The TRESLIN-MTBP complex couples completion of DNA replication with S/G2 transition.

It has been proposed that ATR kinase senses the completion of DNA replication to initiate the S/G2 transition. In contrast to this model, we show here that the TRESLIN-MTBP complex prevents a premature entry into G2 from early S-phase independently of ATR/CHK1 kinases. TRESLIN-MTBP acts transiently at pre-replication complexes (preRCs) to initiate origin firing and is released after the subsequent recruitment of CDC45. This dynamic behavior of TRESLIN-MTBP implements a monitoring system that checks the activation of replication forks and senses the rate of origin firing to prevent the entry into G2. This system detects the decline in the number of origins of replication that naturally occurs in very late S, which is the signature that cells use to determine the completion of DNA replication and permit the S/G2 transition. Our work introduces TRESLIN-MTBP as a key player in cell-cycle control independent of canonical checkpoints.

ULK/Atg1: phasing in and out of autophagy.

Autophagy - a highly regulated intracellular degradation process - is pivotal in maintaining cellular homeostasis. Liquid-liquid phase separation (LLPS) is a fundamental mechanism regulating the formation and function of membrane-less compartments. Recent research has unveiled connections between LLPS and autophagy, suggesting that phase separation events may orchestrate the spatiotemporal organization of autophagic machinery and cargo sequestration. The Unc-51-like kinase (ULK)/autophagy-related 1 (Atg1) family of proteins is best known for its regulatory role in initiating autophagy, but there is growing evidence that the functional spectrum of ULK/Atg1 extends beyond autophagy regulation. In this review, we explore the spatial and temporal regulation of the ULK/Atg1 family of kinases, focusing on their recruitment to LLPS-driven compartments, and highlighting their multifaceted functions beyond their traditional role.

Targeting the NTF2-like domain of G3BP1: Novel modulators of intracellular granule dynamics.

Stress granule (SG) is a temporary cellular structure that plays a crucial role in the regulation of mRNA and protein sequestration during various cellular stress conditions. SG enables cells to cope with stress more effectively, conserving vital energy and resources. Focusing on the NTF2-like domain of G3BP1, a key protein in SG dynamics, we explore to identify and characterize novel small molecules involved in SG modulation without external stressors. Through in silico molecular docking approach to simulate the interaction between various compounds and the NTF2-like domain of G3BP1, we identified three compounds as potential candidates that could bind to the NTF2-like domain of G3BP1. Subsequent immunofluorescence experiments demonstrated that these compounds induce the formation of SG-like, G3BP1-positive granules. Importantly, the granule formation by these compounds occurs independent from the phosphorylation of eIF2α, a common mechanism in SG formation, suggesting that it might offer a new strategy for influencing SG dynamics implicated in various diseases.

In silico analysis of fungal prion-like proteins for elucidating their role in plant-fungi interactions.

Prion-like proteins (PrLPs) have emerged as beneficial molecules with implications in adaptive responses. These proteins possess a conserved prion-like domain (PrLD) which is an intrinsically disordered region capable of adopting different conformations upon perceiving external stimuli. Owing to changes in protein conformation, functional characteristics of proteins harboring PrLDs get altered thereby, providing a unique mode of protein-based regulation. Since PrLPs are ubiquitous in nature and involved in diverse functions, through this study, we aim to explore the role of such domains in yet another important physiological process viz. plant-microbe interactions to get insights into the mechanisms dictating cross-kingdom interactions. We have evaluated the presence and functions of PrLPs in 18 different plant-associated fungi of agricultural importance to unravel their role in plant-microbe interactions. Of the 241,997 proteins scanned, 3,820 (~ 1.6%) were identified as putative PrLPs with pathogenic fungi showing significantly higher PrLP density than their beneficial counterparts. Further, through GO enrichment analysis, we could predict several PrLPs from pathogenic fungi to be involved in virulence and formation of stress granules. Notably, PrLPs involved in (retro)transposition were observed exclusively in pathogenic fungi. We even analyzed publicly available data for the expression alterations of fungal PrLPs upon their interaction with their respective hosts which revealed perturbation in the levels of some PrLP-encoding genes during interactions with plants. Overall, our work sheds light into the probable role of prion-like candidates in plant-fungi interaction, particularly in context of pathogenesis, paving way for more focused studies for validating their role.

Phase II study of enlonstobart (SG001), a novel PD-1 inhibitor in patients with PD-L1 positive recurrent/metastatic cervical cancer.

BACKGROUND: Platinum-based chemotherapy with or without bevacizumab is the first-line treatment for patients with recurrent or metastatic cervical cancer (r/mCC), and the treatment options are limited for r/mCC after first-line treatment. Enlonstobart (SG001) is a fully humanized and high-affinity anti-PD-1 immunoglobulin G4 monoclonal antibody. Previous phase Ib study demonstrated that SG001 had a promising efficacy in patients with PD-L1 positive r/mCC. METHODS: In this multicenter, single-arm, open-label, phase II study, eligible patients were ≥ 18 years with PD-L1-positive cervical cancer who had progression on or intolerance to the first-line platinum-based chemotherapy. Patients received SG001 240 mg every two weeks for 24 months or until disease progression, intolerable toxicities, or other study discontinuation criteria were met. The primary endpoint was confirmed objective response rate (ORR) assessed by RECIST version 1.1 by independent review committee. RESULTS: 107 patients were enrolled with median age of 53 years (range 26-72). 64.5 % of patients had a ECOG of 1. After a median follow-up of 14.0 months (range 0.4-21.9), confirmed ORR was 29.0 %, with two complete responses and twenty-nine partial responses. The disease control rate was 54.2 %. Median duration of response was 16.6 months (95 % CI 10.8-NA), median progression free survival was 3.1 months (95 % CI 2.2-6.9). Median overall survival was not reached. 104 patients (97.2 %) experienced at least one treatment emergent adverse events TEAEs, of which 38 patients (35.5 %) had grade 3 or higher TEAEs. The most common treatment-related adverse events were leukopenia (19.6 %), increased aspartate aminotransferase (18.7 %), anemia (17.8 %), increased alanine aminotransferase (15.9 %), hypothyroidism (15.0 %), neutropenia (15.0 %), and hyperthyroidism (11.2 %). CONCLUSION: SG001 monotherapy demonstrated durable anti-tumor activity with acceptable safety in patients with PD-L1 positive r/mCC with progression on or intolerance to the first-line platinum-based chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04886700).

Third time's a charm: band to sleeve to bypass.

BACKGROUND: Adjustable gastric bands (AGB) are frequently converted to sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) due to weight recurrence or band complications. Such conversions carry a higher-risk than primary procedures. Some patients undergo two conversions-from AGB to SG, and subsequently from SG to RYGB. This presents a unique situation with limited literature on indications and complication rates associated with these double conversions. METHODS: We examined the 2020-2021 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) Participant Use File to evaluate conversions from AGB to SG and then to RYGB. Patient and operative characteristics, along with outcomes, were evaluated. Descriptive statistics were applied. RESULTS: We identified 276 patients who underwent a conversion from AGB to SG and then to RYGB. The primary reason for the second conversion (SG to RYGB) was gastroesophageal reflux disease (GERD) at 55.1%, followed by inadequate weight loss or weight regain (IWL/WR) at 36.9%. The remaining reasons included dysphagia, nausea, vomiting, or others. Patients converted for IWL/WR demonstrated a higher baseline body mass index and prevalence of sleep apnea compared to other cohorts (both p < 0.001). Meanwhile, patients in the "other reasons" group had the highest rate of open surgical approaches (9.1%) and concurrent lysis of adhesions (p = 0.001 and p = 0.022), with correspondingly higher rates of anastomotic leak, reoperations, serious complications, and mortality. CONCLUSIONS: Patients undergoing double conversions (AGB to SG to RYGB) do so primarily for GERD or IWL/WR. Further research is required to better define the optimal primary operation for each patient, aiming to reduce the necessity for multiple conversions.

The association between microvascular and macrovascular diseases and diabetes remission after bariatric surgery.

BACKGROUND: Type-2 diabetes mellitus (T2DM) results in detrimental vascular complications including both microvascular and macrovascular diseases. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective weight-loss therapies that enhance T2DM remission. However, limited data are present regarding the association between diabetes-associated diseases before RYGB and SG with T2DM remission. METHODS: This is a retrospective cohort study in patients with T2DM who underwent RYGB or SG. We collected data on preoperative microvascular (i.e., retinopathy, nephropathy, and neuropathy) and macrovascular (coronary artery disease, cerebrovascular accidents, and peripheral artery disease) diabetes-associated diseases. Our end points included assessment of association and cumulative effect of diabetes-associated diseases and disease remission. We also performed a multivariate logistic regression to evaluate the parameters associated with T2DM remission. RESULTS: A total of 536 patients (67% female, 94% White) were included in this study. Patients without diabetes-associated diseases had an OR of 2.72 (95% CI 1.92 to 3.88) to achieve T2DM remission compared to patients with diabetes-associated diseases (27.9% vs 59.4%; p < 0.001). Importantly, there was an additive effect of the number of diabetes-associated diseases on the T2DM remission (p < 0.001). We demonstrate a significant association between HbA1c (p < 0.001), number of diabetes medications (p < 0.001), T2DM duration (p < 0.001), surgery type (p = 0.009), and insulin use (p = 0.04) with T2DM remission. CONCLUSION: Patients with presurgical diabetes-associated diseases had a lower remission rate after RYGB and SG. Not only do these complications represent a more practical and consistent variable to predict T2DM remission, but also help planning a multidisciplinary management of patients with more severe T2DM.

Feasibility of same-day discharge after laparoscopic sleeve gastrectomy in the Netherlands.

BACKGROUND: There is a trend towards laparoscopic sleeve gastrectomy (SG) with same-day discharge (SDD), as an efficient healthcare pathway to alleviate the burden on clinical capacity. This approach seems to be safe, if patients are carefully selected. In our bariatric center, a protocol for Roux-en-Y gastric bypass with SDD has already been successfully implemented. The aim of this study was to evaluate feasibility of applying the same SDD protocol for SG. METHODS: A single-center prospective feasibility study was conducted at a high-volume bariatric center. Low-risk patients who were scheduled for primary SG were included. Strict criteria were used for approval upon SDD. The primary outcome was the rate of successful SDD without readmission within 48 h. Secondary outcomes included short-term complications, emergency department visits, readmissions, and mortality. RESULTS: Fifty patients were included in the study, of whom 45 were successfully discharged on the same day of the surgery. Nausea and vomiting were the most common reasons for overnight hospitalization (three patients). One patient was readmitted within the first 48 h due to a mild complication related to bleeding, resulting in a success rate of 88% for SDD without readmission within 48 h. No severe complications or mortality were reported in the cohort. CONCLUSION: Our SDD protocol for SG has demonstrated feasibility, with a high success rate of SDD and no severe complications. Strict conditions should be met for the safe implementation of a SDD protocol, including careful patient selection and the establishment of a safety net to detect early complications.

Short-term impact of bariatric surgery on the dietary intake of patients with type 2 diabetes.

BACKGROUND: The prevalence of overweight and obesity and an unhealthy diet and lifestyle are the key causes of rising diabetes burden in India. Bariatric surgery is gaining popularity in India as a favored approach to manage obesity and its accompanying comorbidities. Despite this, there is a scarcity of Indian studies evaluating dietary intake. Our goal was to analyse the dietary intake of Indian patients with type 2 diabetes mellitus (T2DM) who have undergone laparoscopic sleeve gastrectomy (LSG) or duodeno-jejunal bypass with sleeve gastrectomy (DJB-SG) or surgeries. METHODS: The longitudinal observational study included 64 T2DM patients (32 in each procedure) enrolled through purposive sampling. The patients underwent surgery (LSG or DJB-SG procedure) between January 2017 and July 2019. Dietary data was collected at baseline and postsurgery (12 months) using a 24-h dietary recall method for 2 days (one working and one holiday). RESULTS: The total sample consisted of 27 (42.2%) females and 37 (57.8%) males. The mean age was 46.8 years. At 12 months, the follow-up for the LSG and DJB-SG procedures was 100% and 78%, respectively. In the short term, a significant reduction was seen in weight, body mass index and haemoglobin A1C (HbA1C) in both surgical groups. The two procedures were comparable with respect to weight loss but improvement in glycaemia was higher in the DJB-SG group. The dietary intake (food groups and nutrients) was similar in the two surgical groups at baseline and 12 months postsurgery. Dietary intake assessment showed significant reduction in calorie dense foods (cereals, roots and tubers, fats and oils, table sugar, and biscuits) in both surgical groups. Among nutrients, intake of energy, fats, carbohydrates, dietary fibre, thiamine, riboflavin, niacin, folate and iron were reduced significantly in both procedures. Vitamin D (84.4% patients in LSG group and 81.3% patients in DJB-SG) and iron (62.5% patients in LSG group and 68.8% patients in DJB-SG) were commonly prevalent nutritional deficiencies at baseline and were significantly reduced at 12 months. CONCLUSIONS: In the short term, bariatric surgery resulted in weight loss and improvement in glycaemia. Bariatric surgery does significantly affect dietary intake leading to nutritional deficiencies. Therefore, patients should be recommended vitamin and mineral supplements and regular patient education and counselling by a trained bariatric dietitian to prevent nutritional deficiencies and maintain nutritional status.

A Quantitative Evaluation of the Influence of Chemical Variables of Biomasses of Poplar SRC Commercial Clones in Torrefaction.

This study aimed to evaluate the influence in torrefaction of the chemical structure of biomasses from nine poplar commercial SRC clones, evaluated through analytical pyrolysis. The chemical data were integrated into a dataset including LHV gain, representative of torrefaction aptitude and six chemical variables obtained through analytical pyrolysis, which were: (i) CH2Cl2 extractives; (ii) total extractives; (iii) Py-lignin; (iv) holocellulose; (v) (syringil/guaiacyl) ratio; and (vi) (pentosan/hexosan) ratio. Significant univariate and bivariate linear relations were obtained with LHV gain from torrefaction as dependent variable vs. Py-lignin, CH2Cl2 extractives and (cP/cH) ratio. Representative results were: (i) a negative correlation of -0.82 and -0.76 between LHV gain and the (pentosan/hexosan) ratio and Py-lignin, respectively, and (ii) a positive correlation of 0.79 between LHV gain and CH2Cl2 extractive amounts. Factorial and discriminant analysis allowed for clustering the tested clones in three groups, evidencing relevant influences of (S/G) ratio, Py-lignin, and, to a lesser extent, (cP/cH) ratio in the classification of these groups, clearly showing the impact of chemical variables of feedstock in torrefaction. The results contribute: (i) to the validation of use of the expedite analytical pyrolysis technique for classification of biomasses in accordance with their torrefaction aptitude and, thereby, (ii) to optimizing strategies in technological issues as diverse as poplar clone genetic breeding and modeling biomass torrefaction and pyrolysis.

Comparative evaluation of volumetric changes between two pediatric rotary files (Kedo-S plus, Kedo-SG blue) and manual files (hand K-files) during canal preparation of primary mandibular molars: an in-vitro nano-CT analysis.

Pediatric endodontics has become popular due to advancements in cleaning, shaping and irrigation systems, resulting in faster and effective removal of infected pulp, saving time, and creating a pathogen-free environment. The patented rotary file system, Kedo-S, designed for primary teeth, introduced a single file generation for efficient pulp therapy. However, there are currently no studies assessing canal preparation in primary mandibular molars using nano-CT (computed Tomography). To evaluate the volumetric changes of two recently introduced pediatric rotary file systems in comparison with conventional hand file systems in primary mandibular molar using an ultra-high resolution nano-CT. This in-vitro study was performed in extracted primary mandibular molar based on certain inclusion and exclusion criteria. Samples were prepared and working length was determined before the pre-operative scan using a high resolution nano-CT device (SkyScan 2214, Bruker, Kontich, Belgium). A single well-experienced pediatric dentist prepared the canals using three file systems: Kedo-S plus, Kedo-SG blue and Hand K-files. A post-operative scan was performed similar to pre-operative scan. Image reconstruction was performed with NRecon software for 3D volumetric visualization and analysis of the root canals. Kedo-SG blue file systems had the highest mean difference in the canal volume (8.85%). Hand K-files had the least difference at (1.24%) of canal volume. Kedo-S plus file system had a mean canal volume difference (6.14%) which is closer to hand K-files. Rotary file systems resulted in a significant enlargement of canals compared to hand files.

The R2R3-MYB-SG7 transcription factor CaMYB39 orchestrates surface phenylpropanoid metabolism and pathogen resistance in chickpea.

Flavonoids are important plant pigments and defense compounds; understanding the transcriptional regulation of flavonoid biosynthesis may enable engineering crops with improved nutrition and stress tolerance. Here, we characterize R2R3-MYB domain subgroup 7 transcription factor CaMYB39, which regulates flavonol biosynthesis primarily in chickpea trichomes. CaMYB39 overexpression in chickpea was accompanied by a change in flux availability for the phenylpropanoid pathway, particularly flavonol biosynthesis. Lines overexpressing CaMYB39 showed higher isoflavonoid levels, suggesting its role in regulating isoflavonoid pathway. CaMYB39 transactivates the transcription of early flavonoid biosynthetic genes (EBG). FLAVONOL SYNTHASE2, an EBG, encodes an enzyme with higher substrate specificity for dihydrokaempferol than other dihydroflavonols explaining the preferential accumulation of kaempferol derivatives as prominent flavonols in chickpea. Interestingly, CaMYB39 overexpression increased trichome density and enhanced the accumulation of diverse flavonol derivatives in trichome-rich tissues. Moreover, CaMYB39 overexpression reduced reactive oxygen species levels and induced defense gene expression which aids in partially blocking the penetration efficiency of the fungal pathogen, Ascochyta rabiei, resulting in lesser symptoms, thus establishing its role against deadly Ascochyta blight (AB) disease. Overall, our study reports an instance where R2R3-MYB-SG7 member, CaMYB39, besides regulating flavonol biosynthesis, modulates diverse pathways like general phenylpropanoid, isoflavonoid, trichome density, and defense against necrotrophic fungal infection in chickpea.

In the Rat Midbrain, SG2NA and DJ-1 have Common Interactome, Including Mitochondrial Electron Transporters that are Comodulated Under Oxidative Stress.

Scaffold proteins Striatin and SG2NA assemble kinases and phosphatases into the signalling complexes called STRIPAK. Dysfunctional STRIPAKs cause cancer, cerebral cavernous malformations, etc. DJ-1, a sensor for oxidative stress, has long been associated with the Parkinson's disease, cancer, and immune disorders. SG2NA interacts with DJ-1 and Akt providing neuroprotection under oxidative stress. To dissect the role of SG2NA and DJ-1 in neuronal pathobiology, rat midbrain extracts were immunoprecipitated with SG2NA and sixty-three interacting proteins were identified. BN-PAGE followed by the LC-MS/MS showed 1030 comigrating proteins as the potential constituents of the multimeric complexes formed by SG2NA. Forty-three proteins were common between those identified by co-immunoprecipitation and the BN-PAGE. Co-immunoprecipitation with DJ-1 identified 179 interacting partners, of which forty-one also interact with SG2NA. Among those forty-one proteins immunoprecipitated with both SG2NA and DJ-1, thirty-nine comigrated with SG2NA in the BN-PAGE, and thus are bonafide constituents of the supramolecular assemblies comprising both DJ-1 and SG2NA. Among those thirty-nine proteins, seven are involved in mitochondrial oxidative phosphorylation. In rotenone-treated rats having Parkinson's like symptoms, the levels of both SG2NA and DJ-1 increased in the mitochondria; and the association of SG2NA with the electron transport complexes enhanced. In the hemi-Parkinson's model, where the rats were injected with 6-OHDA into the midbrain, the occupancy of SG2NA and DJ-1 in the mitochondrial complexes also increased. Our study thus reveals a new family of potential STRIPAK assemblies involving both SG2NA and DJ-1, with key roles in protecting midbrain from the oxidative stress.

CP-25 inhibits the hyperactivation of rheumatic synoviocytes by suppressing the switch in Gαs-Gαi coupling to the ß2-adrenergic receptor.

In essence, the ß2 adrenergic receptor (ß2AR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration through Gαs coupling, but interestingly, ß2AR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the ß2AR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired ß2AR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of Gαs and Gαi, and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in Gαs-Gαi coupling to ß2AR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This Gαi coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not ß-arrestin2 or protein kinase A-mediated phosphorylation of ß2AR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6'-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in Gαs-Gαi coupling to ß2AR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in ß2AR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. Video Abstract.

The role of diabetes severity scores in predicting disease remission in patients with BMI > 50 kg/m2 undergoing Roux-En-Y gastric bypass and sleeve gastrectomy: a multi-centered study.

BACKGROUND: Roux-En-Y gastric bypass (RYGB) and Sleeve Gastrectomy (SG) have shown to be two of the most effective interventions to enhance weight loss and associated type-2 diabetes mellitus (T2DM) remission. However, a significant number of patients, particularly with BMI ≥ 50 kg/m2, do not achieve T2DM remission after bariatric surgeries. The individualized metabolic surgery (IMS) and Robert et al. scores are two scores that characterize T2DM severity and predict disease remission after bariatric surgeries. We aim to assess the validity of these scores in predicting T2DM remission in our cohort of patients with BMI ≥ 50 kg/m2 with long-term follow-up. METHODS: This is a retrospective cohort study of all patients with T2DM, have a BMI ≥ 50 kg/m2, and underwent RYGB or SG in two different US bariatric surgery centers of excellence. The study endpoints included validating the IMS and Robert et al. scores in our cohort and evaluating the presence of any significant differences between RYGB and SG in terms of T2DM remission predicted by each of these scores. Data are presented as mean (standard deviation). RESULTS: A total of 160 patients (66.3% females, mean age 51.0 [11.8] years) had IMS score and 238 patients (66.4% females, age 50.8 [11.4] years) had Robert et al. score data. Both scores predicted T2DM remission in our patients with BMI ≥ 50 kg/m2 with ROC AUC 0.79 for the IMS score and 0.83 for Robert et al. score. Patients with lower IMS scores and higher Robert et al. scores had higher T2DM remission rates. RYGB and SG had similar T2DM remission rates over the long-term follow-up. CONCLUSION: We demonstrate the ability of the IMS and Robert et al. scores to predict T2DM remission in patients with BMI ≥ 50 kg/m2. T2DM remission was shown to decrease with more severe IMS scores and lower Robert et al. scores.

Sleeve gastrectomy morphology and long-term weight-loss and gastroesophageal reflux disease outcomes.

BACKGROUND: The relationship between sleeve gastrectomy (SG) morphology and long-term weight-loss and gastroesophageal reflux disease (GERD) outcomes is unknown. METHODS: All patients (n = 268) undergoing SG performed by 3 surgeons at a single academic institution from January 1, 2010 to December 31, 2012 were included. Long-term weight-loss and GERD outcomes were available for 90 patients which were incorporated in analyses. SG morphology was determined from postoperative day 1 upper gastrointestinal series (UGIS) available from 50 patients. Images were independently categorized using previously published methodology as Dumbbell (38%), Lower Pouch (22%), Tubular (26%), or Upper Pouch (14%) by Radiologist and Surgeon. Radiologist categorization was used when disagreement occurred (8%). Univariable analyses were conducted to explore potential associations between SG morphology, weight loss, and GERD outcomes. RESULTS: Follow-up was 8.2 ± 0.9 years. Population characteristics included age of 45.1 ± 10.8 years, female sex in 83.3%, and hiatal hernia repair (HHR) performed at index SG in 17.8%. Surgeons did not preferentially achieve a specific SG morphology. Changes from preoperative obesity and associated diseases comprised body mass index (BMI) (49.5 ± 7.6 vs. 39.2 ± 9.4 kg/m2; p < 0.0001), diabetes mellitus (30.0 vs. 12.2%; p = 0.0006), hypertension (70.0 vs. 54.4%; p = 0.0028), hyperlipidemia (42.2 vs. 24.2%;p = 0.0017), obstructive sleep apnea (41.1 vs. 15.6%; p < 0.0001), osteoarthritis (48.9 vs. 13.3%; p < 0.0001), back pain (46.5 vs. 28.9%; p = 0.0035), and medications (4.8 ± 3.3 vs. 3.7 ± 3.5; p < 0.0001). Dumbbell SG morphology was associated with lesser reduction in BMI at follow-up (--6.8 ± 7.2 vs. -12.4 ± 8.3 kg/m2; p = 0.0196) while greater BMI change was appreciated with Lower Pouch SG shape (-16.9 ± 9.9 vs. -8.4 ± 6.8 kg/m2; p = 0.0017). GERD was more prevalent at follow-up than baseline (67.8 vs. 47.8%; p < 0.0001). GERD-specific outcomes included de novo (51.1%), persistent (27.9%), worsened (58.1%), and resolved (14.0%) disease. Ten patients underwent reoperation for refractory GERD with SG morphology corresponding to Dumbbell (n = 5) and Upper Pouch (n = 1) for those with available UGIS. Univariable analyses showed that patients with GERD experienced a larger reduction in BMI compared with patients without GERD (-11.8 ± 7.7 vs. -7.0 ± 5.1 kg/m2; p = 0.0007). Patient age, surgeon, morphology category, and whether a HHR was done at index SG were not associated with the presence of any, de novo, or worsened GERD. Female sex was associated with worsened GERD (96.0 vs. 4.0%; p = 0.0455). Type of calibration device, distance from staple line to pylorus, and whether staple line reinforcement was used were not associated with SG morphology classification. CONCLUSION: This is the first study assessing the impact of SG morphology on long-term weight loss and GERD. Our data suggest an association between SG morphology and long-term weight loss but not with GERD outcomes. Current technical standards may be limited in reproducing the same SG morphology. This information may help guide the technical optimization and standardization of SG. Surgeons did not favor a specific SG morphology (1). Our results signal to a relationship between radiographic assessment of SG morphology and long-term weight-loss outcomes with Dumbbell classification correlated with lesser reduction in BMI (2a) and Lower Pouch morphology associated with superior weight loss (2b). SG, sleeve gastrectomy; BMI, body mass index.

Laser Linewidth Analysis and Filtering/Fitting Algorithms for Improved TDLAS-Based Optical Gas Sensor.

Tunable Diode Laser Absorption Spectroscopy (TDLAS) has been widely applied in in situ and real-time monitoring of trace gas concentrations. In this paper, an advanced TDLAS-based optical gas sensing system with laser linewidth analysis and filtering/fitting algorithms is proposed and experimentally demonstrated. The linewidth of the laser pulse spectrum is innovatively considered and analyzed in the harmonic detection of the TDLAS model. The adaptive Variational Mode Decomposition-Savitzky Golay (VMD-SG) filtering algorithm is developed to process the raw data and could significantly eliminate the background noise variance by about 31% and signal jitters by about 12.5%. Furthermore, the Radial Basis Function (RBF) neural network is also incorporated and applied to improve the fitting accuracy of the gas sensor. Compared with traditional linear fitting or least squares method (LSM), the RBF neural network brings along the enhanced fitting accuracy within a large dynamic range, achieving an absolute error of below 50 ppmv (about 0.6%) for the maximum 8000 ppmv methane. The proposed technique in this paper is universal and compatible with TDLAS-based gas sensors without hardware modification, allowing direct improvement and optimization for current optical gas sensors.

Natural Intelligence as the Brain of Intelligent Systems.

This article discusses the concept and applications of cognitive dynamic systems (CDS), which are a type of intelligent system inspired by the brain. There are two branches of CDS, one for linear and Gaussian environments (LGEs), such as cognitive radio and cognitive radar, and another one for non-Gaussian and nonlinear environments (NGNLEs), such as cyber processing in smart systems. Both branches use the same principle, called the perception action cycle (PAC), to make decisions. The focus of this review is on the applications of CDS, including cognitive radios, cognitive radar, cognitive control, cyber security, self-driving cars, and smart grids for LGEs. For NGNLEs, the article reviews the use of CDS in smart e-healthcare applications and software-defined optical communication systems (SDOCS), such as smart fiber optic links. The results of implementing CDS in these systems are very promising, with improved accuracy, performance, and lower computational costs. For example, CDS implementation in cognitive radars achieved a range estimation error that is as good as 0.47 (m) and a velocity estimation error of 3.30 (m/s), outperforming traditional active radars. Similarly, CDS implementation in smart fiber optic links improved the quality factor by 7 dB and the maximum achievable data rate by 43% compared to those of other mitigation techniques.

Sleeve Gastrectomy Improves Hepatic Glucose Metabolism by Downregulating FBXO2 and Activating the PI3K-AKT Pathway.

Type 2 diabetes mellitus (T2DM), a chronic metabolic disease, is a public health concern that seriously endangers human health. Sleeve gastrectomy (SG) can relieve T2DM by improving glucose homeostasis and enhancing insulin sensitivity. However, its specific underlying mechanism remains elusive. SG and sham surgery were performed on mice fed a high-fat diet (HFD) for 16 weeks. Lipid metabolism was evaluated via histology and serum lipid analysis. Glucose metabolism was evaluated using the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Compared with the sham group, the SG group displayed a reduction in liver lipid accumulation and glucose intolerance, and western blot analysis revealed that the AMPK and PI3K-AKT pathways were activated. Furthermore, transcription and translation levels of FBXO2 were reduced after SG. After liver-specific overexpression of FBXO2, the improvement in glucose metabolism observed following SG was blunted; however, the remission of fatty liver was not influenced by the over expression of FBXO2. Our study explores the mechanism of SG in relieving T2DM, indicating that FBXO2 is a noninvasive therapeutic target that warrants further investigation.

ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity.

Formation of cytoplasmic RNA-protein structures called stress granules (SGs) is a highly conserved cellular response to stress. Abnormal metabolism of SGs may contribute to the pathogenesis of (neuro)degenerative diseases such as amyotrophic lateral sclerosis (ALS). Many SG proteins are affected by mutations causative of these conditions, including fused in sarcoma (FUS). Mutant FUS variants have high affinity to SGs and also spontaneously form de novo cytoplasmic RNA granules. Mutant FUS-containing assemblies (mFAs), often called "pathological SGs", are proposed to play a role in ALS-FUS pathogenesis. However, structural differences between mFAs and physiological SGs remain largely unknown therefore it is unclear whether mFAs can functionally substitute for SGs and how they affect cellular stress responses. Here we used affinity purification to isolate mFAs and physiological SGs and compare their protein composition. We found that proteins within mFAs form significantly more physical interactions than those in SGs however mFAs fail to recruit many factors involved in signal transduction. Furthermore, we found that proteasome subunits and certain nucleocytoplasmic transport factors are depleted from mFAs, whereas translation elongation, mRNA surveillance and splicing factors as well as mitochondrial proteins are enriched in mFAs, as compared to SGs. Validation experiments for a mFA-specific protein, hnRNPA3, confirmed its RNA-dependent interaction with FUS and its sequestration into FUS inclusions in cultured cells and in a FUS transgenic mouse model. Silencing of the Drosophila hnRNPA3 ortholog was deleterious and potentiated human FUS toxicity in the retina of transgenic flies. In conclusion, we show that SG-like structures formed by mutant FUS are structurally distinct from SGs, prone to persistence, likely cannot functionally replace SGs, and affect a spectrum of cellular pathways in stressed cells. Results of our study support a pathogenic role for cytoplasmic FUS assemblies in ALS-FUS.