A (P=0.001), and was significantly better than that in group B (P<0.001). In group A, a significant correlation was found between HRQOL improvement and vitamin D3 levels (P<0.001). CONCLUSION: Tibolone significantly increases the serum vitamin D3 level and improves HRQOL in menopausal women. Clinical Trial Registry India: CTRI/2012/06/002752.

Efficacy of alternate-day versus everyday dosing of atorvastatin.

BACKGROUND: Atorvastatin has a longer duration of action than other hydroxymethylglutaryl coenzyme A reductase inhibitors. OBJECTIVES: The objective was to evaluate the efficacy of alternate day vs. daily dosing of atorvastatin for the treatment of hyperlipidemia. MATERIALS AND METHODS: In this prospective, open label, crossover study, 40 patients with plasma low-density cholesterol (LDL-C) of more than 130 mg/dl and total cholesterol (TC) more than 200 mg/dl were recruited. After baseline tests, they were randomly allocated to two groups. Group A received 20 mg atorvastatin on alternate days and group B received 20 mg atorvastatin daily for 12 weeks. After 4 weeks of washout period, the groups were crossed over to the other treatment regimen for another 12 weeks. Fasting plasma lipid profile and serum alanine transaminase (ALT) and aspartate transaminase (AST) were measured for both groups at 6(th), 12(th), 16(th), 22(nd), and 28(th) weeks. Results were pooled across the periods and data between the two groups were compared using unpaired t-test. RESULTS: Among the 40 enrolled subjects, 38 completed the study. Both treatment regimens significantly reduced LDL-C and TC compared to baseline. There was no statistically significant difference between the two groups in terms of reduction of plasma LDL-C and TC at 6 and 12 weeks of treatment. Both the regimens were well tolerated. CONCLUSION: Alternate-day treatment with atorvastatin is comparable in efficacy and safety to the established daily treatment regimen, thus being a cost effective alternative.

Effects of drospirenone pill in Indian women with polycystic ovary syndrome.

OBJECTIVE: To study the effects of treatment with a drospirenone pill (DRSP) (with ethinyl oestradiol, EE) in Indian women with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: Fifty-one women with PCOS (Androgen excess society criteria, 2006), with preset inclusion-exclusion criteria, treated with a combination of EE 30 mcg and DRSP 3 mg cyclically in the traditional (21+7) regimen, were evaluated at baseline and after six and twelve cycles of treatment. Parameters studied were - body mass index (BMI), abdominal circumference (AC), Ferriman Galwey (FG) score, presence of acne and acanthosis nigricans, serum testosterone, sex hormone binding globulin (SHBG), fasting glucose and fasting insulin levels. Free Androgen Index (FAI) and Glucose: Insulin ratio (G: I) were calculated. RESULTS: Significant improvements in clinical and biochemical hyperandrogenic parameters were found at the two points of study. There were no significant changes in BMI, AC, incidence of acanthosis, or metabolic parameters studied. CONCLUSION: EE/DRSP improves hyperandrogenic parameters significantly without affecting the insulin resistance adversely in Indian women with PCOS.