Aspergillus fumigatus conidial surface-associated proteome reveals factors for fungal evasion and host immunity modulation.

Aspergillus fumigatus causes aspergillosis and relies on asexual spores (conidia) for initiating host infection. There is scarce information about A. fumigatus proteins involved in fungal evasion and host immunity modulation. Here we analysed the conidial surface proteome of A. fumigatus, two closely related non-pathogenic species, Aspergillus fischeri and Aspergillus oerlinghausenensis, as well as pathogenic Aspergillus lentulus, to identify such proteins. After identifying 62 proteins exclusively detected on the A. fumigatus conidial surface, we assessed null mutants for 42 genes encoding these proteins. Deletion of 33 of these genes altered susceptibility to macrophage, epithelial cells and cytokine production. Notably, a gene that encodes a putative glycosylasparaginase, modulating levels of the host proinflammatory cytokine IL-1ß, is important for infection in an immunocompetent murine model of fungal disease. These results suggest that A. fumigatus conidial surface proteins are important for evasion and modulation of the immune response at the onset of fungal infection.

Prevalence of dry eye and Meibomian gland dysfunction in Central and South America: a systematic review and meta-analysis.

BACKGROUND: Dry eye is one of the most common ophthalmic conditions and can significantly impact quality of life. Meibomian gland dysfunction (MGD) is a major cause of evaporative dry eye. We sought to conduct a systematic review and meta-analysis to estimate the prevalence and incidence of dry eye and MGD in Central and South America and to identify factors associated with disease burden. METHODS: Data sources Ovid MEDLINE and Embase. STUDY SELECTION: A search conducted on August 16, 2021, identified studies published between January 1, 2010, and August 16, 2021, with no restrictions regarding participant age or language of publication. Case reports, case series, case-control studies, and interventional studies were excluded. DATA EXTRACTION AND SYNTHESIS: The review was based on a protocol registered on PROSPERO (CRD42021256934). Risk of bias was assessed in duplicate using a risk of bias tool designed for the purposes of descriptive epidemiological studies. Data were extracted by one investigator and verified by another for accuracy. Prevalence of dry eye and MGD were grouped based on study participant characteristics. MAIN OUTCOMES AND MEASURES: Prevalence and incidence of dry eye and MGD in Central and South America. Summary estimates from meta-analysis with 95% confidence intervals (CI). RESULTS: Fourteen studies (11,594 total participants) were included. The population prevalence of dry eye was 13% (95% CI, 12%-14%) in Brazil and 41% (95% CI, 39%-44%) in Mexico based on one study each. Meta-analyses suggested that dry eye prevalence was 70% among indoor workers (95% CI, 56%-80%; I2, 82%; 3 studies), 71% among students (95% CI, 65%-77%; I2, 92%; 3 studies), and 83% in general ophthalmology clinics (95% CI, 77%-88%; I2, 88%; 2 studies). MGD prevalence ranged from 23% among indoor workers (95% CI, 16%-31%; 1 study) to 68% in general ophthalmology clinics (95% CI, 62%-72%; 1 study). No studies reported incidence of dry eye or MGD. CONCLUSIONS: This systematic review and meta-analysis demonstrated considerable variation in the published prevalence of dry eye and MGD among the general population and subpopulations in Central and South America. Local and subpopulation estimates of dry eye disease burden may be valuable to assist needs assessments and implementation of measures to mitigate the condition.

Outcomes and Predictors of Sustained Remission After Drug Withdrawal in Pediatric Crohn Disease.

OBJECTIVES: The primary aim of this study was to determine the proportion of pediatric Crohn disease (CD) subjects in sustained drug-free remission 52 weeks after stopping pharmacological therapy. We also aimed to explore the effects of the Crohn Disease Exclusion Diet (CDED) and microbiome composition on remission. METHODS: We performed a prospective study following 18 CD patients ages 13-21 years in deep clinical remission withdrawing from immunomodulator (n = 7) or anti-TNFα (n = 11) monotherapy at two tertiary care centers. Stool for calprotectin and microbiome analyses was collected over 52 weeks. Participants followed either the CDED or free diet after drug withdrawal. The primary endpoint was sustained relapse-free drug-free remission (calprotectin <250 µg/g) at 52 weeks. RESULTS: Seventeen participants were followed through 52 weeks with 11 (64.7%) in sustained remission. There was no improvement in remission among participants following the CDED (5/9; 55.6%), P = 0.63. By 104 weeks, only 8 (47.1 %) participants remained off immunosuppressive therapies. Analysis of shotgun metagenomic sequence data revealed that taxonomic and gene function abundance in the gut microbiome was relatively stable for participants in remission and relapse. However, a predictive model incorporating gut microbial gene pathway abundance for amino sugar/nucleotide sugar metabolism and galactose metabolism from baseline samples predicted relapse at 52 weeks with 80% accuracy. CONCLUSIONS: After withdrawal of immunomodulator or anti-TNFα monotherapy among a small cohort of pediatric CD subjects in deep remission, nearly 65% sustained remission at 52 weeks. Baseline microbiome alterations predicted relapse. Large prospective studies are needed to better understand outcomes after treatment de-escalation.

Insights into the Chemical Diversity of Selected Fungi from the Tza Itzá Cenote of the Yucatan Peninsula.

Cenotes are habitats with unique physical, chemical, and biological features. Unexplored microorganisms from these sinkholes represent a potential source of bioactive molecules. Thus, a series of cultivable fungi (Aspergillus spp. NCA257, NCA264, and NCA276, Stachybotrys sp. NCA252, and Cladosporium sp. NCA273) isolated from the cenote Tza Itzá were subjected to chemical, coculture, and metabolomic analyses. Nineteen compounds were obtained and tested for their antimicrobial potential against ESKAPE pathogens, Mycobacterium tuberculosis, and nontuberculous mycobacteria. In particular, phenylspirodrimanes from Stachybotrys sp. NCA252 showed significant activity against MRSA, MSSA, and mycobacterial strains. On the other hand, the absolute configuration of the new compound 17-deoxy-aspergillin PZ (1) isolated from Aspergillus sp. NCA276 was established via single-crystal X-ray crystallography. Also, the chemical analysis of the cocultures between Aspergillus and Cladosporium strains revealed the production of metabolites that were not present or were barely detected in the monocultures. Finally, molecular networking analysis of the LC-MS-MS/MS data for each fungus was used as a tool for the annotation of additional compounds, increasing the chemical knowledge on the corresponding fungal strains. Overall, this is the first systematic chemical study on fungi isolated from a sinkhole in Mexico.

New Terpenoids from the Corticioid Fungus Punctularia atropurpurascens and their Antimycobacterial Evaluation.

Chemical investigation of Punctularia atropurpurascens strain HM1 (Punctulariaceae), a corticioid isolated from a decorticated piece of Quercus bark collected in Bosque de Tlalpan, Mexico City, led to the isolation of a new drimane, 1-α-hydroxy-isodrimenine (1: ) and a new tetrahydroxy kauranol, 16-hydroxy-phlebia-nor-kauranol (2: ), together with the known N-phenylacetamide (3: ). Structures of all compounds were elucidated by spectroscopic and spectrometric methods, and the absolute configuration of 1: and 2: was confirmed via single-crystal X-ray crystallography. The isolated compounds showed modest antimycobacterial activity.

Patient Perceptions of Wearable and Smartphone Technologies for Remote Outcome Monitoring in Patients Who Have Hip Osteoarthritis or Arthroplasties.

BACKGROUND: Although there is interest in wearables and smartphone technologies for remote outcome monitoring, little is known regarding the willingness of hip osteoarthritis (OA) and/or total hip arthroplasty (THA) patients to authorize and adhere to such treatment. METHODS: We developed an Institutional Review Board-approved questionnaire to evaluate patient perceptions of remote monitoring technologies in a high-volume orthopedic center. Forty-seven THA patients (60% female; mean age: 66 years) and 50 nonoperative OA hip patients (52% female; mean age: 63 years) participated. Patient perceptions were compared using Pearson's chi-squared analyses. RESULTS: THA patients were similarly interested in the use of smartphone apps (91% vs 94%, P = .695) in comparison to nonoperative hip OA patients. THA patients were more receptive to using wearable sensors (94% vs 44%, P < .001) relative to their nonoperative counterparts. THA patients also expressed stronger interest in learning to use custom wearables (87% vs 32%, P < .001) vs nonoperative patients. Likewise, the majority of THA patients were willing to use Global Positioning System technology (74% vs 26%, P < .001). THA patients also expressed willingness to have their body movement (89%), balance (89%), sleep (87%), and cardiac output (91%) tracked using remote technology. CONCLUSION: Overall, we found that THA patients were highly receptive to using wearable technology in their treatments. Nonoperative OA hip patients were generally unreceptive to using smart technologies, with the exception of smartphone applications. This information may be useful as utilization of these technologies for patient care continues to evolve.

An Insight Into Lyme Prosthetic Joint Infection in Knee Arthroplasty: A Literature Review.

Lyme prosthetic joint infection (PJI) is a rare event, but it is imperative to include Lyme disease as a possible cause of PJI in a Lyme-endemic region. The purpose of this article was to review the reported cases of Lyme PJIs in knee arthroplasty and to initiate the development of a treatment strategy. We found five cases of Lyme PJI in the literature. All patients lived in the northeastern region of the United States. Four patients were successfully treated with surgical intervention and postoperative antibiotics. One patient was successfully treated with intravenous and oral antibiotics for 6 weeks, without surgical intervention. Synovial fluid Lyme polymerase chain reaction and serological tests were positive in all patients. On follow-up visits, after completion of their treatment, all patients were asymptomatic with a painless functional knee. We recommend considering Lyme disease as a cause of culture-negative PJIs in endemic regions. Additional research is needed to clearly define a treatment algorithm. Based on our literature review, we cannot recommend a single best treatment modality for the treatment of Lyme PJI. However, early irrigation and débridement with administration of postoperative antibiotics may improve early clinical outcomes.

Chemical Diversity and Antimicrobial Potential of Cultivable Fungi from Deep-Sea Sediments of the Gulf of Mexico.

A collection of 29 cultivable fungal strains isolated from deep-sea sediments of the Gulf of Mexico were cultivated under the "one strain, many compounds" approach to explore their chemical diversity and antimicrobial potential. From the 87 extracts tested, over 50% showed antimicrobial activity, and the most active ones were those from cultures grown at 4 °C in darkness for 60 days (resembling deep-sea temperature). PCA analysis of the LC-MS data of all the extracts confirmed that culture temperature is the primary factor in the variation of the 4462 metabolite features, accounting for 21.3% of the variation. The bioactivity-guided and conventional chemical studies of selected fungal strains allowed the identification of several active and specialized metabolites. Finally, metabolomics analysis by GNPS molecular networking and manual dereplication revealed the biosynthetic potential of these species to produce interesting chemistry. This work uncovers the chemical and biological study of marine-derived fungal strains from deep-sea sediments of the Gulf of Mexico.

Design of Novel Phosphopantetheine Adenylyltransferase Inhibitors: A Potential New Approach to Tackle Mycobacterium tuberculosis.

BACKGROUND: Tuberculosis (TB) has been a challenging disease worldwide, especially for the neglected poor populations. Presently, there are approximately 2 billion people infected with TB worldwide and 10 million people in the world fell ill with active TB, leading to 1.5 million deaths. INTRODUCTION: The classic treatment is extensive and the drug- and multi-drug resistance of Mycobacterium tuberculosis has been a threat to the efficacy of the drugs currently used. Therefore, the rational design of new anti-TB candidates is urgently needed. METHODS: With the aim of contributing to face this challenge, 78 compounds have been proposed based on SBDD (Structure-Based Drug Design) strategies applied to target the M. tuberculosis phosphopantetheine adenylyltransferase (MtPPAT) enzyme. Ligand-Based Drug Design (LBDD) strategies were also used for establishing Structure-Activity Relationships (SAR) and for optimizing the structures. MtPPAT is important for the biosynthesis of coenzyme A (CoA) and it has been studied recently toward the discovery of new inhibitors. RESULTS: After docking simulations and enthalpy calculations, the interaction of selected compounds with MtPPAT was found to be energetically favorable. The most promising compounds were then synthesized and submitted to anti-M. tuberculosis and MtPPAT inhibition assays. CONCLUSION: One of the compounds synthesized (MCP163), showed the highest activity in both of these assays.

Biofilm Eradication Using Biogenic Silver Nanoparticles.

Microorganisms offer an alternative green and scalable technology for the synthesis of value added products. Fungi secrete high quantities of bioactive substances, which play dual-functional roles as both reducing and stabilizing agents in the synthesis of colloidal metal nanoparticles such as silver nanoparticles, which display potent antimicrobial properties that can be harnessed for a number of industrial applications. The aim of this work was the production of silver nanoparticles using the extracellular cell free extracts of Phanerochaete chrysosporium, and to evaluate their activity as antimicrobial and antibiofilm agents. The 45-nm diameter silver nanoparticles synthesized using this methodology possessed a high negative surface charge close to -30 mV and showed colloidal stability from pH 3-9 and under conditions of high ionic strength ([NaCl] = 10-500 mM). A combination of environmental SEM, TEM, and confocal Raman microscopy was used to study the nanoparticle-E. coli interactions to gain a first insight into their antimicrobial mechanisms. Raman data demonstrate a significant decrease in the fatty acid content of E. coli cells, which suggests a loss of the cell membrane integrity after exposure to the PchNPs, which is also commensurate with ESEM and TEM images. Additionally, these biogenic PchNPs displayed biofilm disruption activity for the eradication of E. coli and C. albicans biofilms.

Short-Term Resistance Training Improves Cardiac Autonomic Modulation and Blood Pressure in Hypertensive Older Women: A Randomized Controlled Trial.

Oliveira-Dantas, FF, Brasileiro-Santos, MdS, Thomas, SG, Silva, AS, Silva, DC, Browne, RAV, Farias-Junior, LF, Costa, EC, and Santos, AdC. Short-term resistance training improves cardiac autonomic modulation and blood pressure in hypertensive older women: a randomized controlled trial. J Strength Cond Res 34(1): 37-45, 2020-This randomized controlled trial investigated the efficacy of short-term resistance training (RT) on cardiac autonomic modulation and peripheral hemodynamic parameters in hypertensive older women. Twenty-five hypertensive older women who were insufficiently active (64.7 ± 4.7 years) participated in this study. Subjects were randomly allocated to a 10-week RT program (2 d·wk in the first 5 weeks; 3 d·wk in the last 5 weeks) or a nonexercise control group. Linear reverse periodization was used for the RT program. Cardiac autonomic modulation, mean blood pressure (MBP), peripheral vascular resistance (PVR), and resting heart rate (RHR) were measured before and after 10 weeks. The RT group reduced cardiac sympathetic modulation (0V%; B = -6.6; 95% confidence interval [CI]: -12.9 to -0.2; p = 0.045; Cohen's d = 0.88) and showed a trend for increased parasympathetic modulation (2V%; B = 12.5; 95% CI: 0-25; p = 0.050; Cohen's d = 0.87) compared with the control group. The RT group reduced MBP (B = -8.5 mm Hg; 95% CI: -13.6 to -3.4; p = 0.001; Cohen's d = 1.27), PVR (B = -14.1 units; 95% CI: -19.9 to -8.4; p < 0.001; Cohen's d = 1.86), and RHR (B = -8.8 b·min; 95% CI: -14.3 to -3.3; p = 0.002; Cohen's d = 1.20) compared with the control group. In the RT group, the changes in 2V% patterns and low-frequency components showed a correlation with changes in MBP (r = -0.60; p = 0.032) and RHR (r = 0.75; p = 0.0003). In conclusion, 10 weeks of RT improved cardiac autonomic modulation and reduced MBP and PVR in hypertensive older women. These results reinforce the importance of RT for this population.

Exploring the Sponge Consortium Plakortis symbiotica-Xestospongia deweerdtae as a Potential Source of Antimicrobial Compounds and Probing the Pharmacophore for Antituberculosis Activity of Smenothiazole A by Diverted Total Synthesis.

Fractionation of the bioactive CHCl3-MeOH (1:1) extracts obtained from two collections of the sponge consortium Plakortis symbiotica-Xestospongia deweerdtae from Puerto Rico provided two new plakinidone analogues, designated as plakinidone B (2) and plakinidone C (3), as well as the known plakinidone (1), plakortolide F (4), and smenothiazole A (5). The structures of 1-5 were characterized on the basis of 1D and 2D NMR spectroscopic, IR, UV, and HRMS analysis. The absolute configurations of plakinidones 2 and 3 were established through chemical correlation methods, VCD/ECD experiments, and spectroscopic data comparisons. When assayed in vitro against Mycobacterium tuberculosis H37Rv, none of the plakinidones 1-3 displayed significant activity, whereas smenothiazole A (5) was the most active compound, exhibiting an MIC value of 4.1 µg/mL. Synthesis and subsequent biological screening of 8, a dechlorinated version of smenothiazole A, revealed that the chlorine atom in 5 is indispensable for anti-TB activity.

QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity.

New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 µM and <10 µM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents.

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum.

Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2-10.98µM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50µM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.

Opioid Prescribing in a Cross Section of US Emergency Departments.

STUDY OBJECTIVE: Opioid pain reliever prescribing at emergency department (ED) discharge has increased in the past decade but specific prescription details are lacking. Previous ED opioid pain reliever prescribing estimates relied on national survey extrapolation or prescription databases. The main goal of this study is to use a research consortium to analyze the characteristics of patients and opioid prescriptions, using a national sample of ED patients. We also aim to examine the indications for opioid pain reliever prescribing, characteristics of opioids prescribed both in the ED and at discharge, and characteristics of patients who received opioid pain relievers compared with those who did not. METHODS: This observational, multicenter, retrospective, cohort study assessed opioid pain reliever prescribing to consecutive patients presenting to the consortium EDs during 1 week in October 2012. The consortium study sites consisted of 19 EDs representing 1.4 million annual visits, varied geographically, and were predominantly academic centers. Medical records of all patients aged 18 to 90 years and discharged with an opioid pain reliever (excluding tramadol) were individually abstracted by standardized chart review by investigators for detailed analysis. Descriptive statistics were generated. RESULTS: During the study week, 27,516 patient visits were evaluated in the consortium EDs; 19,321 patients (70.2%) were discharged and 3,284 (11.9% of all patients and 17.0% of discharged patients) received an opioid pain reliever prescription. For patients prescribed an opioid pain reliever, mean age was 41 years (SD 14 years) and 1,694 (51.6%) were women. Mean initial pain score was 7.7 (SD 2.4). The most common diagnoses associated with opioid pain reliever prescribing were back pain (10.2%), abdominal pain (10.1%), and extremity fracture (7.1%) or sprain (6.5%). The most common opioid pain relievers prescribed were oxycodone (52.3%), hydrocodone (40.9%), and codeine (4.8%). Greater than 99% of pain relievers were immediate release and 90.0% were combination preparations, and the mean and median number of pills was 16.6 (SD 7.6) and 15 (interquartile range 12 to 20), respectively. CONCLUSION: In a study of ED patients treated during a single week across the country, 17% of discharged patients were prescribed opioid pain relievers. The majority of the prescriptions had small pill counts and almost exclusively immediate-release formulations.

The pre-history of urban scaling.

Cities are increasingly the fundamental socio-economic units of human societies worldwide, but we still lack a unified characterization of urbanization that captures the social processes realized by cities across time and space. This is especially important for understanding the role of cities in the history of human civilization and for determining whether studies of ancient cities are relevant for contemporary science and policy. As a step in this direction, we develop a theory of settlement scaling in archaeology, deriving the relationship between population and settled area from a consideration of the interplay between social and infrastructural networks. We then test these models on settlement data from the Pre-Hispanic Basin of Mexico to show that this ancient settlement system displays spatial scaling properties analogous to those observed in modern cities. Our data derive from over 1,500 settlements occupied over two millennia and spanning four major cultural periods characterized by different levels of agricultural productivity, political centralization and market development. We show that, in agreement with theory, total settlement area increases with population size, on average, according to a scale invariant relation with an exponent in the range [Formula: see text]. As a consequence, we are able to infer aggregate socio-economic properties of ancient societies from archaeological measures of settlement organization. Our findings, from an urban settlement system that evolved independently from its old-world counterparts, suggest that principles of settlement organization are very general and may apply to the entire range of human history.

In vitro and in vivo activities of ruthenium(II) phosphine/diimine/picolinate complexes (SCAR) against Mycobacterium tuberculosis.

Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity.

Allylic thiocyanates as a new class of antitubercular agents.

TB is a global public health emergency in which new drugs are desperately needed. Herein we report on the synthesis of a diverse panel of 41 aryl allylic azides, thiocyanates, isothiouronium salts, and N,N'-diacetylisothioureas that were evaluated for their in vitro activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb) H(37)Rv and toxicity to VERO cells. We found a selective group of new and promising compounds having good (micromolar) to excellent (sub-micromolar) potency against replicating Mtb H(37)Rv. Allylic thiocyanates bearing halophenyl (halo=2-Br, 4-Br, 4-Cl, 4-F), 4-methylphenyl and 2-naphthyl moieties were the most active as antitubercular agents. In particular, the 2-bromophenyl-substituted thiocyanate showed MIC=0.25 µM against replicating Mtb, MIC=8.0 µM against non-replicating Mtb and IC(50)=32 µM in the VERO cellular toxicity assay.