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Spinal muscular atrophy is an inherited neurodegenerative illness characterized by muscle wasting and loss of spinal cord motor neurons. It results from homozygous loss, translation, or mutation of the survival motor neuron 1 (SMN1) gene. Despite the lack of a cure, research has revealed potential processes explaining the disease’s molecular etiology. The SMN1 gene region’s distinctive genomic structure has been used to design treatment plans. Several stages of development have been recognized for a number of possible therapeutic agents. The standard of treatment for people having spinal muscular atrophy has evolved as a result of these and other healthcare technological advancements. In this review, we provide a comprehensive review of general introduction, types, symptoms, causes, diagnosis, and possible management of spinal muscular atrophy (SMA)..

Novel dual acting benzofuran-based chromenochalcones were synthesized and assessed for in vitro and in vivo antihyperglycemic and antidyslipidemic activities.

Background: Due to the prevalence of type-2 diabetes across the globe, there is unmet need to explore new molecular targets for the development of cost-effective and safer antihyperglycemic agents. Objective: Structural modification of phytol and evaluation of in vitro, in vivo and in silico antihyperglycemic activity of derivatives establishing the preliminary structure activity relationship (SAR). Methods: The semi-synthetic derivatives of phytol were prepared following previously described methods. The antihyperglycemic potential was measured in vitro in terms of increase in 2- deoxyglucose (2-DG) uptake by L-6 rat skeletal muscle cells as well as in vivo in sucrose-loaded (SLM) and streptozotocin (STZ)-induced diabetic rat models. The blood glucose profile was measured at 30, 60, 90, 120, 180, 240, 300 and 1440 min post administration of sucrose in rats. The in silico docking was performed on peroxisome proliferator-activated receptor gamma (PPARγ) as antidiabetic target along with absorption, distribution, metabolism, excretion and toxicity (ADMET) studies. Results: Nine semi-synthetic ester derivatives: acetyl (1), lauroyl (2), palmitoyl (3), pivaloyl (4), trans-crotonyl (5), benzoyl (6), m-anisoyl (7), 3,4,5-trimethoxy benzoyl (8) cinnamoyl (9) along with bromo derivative (10) of phytol were prepared. The derivatives 9, 8 and 2 caused 4.5, 3.2 and 2.7 times more in vitro uptake of 2-DG respectively than rosiglitazone (ROSI). The derivatives showed significant improvement in oral glucose tolerance both in SLM (29.6-21%) as well as STZ-induced diabetic (30.8-19.0%) rats. The in silico ADMET, docking studies showed non-toxicity and high binding affinity with PPARγ. Conclusion: The potent antihyperglycemic activity with favorable pharmacokinetics supports phytol derivatives as suitable antidiabetic lead.

Muthuperumal et al. (Soft Comput (2020) 24: 18689–18698) proposed two different approaches to find an initial fuzzy basic feasible solution of unbalanced triangular fuzzy transportation problems (unbalanced transportation problems in which each parameter is represented by a triangular fuzzy number). Since, Muthuperumal et al. have claimed that less computational efforts are required to apply their proposed approaches as compared to other existing approaches. Therefore, in future, other researchers may use Muthuperumal et al.’s approaches to find an initial fuzzy basic feasible solution of real-life unbalanced triangular fuzzy transportation problems. However, it is observed that in actual case, the initial fuzzy basic solution, obtained by Muthuperumal et al.’s approaches, is not a fuzzy feasible solution. Hence, it is not appropriate to use Muthuperumal et al.’s approaches. The aim of this note is to point out the inconsistencies that exist in Muthuperumal et al.’s approaches.

MicroRNAs (miRs) are small non-coding RNAs that regulate the target gene expression. A change in miR profile in the pancreatic islets during diabetes is known, and multiple studies have demonstrated that miRs influence the pancreatic β-cell function. The miR-204 is highly expressed in the β-cells and reported to regulate insulin synthesis. Here we investigated whether the absence of miR-204 rescues the impaired glycemic control and obesity in the genetically diabetic (db/db) mice. We found that the db/db mice overexpressed miR-204 in the islets. The db/db mice lacking miR-204 (db/db-204−/−) initially develops hyperglycemia and obesity like the control (db/db) mice but later displayed a gradual improvement in glycemic control despite remaining obese. The db/db-204−/− mice had a lower fasting blood glucose and higher serum insulin level compared to the db/db mice. A homeostatic model assessment (HOMA) suggests the improvement of β-cell function contributes to the improvement in glycemic control in db/db-204−/− mice. Next, we examined the cellular proliferation and endoplasmic reticulum (ER) stress and found an increased frequency of proliferating cells (PCNA + ve) and a decreased CHOP expression in the islets of db/db-204−/− mice. Next, we determined the effect of systemic miR-204 inhibition in improving glycemic control in the high-fat diet (HFD)-fed insulin-resistant mice. MiR-204 inhibition for 6 weeks improved the HFD-triggered impairment in glucose disposal. In conclusion, the absence of miR-204 improves β-cell proliferation, decreases islet ER stress, and improves glycemic control with limited change in body weight in obese mice.

The self-renewal ability is a unique property of fetal-derived innate-like B-1a lymphocytes, which survive and function without being replenished by bone marrow (BM) progenitors. However, the mechanism by which IgM-secreting mature B-1a lymphocytes self-renew is poorly understood. In this study, we showed that Bmi1 was critically involved in this process. Although Bmi1 is considered essential for lymphopoiesis, the number of mature conventional B cells was not altered when Bmi1 was deleted in the B cell lineage. In contrast, the number of peritoneal B-1a cells was significantly reduced. Peritoneal cell transfer assays revealed diminished self-renewal ability of Bmi1-deleted B-1a cells, which was restored by additional deletion of Ink4-Arf, the well-known target of Bmi1. Fetal liver cells with B cell–specific Bmi1 deletion failed to repopulate peritoneal B-1a cells, but not other B-2 lymphocytes after transplantation assays, suggesting that Bmi1 may be involved in the developmental process of B-1 progenitors to mature B-1a cells. Although Bmi1 deletion has also been shown to alter the microenvironment for hematopoietic stem cells, fat-associated lymphoid clusters, the reported niche for B-1a cells, were not impaired in Bmi1−/− mice. RNA expression profiling suggested lysine demethylase 5B (Kdm5b) as another possible target of Bmi1, which was elevated in Bmi1−/− B-1a cells in a stress setting and might repress B-1a cell proliferation. Our work has indicated that Bmi1 plays pivotal roles in self-renewal and maintenance of fetal-derived B-1a cells.

Mahmoodirad et al. (Soft Comput, 2018. https://doi.org/10.1007/s00500-018-3115-z ) proposed an approach for solving fully intuitionistic fuzzy transportation problems (FIFTPs) (transportation problems in which each parameter is represented as a triangular intuitionistic fuzzy number). In this approach, firstly, an unbalanced fully intuitionistic fuzzy transportation problem (FIFTP) is transformed into a balanced FIFTP, and then the intuitionistic fuzzy (IF) optimal solution of the transformed balanced FIFTP is obtained. In this paper, it is shown that Mahmoodirad et al.’s approach fails to transform an unbalanced FIFTP and hence, Mahmoodirad et al.’s approach fails to find the IF optimal solution of unbalanced FIFTPs. It is obvious that to overcome this limitation of Mahmoodirad et al.’s approach, there is need to propose a method to transform an unbalanced FIFTP into a balanced FIFTP. Therefore, in this paper, a new method (named as JMD method) is proposed to transform an unbalanced FIFTP into a balanced FIFTP.

Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse β-cells, LDs are prominent in human β-cells. However, the regulation of LD mobilization (lipolysis) in human β-cells remains unclear. We found that glucose increases lipolysis in nondiabetic human islets but not in islets in patients with type 2 diabetes (T2D), indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets with shRNA targeting ATGL (shATGL) increased triglycerides (TGs) and the number and size of LDs, indicating that ATGL is the principal lipase in human β-cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS), and insulin secretion to 3-isobutyl-1-methylxanthine and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose-responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL-deficient INS1 cells and human pseudoislets showed reduced SNARE protein syntaxin 1a (STX1A), a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL-deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human β-cells and supports insulin secretion by stabilizing STX1A. The dysregulated lipolysis may contribute to LD accumulation and β-cell dysfunction in T2D islets.

Study Question: What are the good practices for the use of ADD-ON Treatments in IVF cycles in INDIA? What is Already Known: Add on treatments in IVF are procedures and technologies which are offered to patients in hope of improving the success rates. A lot of add on treatments exist; most of them have limited evidence and data for the Indian patient population is miniscule. These interventions may have limited effects, so it is imperative that any new technology that is offered is evaluated properly and has enough evidence to suggest that it is safe and effective. Study Design, Size, Duration: This is the report of a 2-day consensus meeting where two moderators were assigned to a group of experts to collate information on Add on treatments in IVF in INDIA. This meeting utilised surveys, available scientific evidence and personal laboratory experience into various presentations by experts on pre-decided specific topics. Participants/Materials, Setting, Methods: Expert professionals from ISAR representing clinical and embryology fields. Main Results and the Role of Chance: The report is divided in various components including the health of the Offspring, the various ADD ons available to an ART center, consensus points for each technology & qualifications and trainings for embryologists, the report and recommendations of the expert panel reflect the discussion on each of the topics and try to lay down good practice points for labs to follow. Limitations, Reasons for Caution: The recommendations are solely based on expert opinion. Future availability of data may warrant an update of the same. Wider Implications of the Findings: These guidelines can help labs across the country to standardise their ART services and improve clinical outcomes, it will also motivate clinics to collect data and report the use of Add ons to the national registry. Study Funding/Competing Interest(S): The consensus meeting and writing of the paper was supported by funds from CooperSurgical India.

Rationale Calcitonin gene-related peptide (CGRP) and its family members adrenomedullin (ADM) and adrenomedullin 2 (ADM2; also known as intermedin) support vascular adaptions in rat pregnancy. Objective This study aimed to assess the relaxation response of uterine artery (UA) for CGRP, ADM, and ADM2 in nonpregnant and pregnant women and identify the involved mechanisms. Findings (1) Segments of UA from nonpregnant women that were precontracted with U46619 (1μM) in vitro are insensitive to the hypotensive effects of CGRP, ADM, and ADM2; (2) CGRP, ADM, and ADM2 (0.1-100nM) dose dependently relax UA segments from pregnant women with efficacy for CGRP > ADM = ADM2; (3) the relaxation responses to CGRP, ADM, and ADM2 are differentially affected by the inhibitors of nitric oxide (NO) synthase (L-NAME), adenylyl cyclase (SQ22536), apamin, and charybdotoxin; (4) UA smooth muscle cells (UASMC) express mRNA for calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP)1 and RAMP2 but not RAMP3; (5) receptor heterodimer comprising CRLR/RAMP1 and CRLR/RAMP2 but not CRLR/RAMP3 is present in UA; (6) soluble fms-like tyrosine kinase (sFLT-1) and TNF-α treatment decrease the expression of RAMP1 mRNA (P Conclusions Relaxation sensitivity of UA for CGRP, ADM, and ADM2 is increased during pregnancy via peptide-specific involvement of NO system and endothelium-derived hyperpolarizing factors; vascular disruptors such as sFLT-1 and TNFα adversely impact their receptor system in UASMC.

Summary Precursors of hematopoietic stem cells (pre-HSCs) have been identified as intermediate precursors during the maturation process from hemogenic endothelial cells to HSCs in the aorta-gonad-mesonephros (AGM) region of the mouse embryo at embryonic day 10.5. Although pre-HSCs acquire an efficient adult-repopulating ability after ex vivo co-culture, their native hematopoietic capacity remains unknown. Here, we employed direct transplantation assays of CD45−VE-cadherin(VC)+KIT+(V+K+) cells (containing pre-HSCs) into immunodeficient neonatal mice that permit engraftment of embryonic hematopoietic precursors. We found that freshly isolated V+K+ cells exhibited significantly greater B-1 lymphocyte-biased repopulating capacity than multilineage repopulating capacity. Additionally, B cell colony-forming assays demonstrated the predominant B-1 progenitor colony-forming ability of these cells; however, increased B-2 progenitor colony-forming ability emerged after co-culture with Akt-expressing AGM endothelial cells, conditions that support pre-HSC maturation into HSCs. Our studies revealed an unexpected B-1 lymphocyte bias of the V+K+ population and acquisition of B-2 potential during commitment to the HSC fate., Graphical Abstract, Highlights • Majority of E10.5 EPCR+VC+KIT+ cells are B-1- (not B-2)-biased repopulating cells • E10.5 CD45−VC+KIT+ cells contain the first B-1a repopulating cells • E10.5 CD45−VC+KIT+ cells acquire B-2 potential after ex vivo co-culture, Yoshimoto and colleagues demonstrate an unexpected inherent B-1-biased repopulation ability of E10.5 pre-HSCs in immunodeficient neonatal mice. The B-1-biased pre-HSCs acquire B-2 potential following ex vivo co-culture, reflecting the developmental process of hemogenic endothelial cells to HSCs through B-1-biased state in vivo. Notably, the E10.5 pre-HSCs are the first B-1a repopulating cells upon direct transplantation without co-culture.

In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II. Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B-binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery.

Summary It is generally considered that mouse embryonic stem cell (ESC) differentiation into blood cells in vitro recapitulates yolk sac (YS) hematopoiesis. As such, similar to YS-derived B-progenitors, we demonstrate here that ESC-derived B-progenitors differentiate into B-1 and marginal zone B cells, but not B-2 cells in immunodeficient mice after transplantation. ESC-derived B-1 cells were maintained in the recipients for more than 6 months, secreting natural IgM antibodies in vivo. Gene expression profiling displayed a close relationship between ESC- and YS-derived B-1 progenitors. Because there are no hematopoietic stem cells (HSCs) detectable in our ESC differentiation culture, successful long-term engraftment of ESC-derived functional B-1 cells supports the presence of HSC-independent B-1 cell development., Graphical Abstract, Highlights • ESC-derived B-progenitors mature into B-1 cells and MZ B cells in vivo • ESC-derived B-1 cells engrafted in vivo long-term and secrete natural antibodies • ESC-derived B-progenitors are molecularly similar to YS-derived B-progenitors • Long-term B-1 cell engraftment represents HSC-independent lymphopoiesis, Yoshimoto and colleagues demonstrate that mouse ESC-derived B-progenitors engraft in the immunodeficient mice long-term without gene manipulation as IgM-secreting B-1 and MZ B cells, but not conventional B-2 cells. These ESC-derived B-progenitors are molecularly similar to YS-derived B-progenitors. Since no HSCs are produced in their ESC differentiation system, this result supports the emerging paradigm-shifting concept of HSC-independent lymphopoiesis.

Perilipin 2 (PLIN2) is a lipid droplet (LD) protein in β cells that increases under nutritional stress. Downregulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was downregulated in mouse β cells, INS1 cells, and human islet cells. β Cell–specific deletion of PLIN2 in mice on a high-fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Downregulation of PLIN2 in INS1 cells blunted GSIS after 24-hour incubation with 0.2 mM palmitic acid. Downregulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Downregulation of PLIN2 decreased specific OXPHOS proteins in all 3 models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2-deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress, as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in β cells has an important role in preserving insulin secretion, β cell metabolism, and mitochondrial function under nutritional stress.

Perilipin 2 (PLIN2) is the lipid droplet (LD) protein in β cells that increases under nutritional stress. Down-regulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was down-regulated in mouse β cells, INS1 cells, and human islet cells. β cell specific deletion of PLIN2 in mice on a high fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Down-regulation of PLIN2 in INS1 cells blunted GSIS after 24 h incubation with 0.2 mM palmitic acids. Down-regulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Down-regulation of PLIN2 decreased specific OXPHOS proteins in all three models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2 deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in β cells have an important role in preserving insulin secretion, β cell metabolism and mitochondrial function under nutritional stress.

Calcitonin gene-related peptide (CALCB), adrenomedullin (ADM), and adrenomedullin2 (ADM2) are hypotensive peptides that belong to CALCB family of peptides. Goal of this study was to identify the effect of fms-like tyrosine kinase (sFLT-1) and angiotensin2 (Ang2) on the function of these peptides in OA smooth muscle cells (OASMC) and assess the sensitivity of OA for these peptides in preeclampsia (PE) and normotensive pregnancy. Methods: Peptide function was assessed by Cyclic adenosine monophosphate (cAMP) assays and wire myograph; mRNA expression by Polymerase chain reaction (PCR) and protein-protein interaction by proximity ligation assay and co-immunoprecipitation. Findings: All three peptides increased cAMP synthesis in the order of efficacy CALCB > ADM = ADM2 and vascular endothelial growth factor (VEGF) mRNA in OASMC (P < 0.05); sFLT-1 mediated decrease in cAMP synthesis (P < 0.05) is differentially rescued by all three CALCB family peptides in OASMC (P < 0.005); sFLT-1 decreased receptor activity-modifying protein (RAMP)1 and RAMP2 mRNA expression (P < 0.05); Ang2 decreased the expression of calcitonin-receptor-like receptor and RAMP1 mRNA and desensitized CALCB and ADM2 receptors in OASMC (P < 0.05); sFLT-1 increased RAMP1and Ang2 type 1 receptor (AT1R) interaction in OASMC which is inhibited in presence of all three peptides; and all three peptides relax OA in PE with enhanced ADM2 response (P < 0.05). Conclusion: sFLT-1 and Ang2 impair OASMC mediated functional responses of CALCB family peptides which can be inhibited by respective peptide treatment. The sensitivity of OA for CALCB, ADM, and ADM2-mediated relaxation is retained in PE.

The aim of this chapter is (i) To make the researchers aware about the inappropriateness of Ebrahimnejad and Verdegay’s approach [3]. (ii) To propose a new approach (named as MEHAR approach) for comparing triangular intuitionistic fuzzy numbers. (iii) To propose a new approach (named as Vaishnavi approach) for solving triangular intuitionistic fuzzy transportation problems of type-2.

The aim of this chapter is (i) To make the researchers aware about the observed limitations and the drawback of Ebrahimnejad and Verdegay’s approach [1]. (ii) To make the researchers aware about a drawback of the approach, used in Ebrahimnejad and Verdegay’s approach [1], for comparing trapezoidal intuitionistic fuzzy numbers. (iii) To propose a valid approach (named as DAUGHTER approach) for comparing trapezoidal intuitionistic fuzzy numbers. (iv) To propose a valid approach [named as JAI MATA DI (JMD)] approach for solving unbalanced fully trapezoidal intuitionistic fuzzy transportation problems. (v) To illustrate the proposed JMD approach with the help of numerical examples.

The aim of this chapter is (i) to make the researchers aware about the inappropriateness of Ebrahimnejad’s methods [1, 3].(ii) to propose a new method (named as Mehar method) for solving balanced fully triangular fuzzy transportation problems to overcome a limitation and to resolve a drawback of Ebrahimnejad’s methods [1, 3].

The aim of this chapter is (i)To make the researchers aware about the observed limitations and a drawback of Chakraborty et al.’s approach [1].(ii)To make the researchers aware about a drawback of the approach, used in Chakraborty et al.’s approach [1], for comparing generalized trapezoidal intuitionistic fuzzy numbers.(iii)To propose a valid approach (named as PRABHUS approach) for comparing generalized trapezoidal intuitionistic fuzzy numbers.(iv)To propose a valid approach (named as JMD (JAI MATA DI)) for solving unbalanced fully generalized trapezoidal intuitionistic fuzzy transportation problems.(v)To illustrate the proposed JMD approach with the help of a numerical example.

Weighted aggregation operator plays an important role in optimization problems. In the last few years, several weighted geometric aggregation operators and several weighted averaging aggregation operators have been proposed in the literature under various extensions of the fuzzy environment.The aim of this chapter is to make the researchers aware about some drawbacks of the existing weighted aggregation operators which have been defined under various extensions of the fuzzy environment. Also, to make the researchers aware about the appropriate existing weighted averaging aggregation operator under some extensions of the fuzzy environment.

Li and Chen (Cognit Comput. 2018; 10:496–505) proposed the concept of the D-intuitionistic hesitant fuzzy set as well as proposed a method for comparing two D-intuitionistic fuzzy sets. Li and Chen have proposed the concept of the D-intuitionistic hesitant fuzzy set by introducing the degree of belief of the decision maker regarding the opinion of an expert in the existing definition of an intuitionistic hesitant fuzzy set. In future, other researchers may use Li and Chen’s comparing method in their research work. However, after a deep study, it is observed that Li and Chen’s comparing method fails to differentiate two distinct D-intuitionistic fuzzy sets. It is inappropriate to use Li and Chen’s comparing method.

Liu and Luo (Pattern Anal Appl https://doi.org/10.1007/s10044-017-0635-6 ) proposed a single-valued neutrosophic hesitant fuzzy ordered weighted aggregation (SVNHFOWA) operator and used it for solving single-valued neutrosophic hesitant fuzzy multi-attribute decision making (MADM) problems. It is pertinent to mention that to show the validity of SVNHFOWA operator, Liu and Luo claimed that this operator satisfies the idempotency, commutativity and monotonicity properties. However, after a deep study, it is observed that the monotonicity property is not satisfying for the SVNHFOWA operator whereas, for the validity of an aggregation operator the monotonicity property should necessarily be satisfied. Therefore, the SVNHFOWA operator, proposed by Liu and Luo, is not valid. Since, in future, the other researchers may use this SVNHFOWA operator in their research work as well as for solving real-life single-valued neutrosophic hesitant fuzzy MADM problems. Therefore, the aim of this paper is to make the researchers aware about the fact that it is scientifically incorrect to use the SVNHFOWA operator.

Study Question: What are the good practices for the use of ADD-ON Treatments in IVF cycles in INDIA? What is Already Known: Add on treatments in IVF are procedures and technologies which are offered to patients in hope of improving the success rates. A lot of add on treatments exist; most of them have limited evidence and data for the Indian patient population is miniscule. These interventions may have limited effects, so it is imperative that any new technology that is offered is evaluated properly and has enough evidence to suggest that it is safe and effective. Study Design, Size, Duration: This is the report of a 2-day consensus meeting where two moderators were assigned to a group of experts to collate information on Add on treatments in IVF in INDIA. This meeting utilised surveys, available scientific evidence and personal laboratory experience into various presentations by experts on pre-decided specific topics. Participants/Materials, Setting, Methods: Expert professionals from ISAR representing clinical and embryology fields. Main Results and the Role of Chance: The report is divided in various components including the health of the Offspring, the various ADD ons available to an ART center, consensus points for each technology & qualifications and trainings for embryologists, the report and recommendations of the expert panel reflect the discussion on each of the topics and try to lay down good practice points for labs to follow. Limitations, Reasons for Caution: The recommendations are solely based on expert opinion. Future availability of data may warrant an update of the same. Wider Implications of the Findings: These guidelines can help labs across the country to standardise their ART services and improve clinical outcomes, it will also motivate clinics to collect data and report the use of Add ons to the national registry. Study Funding/Competing Interest(S): The consensus meeting and writing of the paper was supported by funds from CooperSurgical India.

The enhanced disposal of glucose by the peripheral tissue is an important mechanism to regulate hyperglycemia. Here, we investigated the effect of Arnebin-1 from Arnebia nobilis, on glucose disposal in skeletal muscle cells and explored its in vivo antihyperglycemic potential. In L6 myotubes, Arnebin-1 stimulated glucose uptake, mediated through the enhanced translocation of the glucose transporter-4 (GLUT4) to plasma membrane, without changing the amount of GLUT4 or GLUT1. These effects of Arnebin-1 were synergistic with that of insulin. The effect of Arnebin-1 on glucose uptake was abolished in presence of wortmannin, and Arnebin-1 significantly stimulated the phosphorylation of Akt and downstream marker GSK-3β. Moreover, treatment with Arnebin-1 lowered postprandial blood glucose levels in streptozotocin-induced diabetic rats, and improved glucose tolerance and suppressed the rises in the fasting blood glucose, serum insulin, triglycerides, and total cholesterol in db/db mice, associated with enhanced expression of the major marker of the PI-3-Kinase-mediated signaling cascade in skeletal muscle. These findings suggest that Arnebin-1 exert antihyperglycemic activity through stimulating glucose disposal in peripheral tissues via PI-3-Kinase-dependent pathway.

We report synthesis and in vivo antihyperglycemic evaluation of new 3-substituted phenyl-2-(4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)phenyl)thiazolidin-4-ones (8a–l). The title 4-thiazolidinones were synthesized by one-pot cyclocondensation of new 4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)benzaldehyde (5), anilines, and mercaptoacetic acid in PEG-400. The required aldehyde (5) was also synthesized, starting from 2-chloroquinoline-3-carbaldehyde via a successive multistep route. The newly synthesized products were thoroughly characterized based on their spectral data. Amongst them, compounds 8a–g, j exhibited notable in vivo antihyperglycemic activity. Compounds 8f, g showed percentage improvement in oral glucose tolerance of 18.9 and 20.7, respectively, compared with 28.3 for the reference metformin.

The purpose of this study was to develop Carvedilol nanostructured lipid carriers (CAR-NLCs) using stearic acid and oleic acid as lipid, and to estimate the potential as oral delivery system for poorly water soluble drug. The particle-size analysis revealed that all the developed formulations were within the nanometer range. The EE and loading were found to be between 69.45-88.56% and 9.58-12.56%, respectively. The CAR-NLCopt showed spherical morphology with smooth surface under transmission electron microscope (TEM). The crystallization of the drug in NLC was investigated by powder X-ray diffraction and differential scanning calorimetry (DSC) and revealed that the drug was in an amorphous state in the NLC matrix. The ex vivo gut permeation study showed many folds increment in the permeation of CAR-NLCs compared to Carvedilol suspension (CAR-S). The oral bioavailability study of CAR was carried out using Wistar rats and relative bioavailability of CAR-NLCopt was found to be 3.95 fold increased in comparison with CAR-S. In vivo antihypertensive study in Wistar rats showed significant reduction in mean systolic BP by CAR-NLCopt vis-à-vis CAR-S (p 0.05) owing to the drug absorption through lymphatic pathways. In conclusion, the NLC formulation remarkably improved the oral bioavailability of CAR and demonstrated a promising perspective for oral delivery of poorly water-soluble drugs. The promising findings in this investigation suggest the practicability of these systems for the enhancement of bioavailability of CAR.

Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse beta cells, LDs are prominent in human beta cells, however, the regulation of LD mobilization (lipolysis) in human beta cells remains unclear. We found that glucose increases lipolysis in non-diabetic human islets, but not in type 2 diabetic (T2D) islets, indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets (shATGL) increased triglycerides, and the number and size of LDs indicating that ATGL is the principal lipase in human beta cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS) and insulin secretion to IBMX and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL deficient INS1 cells and human pseudoislets showed reduced Stx1a, a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human beta cells and supports insulin secretion by stabilizing Stx1a. The dysregulated lipolysis may contribute to LD accumulation and beta cell dysfunction in T2D islets.

Garg and Arora (2018) pointed out that it is not appropriate to use the existing intuitionistic fuzzy soft (IFS) aggregations operators (Arora and Garg, 2018a,b), proposed by themselves, as these aggregation operators gives undesirable results under some circumstances. To resolve the flaws of these aggregation operators, Garg and Arora (2018) proposed the improved operational laws of IFS numbers and hence, proposed a new IFS aggregation operator (named as Scaled prioritized intuitionistic fuzzy soft interaction (SPIFSI) aggregation operator). Garg and Arora (2018) also proposed a SPIFSI aggregation operator based intuitionistic fuzzy soft multi criteria decision making (IFSMCDM) approach for solving IFSMCDM problems (Multi criteria decision making problems in which the rating value of each alternative over each criterion is represented by an IFS set). Although, Garg and Arora (2018) have claimed that their proposed SPIFSI aggregation operator is valid as it satisfies the idempotency, boundedness and monotonicity properties. But, in actual case, for the SPIFSI aggregation operator, proposed by Garg and Kumar (2018), the monotonicity property is not satisfying. Therefore, the SPIFSI aggregation operator, proposed by Garg and Arora (2018), and hence, the SPIFSI aggregation operator based IFSMCDM approach, are not valid. Since, in future, other researchers may use the SPIFSI aggregation operator in their research work. Also, the researchers may use the SPIFSI aggregation operator based IFSMCDM approach for solving real life IFSMCDM problems. Therefore, the aim of this note is to make the researchers aware about the discrepancies of the SPIFSI aggregation operator as well as the SPIFSI aggregation operator based IFMCDM approach. Furthermore, to make the researchers aware that improved operational laws of IFS numbers, proposed by Garg and Arora (2018), are also not valid.

In the proposed work machine learning algorithm is applied on Functional Magnetic Resonance Imaging (fMRI) data to analyze the human brain activity and then predicting the word that the subject was thinking. The algorithm that can learn to identify and track the cognitive processes and gives rise to predict the word from observed fMRI data is developed. The major problem here is that we have limited data in very high dimensional feature space. Thereby, making the model susceptible to overfit the data. Also, the data is highly noisy through most of the dimensions, leaving only a few features that are discriminative. Due to high noise domain shift problem is very likely to occur. Most of the previous approach focused only on feature selection and learning the embedding space. Here our main objective is to learn the robust embedding space and handling the domain shift problem [11] in an efficient way. Unlike the previous approach instead of learning the dictionary that projects the visual space to the word embedding space, we are using the joint dictionary learning approach based on the matrix factorization. Our experiment shows that the proposed approach based on the joint dictionary learning and domain adaptation method has the significant advantage over the previous approaches.

Data Mining is exceptionally helpful when it comes to educational field particularly while examining students' conduct in internet learning environment. This is because of the capability of data mining in breaking down and revealing the shrouded data itself which is tough and exceptionally tedious if only manual work is there without automation. Adoption of numerous techniques and tools of data mining is done by almost all the industries for generating business intelligence so as to improve the process of decision making. And as we come to the educational fields, they also begin to use techniques of data mining, so that they can provide improved services and increase grades and performance of student. The main principle of this paper is to focus on the application area of EDM, where we can apply e-learning.

These days' data mining is an emerging trend, which is presently used in different areas especially in student educational and learning analytics. It is very hard and time consuming to analyze data and finding the hidden information manually. To improvise educational data mining, clustering will be used in the paper. As we need to improvise performance as well as unambiguousness of obtained models. We have used 84 under-graduate student data and grouped students according to their final marks they achieved in the course and this we have done by using clustering approach. The result which we get shows that the clarity of specific model is much better than the general model and the unambiguousness of the model is also increase.