Calpain Small Subunit Mediated Secretion of Galectin-3 Regulates Traction Stress.

The complex regulation of traction forces (TF) produced during cellular migration remains poorly understood. We have previously found that calpain 4 (Capn4), the small non-catalytic subunit of the calpain 1 and 2 proteases, regulates the production of TF independent of the proteolytic activity of the larger subunits. Capn4 was later found to facilitate tyrosine phosphorylation and secretion of the lectin-binding protein galectin-3 (Gal3). In this study, recombinant Gal3 (rGal3) was added to the media-enhanced TF generated by capn4-/- mouse embryonic fibroblasts (MEFs). Extracellular Gal3 also rescued defects in the distribution, morphology, and adhesive strength of focal adhesions present in capn4-/- MEF cells. Surprisingly, extracellular Gal3 does not influence mechanosensing. c-Abl kinase was found to affect Gal3 secretion and the production of TF through phosphorylation of Y107 on Gal3. Our study also suggests that Gal3-mediated regulation of TF occurs through signaling pathways triggered by ß1 integrin but not by focal adhesion kinase (FAK) Y397 autophosphorylation. Our findings provide insights into the signaling mechanism by which Capn4 and secreted Gal3 regulate cell migration through the modulation of TF distinctly independent from a mechanosensing mechanism.

Correlation Between Nasal Allergy and the Number of Eosinophils in Adenoid Tissue.

To study adenoid tissue eosinophilia in allergic rhinitis. A single-centre clinical case-control prospective study with 66 subjects enrolled for the study after taking written informed consent from all the participants. All patients underwent adenoidectomy with histopathological evaluation of adenoid tissue samples for eosinophils. 36 patients (cases) with Symptoms for Allergic Rhinitis (SFAR) score indicative of allergic rhinitis. 30 patients (control) with SFAR scores not indicative of allergic rhinitis. All patients were evaluated for serum absolute eosinophil count and total serum immunoglobulin E (Ig-E). There was a significant relationship between allergic rhinitis and serum Ig-E levels using the Kruskal-Wallis rank sum test amongst case and control groups with a p-value of 0.031. Pathologically examined slides of adenoid tissue eosinophil count per 10 random high power fields in these patients showed significant results with a p-value of 0.002432, via the Kruskal-Wallis rank sum test. Statistical analysis, shows that adenoid tissue eosinophil count and serum Ig-E levels can somewhat predict the presence of clinical features of allergic rhinitis. Based on several similar studies with similar results, allergic rhinitis can be gauged with adenoid tissue histopathology and routine evaluation should be considered as a standard of care.

The post-operative tonsillectomy (POPT) study: A multi-centre prospective paediatric cohort study.

OBJECTIVES: Tonsillectomy is the most common operation performed by otolaryngologists in the UK, despite this we have a poor understanding of the post-operative recovery. We aimed to investigate post-operative bleeding and pain following paediatric tonsillectomy using a patient diary. DESIGN: Prospective observational cohort study. SETTING: Multi-centre study involving 12 secondary and tertiary otolaryngology units across the North of England. Patients were recruited from 1st March 2020 to 30th June 2022. Multilevel ordered logistic regression model statistics were performed. PARTICIPANTS: Children (≥4 years, ≤16 years) undergoing tonsillectomy (with or without adenoidectomy) for benign pathology. MAIN OUTCOME MEASURES: Frequency and severity of post-operative bleeding. Intensity and pattern of post-operative pain. RESULTS: In total 297 children were recruited, with 91 (30.6%) diaries eligible for analysis. Post-operative bleeding occurred in 44% of children. Most frequently blood in the saliva was reported (82.9%). Increasing age significantly increased bleeding odds by 17% per year (p = .001). Bleeding frequency decreased with higher surgeon grade (p = .003) and when performing intracapsular coblation tonsillectomy (p = .02) compared with other techniques. Lower age and intracapsular coblation tonsillectomy, against other techniques, significantly reduced rates of pain post-operatively (p < .0001 and p = .0008). CONCLUSION: A high level of low-level post-operative bleeding was observed. Pain scores remained high for 5 days post-operatively then gradually reduce to normal by day 13. Intracapsular coblation tonsillectomy appears to be superior to all other techniques in terms of reducing post-operative bleeding and pain. These findings should be used to guide patients in the consent process to inform them of the expected nature of post-surgical recovery.

LIVE INDIA: Effectiveness of Gla-100 in a Post hoc Pooled Analysis of FINE ASIA and GOAL Registries.

INTRODUCTION: Real-world evidence on insulin glargine 100 U/ml (Gla-100) initiation in Indian type 2 diabetes mellitus (T2DM) individuals is limited. The present study aimed to evaluate the effectiveness of Gla-100 in insulin-naïve T2DM participants from India. METHODS: This post hoc analysis includes real-world data of insulin-naïve Indian participants with T2DM who started Gla-100 treatment in two Asian registries: FINE ASIA and GOAL. Changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, insulin dose, and incidence of hypoglycemia from baseline to 6 months were assessed. RESULTS: A total of 955 participants with T2DM were identified and analyzed. The mean [standard deviation (SD)] age and duration of diabetes were 54.7 (9.8) years and 9.8 (6.3) years, respectively. Mean HbA1c and FPG were significantly reduced after 6 months of Gla-100 treatment [- 2.07 (1.4) %; - 94.4 (65.2) mg/dl, respectively]. HbA1c targets of < 7.0% and < 7.5% were achieved by 292 (30.6%) and 589 (61.7%) study participants, respectively. The overall incidence of hypoglycemia was low (n = 52; 5.4%); only two participants (0.2%) reported severe hypoglycemia. Insulin was titrated with a mean (SD) increment of 2.5 (5.6) U/day after 6 months, leading to a mean Gla-100 dose of 18.2 (8.9) U/day. Mean body weight remained unchanged from baseline to 6 months (- 0.1 kg). CONCLUSION: In routine clinical practice, Gla-100 significantly improved glycemic parameters after 6 months of treatment with a low risk of hypoglycemia and no weight change in participants with T2DM.

The LongitudinAl Nationwide stuDy on Management And Real-world outComes of diabetes in India over 3 years (LANDMARC trial).

INTRODUCTION: LANDMARC (CTRI/2017/05/008452), a prospective, observational real-world study, evaluated the occurrence of diabetes complications, glycemic control and treatment patterns in people with type 2 diabetes mellitus (T2DM) from pan-India regions over a period of 3 years. METHODS: Participants with T2DM (≥25 to ≤60 years old at diagnosis, diabetes duration ≥2 years at the time of enrollment, with/without glycemic control and on ≥2 antidiabetic therapies) were included. The proportion of participants with macrovascular and microvascular complications, glycemic control and time to treatment adaptation over 36 months were assessed. RESULTS: Of the 6234 participants enrolled, 5273 completed 3 years follow-up. At the end of 3-years, 205 (3.3%) and 1121 (18.0%) participants reported macrovascular and microvascular complications, respectively. Nonfatal myocardial infarction (40.0%) and neuropathy (82.0%) were the most common complications. At baseline and 3-years, 25.1% (1119/4466) and 36.6% (1356/3700) of participants had HbA1c <7%, respectively. At 3-years, population with macrovascular and microvascular complications had higher proportion of participants with uncontrolled glycemia (78.2% [79/101] and 70.3% [463/659], respectively) than those without complications (61.6% [1839/2985]). Over 3-years, majority (67.7%-73.9%) of the participants were taking only OADs (biguanides [92.2%], sulfonylureas [77.2%] and DPP-IV inhibitors [62.4%]). Addition of insulin was preferred in participants who were only on OADs at baseline, and insulin use gradually increased from 25.5% to 36.7% at the end of 3 years. CONCLUSION: These 3-year trends highlight the burden of uncontrolled glycemia and cumulative diabetes-related complications, emphasizing the importance of optimizing diabetes management in India.

Two-year trends from the LANDMARC study: A 3-year, pan-India, prospective, longitudinal study on the management and real-world outcome in patients with type 2 diabetes mellitus.

INTRODUCTION: There are limited data on the real-world management of diabetes in the Indian population. In this 2-year analysis of the LANDMARC study, the management of type 2 diabetes mellitus (T2DM) and related complications were assessed. METHOD: This multicenter, observational, prospective study included adults aged ≥25 to ≤60 years diagnosed with T2DM (duration ≥2 years at enrollment) and controlled/uncontrolled on ≥2 anti-diabetic agents. This interim analysis at 2 years reports the status of glycaemic control, diabetic complications, cardiovascular (CV) risks and therapy, pan-India including metropolitan and non-metropolitan cities. RESULTS: Of the 6234 evaluable patients, 5318 patients completed 2 years in the study. Microvascular complications were observed in 17.6% of patients (1096/6234); macrovascular complications were observed in 3.1% of patients (195/6234). Higher number of microvascular complications were noted in patients from non-metropolitan than in metropolitan cities (p < .0001). In 2 years, an improvement of 0.6% from baseline (8.1%) in mean glycated haemoglobin (HbA1c) was noted; 20.8% of patients met optimum glycaemic control (HbA1c < 7%). Hypertension (2679/3438, 77.9%) and dyslipidaemia (1776/3438, 51.7%) were the predominant CV risk factors in 2 years. The number of patients taking oral anti-diabetic drugs in combination with insulin increased in 2 years (baseline: 1498/6234 [24.0%] vs. 2 years: 1917/5763 [33.3%]). While biguanides and sulfonylureas were the most commonly prescribed, there was an evident increase in the use of dipeptidyl peptidase-IV inhibitors (baseline: 3049/6234, 48.9% vs. 2 years: 3526/5763, 61.2%). CONCLUSION: This longitudinal study represents the control of T2DM, its management and development of complications in Indian population. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2017/05/008452.

Improving results management processes in an acute hospital using a multi-faceted approach.

BACKGROUND: Radiological examinations and laboratory tests are routinely ordered by hospital physicians as part of the care plan to diagnose and treat patients. However, the failure to actively review and follow-up on these results pose a significant problem to patient safety. A study team was formed to mitigate the clinical risks of poor results management, which was identified as a top clinical risk in our organization, in order to make improvements to the results management process and to ensure the timely review, acknowledgement and follow-up of test results. OBJECTIVE: This study was carried out to improve results management processes and ensure the timely review, acknowledgment, and follow-up of test results, in order to mitigate the clinical risks posed to patient safety. METHODS: The institutional expectations of results management were set and published as a hospital policy, which was communicated to all clinical departments for compliance. Improvements to the electronic medical records system were made to facilitate the results acknowledgement process, and physicians were engaged to educate them on the importance of results management. RESULTS: The study team observed a decrease in unacknowledged results from approximately 16 000 in March 2017 to 2673 in December 2020. The compliance rate for acknowledgement results increased from a monthly average of 83.7% (from March to December 2017) to a monthly average of 99.3% (in 2020). The risk score for results management decreased from 16 to 6.5 and was excluded from the organization's top clinical risks. CONCLUSION: This study showed the importance of both system improvements and culture changes that are required to improve the process of results management and provides a step forward for the hospital to safeguard patient safety and mitigate clinical risk.

One-year trends from the LANDMARC trial: A 3-year, pan-India, prospective, longitudinal study on the management and real-world outcomes of type 2 diabetes mellitus.

INTRODUCTION: Longitudinal data on management and progression of type 2 diabetes mellitus (T2DM) in India are scarce. LANDMARC (CTRI/2017/05/008452), first-of-its-kind, pan-India, prospective, observational study aimed to evaluate real-world patterns and management of T2DM over 3 years. METHODS: Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrolment; controlled/uncontrolled on ≥2 anti-diabetic agents) were enrolled. The first-year trends for glycaemic control, therapy and diabetic complications, including those from metropolitan and non-metropolitan cities are reported here. RESULTS: Of 6236 enrolled participants, 5654 completed 1 year in the study. Although the overall mean glycated haemoglobin (HbA1c) improved by 0.5% (baseline: 8.1%) at 1 year, only 20% of the participants achieved HbA1c <7%. Participants from metropolitan and non- metropolitan cities showed similar decrease in glycaemic levels (mean change in HbA1c: -0.5% vs. -0.5%; p = .8613). Among diabetic complications, neuropathy was the predominant complication (815/6236, 13.1% participants). Microvascular complications (neuropathy, nephropathy and retinopathy) were significantly (p < .0001) higher in non-metropolitan than metropolitan cities. Hypertension (2623/6236, 78.2%) and dyslipidaemia (1696/6236, 50.6%) continued to be the most commonly reported cardiovascular risks at 1 year. After 1 year, majority of the participants were taking only oral anti-diabetic drugs (OADs) (baseline: 4642/6236 [74.4%]; 1 year: 4045/6013 [67.3%]), while the proportion of those taking insulin along with OADs increased (baseline: 1498/6236 [24.0%] vs. 1 year: 1844/6013 [30.7%]). Biguanides and sulfonylureas were the most used OADs. The highest increase in use was seen for dipeptidyl peptidase-IV inhibitors (baseline: 3047/6236 [48.9%]; 1 year: 3529/6013 [58.7%]). Improvement in all glycaemic parameters was significantly (p < .0001) higher in the insulin vs. the insulin-naïve subgroups; in the insulin-naïve subgroup, no statistical difference was noted in those who received >3 vs. ≤3 OADs. CONCLUSIONS: First-year trends of the LANDMARC study offer insights into real-world disease progression, suggesting the need for controlling risk factors and timely treatment intensification in people with T2DM.

Preparing for the Next Normal: Transformation in the Role of Medical Affairs Following the COVID-19 Pandemic.

The medical affairs function represents one of the scientific interfaces in a pharmaceutical organization. Over the last two decades, medical affairs has evolved from being a support function to a strategic pillar within organizational business units. The COVID-19 pandemic has given rise to unforeseen circumstances resulting in a dramatic change in external stakeholder engagements, catapulting the medical affairs function into leading the way on scientific engagements and patient-centric endeavors. The changes in stakeholder interactions and behavior as a result of the pandemic last year are likely to persist in the foreseeable future for which medical affairs professionals need to enhance existing skill sets and acquire expertise in newer domains. In this paper, the transformation of the medical affairs team to a key strategic partner and the skills required to strengthen this transition, in the next normal of a post-COVID world, is explored.

Baseline characteristics of participants in the LANDMARC trial: A 3-year, pan-india, prospective, longitudinal study to assess management and real-world outcomes of diabetes mellitus.

INTRODUCTION: Longitudinal data on progression, complications, and management of type 2 diabetes mellitus (T2DM) across India are scarce. LANDMARC (CTRI/2017/05/008452), the first pan-India, longitudinal, prospective, observational study, aims to understand the management and real-world outcomes of T2DM over 3 years. METHODS: Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrollment; controlled/uncontrolled on ≥2 anti-diabetic agents) were enrolled. Baseline characteristics were analyzed using descriptive statistics. RESULTS: Of the 6279 recruited participants, 6236 were eligible for baseline assessment (56.6% [n/N = 3528/6236] men; mean ± SD age: 52.1 ± 9.2 years, diabetes duration: 8.6 ± 5.6 years). mean ± SD HbA1c, fasting plasma glucose, and postprandial glucose values were 64 ± 17 mmol/mol (8.1 ± 1.6%), 142.8 ± 50.4 mg/dl, and 205.7 ± 72.3 mg/dl, respectively. Only 25.1% (n/N = 1122/6236) participants had controlled glycemia (HbA1c < 53 mmol/mol, <7%). Macrovascular and microvascular complications were prevalent in 2.3% (n/N = 145/6236) and 14.5% (n/N = 902/6236) participants, respectively. Among those with complications, non-fatal myocardial infarction (n/N = 74/145, 51.0%) and neuropathy (n/N = 737/902, 81.7%) were the most reported macrovascular and microvascular complication, respectively. Hypertension (n/N = 2566/3281, 78.2%) and dyslipidemia (n/N = 1635/3281, 49.8%) were the most reported cardiovascular risks. Majority (74.5%; n/N = 4643/6236) were taking oral anti-diabetic drugs (OADs) only, while 24.4% (n/N = 1522/6236) participants were taking OADs+insulin. Biguanides (n/N = 5796/6236, 92.9%) and sulfonylureas (n/N = 4757/6236, 76.3%) were the most reported OADs. Basal (n/N = 837/6236, 13.4%) and premix (n/N = 684/6236, 11.0%) insulins were the most reported insulins. CONCLUSIONS: Baseline data from LANDMARC help understand the clinical/medical profile of study participants and underscore the extent of suboptimal glycemic control and prevalence of associated complications in a vast majority of Indians with T2DM.

TRIM67 regulates exocytic mode and neuronal morphogenesis via SNAP47.

Neuronal morphogenesis involves dramatic plasma membrane expansion, fueled by soluble N-ethylmaleimide-sensitive factor attachment protein eceptors (SNARE)-mediated exocytosis. Distinct fusion modes described at synapses include full-vesicle fusion (FVF) and kiss-and-run fusion (KNR). During FVF, lumenal cargo is secreted and vesicle membrane incorporates into the plasma membrane. During KNR, a transient fusion pore secretes cargo but closes without membrane addition. In contrast, fusion modes are not described in developing neurons. Here, we resolve individual exocytic events in developing murine cortical neurons and use classification tools to identify four distinguishable fusion modes: two FVF-like modes that insert membrane material and two KNR-like modes that do not. Discrete fluorescence profiles suggest distinct behavior of the fusion pore. Simulations and experiments agree that FVF-like exocytosis provides sufficient membrane material for morphogenesis. We find the E3 ubiquitin ligase TRIM67 promotes FVF-like exocytosis in part by limiting incorporation of the Qb/Qc SNARE SNAP47 into SNARE complexes and, thus, SNAP47 involvement in exocytosis.

The TRIM9/TRIM67 neuronal interactome reveals novel activators of morphogenesis.

TRIM9 and TRIM67 are neuronally enriched E3 ubiquitin ligases essential for appropriate morphogenesis of cortical and hippocampal neurons and fidelitous responses to the axon guidance cue netrin-1. Deletion of murine Trim9 or Trim67 results in neuroanatomical defects and striking behavioral deficits, particularly in spatial learning and memory. TRIM9 and TRIM67 interact with cytoskeletal and exocytic proteins, but the full interactome is not known. Here we performed the unbiased proximity-dependent biotin identification (BioID) approach to define TRIM9 and TRIM67 protein-protein proximity network in developing cortical neurons and identified putative neuronal TRIM interaction partners. Candidates included cytoskeletal regulators, cytosolic protein transporters, exocytosis and endocytosis regulators, and proteins necessary for synaptic regulation. A subset of high-priority candidates was validated, including Myo16, Coro1A, MAP1B, ExoC1, GRIP1, PRG-1, and KIF1A. For a subset of validated candidates, we utilized total internal reflection fluorescence microscopy to demonstrate dynamic colocalization with TRIM proteins at the axonal periphery, including at the tips of filopodia. Further analysis demonstrated that the RNA interference-based knockdown of the unconventional myosin Myo16 in cortical neurons altered growth cone filopodia density and axonal branching patterns in a TRIM9- and netrin-1-dependent manner. Future analysis of other validated candidates will likely identify novel proteins and mechanisms by which TRIM9 and TRIM67 regulate neuronal form and function. [Media: see text].

Recent advances and challenges in electrochemical biosensors for emerging and re-emerging infectious diseases.

The rise of emerging infectious diseases (EIDs) as well as the increase in spread of existing infections is threatening global economies and human lives, with several countries still fighting repeated onslaught of a few of these epidemics. The catastrophic impact a pandemic has on humans and economy should serve as a reminder to be better prepared to the advent of known and unknown pathogens in the future. The goal of having a set of initiatives and procedures to tackle them is the need of the hour. Rapid detection and point-of-care (POC) analysis of pathogens causing these diseases is not only a problem entailing the scientific community but also raises challenges in tailoring appropriate treatment strategies to the healthcare sector. Among the various methods used to detect pathogens, Electrochemical Biosensor Technology is at the forefront in the development of POC devices. Electrochemical Biosensors stand in good stead due to their rapid response, high sensitivity and selectivity and ease of miniaturization to name a few advantages. This review explores the innovations in electrochemical biosensing based on the various electroanalytical techniques including voltammetry, impedance, amperometry and potentiometry and discusses their potential in diagnosis of emerging and re-emerging infectious diseases (Re-EIDs), which are potential pandemic threats.

Suboptimal glycemic control among subjects with diabetes mellitus in India: a subset analysis of cross-sectional wave-7 (2016) data from the International Diabetes Management Practices Study (IDMPS).

OBJECTIVE: To assess the real-world management practices of subjects with type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM) in India. METHODS: This cross-sectional study was conducted between 7 March 2016 and 15 May 2016 in India as part of the seventh wave (2016) of the International Diabetes Management Practices Study (IDMPS). Adult subjects with T1DM or T2DM visiting physicians during a 2-week recruitment period were included. RESULTS: A total of 55 physicians included 539 subjects who met eligibility criteria. Of 495 subjects with T2DM, 303 were treated with oral glucose lowering drugs (OGLDs) only, 158 were treated with OGLD + insulin, and 27 received insulin only. Among 44 subjects with T1DM receiving insulin, 13 (29.5%) were also treated with OGLD therapy. The most commonly used insulin regimens were basal alone (69/184; 37.5%) and premixed alone (63/184; 34.2%) in subjects with T2DM, and basal + prandial insulin (24/44; 54.5%) in subjects with T1DM. Proportions of subjects achieving glycemic targets were low [glycated haemoglobin (HbA1c) <7%: T1DM = 7.3% (3/44), T2DM = 25.2% (106/495); as targeted by the treating physician: T1DM = 31.8% (14/44), T2DM = 32.1% (59/185); global target: T1DM = 4.8% (2/42) and T2DM = 1.7% (8/482)]. In subjects with T2DM, HbA1c <7% was noted in 11/22 subjects receiving insulin only and 76/260 receiving only OGLDs. Lack of experience in self-managing insulin dosing, poor diabetes education and failure to titrate insulin dosages were the main reasons for non-achievement of glycemic targets. CONCLUSION: Timely insulinization, education and empowerment of people with diabetes may help improve glycemic control in India.

Redox-Active Monolayers Self-Assembled on Gold Electrodes-Effect of Their Structures on Electrochemical Parameters and DNA Sensing Ability.

The background: The monolayers self-assembled on the gold electrode incorporated transition metal complexes can act both as receptor ("host" molecules) immobilization sites, as well as transducer for interface recognitions of "guest" molecules present in the aqueous solutions. Their electrochemical parameters influencing the sensing properties strongly depend on the transition metal complex structures. The objectives: The electrochemical characterization of the symmetric terpyridine-M2+-terpyridine and asymmetric dipyrromethene-M2+-terpyridine complexes modified with ssDNA probe covalently attached to the gold electrodes and exploring their ssDNA sensing ability were the main aims of the research presented. The methods: Two transition metal cations have been selected: Cu2+ and Co2+ for creation of redox-active monolayers. The electron transfer coefficients indicating the reversibility and electron transfer rate constant measuring kinetic of redox reactions have been determined for all SAMs studied using: Cyclic Voltammetry, Osteryoung Square-Wave Voltammetry, and Differential Pulse Voltammetry. All redox-active platforms have been applied for immobilization of ssDNA probe. Next, their sensing properties towards complementary DNA target have been explored electrochemically. The results: All SAMs studied were stable displaying quasi-reversible redox activity. The linear relationships between cathodic and anodic current vs. san rate were obtained for both symmetric and asymmetric SAMs incorporating Co2+ and Cu2+, indicating that oxidized and reduced redox sites are adsorbed on the electrode surface. The ssDNA sensing ability were observed in the fM concentration range. The low responses towards non-complementary ssDNA sequences provided evidences for sensors good selectivity. The conclusions: All redox-active SAMs modified with a ssDNA probe were suitable for sensing of ssDNA target, with very good sensitivity in fM range and very good selectivity. The detection limits obtained for SAMs incorporating Cu2+, both symmetric and asymmetric, were better in comparison to SAMs incorporating Co2+. Thus, selection of the right transition metal cation has stronger influence on ssDNA sensing ability, than complex structures.

A pair of E3 ubiquitin ligases compete to regulate filopodial dynamics and axon guidance.

Appropriate axon guidance is necessary to form accurate neuronal connections. Axon guidance cues that stimulate cytoskeletal reorganization within the growth cone direct axon navigation. Filopodia at the growth cone periphery have long been considered sensors for axon guidance cues, yet how they respond to extracellular cues remains ill defined. Our previous work found that the filopodial actin polymerase VASP and consequently filopodial stability are negatively regulated via nondegradative TRIM9-dependent ubiquitination. Appropriate VASP ubiquitination and deubiquitination are required for axon turning in response to the guidance cue netrin-1. Here we show that the TRIM9-related protein TRIM67 outcompetes TRIM9 for interacting with VASP and antagonizes TRIM9-dependent VASP ubiquitination. The surprising antagonistic roles of two closely related E3 ubiquitin ligases are required for netrin-1-dependent filopodial responses, axon turning and branching, and fiber tract formation. We suggest a novel model in which coordinated regulation of VASP ubiquitination by a pair of interfering ligases is a critical element of VASP dynamics, filopodial stability, and axon guidance.

Recent advances in branching mechanisms underlying neuronal morphogenesis.

Proper neuronal wiring is central to all bodily functions, sensory perception, cognition, memory, and learning. Establishment of a functional neuronal circuit is a highly regulated and dynamic process involving axonal and dendritic branching and navigation toward appropriate targets and connection partners. This intricate circuitry includes axo-dendritic synapse formation, synaptic connections formed with effector cells, and extensive dendritic arborization that function to receive and transmit mechanical and chemical sensory inputs. Such complexity is primarily achieved by extensive axonal and dendritic branch formation and pruning. Fundamental to neuronal branching are cytoskeletal dynamics and plasma membrane expansion, both of which are regulated via numerous extracellular and intracellular signaling mechanisms and molecules. This review focuses on recent advances in understanding the biology of neuronal branching.

A Retrospective Study to Assess the Role of Using Fine Needle Aspiration Cytology and Frozen Section in the Diagnosis of Thyroid Swelling.

The most cost-effective test is fine needle aspiration cytology (FNAC). Many surgeons use intraoperative frozen section to confirm the FNAC findings and to guide the extent of thyroid surgery. Though it is a valuable tool in the diagnosis of the thyroid lesion and determining the extent of thyroid surgery, still in certain cases diagnosis can be incorrect or inconclusive, so histopathology of the excised specimen remains the most reliable test. The purpose of this study will be to compare the result attained by FNAC and frozen section of the thyroid to the final histopathological diagnosis, in order to establish their role in thyroid surgery today. A retrospective study with a total of 140 patients who underwent thyroid surgery at the ENT department, of a tertiary hospital in coastal Karnataka. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for FNAC and frozen section. The sensitivity, specificity, positive predictive rate, and negative predictive rate of frozen section was found to be 66.7%, 88.4%,76.6%, 82.4% respectively for detecting malignancy. This was found to be higher than the results of FNAC for the same which were 64.4%, 77.8%, 64.4%, 77.8% respectively. As the sensitivity of FNAC is similar to frozen section in detecting malignant cases, FNAC is a good tool for screening the patient for determining malignancy in thyroid, but frozen section is more specific in confirming the malignancy.