Visible Light-sensitized CO2 Methanation along a Relaxed Heat Available Route.

In photocatalysis, the resulted heat by the relaxation of most of incident light no longer acts as the industrially favorite driving force back to the target photo-reaction due to more or less the negative relation between photocatalytic efficiency and temperature. Here, we reported a visible light-sensitized protocol that completely reversed the negatively temperature-dependent efficiency in photo-driven CO2 methanation with saturated water vapor. Uniform Pt/N-TiO2/PDI self-assembly material decisively injects the excited electron of PDI sensitizer into N-TiO2 forming Ti-H hydride which is crucially temperature-dependent nucleophilic species to dominate CO2 methanation, rather than conventionally separated and trapped electrons on the conductor band. Meanwhile, the ternary composite lifts itself temperature from room temperature to 305.2 °C within 400s only by the failure excitation upon simulated sunlight of 2.5 W/cm2, and smoothly achieves CO2 methanation with a record number of 4.98 mmol g-1 h-1 rate, compared to less than 0.02 mmol g-1 h-1 at classic Pt/N-TiO2/UV photocatalysis without PDI sensitization. This approach can reuse ~53.9% of the relaxed heat energy from the incident light thereby allow high-intensity incident light as strong as possible within a flowing photo-reactor, opening the most likely gateways to industrialization.

Sigma metrics analysis of serology screening assays to enhance quality and efficiency in New Zealand blood services.

Sigma metric analysis was conducted across two New Zealand Blood Services (NZBS) laboratories (Auckland and Christchurch) to optimize quality control (QC) procedures. We evaluated five assays (anti-HCV, HIV Ag/Ab combo, HTLV-I/II, HBsAg, and Syphilis) using internal quality control (IQC) and third-party daily QC data extracted from four Architect i2000SR instruments during Jan 2 -31st, 2023. Mean, standard deviation (SD), and coefficient of variation (CV%) were calculated, assuming zero bias. Sigma metrics were determined using the Total Allowable Error (TEa %) based on difference between positive control mean and signal-to-cutoff (s/co) cut-off. Most assays exhibited CV% values ≤10 % except for HBsAg IQC (18.5 %) and anti-HCV third-party QC (13.4 %) at Christchurch. TEa % ranged from 38 % to 90 %. Overall, the assays demonstrated Six Sigma performance (σ > 6), except for HBsAg IQC (3.97) and anti-HCV third-party QC (5.46) at Christchurch. These high-quality serology assays can benefit from simplified QC design without compromising blood safety.

Tetrel bond affects the self-assembly of acetylcholine and its analogues and is an ancillary interaction in protein binding.

The -N+(CH3)3 residue is present in acetylcholine (ACh) and in many of its analogues which are used as selective ACh agonist or antagonists for human therapy.  The X-ray structures of four ACh derivatives show the presence of short and linear contacts between the C atoms of -N+(CH3)3 groups and lone pair possessing atoms.  These contacts can be rationalized as tetrel bonds (TtBs) thanks to their geometric features.  Interrogation of the Protein Data Bank suggests that similar -N+‒C···nucleophile contacts affect the details of the binding of ACh and its derivatives to proteins.  Quantum theory of atoms in molecules, noncovalent interaction plot, and natural bond orbital analyses consistently confirm that the -N+‒C···nucleophile contacts observed in small molecule crystals and in substrate/protein complexes are attractive in nature and can be rationalized as TtBs.  TtBs involving methyl groups of the -N+(CH3)3 moiety can be proposed as a new item in the palette of interactions allowing the compounds containing this pharmacophoric unit to bind to their target protein and/or to express their biological/pharmacological properties.

The timing of sleep spindles is modulated by the respiratory cycle in humans.

OBJECTIVE: Coupling of sleep spindles with cortical slow waves and hippocampus sharp-waves ripples is crucial for sleep-related memory consolidation. Recent literature evidenced that nasal respiration modulates neural activity in large-scale brain networks. In rodents, this respiratory drive strongly varies according to vigilance states. Whether sleep oscillations are also respiration-modulated in humans remains open. In this work, we investigated the influence of breathing on sleep spindles during non-rapid-eye-movement sleep in humans. METHODS: Full night polysomnography of twenty healthy participants were analysed. Spindles and slow waves were automatically detected during N2 and N3 stages. Spindle-related sigma power as well as spindle and slow wave events were analysed according to the respiratory phase. RESULTS: We found a significant coupling between both slow and fast spindles and the respiration cycle, with enhanced sigma activity and occurrence probability of spindles during the middle part of the expiration phase. A different coupling was observed for slow waves negative peaks which were rather distributed around the two respiration phase transitions. CONCLUSION: Our findings suggest that breathing cycle influences the dynamics of brain activity during non-rapid-eye-movement sleep. SIGNIFICANCE: This coupling may enable sleep spindles to synchronize with other sleep oscillations and facilitate information transfer between distributed brain networks.

Genomic SELEX Screening of Regulatory Targets of Transcription Factors.

The genome of Escherichia coli K-12 is transcribed by a single species of RNA polymerase. The selectivity of transcriptional targets is determined via interaction with one of seven species of the sigma subunit and a total of approximately 300 species of transcription factor (TFs). For comprehensive identification of the regulatory targets of these two groups of regulatory proteins on the genome, we developed an in vitro approach, "Genomic SELEX" (gSELEX) screening. Here we describe a detailed protocol of the gSELEX screening system, which uses purified regulatory proteins and fragments of genomic DNA from E. coli. Moreover, we describe methods and examples of results using cell-free synthetic proteins.

Use of the DMAIC Lean Six Sigma quality improvement framework to improve beta-lactam antibiotic adequacy in the critically ill.

Beta-lactam antibiotics are widely used in the intensive care unit due to their favorable effectiveness and safety profiles. Beta-lactams given to patients with sepsis must be delivered as soon as possible after infection recognition (early), treat the suspected organism (appropriate), and be administered at a dose that eradicates the infection (adequate). Early and appropriate antibiotic delivery occurs in >90% of patients, but less than half of patients with sepsis achieve adequate antibiotic exposure. This project aimed to address this quality gap and improve beta-lactam adequacy using the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework. A multidisciplinary steering committee was formed, which completed a stakeholder analysis to define the gap in practice. An Ishikawa cause and effect (Fishbone) diagram was used to identify the root causes and an impact/effort grid facilitated prioritization of interventions. An intervention that included bundled education with the use of therapeutic drug monitoring (TDM; i.e. drug-level testing) was projected to have the highest impact relative to the amount of effort and selected to address beta-lactam inadequacy in the critically ill. The education and TDM intervention were deployed through a Plan, Do, Study, Act cycle. In the 3 months after "go-live," 54 episodes of beta-lactam TDM occurred in 41 unique intensive care unit patients. The primary quality metric of beta-lactam adequacy was achieved in 94% of individuals after the intervention. Ninety-four percent of clinicians gauged the education provided as sufficient. The primary counterbalance of antimicrobial days of therapy, a core antimicrobial stewardship metric, was unchanged over time (favorable result; P = .73). Application of the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework effectively improved beta-lactam adequacy in critically ill patients. The approach taken in this quality improvement project is widely generalizable to other drugs, drug classes, or settings to increase the adequacy of drug exposure.

Computational Design of Bidentate Hypervalent Iodine Catalysts in Halogen Bond-Mediated Organocatalysis.

In recent years, halogen bond-based organocatalysis has garnered significant attention as an alternative to hydrogen-based catalysis, capturing considerable interest within the scientific community. This transition has witnessed the evolution of catalytic scaffolds from monodentate to bidentate architectures, and from monovalent to hypervalent species. In this DFT-based study, we explored a bidentate hypervalent iodine(III)-based system that has already undergone experimental validation. Additionally, we explore various functionalisations (-CF$_3$, -CH$_3$, -tBu, -OH, -OMe, -NO$_2$, -CN) and scaffold modifications, such as sulfur oxidation, theoretically proposed for an indole-based Michael addition. The investigated systems favour bidentate O-type binding, underlining the importance of ligand coordination in catalytic activity. Electron-deficient scaffolds exhibited stronger binding and lower activation energies, indicating the pivotal role of electronic properties for $\sigma$-hole-based catalysis. Of these groups, Lewis-base-like moieties formed stabilising intramolecular interactions with hypervalent iodines when in the ortho-position. Furthermore, inductive electron withdrawal was deemed more effective than mesomeric withdrawal in enhancing catalytic efficacy for these systems. Lastly, increasing sulfur oxidation was theoretically proven to improve catalytic activity significantly.

Deletions of conserved extracytoplasmic function sigma factors-encoding genes in Streptomyces have a major impact on secondary metabolism.

BACKGROUND: Ethanol shock significantly affects expression of over 1200 genes in Streptomyces venezuelae NRRL B-65,442, including those involved in secondary metabolite biosynthesis and a cryptic gene pepX, which encodes a 19-amino acid peptide with an unknown function. RESULTS: To establish a possible correlation between the PepX peptide and secondary metabolism in S. venezuelae, its gene was deleted, followed by analyses of the transcriptome and secondary metabolome of the mutant. Although the secondary metabolome of the pepX mutant was not strongly affected, pepX deletion, similar to ethanol shock, mostly resulted in downregulated expression of secondary metabolite biosynthesis gene clusters (BGCs). At the same time, there was a reverse correlation between the expression of certain extracytoplasmic function sigma factors (ECFs) and several BGCs. Individual deletions of three selected ECF-coding genes conserved in Streptomyces that were upregulated upon both pepX deletion and ethanol shock, had a profound positive effect on the expression of BGCs, which also correlated with the overproduction of specific secondary metabolites. Deletion of one such ECF-coding gene in a marine sponge-derived Streptomyces sp. also significantly altered the secondary metabolite profile, suggesting an important role of this ECF in the regulation of secondary metabolism. CONCLUSIONS: These findings pave the way for the activation or upregulation of BGCs in Streptomyces bacteria harboring genes for ECFs homologous to those identified in this study, hereby assisting in the discovery of novel bioactive secondary metabolites.

Assessment of risk factors to Green, Lean, Six Sigma adoption in construction sector: Integrated ISM-MICMAC approach.

The construction industry consumes significant resources, emits considerable pollutants, and generates substantial waste. Green, Lean, Six Sigma (GLS) is an emerging paradigm to control waste, carbon footprint, resource conservation, non-value-added activities, and cost. However, limited focus has been given to the risks involved in GLS construction projects (GLSCPs). This research explored risk factors (RFs) to GLSCPs based on literature review and expert judgments. Brainstorming sessions were conducted to validate the RFs and establish mutual interactions among them through experts' opinions. A 4-level structural model was extracted through Interpretive structural modeling (ISM). The Matriced Impacts Croise's Multiplication Appliqée a UN Classement (MICMAC) was integrated to assess the 'driving' and 'dependence' power of the RFs. The results show that all RFs are crucial and impact GLSCPs, but the most critical are 'unstable inflation,' 'fluctuations in interest rate,' and 'fluctuations in exchange rate.' This study enhances managers' and policymakers' understanding of RFs associated with GLSCPs and supports effective risk management for successful GLS implementation in construction projects.

Reducing turnaround time for routine outpatient biochemical tests through Lean Six Sigma: A case study in China.

BACKGROUND: Routine clinical biochemistry tests are crucial for clinical diagnostics and play a key role in enhancing outpatient turnover efficiency and patient satisfaction. This study aimed to implement Lean Six Sigma in the biochemistry laboratory of a hospital in China to improve efficiency and quality by reducing turnaround time. METHODS: The study was conducted from January to December 2023, using the DMAIC (Define, Measure, Analyze, Improve, Control) framework, and employed tools such as the voice of the customer, Value Stream Mapping, '5 whys' technique, Nominal Group Technique, and Pareto chart. RESULTS: The turnaround time for outpatient routine clinical biochemistry tests was reduced from 139 min to 58 min (p < 0.05), effectively increasing both patient and physician satisfaction. CONCLUSIONS: Lean Six Sigma aimed to reduce the turnaround time for biochemical tests have significant advantages. This study confirms the effectiveness of Lean Six Sigma in a Chinese clinical laboratory setting and provides guidance for optimizing efficiency in global clinical laboratories with limited implementation experience, constrained technical and equipment resources, and high demand for medical diagnostics.

Microstructural Evolution of Quaternary AlCoCrNi High-Entropy Alloys during Heat Treatment.

This study examines the microstructural evolution and mechanical properties of quaternary AlCoCrNi high-entropy alloys after heat treatment at 873 K for 72 and 192 h. The changes in nanostructure and phase transformation based on the heat treatment duration were as follows: B2 dendrite + BCC interdendrite and sigma phases after 72 h; B2 dendrite and interdendritic sigma phases + BCC after 192 h. After annealing, the morphology of the dendritic region shifted from spherical to needle-like, and the interdendritic region transformed from a spinodal-like to a plate-like morphology. Additionally, a phase transformation was observed in the dendritic regions of the annealed alloys at the nano-scale. The presence of the sigma phase in AlCoCrNi high-entropy alloys significantly improved the yield strength to around 1172 MPa; nevertheless, it decreased the compressive strain rapidly to 0.62%.

The Effect of KSK-94, a Dual Histamine H3 and Sigma-2 Receptor Ligand, on Adipose Tissue in a Rat Model of Developing Obesity.

BACKGROUND: Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H3/sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott's A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment. METHODS: Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies. RESULTS: The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue. CONCLUSION: Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94.

Enhanced fatty acid biosynthesis by Sigma28 in stringent responses contributes to multidrug resistance and biofilm formation in Helicobacter pylori.

The metabolic state of bacteria significantly contributes to their resistance to antibiotics; however, the specific metabolic mechanisms conferring antimicrobial resistance in Helicobacter pylori remain largely understudied. Employing transcriptomic and non-targeted metabolomics, we characterized the metabolic reprogramming of H. pylori when challenged with antibiotic agents. We observed a notable increase in both genetic and key proteomic components involved in fatty acid biosynthesis. Inhibition of this pathway significantly enhanced the antibiotic susceptibility of the sensitive and multidrug-resistant H. pylori strains while also disrupting their biofilm-forming capacities. Further analysis revealed that antibiotic treatment induced a stringent response, triggering the expression of the hp0560-hp0557 operon regulated by Sigma28 (σ28). This activation in turn stimulated the fatty acid biosynthetic pathway, thereby enhancing the antibiotic tolerance of H. pylori. Our findings reveal a novel adaptive strategy employed by H. pylori to withstand antibiotic stress.

Physiological Roles of an Acinetobacter-specific σ Factor.

The Gram-negative pathogen Acinetobacter baumannii is considered an "urgent threat" to human health due to its propensity to become antibiotic resistant. Understanding the distinct regulatory paradigms used by A. baumannii to mitigate cellular stresses may uncover new therapeutic targets. Many γ-proteobacteria use the extracytoplasmic function (ECF) σ factor, RpoE, to invoke envelope homeostasis networks in response to stress. Acinetobacter species contain the poorly characterized ECF "SigAb;" however, it is unclear if SigAb has the same physiological role as RpoE. Here, we show that SigAb is a metal stress-responsive ECF that appears unique to Acinetobacter species and distinct from RpoE. We combine promoter mutagenesis, motif scanning, and ChIP-seq to define the direct SigAb regulon, which consists of sigAb itself, the stringent response mediator, relA, and the uncharacterized small RNA, "sabS." However, RNA-seq of strains overexpressing SigAb revealed a large, indirect regulon containing hundreds of genes. Metal resistance genes are key elements of the indirect regulon, as CRISPRi knockdown of sigAb or sabS resulted in increased copper sensitivity and excess copper induced SigAb-dependent transcription. Further, we found that two uncharacterized genes in the sigAb operon, "aabA" and "aabB", have anti-SigAb activity. Finally, employing a targeted Tn-seq approach that uses CRISPR-associated transposons, we show that sigAb, aabA, and aabB are important for fitness even during optimal growth conditions. Our work reveals new physiological roles for SigAb and SabS, provides a novel approach for assessing gene fitness, and highlights the distinct regulatory architecture of A. baumannii.

"Sigma-1 receptor modulation by clemastine highlights its repurposing as neuroprotective agent against seizures and cognitive deficits in PTZ-kindled rats".

Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures alongside other neurological comorbidities. Cognitive impairment is the most frequent comorbidity secondary to progressive neurologic changes in epilepsy. Sigma 1 receptors (σ1 receptors) are involved in the neuroprotection and pathophysiology of both conditions and targeting these receptors may have the potential to modulate both seizures and comorbidities. The current research demonstrated the effect of clemastine (10 mg/kg, P.O.), a non-selective σ1 receptor agonist, on pentylenetetrazol (PTZ) (35 mg/kg, i.p., every 48 hours for 14 doses)-kindling rats by acting on σ1 receptors through its anti-inflammatory/antioxidant capacity. Clemastine and phenytoin (30 mg/kg, P.O.) or their combination were given once daily. Clemastine treatment showed a significant effect on neurochemical, behavioural, and histopathological analyses through modulation of σ1 receptors. It protected the kindling animals from seizures and attenuated their cognitive impairment in the Morris water maze test by reversing the PTZ hippocampal neuroinflammation/oxidative stress state through a significant increase in inositol-requiring enzyme 1 (IRE1), x-box binding protein 1 (XBP1), along with a reduction of total reactive oxygen species (TROS) and amyloid beta protein (Aß). The involvement of σ1 receptors in the protective effects of clemastine was confirmed by their abrogation when utilizing NE-100, a selective σ1 receptor antagonist. In light of our findings, modulating σ1 receptors emerges as a compelling therapeutic strategy for epilepsy and its associated cognitive impairments. The significant neuroprotective effects observed with clemastine underscore the potential of σ1 receptor-targeted treatments to address both the primary symptoms and comorbidities of neurological disorders.

Fine-Tuning Gene Expression in Bacteria by Synthetic Promoters.

Promoters are key genetic elements in the initiation and regulation of gene expression. A limited number of natural promoters has been described for the control of gene expression in synthetic biology applications. Therefore, synthetic promoters have been developed to fine-tune the transcription for the desired amount of gene product. Mostly, synthetic promoters are characterized using promoter libraries that are constructed via mutagenesis of promoter sequences. The strength of promoters in the library is determined according to the expression of a reporter gene such as gfp encoding green fluorescent protein. Gene expression can be controlled using inducers. The majority of the studies on gram-negative bacteria are conducted using the expression system of the model organism Escherichia coli while that of the model organism Bacillus subtilis is mostly used in the studies on gram-positive bacteria. Additionally, synthetic promoters for the cyanobacteria, which are phototrophic microorganisms, are evaluated, especially using the model cyanobacterium Synechocystis sp. PCC 6803. Moreover, a variety of algorithms based on machine learning methods were developed to characterize the features of promoter elements. Some of these in silico models were verified using in vitro or in vivo experiments. Identification of novel synthetic promoters with improved features compared to natural ones contributes much to the synthetic biology approaches in terms of fine-tuning gene expression.

Applying the six-sigma methodology to determine the limits of quality control (QC) tests for a specific linear accelerator.

PURPOSE: We aimed to show the framework of the six-sigma methodology (SSM) that can be used to determine the limits of QC tests for the linear accelerator (Linac). Limits for QC tests are individually determined using the SSM. METHODS AND MATERIALS: The SSM is based on the define-measure-analyze-improve-control (DMAIC) stages to improve the process. In the "define" stage, the limits of QC tests were determined. In the "measure" stage, a retrospective collection of daily QC data using a Machine Performance Check platform was performed from January 2020 to December 2022. In the "analyze" stage, the process of determining the limits was proposed using statistical analyses and process capability indices. In the "improve" stage, the capability index was used to calculate the action limits. The tolerance limit was established using the larger one of the control limits in the individual control chart (I-chart). In the "control" stage, daily QC data were collected prospectively from January 2023 to May 2023 to monitor the effect of action limits and tolerance limits. RESULTS: A total of 798 sets of QC data including beam, isocenter, collimation, couch, and gantry tests were collected and analyzed. The Collimation Rotation offset test had the min-Cp, min-Cpk, min-Pp, and min-Ppk at 2.53, 1.99, 1.59, and 1.25, respectively. The Couch Rtn test had the max-Cp, max-Cpk, max-Pp, and max-Ppk at 31.5, 29.9, 23.4, and 22.2, respectively. There are three QC tests with higher action limits than the original tolerance. Some data on the I-chart of the beam output change, isocenter KV offset, and jaw X1 exceeded the lower tolerance and action limit, which indicated that a system deviation occurred and reminded the physicist to take action to improve the process. CONCLUSIONS: The SSM is an excellent framework to use in determining the limits of QC tests. The process capability index is an important parameter that provides quantitative information on determining the limits of QC tests.

Amantadine for Traumatic Brain Injury-Supporting Evidence and Mode of Action.

Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions.

Tanshinone IIA Liposomes Treat Doxorubicin-Induced Glomerulonephritis by Modulating the Microenvironment of Fibrotic Kidneys.

Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-ß1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-ß1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.

Integration of molecular docking and molecular dynamics simulations with subtractive proteomics approach to identify the novel drug targets and their inhibitors in Streptococcus gallolyticus.

Streptococcus gallolyticus (Sg) is a non-motile, gram-positive bacterium that causes infective endocarditis (inflammation of the heart lining). Because Sg has gained resistance to existing antibiotics and there is currently no drug available, developing effective anti-Sg drugs is critical. This study combined core proteomics with a subtractive proteomics technique to identify potential therapeutic targets for Sg. Several bioinformatics approaches were used to eliminate non-essential and human-specific homologous sequences from the bacterial proteome. Then, virulence, druggability, subcellular localization, and functional analyses were carried out to specify the participation of significant bacterial proteins in various cellular processes. The pathogen's genome contained three druggable proteins, glucosamine-1phosphate N-acetyltransferase (GlmU), RNA polymerase sigma factor (RpoD), and pantetheine-phosphate adenylyltransferase (PPAT) which could serve as effective targets for developing novel drugs. 3D structures of target protein were modeled through Swiss Model. A natural product library containing 10,000 molecules from the LOTUS database was docked against therapeutic target proteins. Following an evaluation of the docking results using the glide gscore, the top 10 compounds docked against each protein receptor were chosen. LTS001632, LTS0243441, and LTS0236112 were the compounds that exhibited the highest binding affinities against GlmU, PPAT, and RpoD, respectively, among the compounds that were chosen. To augment the docking data, molecular dynamics simulations and MM-GBSA binding free energy were also utilized. More in-vitro research is necessary to transform these possible inhibitors into therapeutic drugs, though computer validations were employed in this study. This combination of computational techniques paves the way for targeted antibiotic development, which addresses the critical need for new therapeutic strategies against S. gallolyticus infections.