Volatile methyl jasmonate from roots triggers host-beneficial soil microbiome biofilms.

The rhizosphere is a niche surrounding plant roots, where soluble and volatile molecules mediate signaling between plants and the associated microbiota. The preferred lifestyle of soil microorganisms is in the form of biofilms. However, less is known about whether root volatile organic compounds (rVOCs) can influence soil biofilms beyond the 2-10 mm rhizosphere zone influenced by root exudates. We report that rVOCs shift the microbiome composition and growth dynamics of complex soil biofilms. This signaling is evolutionarily conserved from ferns to higher plants. Methyl jasmonate (MeJA) is a bioactive signal of rVOCs that rapidly triggers both biofilm and microbiome changes. In contrast to the planktonic community, the resulting biofilm community provides ecological benefits to the host from a distance via growth enhancement. Thus, a volatile host defense signal, MeJA, is co-opted for assembling host-beneficial biofilms in the soil microbiota and extending the sphere of host influence in the rhizosphere.

Computational antimicrobial peptide design and evaluation against multidrug-resistant clinical isolates of bacteria.

There is a pressing need for new therapeutics to combat multidrug- and carbapenem-resistant bacterial pathogens. This challenge prompted us to use a long short-term memory (LSTM) language model to understand the underlying grammar, i.e. the arrangement and frequencies of amino acid residues, in known antimicrobial peptide sequences. According to the output of our LSTM network, we synthesized 10 peptides and tested them against known bacterial pathogens. All of these peptides displayed broad-spectrum antimicrobial activity, validating our LSTM-based peptide design approach. Our two most effective antimicrobial peptides displayed activity against multidrug-resistant clinical isolates of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and coagulase-negative staphylococci strains. High activity against extended-spectrum ß-lactamase, methicillin-resistant S. aureus, and carbapenem-resistant strains was also observed. Our peptides selectively interacted with and disrupted bacterial cell membranes and caused secondary gene-regulatory effects. Initial structural characterization revealed that our most effective peptide appeared to be well folded. We conclude that our LSTM-based peptide design approach appears to have correctly deciphered the underlying grammar of antimicrobial peptide sequences, as demonstrated by the experimentally observed efficacy of our designed peptides.

Hepatoprotective Activity of Satwa, an Ayurvedic Formulation, Against Alcohol-induced Liver Injury in Rats.

Context • Guduchi Satwa is an Ayurvedic formulation prepared from Tinospora species. It has been used since ancient times to treat liver disorders. Objectives • The study intended to assess the hepatoprotective potential of Satwa prepared from 3 forms of Tinospora against alcohol-induced hepatotoxicity. Design • Male, albino Wistar rats were divided into 6 groups, with 6 rats each: 3 control groups-healthy controls, negative controls, and positive controls-and 3 intervention groups-Tinospora cordifolia, Tinospora sinensis, and Neem-Guduchi. Setting • The study was carried out at the Animal House facility of Bharati Vidyapeeth Deemed University's Medical College (Maharashtra, India). Intervention • Hepatotoxicity was induced by repeated dosing with alcohol for 15 d for all groups except for the healthy controls. To induce hepatotoxicity, the 5 groups received 1 mL of 30% alcohol PO per 100 g of body weight per day. The healthy controls and the negative controls received no hepatoprotective treatments. The other 4 groups received the dosing with alcohol 30 min after the hepatoprotective treatment, which they also received for 15 d: (1) positive controls-100 mg of silymarin per kg of body weight per day PO; (2) intervention group 1 (T cordifolia group)-200 mg of T cordifolia per kg of body weight per day PO; (3) intervention group 2 (T sinensis group)-200 mg of T sinensis per kg of body weight per day PO; and (4) intervention group 3 (Neem-Guduchi group)-200 mg of Neem-Guduchi per kg of body weight per day PO. Outcome Measures • Serum and liver tissue were used for biochemical analysis. Results • For the negative and positive control groups and the 3 intervention groups, the repeated dosing with alcohol produced elevations in the levels of liver-marker enzymes and changes in the lipid-profile status of the animals. Satwa from T cordifolia had a specific action in maintaining the lipid profile: total cholesterol, high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein. Improvement in the hepatic function, normalization of the lipid profile in the serum and liver, and improvements in the levels of antioxidant enzymes and oxidative-stress markers were observed in the animals treated with T sinensis Satwa. Neem-Guduchi Satwa was found to have a specific action in maintaining the lipid profile. The differential hepatoprotective effect of that Satwa was also evident from the liver histology. Conclusions • The data suggest that the 3 Satwa might be used in combination as a liver tonic that can help restore and strengthen the liver functions. The current study shows that the combination has the potential to be an effective liver tonic in animals. Scientific data from clinical trials of the 3 Satwa are not available. Systematic clinical trials are required that can yield information on their effects in humans.

Anti-fatigue effect of Amarkand on endurance exercise capacity in rats.

BACKGROUND: Amarkand tubers are routinely used by many Indian tribes as a specialized food for health and longevity but so far there is no scientific evidence for their activities. Taxonomically, Amarkand belong to genera Eulophia and Dioscorea. METHODS: In this communication, comparative antifatigue potential of Amarkand was analyzed using forced swimming model in rats and evaluated using biomarkers of physical fatigue. RESULTS: Methanol extracts of tubers of D. bulbifera, E. ochreata, E. leghapanensis and bulbils of D. bulbifera exhibited rich polyphenolic content. D. bulbifera bulbils and E. ochreata significantly prolonged the swimming endurance time. Creatine kinase and urea nitrogen were significantly reduced by treatment of D. bulbifera bulbils and E. ochreata as compared to negative control. D. bulbifera bulbils effectively increased creatine (p < 0.001), lactate dehydrogenase (p < 0.01) and hemoglobin (p < 0.001) compared to negative control. D. bulbifera bulbils and E. ochreata treatments significantly increased glycogen (p < 0.05, p < 0.01) and lowered malondialdehyde levels (p < 0.001) in muscles and in liver tissue compared to negative control. CONCLUSION: These results indicate that a treatment with D. bulbifera bulbils and tubers of E. ochreata facilitates aerobic glucose metabolism and endurance by improving various impairments associated with fatigue.

One-Pot Cannizzaro Cascade Synthesis of ortho-Fused Cycloocta-2,5-dien-1-ones from 2-Bromo(hetero)aryl Aldehydes.

An intramolecular Cannizzaro-type hydride transfer to an in situ prepared allene enables the synthesis of ortho-fused 4-substituted cycloocta-2,5-dien-1-ones with unprecedented technical ease for an eight-ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields.

MetBERT: a generalizable and pre-trained deep learning model for the prediction of metastatic cancer from clinical notes.

Distant metastasis is the major cause of cancer-related deaths; however, early diagnosis of cancer metastasis remains a significant challenge. The recent advances in pre-trained natural language processing models coupled with the accumulation of publicly available Electronic Health Records (EHR) data provide an unprecedented opportunity to computationally tackle the challenge. Here, we fine-tuned multiple state-of-the-art BERT-based models using discharge summaries from the open MIMIC-III dataset and derived MetBERT, a novel model tailored to predict cancer metastasis from clinical notes. MetBERT achieved high performance (AUC=0.94) on our in-house validation dataset, suggesting its high generalizability. In addition, MetBERT enabled determining the date of cancer metastasis using the rich information in clinical notes and therefore could be potentially deployed as a tool for early diagnosis. Finally, we interpreted MetBERT at different scales and revealed a possible association between radiation therapy and metastasis risk in multiple cancer types.

Personalized quantitative models of NAD metabolism in hepatocellular carcinoma identify a subgroup with poor prognosis.

Cancer cells are known to undergo metabolic adaptation to cater to their enhanced energy demand. Nicotinamide adenine dinucleotide (NAD) is an essential metabolite regulating many cellular processes within the cell. The enzymes required for NAD synthesis, starting from the base precursor - tryptophan, are expressed in the liver and the kidney, while all other tissues convert NAD from intermediate precursors. The liver, being an active metabolic organ, is a primary contributor to NAD biosynthesis. Inhibition of key enzymes in the NAD biosynthetic pathways is proposed as a strategy for designing anti-cancer drugs. On the other hand, NAD supplementation has also been reported to be beneficial in cancer in some cases. As metabolic adaptation that occurs in cancer cells can lead to perturbations to the pathways, it is important to understand the exact nature of the perturbation in each individual patient. To investigate this, we use a mathematical modelling approach integrated with transcriptomes of patient samples from the TCGA-LIHC cohort. Quantitative profiling of the NAD biosynthesis pathway helps us understand the NAD biosynthetic status and changes in the controlling steps of the pathway. Our results indicate that NAD biosynthesis is heterogeneous among liver cancer patients, and that Nicotinate phosphoribosyl transferase (NAPRT) levels are indicative of the NAD biosynthetic status. Further, we find that reduced NAPRT levels combined with reduced Nicotinamide phosphoribosyl transferase (NAMPT) levels contribute to poor prognosis. Identification of the precise subgroup who may benefit from NAD supplementation in subgroup with low levels of NAPRT and NAMPT could be explored to improve patient outcome.

BGLM: big data-guided LOINC mapping with multi-language support.

Motivation: Mapping internal, locally used lab test codes to standardized logical observation identifiers names and codes (LOINC) terminology has become an essential step in harmonizing electronic health record (EHR) data across different institutions. However, most existing LOINC code mappers are based on text-mining technology and do not provide robust multi-language support. Materials and methods: We introduce a simple, yet effective tool called big data-guided LOINC code mapper (BGLM), which leverages the large amount of patient data stored in EHR systems to perform LOINC coding mapping. Distinguishing from existing methods, BGLM conducts mapping based on distributional similarity. Results: We validated the performance of BGLM with real-world datasets and showed that high mapping precision could be achieved under proper false discovery rate control. In addition, we showed that the mapping results of BGLM could be used to boost the performance of Regenstrief LOINC Mapping Assistant (RELMA), one of the most widely used LOINC code mappers. Conclusions: BGLM paves a new way for LOINC code mapping and therefore could be applied to EHR systems without the restriction of languages. BGLM is freely available at https://github.com/Bin-Chen-Lab/BGLM.

Evaluation of free-radical quenching properties of standard Ayurvedic formulation Vayasthapana Rasayana.

BACKGROUND: Cellular damage induced by free-radicals like Reactive Oxygen and Nitrogen Species (ROS and RNS) has been implicated in several disorders and diseases, including ageing. Hence naturally occurring anti-oxidant rich-herbs play a vital role in combating these conditions. The present study was carried out to investigate the in vitro free-radical quenching capacity of a known Ayurvedic poly-herbal formulation called Vayasthapana Rasayana. METHODS: Methanol extracts of Vayasthapana Rasayana formulation (VRF) were studied for in vitro total antioxidant activity along with phenolic content and reducing power. In vitro assays like DPPH, FRAP, ABTS scavenging to evaluate radical quenching potential were performed. RESULTS: The formulation has shown 94% at 0.1 mg/ml DPPH free-radical scavenging activity as against 84% at 0.1 mg/ml for standard ascorbic acid (IC50 value 5.51 µg/ml for VRF and 39 µg/ml for standard). It has a significant higher ferric reducing potential also (OD 0.87 at 700 nm & 0.21 at 0.1 mg/ml for VRF and standard, respectively). The total phenolic content (gallic acid equivalent) of the VRF is 8.3 mg per g of dry mass. Total antioxidant capacity of the formulation, estimated by FRAP was 1150 ± 5 µM Fe(II)/g dry mass. ABTS radical scavenging activity of VRF was 69.55 ± 0.21% at 100 µg/ml concentration with a IC50 value of 69.87 µg/ml as against 9% and 95% by ascorbic acid and Trolox (at 70.452 µg/ml and 0.250 µg/ml concentrations, respectively). CONCLUSION: In Indian traditional Ayurvedic system, use of VRF is in regular practice for mainly combating age-related disorders and diseases as many of the components of the Rasayana are known for their free-radical scavenging activity. This study has validated the potential use of VRF as an anti-oxidant to fight age-related problems.

Opportunities for Regulatory Changes to Promote Pediatric Device Innovation in the United States: Joint Recommendations From Pediatric Innovator Roundtables.

OBJECTIVE: The purpose of this report is to provide insight from pediatric stakeholders with a shared desire to facilitate a revision of the current United States regulatory pathways for the development of pediatric healthcare devices. METHODS: On August 5, 2020, a group of innovators, engineers, professors and clinicians met to discuss challenges and opportunities for the development of new medical devices for pediatric health and the importance of creating a regulatory environment that encourages and accelerates the research and development of such devices. On January 6, 2021, this group joined regulatory experts at a follow-up meeting. RESULTS: One of the primary issues identified was the need to present decision-makers with opportunities that change the return-on-investment balance between adult and pediatric devices to promote investment in pediatric devices. DISCUSSION/CONCLUSION: Several proposed strategies were discussed, and these strategies can be divided into two broad categories: 1. Removal of real and perceived barriers to pediatric device innovation; 2. Increasing incentives for pediatric device innovation.

A Guide to Chatbots for COVID-19 Screening at Pediatric Health Care Facilities.

The coronavirus disease 2019 (COVID-19) outbreak has required institutions to rapidly adapt to changing public health circumstances. The Centers for Disease Control and Prevention has encouraged health care facilities to explore novel health care delivery modes. However, many institutions may not be prepared to begin offering digital health and telehealth services. Chatbots are one digital health tool that can help evolve triage and screening processes in a scalable manner. Here, we present a decision-making and implementation framework for deploying COVID-19 screening chatbots at pediatric health care facilities.

Graft Retensioning by Dialing of Suture Disk on Tibial-Side Fixation in Arthroscopic Anterior Cruciate Ligament Reconstruction: Pathak Pune Dialing Technique.

Arthroscopic anterior cruciate ligament (ACL) reconstruction is a common procedure performed for symptomatic ACL tears, especially in athletes. The desired surgical end product with any surgical fixation device remains a taut ACL graft, which is crucial during postoperative rehabilitation to reduce the risk of knee instability and rerupture of the ACL graft. The purpose of this Technical Note and accompanying video is to describe a simple and cost-effective technique to easily retension the ACL graft after tibial fixation in ACL reconstruction using a suture disk device. The technique uses a simple suture disk device to provide strong tibial fixation, along with the unique ability to retension the ACL graft by dialing it in a clockwise direction.

Modified Surgical Technique of Making Posteromedial Portal in Knee Arthroscopy Using a Radiofrequency Device.

In knee arthroscopy, a posteromedial portal is used for various indications including arthroscopic posterior cruciate ligament reconstruction, posterior cruciate ligament avulsion fracture fixation, posterior medial meniscal repair, medial ramp lesion repair, and synovectomy. Making the posteromedial portal is challenging for young and even experienced surgeons. Creating the posteromedial portal in knee arthroscopy is challenging and technically demanding for surgeons because of the thick muscular cover, proximity of the neurovascular bundle, tenacious tough capsule, and excessive fat deposition in the posteromedial knee and thigh region. Access for viewing the posteromedial compartment during different procedures is made simple, safe, and replicable with this technique of creating the posteromedial portal. This article describes a simple way to create the posteromedial portal using a radiofrequency device by a modified outside-in surgical technique.

Synthesis and Evaluation of Novel Pyrazole Ethandiamide Compounds as Inhibitors of Human THP-1 Monocytic Cell Neurotoxicity.

Neuroinflammation and microglia-mediated neurotoxicity contribute to the pathogenesis of a broad range of neurodegenerative diseases; therefore, identifying novel compounds that can suppress adverse activation of glia is an important goal. We have previously identified a class of trisubstituted pyrazoles that possess neuroprotective and anti-inflammatory properties. Here, we describe a second generation of pyrazole analogs that were designed to improve their neuroprotective activity toward neurons under inflammatory conditions. Pyrazolyl oxalamide derivatives were designed to explore the effects of steric and electronic factors. Three in vitro assays were performed to evaluate the compounds' anti-neurotoxic, neuroprotective, and cytotoxic activity using human THP-1, PC-3, and SH-SY5Y cells. Five compounds significantly reduced the neurotoxic secretions from immune-stimulated microglia-like human THP-1 monocytic cells. One of these compounds was also found to protect SH-SY5Y neuronal cells when they were exposed to cytotoxic THP-1 cell supernatants. While one of the analogs was discarded due to its interference with the cell viability assay, most compounds were innocuous to the cultured cells at the concentrations used (1-100 µM). The new compounds reported herein provide a design template for the future development of lead candidates as novel inhibitors of neuroinflammation and neuroprotective drugs.

Ω76: A designed antimicrobial peptide to combat carbapenem- and tigecycline-resistant Acinetobacter baumannii.

Drug resistance is a public health concern that threatens to undermine decades of medical progress. ESKAPE pathogens cause most nosocomial infections, and are frequently resistant to carbapenem antibiotics, usually leaving tigecycline and colistin as the last treatment options. However, increasing tigecycline resistance and colistin's nephrotoxicity severely restrict use of these antibiotics. We have designed antimicrobial peptides using a maximum common subgraph approach. Our best peptide (Ω76) displayed high efficacy against carbapenem and tigecycline-resistant Acinetobacter baumannii in mice. Mice treated with repeated sublethal doses of Ω76 displayed no signs of chronic toxicity. Sublethal Ω76 doses co-administered alongside sublethal colistin doses displayed no additive toxicity. These results indicate that Ω76 can potentially supplement or replace colistin, especially where nephrotoxicity is a concern. To our knowledge, no other existing antibiotics occupy this clinical niche. Mechanistically, Ω76 adopts an α-helical structure in membranes, causing rapid membrane disruption, leakage, and bacterial death.

A general approach to intermolecular carbonylation of arene C-H bonds to ketones through catalytic aroyl triflate formation.

The development of metal-catalysed methods to functionalize inert C-H bonds has become a dominant research theme in the past decade as an approach to efficient synthesis. However, the incorporation of carbon monoxide into such reactions to form valuable ketones has to date proved a challenge, despite its potential as a straightforward and green alternative to Friedel-Crafts reactions. Here we describe a new approach to palladium-catalysed C-H bond functionalization in which carbon monoxide is used to drive the generation of high-energy electrophiles. This offers a method to couple the useful features of metal-catalysed C-H functionalization (stable and available reagents) and electrophilic acylations (broad scope and selectivity), and synthesize ketones simply from aryl iodides, CO and arenes. Notably, the reaction proceeds in an intermolecular fashion, without directing groups and at very low palladium-catalyst loadings. Mechanistic studies show that the reaction proceeds through the catalytic build-up of potent aroyl triflate electrophiles.

A Case of 3-month-old Neglected Elbow Dislocation Managed by Open Reduction and Cruciate Ligament Reconstruction Using Tendon Graft.

INTRODUCTION: Old neglected posterior type of elbow dislocations is not very common and generally requires open reduction. It was usually treated with open reduction and K-wire stabilization. We did a newer method in which in addition cruciate type ligament reconstruction; we have reconstructed lateral ulnar collateral ligament (LUCL) and UCL (medial collateral ligament) using semitendinosus graft. This allowed extra stability and early mobilization of the elbow joint. Authors report 3-month-old neglected posterior type of elbow dislocation without any fracture. CASE REPORT: A 42-year-old male presented with pain and tenderness with deformity of the left elbow joint and inability to move the elbow joint after he fell down since 3 months. There was no neurovascular deficit. Radiological examination confirmed posterior dislocation of elbow joint without any fracture. The patient is managed by open reduction and cruciate ligament reconstruction of elbow joint using autologous semitendinosus graft. CONCLUSION: Open reduction with cruciate ligament reconstruction provides excellent stability for early mobilization of old neglected elbow dislocation.

Circulatory adipocytokines and lipid profile variations in type-2 diabetic subjects: desirable side-effects of antidiabetic drugs.

AIM: Inspite of availability of a variety of drugs to treat type 2 diabetes, little is known about their effects on other systems. Normalization of glucose metabolism by these drugs may consequently affect the secretory function in adipocytes. Secretory adipocytokines like adiponectin and leptin are emerging as novel therapeutic targets for type 2 diabetes mellitus (T2DM). The present study was undertaken to analyze the effects of commonly used Oral Hypoglycemic Agents (OHAs) alone, or in combination with other drugs and/or insulin on circulatory adiponectin and leptin levels, lipid profile, and blood pressure in diabetic subjects. METHODS: The study was undertaken at IRSHA and Bharati Vidyapeeth Medical College and Hospital, MS, India. Clinically diagnosed T2DM subjects and age, gender matched healthy controls were recruited. Fasting blood was collected from each subject and the blood samples were analyzed for circulatory adipocytokines and lipid parameters using commercial kits. RESULTS: Serum adiponectin levels were significantly increased while leptin significantly decreased in diabetic men (p<0.05) and women (p<0.001) on OHA, as compared to healthy controls. Triglyceride levels significantly decreased (p<0.05) in diabetic men, however, they remained unchanged in women despite same drug treatment. Serum HDL and LDL levels (p<0.001) were significantly lower in diabetic women as compared to healthy women. Systolic (p<0.05) and diastolic (p<0.001) blood pressure was significantly high in diabetic men but remained unchanged in women. CONCLUSIONS: Frequently used OHAs significantly improve circulatory levels of adipocytokines. Selecting best treatment option for each patient is a key, and 2012 European Association for the Study of Diabetes (EASD) and ADA guidelines recommend diabetes treatment to be individualized depending on various socioeconomic and lifestyle factors. We recommend regular analysis of circulatory adipocytokines in T2DM patients to help clinicians select the best treatment option to normalize levels of these important therapeutic targets.

Influence of six medicinal herbs on collagenase-induced osteoarthritis in rats.

Medicinal herbs have been effectively used for their anti-inflammatory activity, but their exact role has not yet been documented in scientific literature for the management of Osteoarthritis (OA). Since Sida cordifolia L., Piper longum L., Zingiber officinale Rosc., Ricinus communis L., Vitex negundo L. and Tribulus terrestris L. have been widely used in traditional medicine for their anti-inflammatory activity, to evaluate anti-osteoarthritic activity of these herbs, we used a collagenase type II-induced osteoarthritis (CIOA) rat model. Arthritis was induced in wistar rats by intra-articular injection of collagenase type II. Powders of herbs were given orally for 20 days as a suspension in water (270 mg/kg b. wt.). The effects of the treatment in the rats were monitored by physiological parameters like body weight, knee diameter, paw retraction, paw volume, glycosaminoglycan (GAG) release, radiography and histopathology of knee joint. Selected herbs have significantly prevented body weight loss and knee swelling compared to arthritic control (CIOA). All test groups, including indomethacin (standard drug, 3 mg/kg), significantly reduced paw volume compared to CIOA. GAG release in the serum was significantly lowered in herb treated groups compared to indomethacin. The anterior posterior radiographs of S. cordifolia and P. longum treated groups showed a protective effect against OA. Histopathology revealed protection in the structure of the articular cartilage and in chondrocyte pathology as well as reduced clefting. Treatment with herbs has shown chondroid matrix within normal limits. From the results, we observed that S. cordifolia and P. longum possess potent anti-osteoarthritic activity.

Evaluation of comparative free-radical quenching potential of Brahmi (Bacopa monnieri) and Mandookparni (Centella asiatica).

Ayurvedic texts describe rejuvenate measures called Rasayana to impart biological sustenance to bodily tissues. Rasayana acting specifically on brain are called Medhya Rasayana. Brahmi is one of the most commonly practiced herbs for the same. Yet there exist a controversy regarding the exact plant species among Bacopa monnieri L. Penn (BM) and Centella asiatica (L.) Urban (CA) to be used as Brahmi in the formulations. Though the current literature available has suggested a very good nootropic potential of both the drugs, none of the studies have been carried out on comparative potential of these herbs to resolve the controversy. Free-radical scavenging potential for these plants is studied to find out their comparative efficacy. The study revealed a very good in vitro free-radical scavenging properties of aqueous and ethanolic extracts of both the plants as evidenced by FRAP, DPPH, reducing power, and antilipid peroxidation assays. It can be concluded from the studies that both the plants, although taxonomically totally different at family level, showed similar type of in vitro activities. The total phenolic and flavonoid contents also revealed a significant similarity in the two plants. The in vitro study supports the Ayurvedic concept of BM and CA having a similar potential.