Association of genetic polymorphism of interleukin 1-alpha and interleukin 1-beta with external apical root resorption in orthodontic patients.

OBJECTIVE: To assess the allele rs 1143634 in IL-1ß and rs1800587 in IL-1α in patients for orthodontically induced external apical root resorption (EARR). MATERIAL AND METHODS: Intra-oral periapical radiograph (IOPA) of maxillary incisors of 142 Patients were evaluated for resorption at two time points; before the start of fixed mechanotherapy (T1) and after one year of treatment (T2). The individuals with root resorption<2mm were categorized as a control group (group 1; n=90), and resorption>2mm were categorized as case group (group 2; n=52). Buccal swabs of all patients were taken and DNA could be isolated in 95 out of 142 samples (group 1 {n=58}, group 2 {n=37}), which were then screened for the selected two polymorphic targets to determine the nucleotide status of these targets. Tetra-primer ARMS PCR reactions were carried out using all 4 primers for each polymorphism. RESULTS: rs11800587 was not associated with risk of EARR in any inheritance model. Chi-square test for association of alleles with EARR revealed that rs1143634 was associated with the risk of EARR in an allelic model in such a way that A allele of this SNP increased the risk of EARR 4 folds [OR=4.375; P=0.016]. However, the adjusted level of significance using the Holm-Bonferroni method for rs1143634 was P<0.010 for A and G comparison rendering the results non-significant. CONCLUSION: SNP rs1143634 and SNP rs11800587 were not associated with risk of EARR in any inheritance model.

Optimizing QoS and security in agriculture IoT deployments: A bioinspired Q-learning model with customized shards.

Agriculture Internet of Things (AIoTs) deployments require design of high-efficiency Quality of Service (QoS) & security models that can provide stable network performance even under large-scale communication requests. Existing security models that use blockchains are either highly complex or require large delays & have higher energy consumption for larger networks. Moreover, the efficiency of these models depends directly on consensus-efficiency & miner-efficiency, which restricts their scalability under real-time scenarios. To overcome these limitations, this study proposes the design of an efficient Q-Learning bioinspired model for enhancing QoS of AIoT deployments via customized shards. The model initially collects temporal information about the deployed AIoT Nodes, and continuously updates individual recurring trust metrics. These trust metrics are used by a Q-Learning process for identification of miners that can participate in the block-addition process. The blocks are added via a novel Proof-of-Performance (PoP) based consensus model, which uses a dynamic consensus function that is based on temporal performance of miner nodes. The PoP consensus is facilitated via customized shards, wherein each shard is deployed based on its context of deployment, that decides the shard-length, hashing model used for the shard, and encryption technique used by these shards. This is facilitated by a Mayfly Optimization (MO) Model that uses PoP scores for selecting shard configurations. These shards are further segregated into smaller shards via a Bacterial Foraging Optimization (BFO) Model, which assists in identification of optimal shard length for underlying deployment contexts. Due to these optimizations, the model is able to improve the speed of mining by 4.5%, while reducing energy needed for mining by 10.4%, improving the throughput during AIoT communications by 8.3%, and improving the packet delivery consistency by 2.5% when compared with existing blockchain-based AIoT deployment models under similar scenarios. This performance was observed to be consistent even under large-scale attacks.

Achieving pre-eminence of antimicrobial resistance among non-fermenting Gram-negative bacilli causing septicemia in intensive care units: A single center study of a tertiary care hospital.

Introduction: Bloodstream infections in the intensive care unit have always been a global healthcare challenge. The present study was conducted with the aim to evaluate the yearly trend of antibiotic resistance in non-fermenting Gram-negative bacilli (NFGNB) causing septicemia in intensive care units. Methods: Blood samples were collected from the patients admitted in various intensive care units and processed for isolation and identification of non-fermenting Gram-negative bacilli. The isolated bacterial strains were subjected to antibiotic susceptibility testing as per standard operating procedures. Results: Out of 3632 blood samples, 977 (26.9%) samples showed microbial growth, of which 10.1% were Gram positive cocci, 8.7% were Gram negative bacilli (Enterobacterales), 7% were NFGNB and 1% were Candida spp. Increasing resistance among Acinetobacter baumannii complex was observed to ceftazidime, cefepime, amikacin, ciprofloxacin, levofloxacin, meropenem and trimethoprim-sulfamethoxazole. Moreover, Pseudomonas aeruginosa strains were found to be associated with increased resistance to ciprofloxacin, levofloxacin, ceftazidime and meropenem. A substantial increase in resistance levels was observed among Stenotrophomonas maltophilia and Sphingomonas paucimobilis as well. Conclusions: An increasing trend of antimicrobial resistance in NFGNB envisages the worst consequences in ICUs in the coming years. Therefore, reviewing and strict implementation of the antimicrobial policies including 'rational use of antibiotics' is recommended.

Understanding the Needs and Lived Experiences of Patients With Graft-Versus-Host Disease: Real-World European Public Social Media Listening Study.

BACKGROUND: Graft-versus-host disease (GVHD) is the major cause of short- and long-term morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Treatment options beyond corticosteroid therapy remain limited, and prolonged treatment often leads to impaired quality of life (QoL). A better understanding of the needs and experiences of patients with GVHD is required to improve patient care. OBJECTIVE: The aim of this study is to explore different social media (SM) channels for gathering and analyzing the needs and experiences of patients and other stakeholders across 14 European countries. METHODS: We conducted a retrospective analysis of SM data from the public domain. The Talkwalker social analytics tool collected data from open-access forums, blogs, and various social networking sites using predefined search strings. The raw data set derived from the aggregator tool was automatically screened for the relevancy of posts, generating the curated data set that was manually reviewed to identify posts that fell within the predefined inclusion and exclusion criteria. This final data set was then used for the deep-dive analysis. RESULTS: A total of 9016 posts relating to GVHD were identified between April 2019 and April 2021. Deduplication and relevancy checks resulted in 325 insightful posts, with Twitter contributing 250 (77%) posts; blogs, 49 (15%) posts; forums, 13 (4%) posts; Facebook, 7 (2%) posts; and Instagram and YouTube, 4 (1%) posts. Patients with GVHD were the primary stakeholders, contributing 63% of all SM posts. In 234 posts, treatment was the most discussed stage of the patient journey (68%), followed by symptoms (33%), and diagnosis and tests (21%). Among treatment-related posts (n=159), steroid therapy was most frequently reported (54/159, 34%). Posts relating to treatment features (n=110) identified efficacy (45/110, 41%), side effects (38/110, 35%), and frequency and dosage (32/110, 29%), as the most frequently discussed features. Symptoms associated with GVHD were described in 24% (77/325) of posts, including skin-related conditions (49/77, 64%), dry eyes or vision change (13/77, 17%), pain and cramps (16/77, 21%), and fatigue or muscle weakness (12/77, 16%). The impacts of GVHD on QoL were discussed in 51% (165/325) of all posts, with the emotional, physical and functional, social, and financial impacts mentioned in 69% (114/165), 50% (82/165), 5% (8/165), and 2% (3/165) of these posts, respectively. Unmet needs were reported by patients or caregivers in 24% (77/325) of analyzed conversations, with treatment-related side effects being the most common (35/77, 45%) among these posts. CONCLUSIONS: SM listening is a useful tool to identify medical needs. Treatment of GVHD, including treatment-related side effects, as well as its emotional and physical impact on QoL, are the major topics that GVHD stakeholders mention on SM. We encourage a structured discussion of these topics in interactions between health care providers and patients with GVHD. TRIAL REGISTRATION: Not applicable.

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus.

Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 µg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

Synthesis and Anti-Melanoma Activity of Acryloyl Pyridinone Analogues.

A major challenge for clinical management of melanoma is the prevention and treatment of metastatic disease. Drug discovery efforts over the last 10 years have resulted in several drugs that improve the prognosis of metastatic melanoma; however, most patients develop early resistance to these treatments. We designed and synthesized, through a concise synthetic strategy, a series of hybrid olefin-pyridinone compounds that consist of structural motifs from tamoxifen and ilicicolin H. These compounds were tested against a human melanoma cell line and patient-derived melanoma cells that had metastasized to the brain. Three compounds 7 b, 7 c, and 7 g demonstrated promising activity (IC50=0.4-4.3 µM). Cell cycle analysis demonstrated that 7 b and 7 c induce cell cycle arrest predominantly in the G1 phase. Both 7 b and 7c significantly inhibited migration of A375 melanoma cells; greater effects were demonstrated by 7 b. Molecular modelling analysis provides insight into a plausible mechanism of action.

Superficial Dermatophytosis across the World's Populations: Potential Benefits from Nanocarrier-Based Therapies and Rising Challenges.

The most prevalent infection in the world is dermatophytosis, which is a major issue with high recurrence and can affect the entire body including the skin, hair, and nails. The major goal of this Review is to acquire knowledge about cutting-edge approaches for treating dermatophytosis efficiently by adding antifungals to formulations based on nanocarriers in order to overcome the shortcomings of standard treatment methods. Updates on nanosystems and research developments on animal and clinical investigations are also presented. Along with the currently licensed formulations, the investigation also emphasizes novel therapies and existing therapeutic alternatives that can be used to control dermatophytosis. The Review also summarizes recent developments on the prevalence, management approaches, and disadvantages of standard dosage types. There are a number of therapeutic strategies for the treatment of dermatophytosis that have good clinical cure rates but also drawbacks such as antifungal drug resistance and unfavorable side effects. To improve therapeutic activity and get around the drawbacks of the traditional therapy approaches for dermatophytosis, efforts have been described in recent years to combine several antifungal drugs into new carriers. These formulations have been successful in providing improved antifungal activity, longer drug retention, improved effectiveness, higher skin penetration, and sustained drug release.

Klebsiella keratitis presenting as a ring infiltrate in an adolescent girl.

The purpose of the study was to report a unique case of Klebsiella keratitis presenting as a ring infiltrate in an adolescent girl. A 16-year-old girl presented with decreased vision in the right eye preceding an episode of fever with a rash associated with burning micturition. The patient was examined after taking appropriate consent. The slit-lamp examination revealed a ring-shaped corneal infiltrate with an epithelial defect in her right eye. Corneal scrapings were sent for microbiological evaluation which revealed Gram-negative rods and culture identified it as extended-spectrum beta-lactamase-producing Klebsiella pneumoniae colonies. The patient showed a good response to topical fortified amikacin and tobramycin. For her systemic complaints, the pediatrician did a thorough investigative workup out of which blood culture showed growth of K. pneumoniae. Hence, intravenous antibiotics were given based on the antibiogram report and the patient recovered. After 2 weeks, a paracentral infiltrate in her left eye was noted followed by anterior uveitis. The patient responded well to the topical course of steroids along with aminoglycosides. Four months later, she had a recurrence of anterior uveitis in the right eye preceded by fever. Blood investigations were negative. Hence, a diagnosis of recurrent uveitis secondary to endogenous infection was made and the patient was successfully treated with a short course of topical steroids. The patient is on follow-up for the past 6 months and maintaining the best-corrected visual acuity of 20/20 OU with normal intraocular pressure and quiet anterior chamber (AC). This is the first clinical report describing a ring infiltrate in endogenous Klebsiella keratitis and emphasizes thorough workup for prompt treatment.

Development of indolealkylamine derivatives as potential multi-target agents for COVID-19 treatment.

COVID-19 is a complex disease with short-term and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. As many drugs targeting single targets showed only limited effectiveness against COVID-19, here, we aimed to explore a multi-target strategy. We synthesized a focused compound library based on C2-substituted indolealkylamines (tryptamines and 5-hydroxytryptamines) with activity for three potential COVID-19-related proteins, namely melatonin receptors, calmodulin and human angiotensin converting enzyme 2 (hACE2). Two molecules from the library, 5e and h, exhibit affinities in the high nanomolar range for melatonin receptors, inhibit the calmodulin-dependent calmodulin kinase II activity and the interaction of the SARS-CoV-2 Spike protein with hACE2 at micromolar concentrations. Both compounds inhibit SARS-CoV-2 entry into host cells and 5h decreases SARS-CoV-2 replication and MPro enzyme activity in addition. In conclusion, we provide a proof-of-concept for the successful design of multi-target compounds based on the tryptamine scaffold. Optimization of these preliminary hit compounds could potentially provide drug candidates to treat COVID-19 and other coronavirus diseases.

Social Media Listening to Understand the Lived Experience of Individuals in Europe With Metastatic Breast Cancer: A Systematic Search and Content Analysis Study.

Background: Despite a wealth of real-world data on metastatic breast cancer (mBC), insights into the lived experience are lacking. This study aimed to explore how the lived experience of mBC is described on social media. Methods: A predefined search string identified posts relevant to the lived experience of mBC from Twitter, patient forums, and blogs across 14 European countries. The final data set was analyzed using content analysis. Results: A total of 76,456 conversations were identified between November 1, 2018, and November 30, 2020. Twitter was the most commonly used social media platform across all 76,456 conversations from the raw data set (n = 61,165; 80%). Automated and manual relevancy checks followed by a final random sampling filter identified 820 conversations for content analysis. The majority of data from the raw data set was generated from the United Kingdom (n = 31,346; 41%). From this final data set, 61% of posts were authored by patients, 15% by friends and/or family members of patients, and 14% by caregivers. A total of 686 conversations described the patient journey (n = 686/820; 84%); 64% of these (n = 439) concerned breast cancer treatment, with approximately 40% of discussions regarding diagnosis and tests (n = 274/686) and less than 20% of discussions surrounding disease management (n = 123/686; 18%). Key themes relating to a lack of effective treatment, prolonged survival and associated quality of life, debilitating consequences of side effects, and the social impacts of living with mBC were identified. Conclusions: The findings from this study provided an insight into the lived experience of mBC. While retrospective data collection inherently limits the amount of demographic or clinical information that can be obtained from the population sample, social media listening studies offer training to healthcare professionals in communication, the importance of quality of life, organization of healthcare, and even the design of clinical trials. As new targeted therapies are gradually incorporated into clinical practice, innovative technologies, such as social media listening, have the potential to support regulatory procedures and drug toxicity monitoring, as well as provide the patient voice in the regulation of new and existing medicines.

Understanding the Lived Experiences of Patients With Melanoma: Real-World Evidence Generated Through a European Social Media Listening Analysis.

BACKGROUND: Cutaneous melanoma is an aggressive malignancy that is proposed to account for 90% of skin cancer-related mortality. Individuals with melanoma experience both physical and psychological impacts associated with their diagnosis and treatment. Health-related information is being increasingly accessed and shared by stakeholders on social media platforms. OBJECTIVE: This study aimed to assess how individuals living with melanoma across 14 European countries use social media to discuss their needs and provide their perceptions of the disease. METHODS: Social media sources including Twitter, forums, and blogs were searched using predefined search strings of keywords relating to melanoma. Manual and automated relevancy approaches filtered the extracted data for content that provided patient-centric insights. This contextualized data was then mined for insightful concepts around the symptoms, diagnosis, treatment, impacts, and lived experiences of melanoma. RESULTS: A total of 182,400 posts related to melanoma were identified between November 2018 and November 2020. Following exclusion of irrelevant posts and using random sampling methodology, 864 posts were identified as relevant to the study objectives. Of the social media channels included, Twitter was the most commonly used, followed by forums and blogs. Most posts originated from the United Kingdom (n=328, 38%) and Spain (n=138, 16%). Of the relevant posts, 62% (n=536) were categorized as originating from individuals with melanoma. The most frequently discussed melanoma-related topics were treatment (436/792, 55%), diagnosis and tests (261/792, 33%), and remission (190/792, 24%). The majority of treatment discussions were about surgery (292/436, 67%), followed by immunotherapy (52/436, 12%). In total, 255 posts discussed the impacts of melanoma, which included emotional burden (n=179, 70%), physical impacts (n=61, 24%), effects on social life (n=43, 17%), and financial impacts (n=10, 4%). CONCLUSIONS: Findings from this study highlight how melanoma stakeholders discuss key concepts associated with the condition on social media, adding to the conceptual model of the patient journey. This social media listening approach is a powerful tool for exploring melanoma stakeholder perspectives, providing insights that can be used to corroborate existing data and inform future studies.

Alterations of Oxidative Stress Indicators, Antioxidant Enzymes, Soluble Sugars, and Amino Acids in Mustard [Brassica juncea (L.) Czern and Coss.] in Response to Varying Sowing Time, and Field Temperature.

The impact of elevated temperature at the reproductive stage of a crop is one of the critical limitations that influence crop growth and productivity globally. This study was aimed to reveal how sowing time and changing field temperature influence on the regulation of oxidative stress indicators, antioxidant enzymes activity, soluble sugars (SS), and amino acids (AA) in Indian Mustard. The current study was carried out during the rabi 2017-2018 and 2018-2019 where, five varieties of mustard viz. Pusa Mustard 25 (PM-25) (V1), PM-26 (V2), BPR-541-4 (V3), RH-406 (V4), and Urvashi (V5) were grown under the field conditions on October 30 (normal sowing; S1), November 18 (late sowing; S2) and November 30 (very late sowing; S3) situations. The S1 and S3 plants, at mid-flowering stage, showed a significant variation in accumulation of SS (8.5 and 17.3%), free AA (235.4 and 224.6%), and proline content (118.1 and 133%), respectively, and played a crucial role in the osmotic adjustment under stress. The results showed that S3 sowing, exhibited a significant induction of the hydrogen peroxide (H2O2) (110.2 and 86.6%) and malondialdehyde (23.5 and 47.5%) concentrations, respectively, which indicated the sign of oxidative stress in plants. Interestingly, the polyphenol oxidase, peroxidase, superoxide dismutase, and catalase enzyme activities were also significantly increased in S3 plants compared to S1 plants, indicating their significant roles in ameliorating the oxidative stress. Furthermore, the concentration of fatty acid levels such as palmitic, stearic, oleic, and linoleic acids level also significantly increased in S3 plants, which influenced the seed and oil quality. The study suggests that the late sowing significantly impaired the biochemical mechanisms in Indian mustard. Further, the mustard variety V4 (RH-406) was found to be effective for cultivation as well as environmental stress adoption in Indian soils, and it could be highly useful in breeding for developing heat-tolerant genotypes for ensuring the food security.

Understanding the lived experience of lung cancer: a European social media listening study.

BACKGROUND: Social media platforms are increasingly being used by stakeholders to generate, access, and share health-related information and experiences. Lung cancer is the most common cancer, impacting > 2 million patients globally. This observational study utilized a social listening approach to analyze social media trends and gain insights into stakeholder perceptions of lung cancer. METHODS: This social media study retrospectively collated data from open access blogs, forums, and social networking sites. Social media posts were collected between June 2019-May 2020 from 14 European countries. Using social media aggregator tools, posts comprising lung cancer and non-small cell lung cancer-specific terms were extracted. Manual and automated relevancy algorithms filtered the extracted information to provide the relevant dataset. This contextualized dataset was further mined to generate the final data for analysis. RESULTS: Of 1360 conversations analyzed, 42% were generated by patients/caregivers and 14% by healthcare professionals (HCPs). A majority of patients were 51-70 years old (approximately 50%) and 91% (n = 500/550) had late-stage cancer. Treatment (35%) and disease awareness (30%) were among the most discussed topic of the patient journey. Although the overall treatment sentiment was neutral, chemotherapy was the treatment type with the highest associated negative sentiment (28%); fewer negative sentiments were associated with immunotherapy (9%) and targeted therapy (2%), due to perceptions of longer survival outcomes and fewer side effects. In conversations that discussed clinical endpoints, "survivability" and "overall survival" (47 and 30%, respectively; n = 539) were most frequently mentioned by stakeholders. HCPs mostly used technical terms, whereas patients and caregivers used colloquial terms such as "getting rid of cancer". Emotional wellness was identified to have a huge impact on quality of life in lung cancer. Delay or treatment cancellations due to COVID-19, lack of effective treatments and funding, and lack of empathy by physicians emerged as the key unmet needs among patients/caregivers. CONCLUSIONS: Social listening proved to be an effective tool to explore stakeholders' perceptions and their key unmet needs, typically not available in published literature or databases, and provides HCPs with valuable insights into the distress, doubts, and needs of lung cancer patients and caregivers.

Tuning Potency of Bioactive Molecules via Polymorphic Modifications: A Case Study.

Polymorphism in drugs and bioactive molecules is not uncommon, and it has remained as one of the critical issues in drug development processes. While improving physicochemical properties of bioactive molecules has been a prime focus of the pharmaceutical chemists, not much efforts have been put toward the improvement of their potency via polymorphic modifications. Here, we consider five cases of 5-arylidene-2-aminothiazolidinones derivatives, the known anticancer agents, and discover eights polymorphs in three out of the five cases. We perform systematic crystallization experiments and detailed crystal structure analysis of the eight polymorphs and two compounds, estimate both their energetic and thermal stabilities, and compare their solid state properties. We also compare in-solution properties, e.g., equilibrium solubility, intrinsic dissolution rate, and phase stability, of three polymorphs of one of the cases. Further, we study the extent of inhibition imposed by those eight polymorphs and seven bulk and crystal forms of the compounds on the proliferation of MCF7 breast cancer cells and also the extent of their binding to the isozyme γ-enolase. Furthermore, we perform MD simulations on the eight polymorphs and one compound to estimate and compare their binding affinity with γ-enolase. Our experimental and MD simulation analyses in general emphasize the importance of polymorphism in improving the biological potency of individual molecules.

Exploratory studies with NX-13: oral toxicity and pharmacokinetics in rodents of an orally active, gut-restricted first-in-class therapeutic for IBD that targets NLRX1.

Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is an emerging therapeutic target for a spectrum of human diseases. NX-13 is a small molecule therapeutic designed to target and activate NLRX1 to induce immunometabolic changes resulting in lower inflammation and therapeutic responses in inflammatory bowel disease (IBD). This study investigates the safety of NX-13 in a seven-day, repeat-dose general toxicity study in male and female Sprague Dawley rats at oral doses of 500 and 1000 mg/kg. Weights, clinical signs, functional observational battery, clinical pathology and histopathology were used for evaluation. Daily oral dosing of NX-13 up to 1000 mg/kg did not result in any changes in weight, abnormal clinical signs or behavior. No significant differences were observed between treated and control rats in hematology or blood biochemistry. Histopathological evaluation of 12 tissues demonstrated no differences between controls and treated rats. There were no changes in weights of brain, heart, kidney, liver or spleen. Pharmacokinetic analysis of a single oral dose of NX-13 at 10 mg/kg in Sprague Dawley rats provided a maximum plasma concentration of 57 ng/mL at 0.5 h post-dose. Analysis of colon tissue after oral dosing with 1 and 10 mg/kg indicated high peak concentrations (10 and 100 µg/g, respectively) that scale in a dose-proportional manner. These experiments suggest that NX-13 is safe and well-tolerated in rats given oral doses as high as 1000 mg/kg with a favorable gastrointestinal localized pharmacokinetic profile, confirming NX-13 as a promising therapeutic for Crohn's disease and ulcerative colitis.

First-in-class topical therapeutic omilancor ameliorates disease severity and inflammation through activation of LANCL2 pathway in psoriasis.

Psoriasis (PsO) is a complex immune-mediated disease that afflicts 100 million people. Omilancor is a locally-acting, small molecule that selectively activates the Lanthionine Synthetase C-like 2 (LANCL2) pathway, resulting in immunoregulatory effects at the intersection of immunity and metabolism. Topical omilancor treatment in an imiquimod-induced mouse model of PsO ameliorates disease severity, epidermal hyperplasia and acanthosis. Further, pharmacological activation of LANCL2 results in significant downregulation of proinflammatory markers including local reduction of IL17, and infiltration of proinflammatory cell subsets. These therapeutic effects were further validated in an IL-23 PsO model. This model reported increased preservation of homeostatic skin structure, accompanied by a decreased infiltration of proinflammatory T cell subsets. In CD4+ T cells and Th17 cells, the LANCL2 pathway regulates proinflammatory cytokine production, proliferation and glucose metabolism. Metabolically, the loss of Lancl2 resulted in increased glycolytic rates, lactate production and upregulated enzymatic activity of hexokinase and lactate dehydrogenase (LDH). Inhibition of LDH activity abrogated the increased proliferation rate in Lancl2-/- CD4+ T cells. Additionally, topical omilancor treatment decreased the metabolic upregulation in keratinocytes, keratinocyte hyperproliferation and expression of inflammatory markers. Omilancor is a promising topical, LANCL2-targeting therapeutic candidate for the treatment of PsO and other dermatology indications.

Artificial night light alters ecosystem services provided by biotic components.

The global catastrophe of natural biodiversity and ecosystem services are expedited with the growing human population. Repercussions of artificial light at night ALAN are much wider, as it varies from unicellular to higher organism. Subsequently, hastened pollution and over exploitation of natural resources accelerate the expeditious transformation of climatic phenomenon and further cause global biodiversity losses. Moreover, it has a crucial role in global biodiversity and ecosystem services losses via influencing the ecosystem biodiversity by modulating abundance, number and aggregation at every levels as from individual to biome levels. Along with these affects, it disturbs the population, genetics and landscape structures by interfering inter- and intra-species interactions and landscape formation processes. Furthermore, alterations in normal light/dark (diurnal) signalling disrupt the stable physiological, biochemical, and molecular processes and modulate the regulating, cultural and provisioning ecosystem services and ultimately disorganize the stable ecosystem structure and functions. Moreover, ALAN reshapes the abiotic component of the ecosystem, and as a key component of global warming via producing greenhouse gases via emitting light. By taking together the above facts, this review highlights the impact of ALAN on the ecosystem and its living and non-living components, emphasizing to the terrestrial and aquatic ecosystem. Further, we summarize the means of minimizing strategies of ALAN in the environment, which are very crucial to reduce the further spread of night light contamination in the environment and can be useful to minimize the drastic impacts on the ecosystem.

Crucial Cell Signaling Compounds Crosstalk and Integrative Multi-Omics Techniques for Salinity Stress Tolerance in Plants.

In the era of rapid climate change, abiotic stresses are the primary cause for yield gap in major agricultural crops. Among them, salinity is considered a calamitous stress due to its global distribution and consequences. Salinity affects plant processes and growth by imposing osmotic stress and destroys ionic and redox signaling. It also affects phytohormone homeostasis, which leads to oxidative stress and eventually imbalances metabolic activity. In this situation, signaling compound crosstalk such as gasotransmitters [nitric oxide (NO), hydrogen sulfide (H2S), hydrogen peroxide (H2O2), calcium (Ca), reactive oxygen species (ROS)] and plant growth regulators (auxin, ethylene, abscisic acid, and salicylic acid) have a decisive role in regulating plant stress signaling and administer unfavorable circumstances including salinity stress. Moreover, recent significant progress in omics techniques (transcriptomics, genomics, proteomics, and metabolomics) have helped to reinforce the deep understanding of molecular insight in multiple stress tolerance. Currently, there is very little information on gasotransmitters and plant growth regulator crosstalk and inadequacy of information regarding the integration of multi-omics technology during salinity stress. Therefore, there is an urgent need to understand the crucial cell signaling crosstalk mechanisms and integrative multi-omics techniques to provide a more direct approach for salinity stress tolerance. To address the above-mentioned words, this review covers the common mechanisms of signaling compounds and role of different signaling crosstalk under salinity stress tolerance. Thereafter, we mention the integration of different omics technology and compile recent information with respect to salinity stress tolerance.

Developing C2-Aroyl Indoles as Novel Inhibitors of IDO1 and Understanding Their Mechanism of Inhibition via Mass Spectroscopy, QM/MM Calculations and Molecular Dynamics Simulation.

Indoleamine-2,3-dioxygenase (IDO1) and tryptophan dioxygenases are two heme based metalloenzymes that catalyze the tryptophan oxidation reaction by inserting molecular dioxygen to cleave the pyrrole ring. The mechanism of such ring cleavage reaction is of carcinogenic importance as the malignant tumors recruit this mechanism for immune invasion. In the presence study, we have synthesized a Novel C2 aroyl indoles inhibitor, 8d, which shows significant inhibition of 180 nM at IC50 scale. The binding and conformational changes that transpire after inhibitor binding were thoroughly studied by molecular docking and MD simulations. The subsequent QM/MM (Quantum Mechanical/Molecular Mechanical) calculations were used to proposed the mechanism of inhibition. The QM/MM calculations show that the reaction proceeds via multistep processes where the dioxygen insertion to the substrate 8a is the rate determining process. Theoretical mechanism is further supported by mass spectroscopy, and drug metabolism/pharmacokinetics study (DMPK) and metabolic stability of compound 8d was investigated in rat and human liver microsomes.

Acacia from a Breeding and Biotechnological Perspective: A Review.

Members of genus Acacia comprises of trees used as fuelwood, timber and fodder. Moreover, some parts of plants are also used for their therapeutic properties. The development and applications of breeding and biotechnological tools are advancing at a significantly fast rate. Molecular markers and genomics offer vital information with regard to the inherited variation. The aim of this study to complied and discussed the developments in molecular maker technology, genomics and genetic engineering concerning genus Acacia. Overall, this information will be useful to gain awareness about the crucial trees in the genus Acacia from breeding and a biotechnological perspective.