Noncanonical interaction with microtubules via the N-terminal nonmotor domain is critical for the functions of a bidirectional kinesin.

Several kinesin-5 motors (kinesin-5s) exhibit bidirectional motility. The mechanism of such motility remains unknown. Bidirectional kinesin-5s share a long N-terminal nonmotor domain (NTnmd), absent in exclusively plus-end-directed kinesins. Here, we combined in vivo, in vitro, and cryo-electron microscopy (cryo-EM) studies to examine the impact of NTnmd mutations on the motor functions of the bidirectional kinesin-5, Cin8. We found that NTnmd deletion mutants exhibited cell viability and spindle localization defects. Using cryo-EM, we examined the structure of a microtubule (MT)-bound motor domain of Cin8, containing part of its NTnmd. Modeling and molecular dynamic simulations based on the cryo-EM map suggested that the NTnmd of Cin8 interacts with the C-terminal tail of ß-tubulin. In vitro experiments on subtilisin-treated MTs confirmed this notion. Last, we showed that NTnmd mutants are defective in plus-end-directed motility in single-molecule and antiparallel MT sliding assays. These findings demonstrate that the NTnmd, common to bidirectional kinesin-5s, is critical for their bidirectional motility and intracellular functions.

Adult Midgut Malrotation With Chronic Volvulus With Superior Mesenteric Artery (SMA) Thrombosis: A Recherche.

Intestinal malrotation is primarily a surgical condition of neonates due to abnormal intestinal rotation during fetal development. Usually, the presentation is immediately after birth. Adult midgut malrotation is rare and primarily detected at laparotomy or incidental radiological imaging for various conditions. We report a sporadic case of a 35-year-old male who presented to the surgical outpatient department (OPD) complaining of dull aching abdominal pain after taking meals for two months. He was able to tolerate a liquid diet only and able to carry out his routine work comfortably. In imaging studies, it was found to be a case of midgut malrotation with volvulus and superior mesenteric artery (SMA) thrombosis with collaterals without features of intestinal obstruction. The patient underwent diagnostic laparoscopy, and a midgut volvulus was identified with Ladd's bands. He underwent exploratory laparotomy with Ladd's procedure. Postoperatively symptoms were resolved, and the patient was discharged in stable condition. If intestinal malrotation presents in adults, it is challenging to diagnose it as it presents with atypical symptoms like chronic vague abdominal pain and weight loss. Often radiological correlation is essential to diagnose such patients. For surgical intervention, a laparoscopic approach is considered better in expert hands. Even though the disease has a chronic course, a high index of suspicion should arise when treating such cases of intestinal malrotation in an adult male. Timely surgery can do miracles and prevent catastrophic complications.

Giant anterior abdominal wall desmoid tumor successfully managed with abdominal wall reconstruction.

Anterior abdominal wall fibromatosis is a benign soft tissue tumor that is rare, but fast-growing with minimal chances of malignant change. We report a young female with a large abdominal swelling which on evaluation was provisionally diagnosed as anterior abdominal wall fibromatosis on imaging and confirmed by histopathology. She was successfully managed with resection of the tumor with a challenging abdominal wall reconstruction with bilateral inferiorly based external oblique muscle flap followed by a mesh repair. Though rare, these tumors are difficult to miss. The importance of this case report is that it describes the methods of multimodal management of a patient with surgery, reconstruction, and adjuvant therapy leading to better patient outcomes.

Defining Critical View of Safety During Laparoscopic Cholecystectomy: The Preoperative Predictors of Failure.

Background Defining critical view of safety (CVS) is one of the most crucial steps during laparoscopic cholecystectomy (LC). This study aimed to determine the preoperative predictors of failure to achieve CVS during LC. Methods All patients undergoing LC from December 2020 to July 2022 were prospectively included. Results There were 180 females and 93 males. CVS was achieved during LC in 238 (87.2%) patients. Conversion to open surgery was performed for 11 patients. Bile leak occurred in three patients which resolved spontaneously. No patient developed bile duct injury. On univariate analysis, age, male sex, American Society of Anaesthesiologists (ASA) grading, Murphy's sign, emergency surgery, neutrophil percentage, lymphocyte percentage, gallbladder wall thickness > 3mm, and impacted gallstone on abdominal ultrasound were predictors of failure to achieve CVS. On multivariate analysis, neutrophil and lymphocyte percentages were independent predictors of failure to achieve CVS. Patients in whom CVS could not be achieved had significantly longer operative time, higher blood loss, complications, and hospital stays. Discussion Inability to achieve CVS during LC can be predicted preoperatively using various parameters including neutrophil and lymphocyte percentages. Such cases must be operated by senior surgeons or referred to experienced general or hepatobiliary surgeons for cholecystectomy to avoid bile duct injury. The proposed algorithm can help in intraoperative decision-making in difficult cases.

Stability and suitability of genotypes and environment to Ascochyta blight of chickpea.

Ascochyta blight (AB) is a major biotic constraint to chickpea production internationally. The disease caused by the phytopathogenic fungus Ascochyta rabiei is highly favored by prolonged spells of low temperature and high humidity. The disease scenario is expected to aggravate in the near future as a result of rapidly changing climatic conditions and the emergence of fungicide-resistant pathogen strains. Tapping into host-plant resistance is the most logical way to preempt such a crisis. Presently, high levels of stable resistance against AB are yet to be identified from the chickpea gene pool. The present study was aimed at facilitating this process through multi-environment testing of chickpea genotypes. Using the GGE biplot analysis method, we could identify three genotypes, viz., ICCV 16508, ICCV 16513, and ICCV 16516, from the International Ascochyta Blight Nursery, which showed consistent moderate resistance reactions across all the tested environments. Moreover, we were able to evaluate the test locations for their suitability to support AB screening trials. Ludhiana and Palampur locations were identified as the most ideal for continual screening in the future. Controlled environment screening at the ICRISAT location offered to reduce large plant populations to small meaningful sizes through initial screening under controlled environment conditions. This study will further improve the scope of phenotyping and sources of stable resistance to be utilized in future AB resistance breeding programs.

Risk factors of surgical site infection in elective laparotomy in a tertiary care center: an observational study.

INTRODUCTION: Surgical site infections (SSI) encompass 20-25% of all hospital-acquired infections with their prevalence ranging from 2.5 to 41.9% across the world. Prevalence and risk factors of SSI vary greatly between countries and between healthcare institutions within a country. There is limited data on the pattern and risk factors of SSI in the Indian healthcare scenario. This study is an attempt to identify risk factors of SSI in patients who underwent elective laparotomy in the general surgery department of a tertiary care hospital in India. METHODOLOGY: This is an observational cross-sectional retrospective study, conducted over 5 years from January 1, 2015, to December 31, 2019. A total of 112 patients who underwent elective laparotomy in the department of general surgery, were enrolled in the study. Data collection was done from hospital case records and discharge summaries of patients. RESULTS AND DISCUSSION: Out of the 112 patients, a total of 16 patients (14.29%) developed surgical site infections. Preoperative serum total protein (W-465.500, P 0.012) and length of hospital stay (W=1235.000, P≤0.001) were found to have a significant association with surgical site infection. Age, gender, smoking, comorbidity, class of surgical wound and, preoperative albumin did not show any significant association with the development of SSI. Escherichia coli was the predominant organism isolated in culture. CONCLUSION: Measures to curtail SSI can only be adopted after a thorough understanding of its prevalence and predictors. The characteristics and pattern of SSI will help identify prevalent organisms, their resistance pattern and will aid in formulating antibiotic policy tailor-made for the healthcare institution.

What is the impact of COVID-19 pandemic on global carbon emissions?

The coronavirus 2019 (COVID 19, or SARS-CoV-2) pandemic that started in December 2019 has caused an unprecedented impact in most countries globally and continues to threaten human lives worldwide. The COVID-19 and strict lockdown measures have had adverse effects on human health and national economies. These lockdown measures have played a critical role in improving air quality, water quality, and the ozone layer and reducing greenhouse gas emissions. Using Soil Moisture Active Passive (SMAP) Level 4 carbon (SMAP LC4) satellite products, this study investigated the impacts of COVID-19 lockdown measures on annual carbon emissions globally, focusing on 47 greatly affected countries and their 105 cities by December 2020. It is shown that while the lockdown measures significantly reduced carbon emissions globally, several countries and cities observed this reduction as temporary because strict lockdown measures were not imposed for extended periods in 2020. Overall, the total carbon emissions of select 184 countries reduced by 438 Mt in 2020 than in 2019. Since the global economic activities are slowly expected to return to the non-COVID-19 state, the reduction in carbon emissions during the pandemic will not be sustainable in the long run. For sustainability, concerned authorities have to put significant efforts to change transportation, climate, and environmental policies globally that fuel carbon emissions. Overall, the presented results provide directions to the stakeholders and policymakers to develop and implement measures to control carbon emissions for a sustainable environment.

Transverse Testicular Ectopia Presenting as Right Inguinal Hernia in an Adult Patient: An Incidental Finding During Robotic Transabdominal Preperitoneal Repair.

Transverse testicular ectopia (TTE) is a rare anomaly in which both the testes descend through a single inguinal canal and enter the same hemiscrotum. While TTE most commonly occurs in children, a few cases have been reported in adults as well. In this report, we present a case of TTE found accidentally during robotic exploration for right inguinal hernia with left cryptorchidism. Surgeons who frequently engage in the repair of inguinal hernia should be aware of the diagnostic and management options available to them when this condition is found unexpectedly during exploration.

Covid-19 and surgery: Challenging issues in the face of new normal - A narrative review.

This review aims to outline the current perspectives of surgery in the COVID 19 pandemic associated with the pitfalls in implementing the emerging guidelines to continue patient care without compromising safety, both from the surgeons' and the patients' points of view. The fight between the surgeon and the pandemic will be a dragging one since the post-pandemic infflux of surgical patients coupled with the 'new normal' practices to prevent COVID 19 spread requires pertinent resources, well-trained personnel, and co-operation among different departments. Emergency surgeries and cancer care have continued all this while, undoubtedly, with unwanted delays and distress. While we continue to prepare ourselves and work in a whole new environment, surgeons are facing the increased chances of litigations and compromised safety. We review what we have come to understand about safe surgical practices during and after the pandemic and the unanswered questions.

Impact of Direct Acting Antiviral Drugs in Treatment Naïve HCV Cirrhosis on Fibrosis and Severity of Liver Disease: A Real Life Experience from a Tertiary Care Center of North India.

BACKGROUND/AIMS: Treatment of chronic hepatitis C infection with direct-acting antiviral (DAA) drugs has been highly effective, but data regarding benefit in advanced liver disease is relatively scarce in Indian patients. The aim of this study was to determine the effects of DAA in patients with HCV related cirrhosis (compensated/decompensated) who achieved sustained virological response post-therapy at 12 weeks (SVR12). METHODS: Sixty-three patients with HCV related cirrhosis treated with sofosbuvir based regimen were evaluated. Data regarding baseline demographics, the severity of liver disease and treatment regimen were collected. The primary end point was to evaluate the effect of treatment (SVR12) on the severity of liver disease with the secondary end point being to observe for any adverse events related to treatment. RESULTS: Treatment naïve patients with HCV cirrhosis either due to genotype 1 or genotype 3 were divided into two groups: group A (compensated cirrhosis), group B (decompensated cirrhosis). SVR12 in group A was 91.66% (33/37) and in group, B was 73.17% (30/41). Baseline mean liver stiffness measurement (LSM) in group A was 16.81 ± 3.57 kPa which decreased to 11.19 ± 1.75 kPa at SVR12 (P-value <0.0001). Baseline mean APRI and FIB-4 score in group A were 1.228 ± 0.499 and 2.61 ± 1.06 and in group B were 2.156 ± 1.10 and 5.71 ± 2.06 respectively which decrease to 0.415 ± 0.115 and 1.25 ± 0.46 in group A, to 0.759 ± 0.275 and 2.60 ± 1.12 in group B following SVR12 (P value <0.0001). Mean MELD-Na improved from baseline 9.93 ± 2.04, 20.70 ± 4.52 to 7.21 ± 0.92, 14.23 ± 4.51 respectively in group A and B at SVR12 (P-value <0.0001). Child-Turcotte-Pugh score improved by 1 in 27.27% (9/33) and ≥2 in 76.67% (23/30) of patients in group A and group B respectively. CONCLUSION: There was a significant improvement in severity of liver disease as depicted by the decrease in LSM and other noninvasive marker of fibrosis in patients who achieved SVR12 on DAA therapy.

Molecular simulation study of vapor-liquid critical properties of a simple fluid in attractive slit pores: crossover from 3D to 2D.

We present the effect of surface attraction on the vapor-liquid equilibria of square well (SW) fluids in slit pores of varying slit width from quasi 3D to 2D regime using molecular simulation methodologies. Four to five distinct linear regimes are found for shift in the critical temperature with inverse slit width, which is more prominent at higher surface fluid interaction strength. On the other hand, shift in the critical density and the critical pressure does not show any specific trend. Nevertheless, critical density and pressure show the sign of approaching toward the 3D bulk value with increase in the slit pore width, H, beyond 40 molecular diameters. The crossover from 3D to 2D behavior for attractive pores is observed around 14-16 molecular diameters, which is significantly different from the crossover behavior in the hydrophobic slit pore. Critical properties for H 2. However, interfacial properties approaches to the bulk value with increasing slit width. On the other hand, surface tension at a reduced temperature displays a nonmonotonic behavior with the change in H, which is in good agreement with the nature of the corresponding scaled interfacial width.

11H-Isoquino[4,3-c]cinnolin-12-ones; novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity.

Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)ethyl]-11H-isoquino[4,3-c]cinnolin-12-one (1a) as a novel topoisomerase I-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-(N,N-dimethylamino)ethyl, a 2-(N,N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a beta-methyl group to 1a provided an analogue with dramatically reduced TOP1-targeting activity and cytotoxicity. Analogues of 1a wherein the 2-(N,N-dimethylamino)ethyl group was replaced with a (2-tetrahydrofuranyl)methyl, a 2-(piperidin-1-yl)ethyl, or a 2-(4-methylpiperazin-1-yl)ethyl substituent exhibited decreased activity as TOP1-targeting agents. Replacement of the dimethoxy groups of 1a with hydrogen atoms resulted in an analogue with significantly decreased TOP1-targeting activity and cytotoxicity. Removal of both the vicinal dimethoxyl groups and the methylenedioxy moiety resulted in a complete loss of TOP1-targeting activity. The presence of a 9-nitro substituent in place of the 8,9-methylenedioxy group of 1a resulted in a decrease in relative TOP1-targeting activity and cytotoxicity. Compounds 1a and the 11-n-butyl analogue 1d were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays. At dose levels that approached its maximum tolerated dose, 1a proved to be effective in inhibiting tumor growth in vivo when administered orally or by ip injection.

Nitro and amino substitution in the D-ring of 5-(2-dimethylaminoethyl)- 2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-ones: effect on topoisomerase-I targeting activity and cytotoxicity.

5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one exhibits potent TOP1-targeting activity and pronounced antitumor activity. It was hypothesized that replacement of the two methoxyl groups with a nitro substituent would allow for retention of similar activity. In this study 8-, 9-, and 10-nitro-5H-2,3-methylenedioxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-one and their amino derivatives were synthesized and assessed for their relative TOP1-targeting activity and cytotoxicity. In the case of both the 8- and 9-nitro analogues, their TOP1-targeting activity and cytotoxicity are greater than that of camptothecin and comparable to that of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one.

5H-Dibenzo[c,h]1,6-naphthyridin-6-ones: novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity.

5H-Dibenzo[c,h]1,6-naphthyridine-6-ones can exhibit potent antitumor activity. The effect of varied substituents at the 5-position of 5H-8,9-dimethoxy-2,3-methylenedioxydibenzo[c,h]1,6-naphthyridine on relative cytotoxicity and topoisomerase I-targeting activity was evaluated. Potent TOP-1-targeting activity is observed when the 5-position is substituted with either a 2-(N,N-dimethylamino)ethyl group, as in 3a, or a 2-(pyrrolidin-1-yl)ethyl substituent, 3c. In contrast, the addition of a beta-methyl group or a beta-hydroxymethyl group to compound 3a, as in 3b and 3j, results in a loss of significant TOP1-targeting activity. While the presence of a 3-(N,N-dimethylamino)propyl substituent at the 5-position or a methyl(2-tetrahydrofuranyl) group allows for retention of TOP1-targeting activity, the 2-(4-methyl-1-piperazinyl)ethyl analogue, 3d, did not exhibit significant activity. Replacement of the N,N-dimethylamino group of 3a with either C(2)H(5) or OH, as in 3f and 3h, respectively, also had a negative impact on both cytotoxicity and TOP1-targeting activity. Treatment of 3a with LAH gave the 5,6-dihydrodibenzo[c,h]naphthyridine, 4a. This dihydro derivative has approximately 2/3 the potency of 3a as a TOP1-targeting agent. Compounds 3a, 3b, 3h, 3i, and 4a were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line, MDA-MB-435, was used in these assays. Compound 3a proved to be effective in regressing tumor growth in vivo when administered either by ip injection or orally 3x week at a dose of 2.0mg/kg. Compound 4a when administered orally 5x weekly at a dose of 40 mg/kg also suppressed tumor growth.

Substituted dibenzo[c,h]cinnolines: topoisomerase I-targeting anticancer agents.

Several substituted dibenzo[c,h]cinnolines were synthesized and evaluated for their potential to target topoisomerase I and for their relative cytotoxic activity. Select benzo[i]phenanthridines are capable of stabilizing the cleavable complex formed with topoisomerase I and DNA. This study was initiated to examine whether dibenzo[c,h]cinnolines, which are in essence aza analogues of benzo[i]phenanthridines, possess similar pharmacological properties. 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine is one of the more potent benzo[i]phenanthridine derivatives in regard to topoisomerase I-targeting activity and cytotoxicity. The structure-activity relationship observed with these substituted dibenzo[c,h]cinnolines parallels that observed for benzo[i]phenanthridine derivatives. Compared to similarly substituted benzo[i]phenanthridines, the dibenzo[c,h]cinnoline analogues exhibit more potent topoisomerase I-targeting activity and cytotoxicity. The relative IC(50) values obtained in assessing the cytotoxicity of 2,3-dimethoxy-8,9-methylenedioxydibenzo[c,h]cinnoline and 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine in the human lymphoblastma cell line, RPMI8402, are 70 and 400 nM, respectively. In tumor cell lines selected for resistance to camptothecin and known to express mutant topoisomerase I, benzo[i]phenanthridine derivatives were not cross-resistant. In contrast, similarly substituted dibenzo[c,h]cinnolines with significant topoisomerase I-targeting activity did exhibit cross-resistance in these camptothecin-resistant cell lines. The cytotoxicity of these dibenzo[c,h]cinnolines was not diminished in cells overexpressing the efflux transporter, MDR1. These data indicate that substituted dibenzo[c,h]cinnolines can exhibit potent topoisomerase I-targeting activity and are capable of overcoming the multi-drug resistance associated with this efflux transporter.

Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435.

Several 5,12-diazachrysen-6-ones and 5,6,11-triazachrysen-12-ones were synthesized with varied substituents at the 5- or 11-position, respectively. Each compound was evaluated for its potential to stabilize the cleavable complex formed with TOP1 and DNA. Two analogues with very potent TOP1-targeting activity, 3a and 4a, exhibited cytotoxic activity with IC(50) values at or below 2nM against RPMI8402. Compound 3a was active in vivo by either ip or po administration in the human tumor xenograft athymic nude mice model.