IL-4-STAT6 axis amplifies histamine-induced vascular endothelial dysfunction and hypovolemic shock.

BACKGROUND: Mast cell (MC)-derived mediators induce vasodilatation and fluid extravasation, leading to cardiovascular failure in severe anaphylaxis. We have previously revealed a synergistic interaction between the cytokine IL-4 and the MC-derived mediator histamine in modulating vascular endothelial (VE) dysfunction and severe anaphylaxis. The mechanism by which IL-4 exacerbates histamine-induced VE dysfunction and severe anaphylaxis are unknown. OBJECTIVE: To identify the IL-4-induced molecular processes regulating the amplification of histamine-induced VE barrier dysfunction and the severity of IgE-mediated anaphylaxic reactions. METHODS: RNAseq, Western blot, Ca2+ imaging and barrier functional analyses on the vascular endothelial cell line (EA.hy926). Pharmacologic degraders (selective PROTAC (proteolysis-targeting chimera) and genetic (lentiviral shRNA) inhibitors were used to determine the roles of STAT3 and STAT6 in conjunction with in vivo model systems of histamine-induced hypovolemic shock. RESULTS: IL-4 enhancement of histamine-induced VE barrier dysfunction was associated with increased VE-Cadherin degradation, intracellular calcium flux, phospho-Src levels and required transcription and de novo protein synthesis. RNAseq analyses of IL-4 stimulated VE cells identified dysregulation of genes involved in cell proliferation, cell development, and cell growth and transcription factor motif analyses revealed a significant enrichment of differential expressed genes (DEGs) with putative STAT3 and STAT6 motif. IL-4 stimulation in EA.hy926 cells induced both STAT3Y705 and STAT3S727 phosphorylation. Genetic and pharmacologic ablation of VE STAT3 activity revealed a role for STAT3 in basal VE barrier function, however IL-4 enhancement and histamine-induced VE barrier dysfunction was predominantly STAT3-independent. In contrast, IL-4 enhancement and histamine-induced VE barrier dysfunction was STAT6-dependent. Consistent with this finding, pharmacologic knockdown of STAT6 abrogated IL-4-mediated amplification of histamine-induced hypovolemia. CONCLUSIONS: These studies unveil a novel role of the IL-4/ STAT6 signaling axis in the priming of VE cells predisposing to exacerbation of histamine-induced anaphylaxis.

Universal digital high-resolution melting for the detection of pulmonary mold infections.

Invasive mold infections (IMIs) are associated with high morbidity, particularly in immunocompromised patients, with mortality rates between 40% and 80%. Early initiation of appropriate antifungal therapy can substantially improve outcomes, yet early diagnosis remains difficult to establish and often requires multidisciplinary teams evaluating clinical and radiological findings plus supportive mycological findings. Universal digital high-resolution melting (U-dHRM) analysis may enable rapid and robust diagnoses of IMI. A universal fungal assay was developed for U-dHRM and used to generate a database of melt curve signatures for 19 clinically relevant fungal pathogens. A machine learning algorithm (ML) was trained to automatically classify these pathogen curves and detect novel melt curves. Performance was assessed on 73 clinical bronchoalveolar lavage samples from patients suspected of IMI. Novel curves were identified by micropipetting U-dHRM reactions and Sanger sequencing amplicons. U-dHRM achieved 97% overall fungal organism identification accuracy and a turnaround time of ~4 hrs. U-dHRM detected pathogenic molds (Aspergillus, Mucorales, Lomentospora, and Fusarium) in 73% of 30 samples classified as IMI, including mixed infections. Specificity was optimized by requiring the number of pathogenic mold curves detected in a sample to be >8 and a sample volume to be 1 mL, which resulted in 100% specificity in 21 at-risk patients without IMI. U-dHRM showed promise as a separate or combination diagnostic approach to standard mycological tests. U-dHRM's speed, ability to simultaneously identify and quantify clinically relevant mold pathogens in polymicrobial samples, and detect emerging opportunistic pathogens may aid treatment decisions, improving patient outcomes. IMPORTANCE: Improvements in diagnostics for invasive mold infections are urgently needed. This work presents a new molecular detection approach that addresses technical and workflow challenges to provide fast pathogen detection, identification, and quantification that could inform treatment to improve patient outcomes.

All-Oxide Metasurfaces Formed by Synchronized Local Ionic Gating.

Ionic gating of oxide thin films has emerged as a novel way of manipulating the properties of thin films. Most studies have been carried out on single devices with a three-terminal configuration but, by exploring the electrokinetics during the ionic gating, such a configuration with initially insulating films leads to a highly non-uniform gating response of individual devices within large arrays of the devices. We show that such an issue can be circumvented by the formation of a uniform charge potential by the use of a thin conducting underlayer. This synchronized local ionic gating allows for the simultaneous manipulation of the electrical, magnetic, and/or optical properties of large arrays of devices. Designer metasurfaces formed in this way from SrCoO2.5 thin films display anomalous optical reflection of light that relies on the uniform and coherent response of all the devices. Beyond oxides, almost any material whose properties can be controlled by the addition or removal of ions via gating can form novel metasurfaces using this technique. Our findings provide insights into the electrokinetics of ionic gating and a wide range of applications using synchronized local ionic gating. This article is protected by copyright. All rights reserved.

Tata Memorial Centre Evidence Based Management of Colorectal cancer.

ABSTRACT: This review article examines the evidence-based management of colorectal cancers, focusing on topics characterized by ongoing debates and evolving evidence. To contribute to the scientific discourse, we intentionally exclude subjects with established guidelines, concentrating instead on areas where the current understanding is dynamic. Our analysis encompasses a thorough exploration of critical themes, including the evidence surrounding complete mesocolic excision and D3 lymphadenectomy in colon cancers. Additionally, we delve into the evolving landscape of perioperative chemotherapy in both colon and rectal cancers, considering its nuanced role in the context of contemporary treatment strategies. Advancements in surgical techniques are a pivotal aspect of our discussion, with an emphasis on the utilization of minimally invasive approaches such as laparoscopy and robotic surgery in both colon and rectal cancers, including advanced rectal cases. Moving beyond conventional radical procedures, we scrutinize the feasibility and implications of endoscopic resections for small tumors, explore the paradigm of organ preservation in locally advanced rectal cancers, and assess the utility of total neoadjuvant therapy in the current treatment landscape. Our final segment reviews pivotal trials that have significantly influenced the management of colorectal liver and peritoneal metastasis.

Universal Digital High-Resolution Melt Analysis for the Diagnosis of Bacteremia.

Fast and accurate diagnosis of bloodstream infection is necessary to inform treatment decisions for septic patients, who face hourly increases in mortality risk. Blood culture remains the gold standard test but typically requires approximately 15 hours to detect the presence of a pathogen. We, therefore, assessed the potential for universal digital high-resolution melt (U-dHRM) analysis to accomplish faster broad-based bacterial detection, load quantification, and species-level identification directly from whole blood. Analytical validation studies demonstrated strong agreement between U-dHRM load measurement and quantitative blood culture, indicating that U-dHRM detection is highly specific to intact organisms. In a pilot clinical study of 17 whole blood samples from pediatric patients undergoing simultaneous blood culture testing, U-dHRM achieved 100% concordance when compared with blood culture and 88% concordance when compared with clinical adjudication. Moreover, U-dHRM identified the causative pathogen to the species level in all cases where the organism was represented in the melt curve database. These results were achieved with a 1-mL sample input and sample-to-answer time of 6 hours. Overall, this pilot study suggests that U-dHRM may be a promising method to address the challenges of quickly and accurately diagnosing a bloodstream infection.

Thickness-Tunable Zoology of Magnetic Spin Textures Observed in Fe5GeTe2.

The family of two-dimensional (2D) van der Waals (vdW) materials provides a playground for tuning structural and magnetic interactions to create a wide variety of spin textures. Of particular interest is the ferromagnetic compound Fe5GeTe2 that we show displays a range of complex spin textures as well as complex crystal structures. Here, using a high-brailliance laboratory X-ray source, we show that the majority (1 × 1) Fe5GeTe2 (FGT5) phase exhibits a structure that was previously considered as being centrosymmetric but rather lacks inversion symmetry. In addition, FGT5 exhibits a minority phase that exhibits a long-range ordered (√3 × âˆš3)-R30° superstructure. This superstructure is highly interesting in that it is innately 2D without any lattice periodicity perpendicular to the vdW layers, and furthermore, the superstructure is a result of ordered Te vacancies in one of the topmost layers of the FGT5 sheets rather than being a result of vertical Fe ordering as earlier suggested. We show, from direct real-space magnetic imaging, evidence for three distinct magnetic ground states in lamellae of FGT5 that are stabilized with increasing lamella thickness, namely, a multidomain state, a stripe phase, and an unusual fractal state. In the stripe phase we also observe unconventional type-I and type-II bubbles where the spin texture in the central region of the bubbles is nonuniform, unlike conventional bubbles. In addition, we find a bobber or a cocoon-like spin texture in thick (∼170 µm) FGT5 that emerges from the fractal state in the presence of a magnetic field. Among all the 2D vdW magnets we have thus demonstrated that FGT5 hosts perhaps the richest variety of magnetic phases that, thereby, make it a highly interesting platform for the subtle tuning of magnetic interactions.

Medical Imaging and Analysis of Thermal Necrosis During Bone Grinding: Implementation of Non-dominated Sorting Genetic Algorithm (NSGA-III) in Healthcare.

BACKGROUND: Medical imaging plays a key role in neurosurgery; thereby, imaging and analysis of the soft and hard tissues during bone grinding is of paramount importance for neurosurgeons. Bone grinding, a minimally invasive operation in the field of neurosurgery amid osteotomy, has been used during brain cancer surgery. AIMS AND OBJECTIVES: With increasing attention to neural tissue damage in machining operations, imaging of these neural tissues becomes vital and reducing temperature is imperative. METHOD: In the present study, a novel attempt has been made to perform the imaging of bone tissues during the bone grinding procedure and further investigate the relationship between rotational speed, feed rate, depth of cut with cutting forces, and temperature. The role of cutting forces and temperature has been addressed as per the requirements of neurosurgeons. Firstly, a three-factor, three-level design was constructed with a full factorial design. Regression models were employed to construct the models between input parameters and response characteristics. Medical imaging techniques were used to perform a thorough analysis of thermal necrosis and damage to the bone. Subsequently, the non-dominated sorting genetic algorithm (NSGA-III) was used to optimize the parameters for reduction in the cutting forces and temperature during bone grinding while reducing neural tissue damage. RESULTS: The results revealed that the maximum value of tangential force was 21.32 N, thrust force was 9.25 N, grinding force ratio was 0.453, torque was 4.55 N-mm, and temperature was 59.3°C. It has been observed that maximum temperature was generated at a rotational speed of 55000 rpm, feed rate of 60 mm/min, and depth of cut of 1.0 mm. Histopathological imaging analysis revealed the presence of viable lacunas, empty lacunas, haversian canals, and osteocytes in the bone samples. Furthermore, the elemental composition of the bone highlights the presence of carbon (c) 59.49%, oxygen (O) 35.82%, sodium (Na) 0.11%, phosphorous 1.50%, sulphur 0.33%, chlorine 0.98%, and calcium 1.77%. CONCLUSION: The study revealed that compared to the initial scenario, NSGA-III can produce better results without compromising the trial results. According to a statistical study, the rise in temperature during bone grinding was significantly influenced by rotating speed. The density of osteocytes in the lacunas was higher at lower temperatures. Furthermore, the results of surface electron microscopy and energy dispersive spectroscopy revealed the presence of bone over the surface of the grinding burr, which resulted in the loading of the grinding burr. The results of the present investigation will be beneficial for researchers and clinical practitioners worldwide.

White light emission from helically stacked humin-mimic based H-aggregates in heteroatom free carbon dots.

White light emission (WLE), particularly from heteroatom free carbon dots (CDs), is unusual. Besides, deciphering the origin of WLE from a H-aggregated molecular fluorophore in such kinds of CDs is a challenging task due to their non-fluorescent character resulting from a forbidden transition from a lower-energy excitonic state. Therefore, rigorous investigation on their elusive excited state photophysical properties along with their steady-state optical phenomena has to be carried out to shed light on the nature of distinct emissive states formed in the CDs. Herein, for the first time, we report WLE from imperfect H-aggregates of co-facially π-π stacked humin-like structures comprising furfural monomer units as a unique molecular fluorophore in CDs, as revealed from combined spectroscopic and microscopic studies, synthesized through hydrothermal treatment of the single precursor, dextrose. H-aggregates in CDs show a broad range of excitation-dependent emission spectra with color coordinates close to pure white light, i.e., CIE (0.35, 0.37) and a color temperature of 6000 K. Imperfect orientation between the transition dipole moments of adjacent monomer units in the H-aggregate's molecular arrangement is expected to cause ground state symmetry breaking, as confirmed by Circular Dichroism (CD) studies, which established helically stacked nature in molecular aggregates and produced significant oscillatory strength at lower energy excitonic states to enable fluorescence. TRES and TAS investigations have been performed to minimise the intricacies associated with excited state photophysics, which is regarded as an essential step in gaining a grasp on emissive states. Based on the observation of two isoemissive spots in the time-resolved area normalized emission spectra (TRANES), the existence of three oligomeric species in the excited state equilibrium of the pure/hybrid H-aggregates has been established. The exciton dynamics through electron relaxation from the higher to the lower excitonic states, charge transfer (CT) states, and surface trap mediated emission in excimer states of H-aggregates have also been endorsed as three distinct emissive states from femtosecond transient absorption spectroscopy (TAS) studies corroborating with their steady-state absorption and emission behavior. The results would demonstrate the usage of CDs as a cutting-edge fluorescent material for creating aggregate-induced white light emission.

Efficacy of fixed-dose phenylephrine bolus for treating post-spinal hypotension: Comparison between pre-eclamptics and normotensives.

Background and Aims: Pre-eclamptic parturients may have an exaggerated response to vasopressors. This study compares the efficacy of a 50 µg fixed bolus of phenylephrine for treatment of post-spinal hypotension in pre-eclamptic versus normotensive parturients. Material and Methods: After written informed consent and ethics committee approval, 30 normotensive and 30 pre-eclamptic parturients between 18 and 40 years with singleton term pregnancy about to undergo cesarean section (CS) under spinal anesthesia were included. Post-spinal hypotension was treated with a 50 µg fixed bolus of phenylephrine. The cumulative dose of phenylephrine, the number of boluses, and the median dose required to treat the first hypotensive episode, total number of hypotensive episodes, maternal side effects, neonatal appearance, pulse, grimace, activity, and respiration (APGAR) scores, and umbilical arterial cord blood pH were noted. Statistical analysis was done using Student's t-test, Mann-Whitney U-test, Chi-square test/Fisher's exact test as appropriate. A P <0.05 was considered significant. Results: The cumulative dose and number of boluses of phenylephrine required to treat post-spinal hypotension were comparable. The median dose required to treat the first episode of post-spinal hypotension was also similar (p = 0.792). The time to develop the first hypotensive episode was significantly earlier for group N (p = 0.002). The efficacy of a single fixed bolus of 50 µg phenylephrine was similar in both groups (p = 1.000). Neonatal median APGAR scores at 1 min after birth were significantly higher for group N (p = 0.016). Conclusion: A fixed-dose bolus of 50 µg phenylephrine is safe and effective in treating post-spinal hypotension in pre-eclampsia. The efficacy of phenylephrine is comparable in pre-eclamptic and normotensive parturients.

Comparison of Intralesional Placentrex Versus Hyaluronidase and Dexamethasone Injection in the Symptomatic Management of Stage II Oral Submucous Fibrosis - a Prospective Study.

AIM: The present study aimed to compare the effectiveness of intralesional placentrex versus hyaluronidase + dexamethasone injection in the symptomatic management of stage II OSMF. MATERIALS AND METHODS: This was a non-randomized prospective study conducted over a period of 14 months at a tertiary referral center. Patients with clinical stage II OSMF were randomly grouped into A(n = 18) and B(n = 17). These patients were treated with weekly intralesional injection of placentrex and hyaluronidase + dexamethasone respectively, over a period of six weeks. Variables such as mouth opening, burning sensation and colour of mucosa were evaluated at baseline(T0), second week(T1), fourth week(T3), sixth week(T4) of follow up. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 15 patients completed the study in each group with regular follow up. The mean improvement in mouth opening was 4.3 ± 0.57 mms in group A(p-value < 0.001) and 7.2 ± 0.76 mms in group B(p-value < 0.001) which were significant at the end of six weeks. Mean change in burning sensation at the end of six weeks in group A was 1.2 ± 0.73(p-value < 0.001), and 3.6 ± 0.63(p-value < 0.001) in group B. Mean change in colour of mucosa at the end of six weeks was 1.4 in group A(p-value > 0.05) and 2 in group B(p-value > 0.05). On comparison between both groups, patients in group B exhibited better mouth opening and reduction of burning sensation than patients in group A(p-value < 0.001). CONCLUSION: Both intralesional placentrex and hyaluronidase + dexamethasone injection are effective in alleviating the symptoms of stage II OSMF. However, hyaluronidase + dexamethasone injection showed slightly better improvement in mouth opening and burning sensation after six weeks.

Universal Digital High Resolution Melt for the detection of pulmonary mold infections.

Background: Invasive mold infections (IMIs) such as aspergillosis, mucormycosis, fusariosis, and lomentosporiosis are associated with high morbidity and mortality, particularly in immunocompromised patients, with mortality rates as high as 40% to 80%. Outcomes could be substantially improved with early initiation of appropriate antifungal therapy, yet early diagnosis remains difficult to establish and often requires multidisciplinary teams evaluating clinical and radiological findings plus supportive mycological findings. Universal digital high resolution melting analysis (U-dHRM) may enable rapid and robust diagnosis of IMI. This technology aims to accomplish timely pathogen detection at the single genome level by conducting broad-based amplification of microbial barcoding genes in a digital polymerase chain reaction (dPCR) format, followed by high-resolution melting of the DNA amplicons in each digital reaction to generate organism-specific melt curve signatures that are identified by machine learning. Methods: A universal fungal assay was developed for U-dHRM and used to generate a database of melt curve signatures for 19 clinically relevant fungal pathogens. A machine learning algorithm (ML) was trained to automatically classify these 19 fungal melt curves and detect novel melt curves. Performance was assessed on 73 clinical bronchoalveolar lavage (BAL) samples from patients suspected of IMI. Novel curves were identified by micropipetting U-dHRM reactions and Sanger sequencing amplicons. Results: U-dHRM achieved an average of 97% fungal organism identification accuracy and a turn-around-time of 4hrs. Pathogenic molds (Aspergillus, Mucorales, Lomentospora and Fusarium) were detected by U-dHRM in 73% of BALF samples suspected of IMI. Mixtures of pathogenic molds were detected in 19%. U-dHRM demonstrated good sensitivity for IMI, as defined by current diagnostic criteria, when clinical findings were also considered. Conclusions: U-dHRM showed promising performance as a separate or combination diagnostic approach to standard mycological tests. The speed of U-dHRM and its ability to simultaneously identify and quantify clinically relevant mold pathogens in polymicrobial samples as well as detect emerging opportunistic pathogens may provide information that could aid in treatment decisions and improve patient outcomes.

Universal digital high resolution melt analysis for the diagnosis of bacteremia.

Fast and accurate diagnosis of bloodstream infection is necessary to inform treatment decisions for septic patients, who face hourly increases in mortality risk. Blood culture remains the gold standard test but typically requires ∼15 hours to detect the presence of a pathogen. Here, we assess the potential for universal digital high-resolution melt (U-dHRM) analysis to accomplish faster broad-based bacterial detection, load quantification, and species-level identification directly from whole blood. Analytical validation studies demonstrated strong agreement between U-dHRM load measurement and quantitative blood culture, indicating that U-dHRM detection is highly specific to intact organisms. In a pilot clinical study of 21 whole blood samples from pediatric patients undergoing simultaneous blood culture testing, U-dHRM achieved 100% concordance when compared with blood culture and 90.5% concordance when compared with clinical adjudication. Moreover, U-dHRM identified the causative pathogen to the species level in all cases where the organism was represented in the melt curve database. These results were achieved with a 1 mL sample input and sample-to-answer time of 6 hrs. Overall, this pilot study suggests that U-dHRM may be a promising method to address the challenges of quickly and accurately diagnosing a bloodstream infection. Universal digital high resolution melt analysis for the diagnosis of bacteremia: April Aralar, Tyler Goshia, Nanda Ramchandar, Shelley M. Lawrence, Aparajita Karmakar, Ankit Sharma, Mridu Sinha, David Pride, Peiting Kuo, Khrissa Lecrone, Megan Chiu, Karen Mestan, Eniko Sajti, Michelle Vanderpool, Sarah Lazar, Melanie Crabtree, Yordanos Tesfai, Stephanie I. Fraley.

IL-13-induced STAT3-dependent signaling networks regulate esophageal epithelial proliferation in eosinophilic esophagitis.

BACKGROUND: Basal zone hyperplasia (BZH) and dilated intercellular spaces (DISs) are thought to contribute to the clinical manifestations of eosinophilic esophagitis (EoE); however, the molecular pathways that drive BZH remain largely unexplored. OBJECTIVE: We sought to define the role of IL-13-induced transcriptional programs in esophageal epithelial proliferation in EoE. METHODS: We performed RNA sequencing, bioinformatics, Western blot, reverse transcriptase quantitative PCR, and histologic analyses on esophageal biopsies from healthy control and patients with EoE, primary esophageal cells derived from patients with EoE, and IL-13-stimulated esophageal epithelial keratinocytes grown at the air-liquid interface (EPC2-ALI). Genetic (shRNA) and pharmacologic (proteolysis-targeting chimera degrader) approaches and in vivo model of IL-13-induced esophageal epithelial remodeling (Krt5-rtTA x tetO-IL-13Tg) were used to define the role of signal transducer and activator of transcription 3 (STAT3) and STAT6 and secreted frizzled-related protein 1 (SFRP1) in esophageal epithelial proliferation. RESULTS: RNA-sequencing analysis of esophageal biopsies (healthy control vs EoE) and EPC2-ALI revealed 82 common differentially expressed genes that were enriched for putative STAT3 target genes. In vitro and in vivo analyses revealed a link between IL-13-induced STAT3 and STAT6 phosphorylation, SFRP1 mRNA expression, and esophageal epithelial proliferation. In vitro studies showed that IL-13-induced esophageal epithelial proliferation was STAT3-dependent and regulated by the STAT3 target SFRP1. SFRP1 mRNA is increased in esophageal biopsies from patients with active EoE compared with healthy controls or patients in remission and identifies an esophageal suprabasal epithelial cell subpopulation that uniquely expressed the core EoE proinflammatory transcriptome genes (CCL26, ALOX15, CAPN14, ANO1, and TNFAIP6). CONCLUSIONS: These studies identify SFRP1 as a key regulator of IL-13-induced and STAT3-dependent esophageal proliferation and BZH in EoE and link SFRP1+ esophageal epithelial cells with the proinflammatory and epithelial remodeling response in EoE.

Topology and adenocarcinoma cell localization dataset on the labyrinthin diapeutic biomarker.

OBJECTIVE: The discovery and characterization of tumor associated antigens is increasingly important to advance the field of immuno-oncology. In this regard, labyrinthin has been implicated as a neoantigen found on the cell surface of adenocarcinomas. Data on the (1) topology, (2) amino acid (a.a.) homology analyses and (3) cell surface localization of labyrinthin by fluorescent activated cell sorter (FACS) are studied in support of labyrinthin as a novel, pan-adenocarcinoma marker. RESULTS: Bioinformatics analyses predict labyrinthin as a type II protein with calcium binding domain(s), N-myristoylation sites, and kinase II phosphorylation sites. Sequence homologies for labyrinthin (255 a.a.) were found vs. the intracellular aspartyl/asparaginyl beta-hydroxylase (ASPH; 758 a.a.) and the ASPH-gene related protein junctate (299 a.a.), which are both type II proteins. Labyrinthin was detected by FACS on only non-permeablized A549 human lung adenocarcinoma cells, but not on normal WI-38 human lung fibroblasts nor primary cultures of normal human glandular-related cells. Microscopic images of immunofluorescent labelled MCA 44-3A6 binding to A549 cells at random cell cycle stages complement the FACS results by further showing that labyrinthin persisted on the cell surfaces along with some cell internalization for greater than 20 min.

Restoration of Sleep and Circadian Behavior by Autophagy Modulation in Huntington's Disease.

Circadian and sleep defects are well documented in Huntington's disease (HD). Modulation of the autophagy pathway has been shown to mitigate toxic effects of mutant Huntingtin (HTT) protein. However, it is not clear whether autophagy induction can also rescue circadian and sleep defects. Using a genetic approach, we expressed human mutant HTT protein in a subset of Drosophila circadian neurons and sleep center neurons. In this context, we examined the contribution of autophagy in mitigating toxicity caused by mutant HTT protein. We found that targeted overexpression of an autophagy gene, Atg8a in male flies, induces autophagy pathway and partially rescues several HTT-induced behavioral defects, including sleep fragmentation, a key hallmark of many neurodegenerative disorders. Using cellular markers and genetic approaches, we demonstrate that indeed the autophagy pathway is involved in behavioral rescue. Surprisingly, despite behavioral rescue and evidence for the involvement of the autophagy pathway, the large visible aggregates of mutant HTT protein were not eliminated. We show that the rescue in behavior is associated with increased mutant protein aggregation and possibly enhanced output from the targeted neurons, resulting in the strengthening of downstream circuits. Overall, our study suggests that, in the presence of mutant HTT protein, Atg8a induces autophagy and improves the functioning of circadian and sleep circuits.SIGNIFICANCE STATEMENT Defects in sleep and circadian rhythms are well documented in Huntington's disease. Recent literature suggests that circadian and sleep disturbances can exacerbate neurodegenerative phenotypes. Hence, identifying potential modifiers that can improve the functioning of these circuits could greatly improve disease management. We used a genetic approach to enhance cellular proteostasis and found that overexpression of a crucial autophagy gene, Atg8a, induces the autophagy pathway in the Drosophila circadian and sleep neurons and rescues sleep and activity rhythm. We demonstrate that the Atg8a improves synaptic function of these circuits by possibly enhancing the aggregation of the mutant protein in neurons. Further, our results suggest that differences in basal levels of protein homeostatic pathways is a factor that determines selective susceptibility of neurons.

Laparoscopic liver metastasectomy, retroperitoneal lymph node dissection and abdominoperineal resection for rectal cancer.

Video demonstrating the technical details of minimally invasive, simultaneous liver resection, retroperitoneal lymph node dissection, and abdominoperineal resection for synchronous metastasis.

Age Estimation Using the Tooth Coronal Index on Mandibular First Premolars on Digital Panoramic Radiographs in an Indian Population.

Objectives: Age estimation is a crucial aspect of forensic odontology, and the Tooth Coronal Index (TCI) has been widely used for forensic purposes in determining age. The aim of this research was to evaluate the effectiveness of TCI in age estimation. Materials and Methods: A retrospective study was conducted, and TCI was calculated for the mandibular first premolar in 700 digital panoramic radiographs. Age was divided into five groups: 20-30 years, 31-40 years, 41-50 years, 51-60 years, and >61 years. Bivariate correlation was used to establish the relationship between TCI and age. Linear regression was calculated for the different age groups and genders. Inter-observer reliability and agreement were assessed using one-way ANOVA. P-values less than 0.05 were considered statistically significant. Results: Comparison of the mean difference from actual age showed underestimation in males aged 20-30 years and overestimation in males over 60 years of age. The least difference between actual and calculated age was found in females aged 31-40 years. Inter-age comparison using ANOVA for females demonstrated a statistically highly significant difference from actual age in all age groups (P<0.01), with the highest mean in females aged 51-60 years and the lowest in females aged 31-40 years. Inter-group comparison of mean TCI revealed statistically non-significant differences in males and statistically highly significant differences in females (P<0.01). Conclusion: Age estimation using TCI on mandibular first premolars can be recommended as an easy, non-invasive, and less time-consuming method. This study suggests that regression formulas were more accurate for males aged 31-40 years.