Evolutionary relevance of metabolite production in relation to marine sponge bacteria symbiont.

Sponges are habitats for a diverse community of microorganisms. Sponges provide shelter, whereas microbes provide a complementary defensive mechanism. Here, a symbiotic bacterium, identified as Bacillus spp., was isolated from a marine sponge following culture enrichment. Fermentation-assisted metabolomics using thin-layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS) indicated that marine simulated nutrition and temperature was the optimum in metabolite production represented by the highest number of metabolites and the diverse chemical classes when compared to other culture media. Following large-scale culture in potato dextrose broth (PDB) and dereplication, compound M1 was isolated and identified as octadecyl-1-(2',6'-di-tert-butyl-1'-hydroxyphenyl) propionate. M1, at screening concentrations up to 10 mg/ml, showed no activity against prokaryotic bacteria including Staphylococcus aureus and Escherichia coli, while 1 mg/ml of M1 was sufficient to cause a significant killing effect on eukaryotic cells including Candida albicans, Candida auris, and Rhizopus delemar fungi and different mammalian cells. M1 exhibited MIC50 0.97 ± 0.006 and 7.667 ± 0.079 mg/ml against C. albicans and C. auris, respectively. Like fatty acid esters, we hypothesize that M1 is stored in a less harmful form and upon pathogenic attack is hydrolyzed to a more active form as a defensive metabolite. Subsequently, [3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionic acid] (DTBPA), the hydrolysis product of M1, exhibited ~ 8-fold and 18-fold more antifungal activity than M1 against C. albicans and C. auris, respectively. These findings indicated the selectivity of that compound as a defensive metabolite towards the eukaryotic cells particularly the fungi, a major infectious agent to sponges. Metabolomic-assisted fermentation can provide a significant understanding of a triple marine-evolved interaction. KEY POINTS: • Bacillus species, closely related to uncultured Bacillus, is isolated from Gulf marine sponge • Metabolomic-assisted fermentations showed diverse metabolites • An ester with a killing effect against eukaryotes but not prokaryotes is isolated.

Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment.

The main protease of SARS-CoV-2 virus, Mpro, is an essential element for viral replication, and inhibitors targeting Mpro are currently being investigated in many drug development programs as a possible treatment for COVID-19. An in vitro pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for Mpro. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC50 value of 20.7 µM. Molecular modeling studies were performed to understand the binding characteristics of the identified compounds. The presence of a cyclohexenone warhead group facilitated covalent binding with the Cys145 residue of Mpro. Our results highlight the challenges of targeting Mpro protease and pave the way toward the discovery of potent lead molecules.

Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures.

Nitrogen and oxygen medium rings, in particular nine-membered rings, epitomize a unique area of chemical space that occurs in many natural products and biologically appealing compounds. The scarcity of 8- to 12-membered rings among clinically approved drugs is indicative of the difficulties associated with their synthesis, principally owing to the unfavorable entropy and transannular strain. We report here a scandium triflate-catalyzed reaction that allows for a modular access to a diverse collection of nine-membered ring heterocycles in a one-pot cascade and with complete diastereocontrol. This cascade features an intramolecular addition of an acyl group-derived enol to a α,ß-unsaturated carbonyl moiety, leading to N- and O-derived medium-ring systems. Computational studies using the density functional theory support the proposed mechanism. Additionally, a one-pot cascade leading to hexacyclic chromeno[3',4':2,3]indolizino[8,7-b]indole architectures, with six fused rings and four contiguous chiral centers, is reported. This novel cascade features many concerted events, including the formation of two azomethine ylides, [3 + 2]-cycloaddition, 1,3-sigmatropic rearrangement, Michael addition, and Pictet-Spengler reaction among others. Phenotypic screening of the resulting oxazonine collection identified chemical probes that regulate mitochondrial membrane potential, adenosine 5'-triphosphate contents, and reactive oxygen species levels in hepatoma cells (Hepa1-6), a promising approach for targeting cancer and metabolic disorders.

Escherichia coli and Pseudomonas aeruginosa lipopolysaccharide O-antigen ligases share similar membrane topology and biochemical properties.

WaaL is an inner membrane glycosyltransferase that catalyzes the transfer of O-antigen polysaccharide from its lipid-linked intermediate to a terminal sugar of the lipid A-core oligosaccharide, a conserved step in lipopolysaccharide biosynthesis. Ligation occurs at the periplasmic side of the bacterial cell membrane, suggesting the catalytic region of WaaL faces the periplasm. Establishing the membrane topology of the WaaL protein family will enable understanding its mechanism and exploit it as a potential antimicrobial target. Applying oxidative labeling of native methionine/cysteine residues, we previously validated a topological model for Escherichia coli WaaL, which differs substantially from the reported topology of the Pseudomonas aeruginosa WaaL, derived from the analysis of truncated protein reporter fusions. Here, we examined the topology of intact E. coli and P. aeruginosa WaaL proteins by labeling engineered cysteine residues with the membrane-impermeable sulfhydryl reagent polyethylene glycol maleimide (PEG-Mal). The accessibility of PEG-Mal to targeted engineered cysteine residues in both E. coli and P. aeruginosa WaaL proteins demonstrates that both ligases share similar membrane topology. Further, we also demonstrate that P. aeruginosa WaaL shares similar functional properties with E. coli WaaL and that E. coli WaaL may adopt a functional dimer conformation.

The LpxL acyltransferase is required for normal growth and penta-acylation of lipid A in Burkholderia cenocepacia.

Lipid A anchors the lipopolysaccharide (LPS) to the outer membrane and is usually composed of a hexa-acylated diglucosamine backbone. Burkholderia cenocepacia, an opportunistic pathogen, produces a mixture of tetra- and penta-acylated lipid A. "Late" acyltransferases add secondary acyl chains to lipid A after the incorporation of four primary acyl chains to the diglucosamine backbone. Here, we report that B. cenocepacia has only one late acyltransferase, LpxL (BCAL0508), which adds a myristoyl chain to the 2' position of lipid A resulting in penta-acylated lipid A. We also identified PagL (BCAL0788), which acts as an outer membrane lipase by removing the primary ß-hydroxymyristate (3-OH-C14:0) chain at the 3 position, leading to tetra-acylated lipid A. Unlike PagL, LpxL depletion caused reduced cell growth and defects in cell morphology, both of which were suppressed by overexpressing the LPS flippase MsbA (BCAL2408), suggesting that lipid A molecules lacking the fifth acyl chain contributed by LpxL are not good substrates for the flippase. We also show that intracellular B. cenocepacia within macrophages produced more penta-acylated lipid A, suggesting lipid A penta-acylation in B. cenocepacia is required not only for bacterial growth and morphology but also for adaptation to intracellular lifestyle.

Psychometric characteristics of the "General Oral Health Assessment Index (GOHAI) ¼ in a French representative sample of patients with schizophrenia.

BACKGROUND: The "General Oral Health Assessment Index" (GOHAI) was widely used in clinical or epidemiological studies worldwide, as it was available for use in different languages. Therefore, the aim of this study was to evaluate the psychometric characteristics of the GOHAI in a representative sample of patients with schizophrenia. METHODS: A total of 90 schizophrenic patients (in-patients and out-patients) were recruited from the participants of the "buccodor study" (NCT02167724) between March and September 2015. They were selected using a random stratified sampling method according to their age, sex, or residential area (urban/rural area). GOHAI validity (construct, predictive, concurrent and known group validity) and internal consistency (reliability) were tested. Test-retest reliability was evaluated in 32 subjects. RESULTS: The mean age was 47.34 (SD = 12.17). Internal consistency indicated excellent agreement, with a Cronbach's α value of 0.82 and average inter-item correlation of 0.65. Intraclass correlation coefficients for test-retest reliability with 95% confidence intervals were not significantly different (p > 0.05). Construct validity was supported by three factor that accounted for 60.94% of the variance observed. Predictive validity was corroborated as statistically significant differences were observed between a high GOHAI score, which was associated with self-perceived satisfaction with oral health, lower age and high frequency of toothbrushing. Concurrent validity was corroborated as statistically significant relationships were observed between the GOHAI scores and most objective measures of dental status. For known group validity, they was no significant difference of the mean GOHAI score between out or in-patients (p > 0.05). CONCLUSION: Acceptable psychometric characteristics of the GOHAI could help caregivers to develop ways to improve the Oral Health related Quality Of Life of schizophrenic patients. TRIAL REGISTRATION: Clinical Trials Gov NCT02167724 . Date registered 17 June, 2014.

Activation of Human Toll-like Receptor 4 (TLR4)·Myeloid Differentiation Factor 2 (MD-2) by Hypoacylated Lipopolysaccharide from a Clinical Isolate of Burkholderia cenocepacia.

Lung infection by Burkholderia species, in particular Burkholderia cenocepacia, accelerates tissue damage and increases post-lung transplant mortality in cystic fibrosis patients. Host-microbe interplay largely depends on interactions between pathogen-specific molecules and innate immune receptors such as Toll-like receptor 4 (TLR4), which recognizes the lipid A moiety of the bacterial lipopolysaccharide (LPS). The human TLR4·myeloid differentiation factor 2 (MD-2) LPS receptor complex is strongly activated by hexa-acylated lipid A and poorly activated by underacylated lipid A. Here, we report that B. cenocepacia LPS strongly activates human TLR4·MD-2 despite its lipid A having only five acyl chains. Furthermore, we show that aminoarabinose residues in lipid A contribute to TLR4-lipid A interactions, and experiments in a mouse model of LPS-induced endotoxic shock confirmed the proinflammatory potential of B. cenocepacia penta-acylated lipid A. Molecular modeling combined with mutagenesis of TLR4-MD-2 interactive surfaces suggests that longer acyl chains and the aminoarabinose residues in the B. cenocepacia lipid A allow exposure of the fifth acyl chain on the surface of MD-2 enabling interactions with TLR4 and its dimerization. Our results provide a molecular model for activation of the human TLR4·MD-2 complex by penta-acylated lipid A explaining the ability of hypoacylated B. cenocepacia LPS to promote proinflammatory responses associated with the severe pathogenicity of this opportunistic bacterium.

Elucidation of the Burkholderia cenocepacia hopanoid biosynthesis pathway uncovers functions for conserved proteins in hopanoid-producing bacteria.

Hopanoids are bacterial surrogates of eukaryotic membrane sterols and among earth's most abundant natural products. Their molecular fossils remain in sediments spanning more than a billion years. However, hopanoid metabolism and function are not fully understood. Burkholderia species are environmental opportunistic pathogens that produce hopanoids and also occupy diverse ecological niches. We investigated hopanoids biosynthesis in Burkholderia cenocepacia by deletion mutagenesis and structural characterization of the hopanoids produced by the mutants. The enzymes encoded by hpnH and hpnG were essential for production of all C35 extended hopanoids, including bacteriohopanetetrol (BHT), BHT glucosamine and BHT cyclitol ether. Deletion of hpnI resulted in BHT production, while ΔhpnJ produced only BHT glucosamine. Thus, HpnI is required for BHT glucosamine production while HpnJ is responsible for its conversion to the cyclitol ether. The ΔhpnH and ΔhpnG mutants could not grow under any stress condition tested, whereas ΔhpnI, ΔhpnJ and ΔhpnK displayed wild-type growth rates when exposed to detergent, but varying levels of sensitivity to low pH and polymyxin B. This study not only elucidates the biosynthetic pathway of hopanoids in B. cenocepacia, but also uncovers a biosynthetic role for the conserved proteins HpnI, HpnJ and HpnK in other hopanoid-producing bacteria.

Assessment of Helicobacter pylori cytotoxin-associated Gene A (Cag A) protein and its association with ferritin and vitamin B12 deficiencies among adult healthy asymptomatic residents in Sharjah, United Arab Emirates.

The United Arab Emirates (UAE) serves as an effective epidemiological site for assessing Helicobacter pylori (H. pylori) infection due to its diverse population. However, comprehensive studies on the prevalence of H. pylori in the UAE are notably scarce. In depth prevalence studies are needed as a preventive measure against gastric cancer and other emerging extra gastric diseases associated with H. pylori infection. Aim: This study aimed to assess H. pylori infection and its virulent oncoprotein, the Cytotoxin-Associated Gene (Cag A) and its association with ferritin and vitamin B12 deficiencies. Methods: The study was conducted on 1094 healthy asymptomatic volunteers residents in the Sharjah Emirate, UAE. Enzyme-linked immunosorbent assay (ELISA) was performed to assess H. pylori infection using H. pylori antibodies (IgG), and detection of CagA protein using Cag A antibody (IgG) in the human serum. Ferritin and vitamin B12 serum levels were assessed and correlated to H. pylori infection. Results: This study focuses mainly on the assessment of H. pylori and its virulent factor CagA, in relation to vitamin B12 and ferritin deficiencies. Remarkably, 49.6 % of the participants were detected positive for H. pylori, with over half of these cases involving CagA positive strains. Notably, among Emirati participants, 76.11 % of those with H. pylori infection were CagA positive. Statistical analysis revealed a significant correlation between H. pylori, CagA level, and ferritin/vitamin B12 deficiencies. Conclusion: These findings emphasize the importance of timely detection and eradication of H. pylori not only as a preventive strategy against gastric cancer but also as an effective strategy to rescue the adverse effects from ferritin and vitamin B12 deficiencies, thereby improving the overall health outcomes of individuals affected by H. pylori infection.

Aminoarabinose is essential for lipopolysaccharide export and intrinsic antimicrobial peptide resistance in Burkholderia cenocepacia(†).

One common mechanism of resistance against antimicrobial peptides in Gram-negative bacteria is the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) to the lipopolysaccharide (LPS) molecule. Burkholderia cenocepacia exhibits extraordinary intrinsic resistance to antimicrobial peptides and other antibiotics. We have previously discovered that unlike other bacteria, B. cenocepacia requires L-Ara4N for viability. Here, we describe the isolation of B. cenocepacia suppressor mutants that remain viable despite the deletion of genes required for L-Ara4N synthesis and transfer to the LPS. The absence of L-Ara4N is the only structural difference in the LPS of the mutants compared with that of the parental strain. The mutants also become highly sensitive to polymyxin B and melittin, two different classes of antimicrobial peptides. The suppressor phenotype resulted from a single amino acid replacement (aspartic acid to histidine) at position 31 of LptG, a protein component of the multi-protein pathway responsible for the export of the LPS molecule from the inner to the outer membrane. We propose that L-Ara4N modification of LPS provides a molecular signature required for LPS export and proper assembly at the outer membrane of B. cenocepacia, and is the most critical determinant for the intrinsic resistance of this bacterium to antimicrobial peptides.

The Burkholderia cenocepacia sensor kinase hybrid AtsR is a global regulator modulating quorum-sensing signalling.

Burkholderia cenocepacia is commonly found in the environment and also as an important opportunistic pathogen infecting patients with cystic fibrosis. Successful infection by this bacterium requires coordinated expression of virulence factors, which is achieved through different quorum sensing (QS) regulatory systems. Biofilm formation and Type 6 secretion system (T6SS) expression in B. cenocepacia K56-2 are positively regulated by QS and negatively regulated by the sensor kinase hybrid AtsR. This study reveals that in addition to affecting biofilm and T6SS activity, the deletion of atsR in B. cenocepacia leads to overproduction of other QS-regulated virulence determinants including proteases and swarming motility. Expression of the QS genes, cepIR and cciIR, was upregulated in the ΔatsR mutant and resulted in early and increased N-acylhomoserine lactone (AHL) production, suggesting that AtsR plays a role in controlling the timing and fine-tuning of virulence gene expression by modulating QS signalling. Furthermore, a ΔatsRΔcepIΔcciI mutant could partially upregulate the same virulence determinants indicating that AtsR also modulates the expression of virulence genes by a second mechanism, independently of any AHL production. Together, our results strongly suggest that AtsR is a global virulence regulator in B. cenocepacia.

GDF15 plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets.

Mounting evidence points to a link between growth differentiation factor-15 (GDF15) expression and the onset and progression of diabetes mellitus. However, the exact role of GDF15 in pancreatic ß-cell function is unclear. To examine the role of GDF15 in ß-cell function, bioinformatics analysis and functional experiments involving GDF15 silencing and overexpression were performed in INS-1 cells and human islets. Public microarray and RNA-seq expression data showed that islets obtained from diabetic donors express high levels of GDF15 compared to islets obtained from normal donors. Moreover, analysis of RNA-seq expression data revealed that GDF15 expression correlates positively with that of insulin (INS), KCNJ11, GLUT1, MAFA, INSR and negatively with that of Glucokinase (GCK) and Alpha-Ketoglutarate Dependent Dioxygenase (FTO). No T2D-associated genetic variants in the GDF15 were found to pass genome-wide significance in the TIGER portal. Expression silencing of Gdf15 in INS-1 cells reduced insulin release, glucose uptake levels, increased reactive oxygen species (ROS) production and apoptosis levels. While Gdf15-silenced cells downregulated mRNA expression of Ins, Pdx1, Mafa, and Glut2 genes, its overexpression human islets was associated with increased insulin secretion and upregulated expression of MAFA and GLUT1 but not INS or GCK. Silencing of Pdx1 or Mafa in INS-1 cells did not affect the expression of GDF15. These findings suggest that GDF15 plays a significant role in pancreatic ß-cell function.

Alpha to Omicron (Variants of Concern): Mutation Journey, Vaccines, and Therapy.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initially emerged in December 2019 and has subsequently expanded globally, leading to the ongoing pandemic. The extensive spread of various SARS-CoV-2 variants possesses a serious public health threat. An extensive literature search along with deep analysis was performed to describe and evaluate the characteristics of SARS-CoV-2 variants of concern in relation to the effectiveness of the current vaccines and therapeutics. The obtained results showed that several significant mutations have evolved during the COVID-19 pandemic. The developed variants and their various structural mutations can compromise the effectiveness of several vaccines, escape the neutralizing antibodies, and limit the efficiency of available therapeutics. Furthermore, deep analysis of the available data enables the prediction of the future impact of virus mutations on the ongoing pandemic along with the selection of appropriate vaccines and therapeutics.

Antimicrobial activity of nature-inspired molecules against multidrug-resistant bacteria.

Multidrug-resistant bacterial infections present a serious challenge to global health. In addition to the spread of antibiotic resistance, some bacteria can form persister cells which are tolerant to most antibiotics and can lead to treatment failure or relapse. In the present work, we report the discovery of a new class of small molecules with potent antimicrobial activity against Gram-positive bacteria and moderate activity against Gram-negative drug-resistant bacterial pathogens. The lead compound SIMR 2404 had a minimal inhibitory concentration (MIC) of 2 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA). The MIC values against Gram-negative bacteria such as Escherichia coli and Actinobacteria baumannii were between 8-32 µg/mL. Time-kill experiments show that compound SIMR 2404 can rapidly kill tested bacteria. Compound SIMR 2404 was also found to rapidly kill MRSA persisters which display high levels of tolerance to conventional antibiotics. In antibiotic evolution experiments, MRSA quickly developed resistance to ciprofloxacin but failed to develop resistance to compound SIMR 2404 even after 24 serial passages. Compound SIMR 2404 was not toxic to normal human fibroblast at a concentration of 4 µg/mL which is twice the MIC concentration against MRSA. However, at a concentration of 8 µg/mL or higher, it showed cytotoxic activity indicating that it is not ideal as a candidate against Gram-negative bacteria. The acceptable toxicity profile and rapid antibacterial activity against MRSA highlight the potential of these molecules for further studies as anti-MRSA agents.

The Achromobacter type 3 secretion system drives pyroptosis and immunopathology via independent activation of NLRC4 and NLRP3 inflammasomes.

How the opportunistic Gram-negative pathogens of the genus Achromobacter interact with the innate immune system is poorly understood. Using three Achromobacter clinical isolates from two species, we show that the type 3 secretion system (T3SS) is required to induce cell death in human macrophages by inflammasome-dependent pyroptosis. Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 undergo pyroptosis upon bacterial internalization, but those deficient in both NLRC4 and NLRP3 do not, suggesting either sensor mediates pyroptosis in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicates that the intracellular bacteria reside in a late phagolysosome. Using an intranasal mouse infection model, we observe that Achromobacter damages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate that Achromobacter species can survive phagocytosis by promoting macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction in a T3SS-dependent manner.

Multi-Omics Profiling of Candida albicans Grown on Solid Versus Liquid Media.

Candida albicans is a common pathogenic fungus that presents a challenge to healthcare facilities. It can switch between a yeast cell form that diffuses through the bloodstream to colonize internal organs and a filamentous form that penetrates host mucosa. Understanding the pathogen's strategies for environmental adaptation and, ultimately, survival, is crucial. As a complementary study, herein, a multi-omics analysis was performed using high-resolution timsTOF MS to compare the proteomes and metabolomes of Wild Type (WT) Candida albicans (strain DK318) grown on agar plates versus liquid media. Proteomic analysis revealed a total of 1793 proteins and 15,013 peptides. Out of the 1403 identified proteins, 313 proteins were significantly differentially abundant with a p-value < 0.05. Of these, 156 and 157 proteins were significantly increased in liquid and solid media, respectively. Metabolomics analysis identified 192 metabolites in total. The majority (42/48) of the significantly altered metabolites (p-value 0.05 FDR, FC 1.5), mainly amino acids, were significantly higher in solid media, while only 2 metabolites were significantly higher in liquid media. The combined multi-omics analysis provides insight into adaptative morphological changes supporting Candida albicans' life cycle and identifies crucial virulence factors during biofilm formation and bloodstream infection.

Study of the Unidimensionality of the Subjective Measurement Scale of Schizophrenia Coping Oral Health Profile and Index: SCOOHPI.

BACKGROUND: The Schizophrenia Coping Oral Health Profile and Index (SCOOHPI) scale studies the coping strategies of schizophrenic patients with regard to oral health. The structural validity of this scale is studied has been studied using factor analyses. In this article, we study the unidimensionality of the SCOOHPI scale to use it as an index. METHODS: We studied the internal consistency of the items of the SCOOHPI scale. Then, we studied the construct validity. The unidimensionality of the SCOOHPI scale was studied by the partial credit model. RESULTS: The data used in this study come from five hospitals, and the total number of individuals participating in this study is 96, of which 72% are men and 59% are smokers. The SCOOHPI scale has good internal consistency (α = 0.84). The validity of divergence was checked by the absence of correlation between the SCOOHPI scale and the GOHAI (General Oral Health Assessment Index) scale. The unidimensionality of the SCOOHPI scale with data smoothing was demonstrated by the partial credit model. CONCLUSION: In this study, we completed the study of the psychometric validation of the SCOOHPI. The SCOOHPI scale can then contribute to improving evaluation of the coping strategies of schizophrenic patients with regard to oral health.

Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters.

The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The compounds were efficiently synthesized in one-pot employing a cascade of Groebke-Blackburn-Bienaymé and aza-Michael addition reactions. Phenotypic screening of the pilot library against various bacterial species including methicillin-sensitive and MRSA strains, has identified potent chemotypes with minimal inhibitory concentrations (MIC) of 3.125-6.25 µg/ml. The most potent compounds were fast-acting at eradicating exponentially growing MRSA, with killing achieved after 30 min of exposure to the compounds. They were also able to kill MRSA persister cells which are tolerant to most available medications. Microscopic analysis using fluorescence microscope and atomic force microscope indicate that these compounds lead to disruption of bacterial cell envelopes. Most notably, bacterial resistance toward these compounds was not observed after 20 serial passages in stark contrast to the significant resistance developed rapidly upon exposure to a clinically relevant antibiotic. Furthermore, the compounds did not induce significant hemolysis to human red blood cells. In vivo safety studies revealed a high safety profile of these motifs. These small molecules hold a promise for further studies and development as new antibacterial agents against MRSA infections.

Perception of the Impact of Artificial Intelligence in the Decision-Making Processes of Public Healthcare Professionals.

Technologies are increasingly independent and play important roles in society. Artificial intelligence (AI) is a branch of science that can improve various environments and processes. The health sector stands out among these contexts, especially ophthalmology and dentistry. Studies evaluating the impact of using these technologies in these contexts are still developing. There are still few studies that assess how AI can impact the decision-making process of health professionals and how it can improve the quality of care provided to these professionals. In this sense, this study aims to evaluate the perception of the impact of AI on the decision-making process of health professionals and the quality of patient care from the perspective of ophthalmologists and dentists. The methodological strategy used was the application of an online questionnaire with eighteen professionals in these areas. Based on the respondents' opinions, we sought to assess how these decision-making processes are affected by the use of technologies and how they impact the quality of patient care. As a result, it was observed that AI has become essential and a facilitator of the diagnostic processes. However, it presents some challenges related to cost, accessibility, AI x professional responsibility, and incentive of agreements.

Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers.

Colorectal cancer (CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon (CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD (l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancer-associated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer.