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The potato tuber moth (PTM; caused by Phthorimaea operculella) is one of the most serious insect pests that causes damage to crop production and storage of potatoes. It causes damage to the potato, while larvae of P. operculella feed on and grow in the leaves and tubers of potatoes, resulting in direct product losses. The larvae construct tunnels through tubers and mine leaves, stems, and petioles, resulting in uneven galleries. Foliar damage to the potato crop does not normally result in major output losses, although contaminated tubers may have lower marketability and storage losses of up to 100%. Light watering every 4 days and mulching with neem leaves during the last 4 weeks before the harvest was found to be a successful treatment. Spraying a thin layer of testing natural oils also acts as a defensive layer, which causes confusion or disturbance to the searching neonate larvae. The pest is tough to eradicate, so producers rely heavily on insecticides and biological approaches. Potato tuberworm damage was reduced by rotating esfenvalerate and indoxacarb treatments before and after vine kill. At 5 g/kg potato tuber in farmer rustic storage, Acorus calamus dust exhibited great efficiency in preventing PTM tuber damage. In different regions of the world, parasitoids such as Copidosoma spp. and Apanteles spp. are significant in PTM management. Pheromone traps are used for pest population monitoring as well as pest management in the field and during storage.

Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being inhibited. A series of tryptamine-based pan-SHIP1/2 inhibitors have been synthesized and evaluated for their ability to inhibit the SHIP paralogs. The most active compounds were also evaluated for their effects on cancer cell lines.

Members of the human gut microbiome enzymatically process many bioactive molecules in the gastrointestinal tract. Most gut bacterial modifications characterized so far are hydrolytic or reductive in nature. Here we report that abundant human gut bacteria from the phylum Bacteroidetes perform conjugative modifications by selectively sulfonating steroidal metabolites. While sulfonation is a ubiquitous biochemical modification, this activity has not yet been characterized in gut microbes. Using genetic and biochemical approaches, we identify a widespread biosynthetic gene cluster that encodes both a sulfotransferase (BtSULT, BT0416) and enzymes that synthesize the sulfonate donor adenosine 3'-phosphate-5'-phosphosulfate (PAPS), including an APS kinase (CysC, BT0413) and an ATP sulfurylase (CysD and CysN, BT0414-BT0415). BtSULT selectively sulfonates steroidal metabolites with a flat A/B ring fusion, including cholesterol. Germ-free mice monocolonized with Bacteroides thetaiotaomicron ΔBT0416 exhibited reduced gastrointestinal levels of cholesterol sulfate (Ch-S) compared with wild-type B. thetaiotaomicron-colonized mice. The presence of BtSULT and BtSULT homologues in bacteria inhibited leucocyte migration in vitro and in vivo, and abundances of cluster genes were significantly reduced in patients with inflammatory bowel disease. Together, these data provide a mechanism by which gut bacteria sulfonate steroidal metabolites and suggest that these compounds can modulate immune cell trafficking in the host., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Altered host-microbe interactions and increased intestinal permeability have been implicated in disease pathogenesis. However, the mechanisms by which intestinal microbes affect epithelial barrier integrity remain unclear. Here, we investigate the impact of bacterial metabolism of host-produced bile acid (BA) metabolites on epithelial barrier integrity. We observe that rats fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) exhibit reduced intestinal abundance of host-produced conjugated BAs at early time points, coinciding with increased gut permeability. We show that in vitro, conjugated BAs protect gut epithelial monolayers from damage caused by bacterially produced unconjugated BAs through micelle formation. We then demonstrate that inhibition of bacterial BA deconjugation with a small-molecule inhibitor prevents the development of pathologic intestinal permeability and hepatic inflammation in CDAHFD-fed rats. Our study identifies a signaling-independent, physicochemical mechanism for conjugated BA-mediated protection of epithelial barrier function and suggests that rational manipulation of microbial BA metabolism could be leveraged to regulate gut barrier integrity.

Bile acids play crucial roles in host physiology by acting both as detergents that aid in digestion and as signaling molecules that bind to host receptors. Gut bacterial bile salt hydrolase (BSH) enzymes perform the gateway reaction leading to the conversion of host-produced primary bile acids into bacterially modified secondary bile acids. Small molecule probes that target BSHs will help elucidate the causal roles of these metabolites in host physiology. We previously reported the development of a covalent BSH inhibitor with low gut permeability. Here, we build on our previous findings and describe the development of a second-generation gut-restricted BSH inhibitor with enhanced potency, reduced off-target effects, and durable in vivo efficacy. Structure-activity relationship (SAR) studies focused on the bile acid core identified a compound, AAA-10, containing a C3-sulfonated lithocholic acid scaffold and an alpha-fluoromethyl ketone warhead as a potent pan-BSH inhibitor. This compound inhibits BSH activity in mouse and human fecal slurry, bacterial cultures, and purified BSH proteins and displays reduced toxicity against mammalian cells compared to first generation compounds. Oral administration of AAA-10 to wild-type mice for 5 days resulted in a decrease in the abundance of the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) in the mouse GI tract with low systemic exposure of AAA-10, demonstrating that AAA-10 is an effective tool for inhibiting BSH activity and modulating bile acid pool composition in vivo .

Bariatric surgery is the most effective treatment for type 2 diabetes and is associated with changes in gut metabolites. Previous work uncovered a gut-restricted TGR5 agonist with anti-diabetic properties-cholic acid-7-sulfate (CA7S)-that is elevated following sleeve gastrectomy (SG). Here, we elucidate a microbiome-dependent pathway by which SG increases CA7S production. We show that a microbial metabolite, lithocholic acid (LCA), is increased in murine portal veins post-SG and by activating the vitamin D receptor, induces hepatic mSult2A1/hSULT2A expression to drive CA7S production. An SG-induced shift in the microbiome increases gut expression of the bile acid transporters Asbt and Ostα, which in turn facilitate selective transport of LCA across the gut epithelium. Cecal microbiota transplant from SG animals is sufficient to recreate the pathway in germ-free (GF) animals. Activation of this gut-liver pathway leads to CA7S synthesis and GLP-1 secretion, causally connecting a microbial metabolite with the improvement of diabetic phenotypes., Competing Interests: Declaration of interests CA7S is a subject of patents held by HMS and BWH on which S.N.C., D.A.H., E.G.S., and A.S.D. are inventors. A.S.D. is a consultant for Takeda Pharmaceuticals and HP Hood. E.G.S. is a consultant for Vicarious Surgical, Inc. and was previously on the scientific advisory board of Kitotech, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bile salt hydrolase (BSH) enzymes are widely expressed by human gut bacteria and catalyze the gateway reaction leading to secondary bile acid formation. Bile acids regulate key metabolic and immune processes by binding to host receptors. There is an unmet need for a potent tool to inhibit BSHs across all gut bacteria to study the effects of bile acids on host physiology. Here, we report the development of a covalent pan-inhibitor of gut bacterial BSHs. From a rationally designed candidate library, we identified a lead compound bearing an alpha-fluoromethyl ketone warhead that modifies BSH at the catalytic cysteine residue. This inhibitor abolished BSH activity in conventional mouse feces. Mice gavaged with a single dose of this compound displayed decreased BSH activity and decreased deconjugated bile acid levels in feces. Our studies demonstrate the potential of a covalent BSH inhibitor to modulate bile acid composition in vivo.

We show here that both SHIP1 ( Inpp5d ) and its paralog SHIP2 ( Inppl 1) are expressed at protein level in microglia. To examine whether targeting of SHIP paralogs might influence microglial physiology and function, we tested the capacity of SHIP1-selective, SHIP2-selective and pan-SHIP1/2 inhibitors for their ability to impact on microglia proliferation, lysosomal compartment size and phagocytic function. We find that highly potent pan-SHIP1/2 inhibitors can significantly increase lysosomal compartment size, and phagocytosis of dead neurons and amyloid beta (Aβ) 1-42 by microglia in vitro We show that one of the more-potent and water-soluble pan-SHIP1/2 inhibitors, K161, can penetrate the blood-brain barrier. Consistent with this, K161 increases the capacity of CNS-resident microglia to phagocytose Aβ and apoptotic neurons following systemic administration. These findings provide the first demonstration that small molecule modulation of microglia function in vivo is feasible, and suggest that dual inhibition of the SHIP1 and 2 paralogs can provide a novel means to enhance basal microglial homeostatic functions for therapeutic purposes in Alzheimer's disease and, possibly, other types of dementia where increased microglial function could be beneficial., Competing Interests: Competing interestsW.G.K., C.P., S.F. and J.D.C. have patents, pending and issued, concerning the analysis and targeting of SHIP1 and SHIP2 in disease. W.G.K. is Chief Scientific Officer and J.D.C. serves on the Scientific Advisory Board of Alterna Therapeutics, which is devoted to developing and commercializing SHIP inhibitor therapeutics and hold equity. The other authors have no conflicts to disclose., (© 2020. Published by The Company of Biologists Ltd.)

2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry.

Trichloroacetimidates are useful reagents for the synthesis of esters under mild conditions that do not require an exogenous promoter. These conditions avoid the undesired decomposition of substrates with sensitive functional groups that are often observed with the use of strong Lewis or Brønsted acids. With heating, these reactions have been extended to benzyl esters without electron-donating groups. These inexpensive and convenient methods should find application in the formation of esters in complex substrates.

The human gut microbiota impacts host metabolism and has been implicated in the pathophysiology of obesity and metabolic syndromes. However, defining the roles of specific microbial activities and metabolites on host phenotypes has proven challenging due to the complexity of the microbiome-host ecosystem. Here, we identify strains from the abundant gut bacterial phylum Bacteroidetes that display selective bile salt hydrolase (BSH) activity. Using isogenic strains of wild-type and BSH-deleted Bacteroides thetaiotaomicron , we selectively modulated the levels of the bile acid tauro-β-muricholic acid in monocolonized gnotobiotic mice. B. thetaiotaomicron BSH mutant-colonized mice displayed altered metabolism, including reduced weight gain and respiratory exchange ratios, as well as transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver. Our results demonstrate that metabolites generated by a single microbial gene and enzymatic activity can profoundly alter host metabolism and gene expression at local and organism-level scales., Competing Interests: LY, SN, AA, ND, AM, AB, LB No competing interests declared, SS is currently affiliated with Indigo Agriculture, but the research was conducted when she was a Research Associate at Harvard Medical School. The author has no other competing interests to declare, AD is a consultant for Kintai Therapeutics, (© 2018, Yao et al.)

Trichloroacetimidates function as effective electrophiles for the selective C3-alkylation of 2,3-disubstituted indoles to provide 3,3'-disubstituted indolenines. These indolenines are common synthetic intermediates that are often utilized in the synthesis of complex molecules. Effective reaction conditions utilizing Lewis acid catalysts have been determined, and the scope of the reaction with respect to indole and imidate reaction partner has been investigated. This chemistry provides an alternative to base promoted and transition metal catalyzed methods that are more commonly utilized to access similar indolenines.

The rearrangement of allylic trichloroacetimidates is a well-known transformation, but the corresponding rearrangement of benzylic trichloroacetimidates has not been explored as a method for the synthesis of benzylic amines. Conditions that provide the trichloroacetamide product from a benzylic trichloroacetimidate in high yield have been developed. Methods were also investigated to transform the trichloroacetamide product directly into the corresponding amine, carbamate, and urea. A cationic mechanism for the rearrangement is implicated by the available data.

The pyrroloindoline core is found in many natural products. These structures often differ at the C3a position, which may be substituted with an oxygen, nitrogen, or sp(3)- or sp(2)-hybridized carbon. Utilizing a trichloroacetimidate leaving group, a diversity-oriented approach to these structures has been developed. The trichloroacetimidate intermediate allows for the rapid incorporation of anilines, alcohols, thiols, and carbon nucleophiles. This method was applied in the synthesis of arundinine and a formal synthesis of psychotriasine.

Recently, inhibition of the SH2-containing inositol 5'-phosphatase 1 (SHIP1) has become an attractive strategy for facilitating engraftment of MHC-I mismatched bone marrow grafts, increasing the number of adult stem cells in vivo, and inducing mobilization of hematopoietic stem cells. Utilizing high-throughput screening, two quinoline small molecules (NSC13480 and NSC305787) that inhibit SHIP1 enzymatic activity were discovered. New syntheses of these inhibitors have been developed which verified the relative stereochemistry of these structures. Utilizing this synthetic route, some analogs of these quinolines have been prepared and tested for their ability to inhibit SHIP. These structure activity studies determined that an amine tethered to the quinoline core is required for SHIP inhibition. SHIP inhibition may explain the antitumor effects of similar quinoline amino alcohols and provides an impetus for further synthetic studies in this class of compounds., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Cardiac effects following the bite of Burmese Russell's vipers and European vipers are well known. The question whether envenomation caused by Sri Lankan viper bites results in myocardial damage remains largely unanswered. The aim of this prospective study was to investigate whether myocardial damage occurs after Sri Lankan viper bites, using a highly specific and sensitive marker, troponin T., Methods: 45 patients admitted after a definite viper bite [Russell's viper (RV), n = 13, hump-nosed viper (HNV), n = 32] were studied with regard to cardiac symptoms, ECG changes, and troponin T levels. There were no admissions with bites of other types of Sri Lankan vipers during the study period., Results: Cardiac symptoms were present in a number of patients following the bite. Two patients had transient ECG changes. However, troponin T levels were not elevated in any of them., Comment: Myocardial damage does not seem to be an important feature of Sri Lankan Russell's and hump-nosed viper bites. This may be because of venom heterogeneity in vipers, that is based on their geographical distribution.

Introduction: Evidence obtained from large clinical trials would be of limited value, if such evidence does not reach the provider of care, and even when it reaches them, if they do not change their clinical behaviour accordingly. The aim of our study was to assess the effectiveness of intervention, aimed at changing prescribing behaviour of general practitioners (GPs) with regard to early low dose aspirin in patients with suspected acute myocardial infarction (MI)., Methods: A total of 96 GPs were sent a questionnaire assessing their knowledge and practices with regard to use of low dose aspirin in acute MI in November 1995 (Q1), June 1996 (Q2) and September 1996 (Q3). An 'intervention' was carried out with a view to changing GP prescribing of low dose aspirin is suspected acute MI after the first two questionnaires were sent., Results: The results of this study seem to show that an intensive 'intervention' achieved success in changing prescribing behaviour of GPs. Although the intervention resulted in a overall significant increase in the prescription of low dose aspirin in suspected acute MI, it was seen that in the GPs who were aged <40 years the success achieved with the 'intervention' was greater when compared with that seen in those older than 40 years., Conclusion: Dissemination of information on new practices in medicine are important in the process of continuing medical education for doctors. A 'personal intervention' such as is described in this study seems to have good effect.

Regulations regarding driving for patients with epilepsy vary from country to country. They are well implemented in developed countries, but this is not the case in countries such as Sri Lanka. The aims of this study were to study characteristics of a cohort of patients with epilepsy who were driving or riding a vehicle at present, and study the attitudes of a representative sample of doctors, patients with epilepsy and the general population regarding aspects of driving by patients with epilepsy. Patients with epilepsy attending the medical clinics at the Colombo North General Hospital, Ragama, who were driving, were given a questionnaire and interviewed in order to assess their seizure characteristics. Another questionnaire was administered to epileptic patients visiting the clinics, a sample from the general population (relatives visiting in-patients at the University Medical Unit selected randomly), doctors working at the General Hospital in Ragama and the Base Hospital in Negombo, and general practitioners in the Gampaha district, where these two hospitals are situated, which was designed to assess their views regarding driving by persons with epilepsy. Of the patients with epilepsy interviewed 24.8% were presently driving a vehicle, of them 51% were riding a motorcycle. The attitudes of the general public and patients to driving by epileptic patients were at opposite ends of the spectrum; 97% of the general public being opposed to driving by persons with epilepsy, while epileptics themselves being of the view that the rules should be lax. Doctors thought that there should be some regulations against driving by epileptic patients. These facts must be considered when setting implementable regulations regarding driving by epileptics in developing countries.