Diversity and functional characteristics of culturable bacterial endosymbionts from cassava whitefly biotype Asia II-5, Bemisia tabaci.

Whitefly Bemisia tabaci, a carrier of cassava mosaic disease (CMD), poses a significant threat to cassava crops. Investigating culturable bacteria and their impact on whiteflies is crucial due to their vital role in whitefly fitness and survival. The whitefly biotype associated with cassava and transmitting CMD in India has been identified as Asia II 5 through partial mitochondrial cytochrome oxidase I gene sequencing. In this study, bacteria associated with adult B. tabaci feeding on cassava were extracted using seven different media. Nutrient Agar (NA), Soyabean Casein Digest Medium (SCDM), Luria Bertani agar (LBA), and Reasoner's 2A agar (R2A) media resulted in 19, 6, 4, and 4 isolates, respectively, producing a total of 33 distinct bacterial isolates. Species identification through 16SrRNA gene sequencing revealed that all isolates belonged to the Bacillota and Pseudomonadota phyla, encompassing 11 genera: Bacillus, Cytobacillus, Exiguobacterium, Terribacillus, Brevibacillus, Enterococcus, Staphylococcus, Brucella, Novosphingobium, Lysobacter, and Pseudomonas. All bacterial isolates were tested for chitinase, protease, siderophore activity, and antibiotic sensitivity. Nine isolates exhibited chitinase activity, 28 showed protease activity, and 23 displayed siderophore activity. Most isolates were sensitive to antibiotics such as Vancomycin, Streptomycin, Erythromycin, Kanamycin, Doxycycline, Tetracycline, and Ciprofloxacin, while they demonstrated resistance to Bacitracin and Colistin. Understanding the culturable bacteria associated with cassava whitefly and their functional significance could contribute to developing effective cassava whitefly and CMD control in agriculture. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03949-0.

Fibro-Adipose Vascular Anomaly (FAVA): Not Another Vascular Anagram.

Background. Fibro-adipose vascular anomaly (FAVA) is a rare benign mesenchymal lesion. Characterized primarily by intramuscular vascular malformation with secondary overgrowth of other mesenchymal elements, particularly fibro-adipose tissue, the condition is sometimes complicated by nonspecific clinical and imaging features, causing diagnostic dilemma. Herein, we attempted to outline and correlate the clinical characteristics, imaging findings, and histopathological features of this unusual entity. Method. The study design was retrospective in nature. Computerized database of our institute was searched for tumors, and archived slides were reviewed. Pertinent clinical data including imaging findings and treatment details were also recovered for correlation. Result. Among total of 24 patients identified, mean age was approximately 16 years, with the presence of nearly equal gender distribution. Pain along with swelling was most common symptoms with the presence of movement limitation, in few. Most lesions were long-standing and anatomically confined to lower limb with no side predilection. Using imaging, the majority of the lesions were identified as vascular anomaly or venous malformation, with FAVA being a differential diagnosis in few lesions. However, in a couple of patients, likelihood of mesenchymal tumors was also suggested, radiologically. On histology, the lesions showed the presence of clustered back to back, abnormal thin-walled, variably dilated, blood-filled sac-like vessels amid skeletal muscle bundles, along with extensive fibro-adipose tissue and variably atrophic skeletal muscle bundles, at the periphery, diagnostic of FAVA. Conclusion. Owing to the presence of overlapping clinical and imaging features, FAVA is often misdiagnosed, causing dilemma in clinical management. Clinical, radiological, and histopathological correlation is thereby warranted for clinching the correct diagnosis.

Conserved recombination patterns across coronavirus subgenera.

Recombination contributes to the genetic diversity found in coronaviruses and is known to be a prominent mechanism whereby they evolve. It is apparent, both from controlled experiments and in genome sequences sampled from nature, that patterns of recombination in coronaviruses are non-random and that this is likely attributable to a combination of sequence features that favour the occurrence of recombination break points at specific genomic sites, and selection disfavouring the survival of recombinants within which favourable intra-genome interactions have been disrupted. Here we leverage available whole-genome sequence data for six coronavirus subgenera to identify specific patterns of recombination that are conserved between multiple subgenera and then identify the likely factors that underlie these conserved patterns. Specifically, we confirm the non-randomness of recombination break points across all six tested coronavirus subgenera, locate conserved recombination hot- and cold-spots, and determine that the locations of transcriptional regulatory sequences are likely major determinants of conserved recombination break-point hotspot locations. We find that while the locations of recombination break points are not uniformly associated with degrees of nucleotide sequence conservation, they display significant tendencies in multiple coronavirus subgenera to occur in low guanine-cytosine content genome regions, in non-coding regions, at the edges of genes, and at sites within the Spike gene that are predicted to be minimally disruptive of Spike protein folding. While it is apparent that sequence features such as transcriptional regulatory sequences are likely major determinants of where the template-switching events that yield recombination break points most commonly occur, it is evident that selection against misfolded recombinant proteins also strongly impacts observable recombination break-point distributions in coronavirus genomes sampled from nature.

Outcome of simultaneous angioembolization and nephron sparing surgery in large renal angiomyolipomas.

AIM: To study the outcome of simultaneous angioembolization and nephron sparing surgery in large renal angiomyolipomas. MATERIALS AND METHODS: A prospective study of carried out from 2016 to 2019. A total of 15 patients were included in the study with a lesion (angiomyolipoma) more than 10 cm in size, suitable for nephron sparing surgery. The workup of the patients included history, baseline blood investigations, ultrasonography, and CT urography including angiographic films. All the patients were taken up for selective of angioembolization of the feeding vessels of the AML carried out by the interventional radiologist followed by nephron sparing surgery in the same sitting. The short term outcomes studied were warm ischemia time, average blood loss, and length of post-operative hospital stay. The oncological outcome was evaluated by noting the surgical margins of histopathological specimen and functional outcome by assessing the function of the preserved renal parenchyma. RESULTS: Twelve out of fifteen cases were female. The mean age was 42.25 years. All the patients had lesion more than 10 cm with seven tumors located at the lower pole, four at mid-pole, and four at upper pole. Eight patients had low complexity score on RENAL score (i.e. 4-6), five patients medium complexity score (i.e. 7-9), and two had high complexity score (i.e. ⩾10). Average blood loss was 200 ml, warm ischemia time was 18.46 min and postoperative stay was 3.55 days. All the 15 specimens sent for histopathology were confirmed as AML (angiomyolipomas) with margins free of tumor. Follow up CECT done at 4 months postoperatively revealed functioning residual renal parenchyma with prompt excretion of contrast. CONCLUSION: Large AML's are also amenable to nephron sparing surgery. However patient should always be warned about the possibility of total nephrectomy. Selective angioembolization helps in reducing the blood supply and risk of torrential bleeding thus facilitates in the removal of the tumor and increasing the chances of nephron sparing surgery.

RDP5: a computer program for analyzing recombination in, and removing signals of recombination from, nucleotide sequence datasets.

For the past 20 years, the recombination detection program (RDP) project has focused on the development of a fast, flexible, and easy to use Windows-based recombination analysis tool. Whereas previous versions of this tool have relied on considerable user-mediated verification of detected recombination events, the latest iteration, RDP5, is automated enough that it can be integrated within analysis pipelines and run without any user input. The main innovation enabling this degree of automation is the implementation of statistical tests to identify recombination signals that could be attributable to evolutionary processes other than recombination. The additional analysis time required for these tests has been offset by algorithmic improvements throughout the program such that, relative to RDP4, RDP5 will still run up to five times faster and be capable of analyzing alignments containing twice as many sequences (up to 5000) that are five times longer (up to 50 million sites). For users wanting to remove signals of recombination from their datasets before using them for downstream phylogenetics-based molecular evolution analyses, RDP5 can disassemble detected recombinant sequences into their constituent parts and output a variety of different recombination-free datasets in an array of different alignment formats. For users that are interested in exploring the recombination history of their datasets, all the manual verification, data management and data visualization components of RDP5 have been extensively updated to minimize the amount of time needed by users to individually verify and refine the program's interpretation of each of the individual recombination events that it detects.

Effect of a novel technique of posterior reconstruction of pubourethralis on 'early' return of continence after robot assisted radical prostatectomy (RARP): A comparative study.

OBJECTIVE: To study the effect of a novel technique of posterior reconstruction of pubourethralis on early return of continence after robot assisted radical prostatectomy (RARP). MATERIALS AND METHODS: The study included 206 patients of organ confined prostate cancer managed at our centre between March 2014 and December 2018.The patients were randomly distributed into two comparable groups with respect to age, height, weight and BMI, with 100 patients in control and 106 patients in study group. After standard excision of the specimen, the posterior reconstruction in the form of Rocco stitch was done in control group while in addition to Rocco stitch pubourethralis was approximated posteriorly in midline at the proposed site of vesicourethral anastomosis in study group. Continence was defined as the need to use 0-1 pad in 24 h. The data was collected on day 0, 3, 7, 15, 30, 90 and 180 after removal of catheter. RESULTS: At day zero, 3,7, 15, 30, 90 and 180 days after catheter removal continence rates (⩽1 pad usage per day) were observed to be 18.8% versus 0%, 22.6% versus 0%, 50.9% versus 5%, 72.6% versus 20%, 84.9 versus 32%, 97.1% versus 83%, and 97.1% versus 91% in the study and control group respectively. CONCLUSION: Despite small number of patients in this study the results with respect to early return of continence are encouraging in the reconstruction group and there by in favour of this technique .Furthermore the technique is easily reproducible and may be seen as one more additional step to be applied in order to enhance the recovery of continence after RARP. However it is necessary to further validate the efficacy of this procedure through multicenteric controlled trials.

Posttraumatic thoracic epidural capillary hemangioma - A rare case report.

BACKGROUND: Capillary hemangiomas are benign vascular lesions commonly seen in subcutaneous tissues. The most common site of origin is from the vertebral body, and only a few cases of isolated lesions in thoracic epidural space, especially after trauma, have been reported in the literature. CASE DESCRIPTION: We report a case of 63-year-old male with progressive bilateral lower limb weakness and exaggerated lower limb deep tendon reflexes without bowel and bladder involvement. His history revealed T7 fracture with paraparesis which was treated surgically, and implants were removed a year later. MRI showed an epidural lesion from T6-T8 extending into the right T7-8 foramen which showed hypointensity on T1, hyperintensity on T2, and homogenous enhancement in contrast images with severe cord compression. Laminectomy was done and the lesion was removed en bloc. Histopathological examination revealed it to be capillary hemangioma. The neurology came back to normal after 3 months. CONCLUSION: Although capillary hemangiomas are rare lesions, it has to be considered in the differential diagnosis of epidural space-occupying lesions which require early surgical removal to prevent a progressive and permanent neurological deficit.

Does Type II Diabetes Induce Early Senescence and Degeneration in Human Intervertebral Discs? A Tissue Biomarker Evaluation.

BACKGROUND: Diabetes mellitus is one of the leading causes of morbidity resulting in multi-organ dysfunction. Animal studies have shown that hyperglycemia results in stress-induced senescence through the p16-pRb pathway, thereby accelerating early disc degeneration. There is a paucity of literature on the effect of hyperglycemia in human intervertebral disc cells. We aimed to analyze the effect of diabetes mellitus in human intervertebral disc cells. METHODS: This is a prospective study done in patients with degenerative disc disease. Patients were categorized into a control group (no diabetes: 26 patients) and a study group (type 2 diabetes for > 3 years: 24 patients). All patients underwent either discectomy or transforaminal lumbar interbody fusion and the removed disc was transported to pathology department. Tissue was prepared and histopathological grading was done followed by immunohistochemistry studies using antibodies for MMP-1, p21, p16, and pRb. RESULTS: Samples from diabetic patients had severe (grade 2) degenerative changes compared with the control group (grade 1). Changes were more intense in the nucleus pulposus with increased cellularity and clustering of chondrocytes, and disorganization and loss of nuclear matrix. Immunohistochemical staining for MMP1, p16, and pRb was more intense (Q score = 4) whereas the staining for p21 was less intense (Q score = 1) in the diabetic group compared with the control group. CONCLUSION: Our study demonstrates that type 2 diabetes mellitus accelerates stress-induced senescence in human intervertebral discs resulting in early disc degeneration. Also, the severity of disc degeneration is severe compared with the normal subjects. CLINICAL RELEVANCE: Hyperglycemia can affect the intervertebral discs similar to other organs and hence adequate control of blood glucose in diabetics can prevent the disc degeneration, which is the initiator of degeneration cascade in spine.

Long-read amplicon denoising.

Long-read next-generation amplicon sequencing shows promise for studying complete genes or genomes from complex and diverse populations. Current long-read sequencing technologies have challenging error profiles, hindering data processing and incorporation into downstream analyses. Here we consider the problem of how to reconstruct, free of sequencing error, the true sequence variants and their associated frequencies from PacBio reads. Called 'amplicon denoising', this problem has been extensively studied for short-read sequencing technologies, but current solutions do not always successfully generalize to long reads with high indel error rates. We introduce two methods: one that runs nearly instantly and is very accurate for medium length reads and high template coverage, and another, slower method that is more robust when reads are very long or coverage is lower. On two Mock Virus Community datasets with ground truth, each sequenced on a different PacBio instrument, and on a number of simulated datasets, we compare our two approaches to each other and to existing algorithms. We outperform all tested methods in accuracy, with competitive run times even for our slower method, successfully discriminating templates that differ by a just single nucleotide. Julia implementations of Fast Amplicon Denoising (FAD) and Robust Amplicon Denoising (RAD), and a webserver interface, are freely available.

Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance.

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (TFH) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.

Full-Length Envelope Analyzer (FLEA): A tool for longitudinal analysis of viral amplicons.

Next generation sequencing of viral populations has advanced our understanding of viral population dynamics, the development of drug resistance, and escape from host immune responses. Many applications require complete gene sequences, which can be impossible to reconstruct from short reads. HIV env, the protein of interest for HIV vaccine studies, is exceptionally challenging for long-read sequencing and analysis due to its length, high substitution rate, and extensive indel variation. While long-read sequencing is attractive in this setting, the analysis of such data is not well handled by existing methods. To address this, we introduce FLEA (Full-Length Envelope Analyzer), which performs end-to-end analysis and visualization of long-read sequencing data. FLEA consists of both a pipeline (optionally run on a high-performance cluster), and a client-side web application that provides interactive results. The pipeline transforms FASTQ reads into high-quality consensus sequences (HQCSs) and uses them to build a codon-aware multiple sequence alignment. The resulting alignment is then used to infer phylogenies, selection pressure, and evolutionary dynamics. The web application provides publication-quality plots and interactive visualizations, including an annotated viral alignment browser, time series plots of evolutionary dynamics, visualizations of gene-wide selective pressures (such as dN/dS) across time and across protein structure, and a phylogenetic tree browser. We demonstrate how FLEA may be used to process Pacific Biosciences HIV env data and describe recent examples of its use. Simulations show how FLEA dramatically reduces the error rate of this sequencing platform, providing an accurate portrait of complex and variable HIV env populations. A public instance of FLEA is hosted at http://flea.datamonkey.org. The Python source code for the FLEA pipeline can be found at https://github.com/veg/flea-pipeline. The client-side application is available at https://github.com/veg/flea-web-app. A live demo of the P018 results can be found at http://flea.murrell.group/view/P018.

Improving Diagnosis of Primary Prostate Cancer With Combined 68Ga-Prostate-Specific Membrane Antigen-HBED-CC Simultaneous PET and Multiparametric MRI and Clinical Parameters.

OBJECTIVE: The current study was designed to test the diagnostic performance of 68Ga-prostate-specific membrane antigen (PSMA) PET and multiparametric MRI along with clinical parameters in the characterization of prostatic lesions. MATERIALS AND METHODS: Eighty-two men with 63 malignant and 21 benign histologically proven prostate lesions who underwent complete clinical workup were included in this retrospective study. All patients underwent simultaneous whole-body 68Ga-PSMA PET/MRI with dedicated multiparametric MRI. Prostate Imaging-Reporting and Data System (PI-RADS) version 2 assessment was used for predicting the likelihood of cancer. Uptake of 68Ga-PSMA was recorded by adopting the copy-and-paste function of ROIs defined on MR images. ROC and combined ROC analyses were performed to test the diagnostic accuracy of individual and combined parameters. Spearman analysis was used to assess the correlations. RESULTS: PSMA uptake (maximum standardized uptake value) was significantly different among tumors with Gleason scores of 7, 8, and 9, with the lowest uptake in tumors with a score of 7 and the highest uptake in tumors with a score of 9. There was a significant difference between early- and delayed-phase PSMA uptake in malignant prostatic lesions (p < 0.01). Significant correlations were observed between delayed and differential PSMA uptake and PI-RADS category (p < 0.01 and < 0.01, respectively), digital rectal examination findings (p = 0.01 and < 0.01, respectively), Gleason score (p = 0.05 and < 0.05, respectively), and prostate-specific antigen levels (p = 0.01 for both). Combined ROC analysis of prostate-specific antigen levels, digital rectal examination findings, multiparametric MRI, and differential PSMA uptake were able to characterize prostatic lesions with a mean (± SD) AUC of 0.94 ± 0.03, compared with their individual AUCs of 0.77, 0.70, 0.82, and 0.88. CONCLUSION: Gallium-68-PSMA PET combined with multiparametric MRI showed high diagnostic accuracy for prostate cancer diagnosis compared with either multiparametric MRI or PET alone or with clinical factors (e.g., digital rectal examination or prostate-specific antigen level) alone, and the combination further improves characterization of prostatic lesions.

Clinical and Radiological Outcomes of Modified Mini-Open and Open Transforaminal Lumbar Interbody Fusion: A Comparative Study.

STUDY DESIGN: Retrospective cohort study. PURPOSE: To compare the clinical and radiological outcomes of modified mini-open transforaminal lumbar interbody fusion (modMOTLIF) and open TLIF (OTLIF). OVERVIEW OF LITERATURE: Minimally invasive transforaminal lumbar interbody fusion (MTLIF) is associated with less blood loss, shorter hospital stay, and less pain. However, it has concerns like increased radiation exposure, steep learning curve, and instrumentation cost. We modified the MTLIF technique by direct freehand insertion of pedicle screws using stab incisions without tubular retractors. METHODS: The study included 24 patients in the modMOTLIF group and 27 patients in the OTLIF group. The average follow-up period was 25.6 months. Clinical outcomes were measured using Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) scores. Serial X-rays were acquired at 1, 3, 6, 12, and 24 months to assess the union and presence of instability. We also compared blood loss and length of hospital stay in both groups. RESULTS: All patients showed progressive improvement in VAS and ODI scores. No differences were observed in the preoperative and postoperative ODI and VAS leg scores between the groups. The immediate postoperative VAS back score was significantly higher in the OTLIF group than in the modMOTLIF group; however, no difference was observed at 1 and 2 years. Radiological analysis showed nonunion in one and two patients in the OTLIF and modMOTLIF groups, respectively. The average blood loss was 63 mL in the mod-MOTLIF group and 254 mL in the OTLIF group. The mean hospital stay was 3 days for the modMOTLIF group and 5 days for the OTLIF group. CONCLUSIONS: modMOTLIF was associated with reduced blood loss and shorter hospital stay compared with OTLIF. No significant differences were observed in the clinical and radiological outcomes between the groups after 2 years despite reduced back pain in the immediate postoperative period in patients who underwent modMOTLIF.

Legal Terms Used in Reception Order and their Relevance to Judicial Process.

INTRODUCTION: Law governs the admission and management of involuntary admissions of mentally ill persons who are admitted under the provisions of the mental health act. The court directs the doctor to take charge of such persons. In the further dealings of such person the medical officer of the psychiatric facility comes across legal terms, which require understanding so that patients could be dealt with properly. Various terms such as accused, under police custody, judicial custody, remand prisoner, or under trial prisoner are used to denote their legal status. It is imperative for the medical officer to understand the nuances in the meanings of these terms. There are many times when the relevant section under which the admission is ordered is not found in the reception order. In these cases the terminology by which the patient is mentioned throws a light on the status of the patient. Towards this aim a study was carried out to assess the awareness and understanding of such terms by the faculty and post- graduates of a tertiary care hospital that deals with the admission and care of such patients. METHOD: They were administered a questionnaire containing these terms and asked to provide the meaning of these terms. RESULTS: The results showed that nearly half the faculty and students were not having clarity in awareness or understanding of the terms. DISCUSSION: Hence these terms and their meanings were gleaned from various judgments. The proper meaning of these terms and their use in judicial process and their importance is discussed.

A review of reception order in the management of mentally ill persons in a psychiatric institute.

BACKGROUND: Mentally ill prisoners, when requiring admission in a psychiatric facility, have to be admitted only by a reception order of a judicial magistrate and convicts by warrants issued by the Government to jail superintendents and the superintendent of the hospital. Both can be only under Section 27 of The Mental Health Act, 1987. MATERIALS AND METHODS: A study of the contents of reception order and warrants regarding the acts and section under which they were issued over 1 year period for the admission of the patients in the criminal ward of the Institute of Mental Health was carried out. RESULTS: Only three reception orders quoted Section 27 out of 54 patients admitted under a reception order. Nineteen patients were admitted by the jail superintendents. DISCUSSION: Various issues that were found in the reception order and their consequences are discussed, and a possible response to these issues is mooted. CONCLUSION: Almost none of the reception orders were found to be proper. This deficit needs to be rectified by sensitizing the various authorities.

Dual inhibition of arachidonic acid pathway by mulberry leaf extract.

The present work investigates the anti-inflammatory, analgesic and antipyretic activity of methanolic extract of mulberry leaves of variety S-1, S-13 and S-146. The S-146 extract was further evaluated for its efficacy against adjuvant arthritis in albino rats followed by inhibitory potential for COX 1, COX 2 and 5 LOX. The HPLC analysis enumerated the presence of morin, reversterol, scopoletin and 7-hydroxy coumarin as the major constituents. The anti-inflammatory, antipyretic and analgesic activity observed in the present experiment could be accredited to the dual inhibition in the AA pathway. The inhibition of COX and LOX enzymes could be imparted to the presence of resveraterol, morin, scopoletin and 7-hydroxy coumarin.

A novel 11ß-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits.

BACKGROUND: 11ß-hydroxysteroid dehydrogenase type1 (11ß-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11ß-HSD1 in metabolically active tissues such as liver, muscle and adipose are implicated in tissue specific dysregulation which collectively contribute to the whole body pathology seen in metabolic syndrome. In the present study we have evaluated CNX-010-49, a highly potent, selective and 'pan tissue' acting 11ß-HSD1 inhibitor, for its potential to modulate multiple risk factors of the metabolic syndrome. METHODS: Male C57B6/J mice on high fat diet (DIO mice) were orally dosed with CNX-010-49 (30 mg/kg twice daily; n = 8) or vehicle for 10 weeks. Fasting glucose, triglycerides, glycerol, free fatty acids, body weight and feed intake were measured at selected time points. At the end of the treatment an OGTT and subsequently organ histology was performed. In vitro, CNX-010-49 was evaluated in 3T3-L1 preadipocytes to assess impact on adipocytes differentiation, hypertrophy and lipolysis whereas in fully differentiated C2C12 cells and in primary mouse hepatocytes to assess the impact on glucose metabolism and hepatic glucose output respectively. RESULTS: CNX-010-49 a highly potent and selective pan tissue acting 11ß-HSD1 inhibitor (EC50 = 6 nM) significantly inhibits glucocorticoids and isoproterenol mediated lipolysis in mature 3T3-L1 adipocytes, improves muscle glucose oxidation, reduces proteolysis and enhances mitochondrial biogenesis. Also a significant inhibition of gluconeogenesis in primary mouse hepatocytes was observed. The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance. Treatment also resulted in a significant decrease in serum triglycerides levels and a complete inhibition of body weight gain without affecting feed consumption. A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits. CONCLUSIONS: These results indicate that inhibition of 11ß-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

CNX-012-570, a direct AMPK activator provides strong glycemic and lipid control along with significant reduction in body weight; studies from both diet-induced obese mice and db/db mice models.

OBJECTIVES: AMP activated protein kinase (AMPK) regulates the coordination of anabolic and catabolic processes and is an attractive therapeutic target for T2DM, obesity and metabolic syndrome. We report the anti-hyperglycemic and anti-hyperlipidemic effects of CNX-012-570 is an orally bioavailable small molecule (molecular weight of 530 Daltons) that directly activates AMPK in DIO and db/db animal models of diabetes. METHODS: Activity and efficacy of the compound was tested in cell based as well as cell free systems in vitro. Male C57BL/6 mice fed with high fat diet (HFD) were assigned to either vehicle or CNX-012-570 (3 mg/kg, orally once a day) for 8 weeks (n = 8). Genetically diabetic db/db mice on chow diet were dosed with vehicle control or CNX-012-570 (2.5 mg/kg, orally once a day) for 6 weeks (n = 8). RESULTS: CNX-012-570 is a highly potent and orally bioavailable compound activating AMPK in both cell and cell free systems. It inhibits lipolysis (33%) and gluconeogenesis (28%) in 3T3L1 cells and rat primary hepatocytes respectively. The efficacy of the molecule was translated to both DIO and db/db animal models of diabetes. CNX-012-570 has reduced fasting blood glucose levels by 14%, body weight by 24% and fasting serum triglycerides (TG) by 24%. CNX-012-570 showed a 22% reduction in fed serum cholesterol levels and 19% increase in HDL levels.In db/db mice model, CNX-012-570 has shown 18% decrease in fed glucose and 32% decrease in fasting glucose with a 2.57% reduction in absolute HbA1c. Decrease in serum insulin and glucose AUC indicates the increased insulin sensitivity. Body weight was reduced by 13% with increased browning of adipose tissue and decreased inguinal and mesenteric fat mass. There was significant reduction in liver TG and liver total cholesterol. CONCLUSIONS: CNX-012-570 has the potential to control hyperglycemia and hyperlipidemia. It also reduces body weight gain with an additional benefit of minimizing cardiovascular risks in diabetics.