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The authors summarize results from calculations using the density functional theory for atoms and small silver clusters on surfaces of nanostructured cerium(IV) oxide, along with the adsorption and transformations of O2 and CO molecules on these systems. Stoichiometric Ce21O42, which has {100} and {111} nanofacets with adsorption centers containing four and three oxygen atoms, is used to model surfaces of cerium oxide. It is shown the O4-center is a center of the selective adsorption of metal atoms. A silver atom on an O3‑center is less stable but it shows a greater ability to activate an O2 molecule. Results from calculations on the {100} and {111} faces of Ce21O42 nanoparticles are compared to data for infinite CeO2(100) and CeO2(111) surfaces. The efficiency of Ag/Ce21O42 atomic complexes is shown in the oxidation of carbon monoxide. Keywords: cerium oxide silver adsorption CO oxidation density functional theory [ABSTRACT FROM AUTHOR]

The review is dedicated to the elaboration and application of hybrid quantum mechani-cal/molecular mechanical methods for heterogeneous catalytic systems, including single atoms and clusters of transition metals immobilized on covalent oxide supports. The following issues are considered: (1) elaboration of the hybrid covEPE method for modeling of covalent sys-tems of the zeolite and silicate types, (2) computations of the properties of atoms and small titanium, rhodium, iridium, and gold clusters localized in cavities or embedded in the zeolite framework, and (3) computations of small silver and tantalum clusters anchored at the dehydr-oxylated and hydroxylated silica surfaces. The calculations were performed by the density functional theory (DFT) with the Becke-Perdew (BP) exchange-correlation potential. [ABSTRACT FROM AUTHOR]

Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting β-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like Candida glabrata, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (FKS1 and FKS2 in C. glabrata) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of C. glabrata colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this C. glabrata population during treatment and the emergence of both drug target (FKS2) and non-drug target mutations, the latter predominantly in the FEN1 gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The fen1 mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of YPC1 gene hypersensitized the wild type strain to caspofungin and was epistatic to fen1Δ. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in fen1Δ cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different fen1 mutations in clinical C. glabrata isolates, which phenocopied the fen1Δ mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with C. glabrata., Competing Interests: DSP received an honorarium from N8 Biomedical, a mutual fund with more than $5,000 Merck stock, and an unlicensed patent for echinocandin resistance., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

We analyze 391 news reports in Israeli newspapers between 2013 and 2015, covering murders of women and their family members by other family members and intimate partners. We compare articles where the perpetrators and victims are Jewish to those where the perpetrators and victims are Palestinian citizens of Israel (henceforth PCI). We found that articles tend to provide much more details about Jewish culprits than about PCI ones. As for ascribed motives, most murder cases by Jews were framed as an outcome of individual personality or the pathology of the culprit. Conversely, when Palestinian citizens were the killers, culture and tradition were invoked as the main motives. We suggest that the routine work of narration that the Israeli media preform when covering femicide is a case of political use of cultural stereotypes to gain moral ground in the intractable conflict between Jews and Palestinians., (© 2024 The Authors. The British Journal of Sociology published by John Wiley & Sons Ltd on behalf of London School of Economics and Political Science.)

Fungal plasma membrane proteins represent key therapeutic targets for antifungal agents, yet their structure and spatial distribution in the native context remain poorly characterized. Herein, we employ an integrative multimodal approach to elucidate the structural and functional organization of plasma membrane protein complexes in Candida glabrata , focusing on prominent and essential membrane proteins, the polysaccharide synthase β-(1,3)-glucan synthase (GS) and the proton pump Pma1. Cryo-electron tomography (cryo-ET) and live cell imaging reveal that GS and Pma1 are heterogeneously distributed into distinct plasma membrane microdomains. Treatment with caspofungin, an echinocandin antifungal that targets GS, alters the plasma membrane and disrupts the native distribution of GS and Pma1. Based on these findings, we propose a model for echinocandin action that considers how drug interactions with the plasma membrane environment lead to inhibition of GS. Our work underscores the importance of interrogating the structural and dynamic characteristics of fungal plasma membrane proteins in situ to understand function and facilitate precisely targeted development of novel antifungal therapies.

Floral scent emission of petunia flowers is regulated by light conditions, circadian rhythms, ambient temperature and the phytohormones GA and ethylene, but the mechanisms underlying sensitivity to these factors remain obscure. PHYTOCHROME INTERACTING FACTORs (PIFs) have been well studied as components of the regulatory machinery for numerous physiological processes. Acting redundantly, they serve as transmitters of light, circadian, metabolic, thermal and hormonal signals. Here we identified and characterized the phylogenetics of petunia PIF family members (PhPIFs). PhPIF4/5 was revealed as a positive regulator of floral scent: TRV-based transient suppression of PhPIF4/5 in petunia petals reduced emission of volatiles, whereas transient overexpression increased scent emission. The mechanism of PhPIF4/5-mediated regulation of volatile production includes activation of the expression of genes encoding biosynthetic enzymes and a key positive regulator of the pathway, EMISSION OF BENZENOIDS II (EOBII). The PIF-binding motif on the EOBII promoter (G-box) was shown to be needed for this activation. As PhPIF4/5 homologues are sensors of dawn and expression of EOBII also peaks at dawn, the prior is proposed to be part of the diurnal control of the volatile biosynthetic machinery. PhPIF4/5 was also found to transcriptionally activate PhDELLAs; a similar positive effect of PIFs on DELLA expression was further confirmed in Arabidopsis seedlings. The PhPIF4/5-PhDELLAs feedback is proposed to fine-tune GA signaling for regulation of floral scent production., (© 2024. The Author(s).)

Empirical studies in multiple disciplines have frequently observed an immigrant mortality advantage. Yet, questions remain regarding the possible mechanisms underlying this phenomenon. We obtained data from 61 studies of relative immigrant mortality from single origin-destination country pairings, providing information on immigrants from 77 origin countries. We systematically review the arguments made in these studies about origin-country factors that might influence immigrant mortality and then use meta-analyses to examine the veracity of these arguments. We find that most existing origin-country explanations for immigrant mortality patterns (e.g., health behaviors, genetic characteristics, environmental conditions, and socioeconomic conditions) are problematic or insufficient when accounting for differential mortality by origin country. We identify non-comparative analyses and geographic aggregation as the two major obstacles to understanding the mechanisms underlying the immigrant mortality advantage. We conclude by advocating for a risk-factor-based, cross-national approach., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to develop and evaluate a mobile health (mHealth)-delivered, theory-guided, culturally tailored storytelling narrative (STN) intervention to increase cervical cancer screening among Malawian women living with human immunodeficiency virus (HIV)., Methods: This study involved two phases: Phase 1: development of a theory-guided and culturally adapted STN intervention and Phase 2: a pilot randomized controlled trial was conducted. Participants were randomly assigned to one of three arms: Arm 1: tablet-based video (mHealth) with STN ( n  = 60); Arm 2: mHealth with a video of nonnarrative educational materials ( n  = 59); and Arm 3: control group with only reading nonnarrative educational materials in person ( n  = 60). Cervical cancer screening was measured using visual inspection with acetic acid (VIA) uptakes by self-report and health passport record review at 2 and 6 months after intervention., Results: Both arms 1 and 2 had nearly twice the rate of VIA uptakes than those in Arm 3 (51.0% and 50.0%, respectively, vs. 35.0%, P  = 0.01) at 2 months follow-up, but there were no differences among groups from 2- to 6-month follow-ups. All groups demonstrated significant improvement of knowledge about risk factors, intention, and VIA uptakes., Conclusions: The findings demonstrate the preliminary effectiveness of the intervention on cervical cancer screening behavior and the feasibility of the study regarding recruitment, retention, treatment fidelity, and acceptability of the single 30-min session. The feasibility and the preliminary results of the effectiveness of the proposed study indicate scaling up the STN intervention to a larger population of women to increase cervical cancer screening uptake to prevent deaths due to cervical cancer in Malawi., Competing Interests: All authors declare no conflicts of interest. Professor Haeok Lee, the corresponding author, serves on the editorial board of the Asia-Pacific Journal of Oncology Nursing. The article underwent standard review procedures of the journal, with peer review conducted independently of Professor Lee and their research groups., (© 2024 The Author(s).)

Drug-resistant microbes typically carry mutations in genes involved in critical cellular functions and may therefore be less fit under drug-free conditions than susceptible strains. Candida glabrata is a prevalent opportunistic yeast pathogen with a high rate of fluconazole resistance (FLZR), echinocandin resistance (ECR), and multidrug resistance (MDR) relative to other Candida. However, the fitness of C. glabrata MDR isolates, particularly in the host, is poorly characterized, and studies of FLZR isolate fitness have produced contradictory findings. Two important host niches for C. glabrata are macrophages, in which it survives and proliferates, and the gut. Herein, we used a collection of clinical and lab-derived C. glabrata isolates to show that FLZR C. glabrata isolates are less fit inside macrophages than susceptible isolates and that this fitness cost is reversed by acquiring ECR mutations. Interestingly, dual-RNAseq revealed that macrophages infected with drug-resistant isolates mount an inflammatory response whereas intracellular drug-resistant cells downregulate processes required for in-host adaptation. Furthermore, drug-resistant isolates were outcompeted by their susceptible counterparts during gut colonization and in infected kidneys, while showing comparable fitness in the spleen. Collectively, our study shows that macrophage-rich organs, such as the spleen, favor the retention of MDR isolates of C. glabrata., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

The epidermal cells of petunia (Petunia × hybrida) flowers are the main site of volatile emission. However, the mechanisms underlying the release of volatiles into the environment are still being explored. Here, using cell-layer-specific transcriptomic analysis, reverse genetics by virus-induced gene silencing and clustered regularly interspaced short palindromic repeat (CRISPR), and metabolomics, we identified EPIDERMIS VOLATILE EMISSION REGULATOR (EVER)-a petal adaxial epidermis-specific MYB activator that affects the emission of volatiles. To generate ever knockout lines, we developed a viral-based CRISPR/Cas9 system for efficient gene editing in plants. These knockout lines, together with transient-suppression assays, revealed EVER's involvement in the repression of low-vapor-pressure volatiles. Internal pools and annotated scent-related genes involved in volatile production and emission were not affected by EVER. RNA-Seq analyses of petals of ever knockout lines and EVER-overexpressing flowers revealed enrichment in wax-related biosynthesis genes. Liquid chromatography/gas chromatography-MS analyses of petal epicuticular waxes revealed substantial reductions in wax loads in ever petals, particularly of monomers of fatty acids and wax esters. These results implicate EVER in the emission of volatiles by fine-tuning the composition of petal epicuticular waxes. We reveal a petunia MYB regulator that interlinks epicuticular wax composition and volatile emission, thus unraveling a regulatory layer in the scent-emission machinery in petunia flowers., Competing Interests: Conflict of interest statement. None declared., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Socioeconomic factors such as financial stress and unemployment are known predictors of suicide. However, no large-scale meta-analyses exist. Aims: Determine the suicide risk following unemployment or financial stress. Method: Literature searched through July 31, 2021. Robust meta-analysis and metaregression of the risk of suicide following financial stress (23 studies) or unemployment (43 studies), from 20 nations. Subgroup meta-analyses by sex, age, year, country, and methodology. Results: The suicide risk following financial stress or unemployment was not significantly elevated among those with diagnosed mental illness. In the general population, we found significantly elevated suicide risks for financial stress (RR: 1.742; 95% CI: 1.339, -2.266) and unemployment (RR: 1.874; CI: 1.501, -2.341). However, neither was significant among studies controlling for physical/mental health (perhaps partially due to lower statistical power). We observed no significant differences by sex, age, or by GDP. We observed a higher suicide risk following unemployment in more recent years. Limitations: Publication bias was evident. We could not examine some individual-level characteristics, most notably the severity/duration of unemployment/financial stress. Heterogeneity was high for some meta-analyses. Studies from non-OECD countries are under-represented. Conclusion: After accounting for physical/mental health, financial stress and unemployment weakly associated with suicide, and the associations may be nonsignificant.

Importance: Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called "petite." This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates., Competing Interests: The authors declare no conflict of interest.

Reactive oxidant species (ROS) are unstable, highly reactive molecules that are produced by cells either as byproducts of metabolism or synthesized by specialized enzymes. ROS can be detrimental, e.g., by damaging cellular macromolecules, or beneficial, e.g., by participating in signaling. An increasing body of evidence shows that various fungal species, including both yeasts and molds, increase ROS production upon exposure to the antifungal drugs currently used in the clinic: azoles, polyenes, and echinocandins. However, the implications of these findings are still largely unclear due to gaps in knowledge regarding the chemical nature, molecular origins, and functional consequences of these ROS. Because the detection of ROS in fungal cells has largely relied on fluorescent probes that lack specificity, the chemical nature of the ROS is not known, and it may vary depending on the specific fungus-drug combination. In several instances, the origin of antifungal drug-induced ROS has been identified as the mitochondria, but further experiments are necessary to strengthen this conclusion and to investigate other potential cellular ROS sources, such as the ER, peroxisomes, and ROS-producing enzymes. With respect to the function of the ROS, several studies have shown that they contribute to the drugs' fungicidal activities and may be part of drug-induced programmed cell death (PCD). However, whether these "pro-death" ROS are a primary consequence of the antifungal mechanism of action or a secondary consequence of drug-induced PCD remains unclear. Finally, several recent studies have raised the possibility that ROS induction can serve an adaptive role, promoting antifungal drug tolerance and the evolution of drug resistance. Filling these gaps in knowledge will reveal a new aspect of fungal biology and may identify new ways to potentiate antifungal drug activity or prevent the evolution of antifungal drug resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gonzalez-Jimenez, Perlin and Shor.)

In moth-pollinated petunias, production of floral volatiles initiates when the flower opens and occurs rhythmically during the day, for optimal flower-pollinator interaction. To characterize the developmental transcriptomic response to time of day, we generated RNA-Seq databases for corollas of floral buds and mature flowers in the morning and in the evening. Around 70% of transcripts accumulating in petals demonstrated significant changes in expression levels in response to the flowers' transition from a 4.5-cm bud to a flower 1 day postanthesis (1DPA). Overall, 44% of the petal transcripts were differentially expressed in the morning vs. evening. Morning/evening changes were affected by flower developmental stage, with a 2.5-fold larger transcriptomic response to daytime in 1DPA flowers compared to buds. Analyzed genes known to encode enzymes in volatile organic compound biosynthesis were upregulated in 1DPA flowers vs. buds-in parallel with the activation of scent production. Based on analysis of global changes in the petal transcriptome, PhWD2 was identified as a putative scent-related factor. PhWD2 is a protein that is uniquely present in plants and has a three-domain structure: RING-kinase-WD40. Suppression of PhWD2 (termed UPPER - Unique Plant PhEnylpropanoid Regulator ) resulted in a significant increase in the levels of volatiles emitted from and accumulated in internal pools, suggesting that it is a negative regulator of petunia floral scent production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shor, Skaliter, Sharon, Kitsberg, Bednarczyk, Kerzner, Vainstein, Tabach and Vainstein.)

Emission of scent volatiles by flowers is important for successful pollination and consequently, reproduction. Petunia (Petunia hybrida) floral scent is formed mainly by volatile products of the phenylpropanoid pathway. We identified and characterized a regulator of petunia scent production: the GRAS protein PHENYLPROPANOID EMISSION-REGULATING SCARECROW-LIKE (PES). Its expression increased in petals during bud development and was highest in open flowers. Overexpression of PES increased the production of floral volatiles, while its suppression resulted in scent reduction. We showed that PES upregulates the expression of genes encoding enzymes of the phenylpropanoid and shikimate pathways in petals, and of the core regulator of volatile biosynthesis ODORANT1 by activating its promoter. PES is an ortholog of Arabidopsis (Arabidopsis thaliana) PHYTOCHROME A SIGNAL TRANSDUCTION 1, involved in physiological responses to far-red (FR) light. Analyses of the effect of nonphotosynthetic irradiation (low-intensity FR light) on petunia floral volatiles revealed FR light as a scent-activating factor. While PHYTOCHROME A regulated scent-related gene expression and floral scent production under FR light, the influence of PES on volatile production was not limited by FR light conditions., Competing Interests: Conflict of interest statement. The authors declare no conflict of interest., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir., (© 2023. The Author(s).)

Patients presenting with severe COVID-19 are predisposed to acquire secondary fungal infections such as COVID-19-associated candidemia (CAC), which are associated with poor clinical outcomes despite antifungal treatment. The extreme burden imposed on clinical facilities during the COVID-19 pandemic has provided a permissive environment for the emergence of clonal outbreaks of multiple Candida species, including C. auris and C. parapsilosis . Here we report the largest clonal CAC outbreak to date caused by fluconazole resistant (FLZR) and echinocandin tolerant (ECT) C. parapsilosis . Sixty C. parapsilosis strains were obtained from 57 patients at a tertiary care hospital in Brazil, 90% of them were FLZR and ECT. Although only 35.8% of FLZR isolates contained an ERG11 mutation, all of them contained the TAC1 L518F mutation and significantly overexpressed CDR1 . Introduction of TAC1 L518F into a susceptible background increased the MIC of fluconazole and voriconazole 8-fold and resulted in significant basal overexpression of CDR1 . Additionally, FLZR isolates exclusively harboured E1939G outside of Fks1 hotspot-2, which did not confer echinocandin resistance, but significantly increased ECT. Multilocus microsatellite typing showed that 51/60 (85%) of the FLZR isolates belonged to the same cluster, while the susceptible isolates each represented a distinct lineage. Finally, biofilm production in FLZR isolates was significantly lower than in susceptible counterparts Suggesting that it may not be an outbreak determinant. In summary, we show that TAC1 L518F and FKS1 E1393G confer FLZR and ECT, respectively, in CAC-associated C. parapsilosis . Our study underscores the importance of antifungal stewardship and effective infection control strategies to mitigate clonal C. parapsilosis outbreaks.

A large body of research has documented an immigrant mortality advantage. However, we still do not know enough about how interactions between the characteristics of origin and destinations countries shape variabilities in immigrants' experiences and health. In this paper, we examine the effects of ethno-cultural similarities and differences between the country of origin and the country of destination on immigrants' longevity. We use meta-regression methods to examine data on 78 origin and 16 destination countries (1092 risk estimates from 69 studies). In contrast to expectations from approaches that focus on immigration/acculturation stress, we found that a shared official linguistic family, moving to a country where one is not likely to be considered a visible minority, and more integrative immigration policies actually reduce or even eliminate the immigrant mortality advantage. We discuss potential explanations for these findings and argue that selection mechanisms provide a better account., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Accurate early diagnosis of a gastrointestinal anastomotic leak remains a challenge. When an anastomotic leak develops, the electrical properties of the tissue undergoing inflammatory processes change, resulting from the extravasation of inflammatory fluid and cellular infiltration. The method described here intends to provide a novel early anastomotic leak warning system based upon measurable changes in tissue impedance nearby an acute inflammatory process., Methods: A biodegradable Mg-alloy was compared with a nonabsorbable stainless steel (STS) electrode connected to a wireless recording system for impedance measurement. In vitro measurements were made in physiological solutions and small animal (eight mice) and large animal (eight pigs) models with an anastomotic leak simulated by an open colotomy. Measurements were made at 10 mm intervals from the open colon at baseline and up to 120 min comparing these with a sutured colonic wound and normal tissue., Results: In-vitro biodegradable magnesium electrode impedance evaluation showed good sensitivity to different media due to its environmental corrosion properties. The impedance of an acidic environment (1.06 ± 0.02 kΩ for citric acid) was twice that of phosphate-buffered saline (PBS) (0.64 ± 0.008 kΩ) with a distinction between Normal Saline (0.42 ± 0.013 kΩ) and PBS (0.64 ± 0.008 kΩ). This was in contrast to the performance characteristics of the control STS electrodes, where impedance in an acidic environment was lower than saline or PBS (citric acid:0.76 ± 0.01 kΩ versus PBS: 1.32 ± 0.014 kΩ). In a mouse model simulating an anastomotic leak, there was a significant increase in impedance after 120 min when compared with controls (99.7% increase versus 9.6% increase, respectively; P < 0.02). This effect was confirmed in a pig model when relative impedance measurements of the leak and control groups were compared (1.86 ± 0.46 versus 1.07 ± 0.02, respectively; P < 0.027)., Conclusions: Electrophysiological measurement shows diagnostic sensitivity for a gastrointestinal leak with potential clinical utility in the postoperative detection of early intra-abdominal sepsis. Further investigation of biodegradable tissue sensors capable of monitoring an early anastomotic leak is required., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Fluconazole-resistant Candida parapsilosis (FLZR-CP) outbreaks are a growing public health concern and have been reported in numerous countries. Patients infected with FLZR-CP isolates show fluconazole therapeutic failure and have a significantly increased mortality rate. Because fluconazole is the most widely used antifungal agent in most regions with outbreaks, it is paramount to restore its antifungal activity. Milbemycin oxim (MOX), a well-known canine endectocide, is a potent efflux pump inhibitor that significantly potentiates the activity of fluconazole against FLZR C . glabrata and C . albicans. However, the FLZ-MOX combination has not been tested against FLZR-CP isolates, nor is it known whether MOX may also potentiate the activity of echinocandins, a different class of antifungal drugs. Furthermore, the extent of involvement of efflux pumps CDR1 and MDR1 and ergosterol biosynthesis enzyme ERG11 and their link with gain-of-function (GOF) mutations in their transcription regulators ( TAC1 , MRR1 , and UPC2 ) are poorly characterized among FLZR-CP isolates. We analyzed 25 C. parapsilosis isolates collected from outbreaks in Turkey and Brazil by determining the expression levels of CDR1 , MDR1 , and ERG11 , examining the presence of potential GOF mutations in their transcriptional regulators, and assessing the antifungal activity of FLZ-MOX and micafungin-MOX against FLZR and multidrug-resistant (MDR) C . parapsilosis isolates. ERG11 was found to be universally induced by fluconazole in all isolates, while expression of MDR1 was unchanged. Whereas mutations in MRR1 and UPC2 were not detected, CDR1 was overexpressed in three Brazilian FLZR-CP isolates, which also carried a novel TAC1 L518F mutation. Of these three isolates, one showed increased basal expression of CDR1 , while the other two overexpressed CDR1 only in the presence of fluconazole. Interestingly, MOX showed promising antifungal activity against FLZR isolates, reducing the FLZ MIC 8- to 32-fold. However, the MOX and micafungin combination did not exert activity against an MDR C . parapsilosis isolate. Collectively, our study documents that the mechanisms underpinning FLZR are region specific, where ERG11 mutations were the sole mechanism of FLZR in Turkish FLZR-CP isolates, while simultaneous overexpression of CDR1 was observed in some Brazilian counterparts. Moreover, MOX and fluconazole showed potent synergistic activity, while the MOX-micafungin combination showed no synergy., Competing Interests: AC received educational Grants from Angem, Eurofarma, Knight-United Medical, Gilead, Pfizer and travel grant support from Eurofarma and Knight-United Medical. DP receives research support and/or serves on advisory boards for Amplyx, Cidara, Scynexis, N8 Medical, Merck, Regeneron, and Pfizer. He also has a patent covering the detection of fungal species and drug resistance, as well as a pending patent on COVID-19 detection licensed to T2 Biosystems. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daneshnia, Hilmioğlu Polat, Ilkit, Shor, de Almeida Júnior, Favarello, Colombo, Arastehfar and Perlin.)

Several Sustainable Development Goals (SDGs) (3, 16, 17) point to the need to systematically address massive shortages of human resources for health (HRH), build capacity and leverage partnerships to reduce the burden of global illness. Addressing these complex needs remain challenging, as simple increases in absolute numbers of healthcare providers trained is insufficient; substantial investment into long-term high-quality training programs is needed, as are incentives to retain qualified professionals within local systems of care delivery. We describe a novel HRH initiative, the Global Health Service Partnership (GHSP), involving collaboration between the US government (President's Emergency Plan for AIDS Relief [PEPFAR], Peace Corps), 5 African countries, and a US-based non-profit, Seed Global Health. GHSP was formed to enlist US health professionals to assist in strengthening teaching and training capacity and focused on pre-and in-service medical and nursing education in Malawi, Tanzania, Uganda, Eswatini and Liberia. From 2013-2018, GHSP sent 186 US health professionals to 27 institutions in 5 countries, helping to train 16 280 unique trainees of all levels. Qualitative impacts included cultivating a supportive classroom learning environment, providing a pedagogical bridge to clinical service, and fostering a supportive clinical learning and practice environment through role modeling, mentorship and personalized learning at the bedside. GHSP represented a novel, multilateral, public-private collaboration to help address HRH needs in Africa. It offers a plausible, structured template for engagement and partnership in the field., (© 2022 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Background: Cardiovascular disease (CVD) risk factors are transmitted from parents to children. We prospectively examined the association between parental cardiovascular health (CVH) and time to onset of CVD in the offspring., Methods and Results: The study consisted of a total of 5967 offspring-mother-father trios derived from the Framingham Heart Study. Cardiovascular health score was defined using the seven American Heart Association's CVH metrics attained at ideal levels: poor (0-2), intermediate (3-4), and ideal CVH (5-7). Multivariable-adjusted Cox proportional hazards regression models, Kaplan-Meier plots, and Irwin's restricted mean were used to examine the association and sex-specific differences between parental CVH and offspring's CVD-free survival. In a total of 71 974 person-years of follow-up among the offspring, 718 incident CVD events occurred. The overall CVD incidence rate was 10 per 1000 person-years [95% confidence interval (CI) 9.3-10.7]. Offspring of mothers with ideal CVH lived 9 more years free of CVD than offspring of mothers with poor CVH (P < 0.001). Maternal poor CVH was associated with twice as high hazard of early onset of CVD compared with maternal ideal CVH (adjusted Hazard Ratio 2.09, 95% CI 1.50-2.92). No statistically significant association was observed in the hazards of CVD-free survival by paternal CVH categories., Conclusions: We found that offspring of parents with ideal CVH had a greater CVD-free survival. Maternal CVH was a more robust predictor of offspring's CVD-free survival than paternal CVH, underscoring the need for clinical and policy interventions that involve mothers to break the intergenerational cycle of CVD-related morbidity and mortality., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

How do members of extremist groups think about violence conducted by individual members on the group's behalf? We examine the link between extremism-motivated violence and extremist groups through a case study of misogynist incels, a primarily online community of men who lament their lack of sexual success with women. To learn how misogynist incels talk about mass violence committed by members of their group, we conduct a qualitative content analysis of 3,658 comments relating to the 2018 Toronto van attack, in which self-declared incel Alek Minassian drove a van into pedestrians, killing 10 and injuring 16. We find overwhelming support among self-proclaimed incels for the attack and violence more generally. Incels viewed mass violence as instrumental, serving the following four main purposes: garnering increased attention, exacting revenge, reinforcing masculinity, and generating political change. Our findings indicate the need to examine misogynist incels as a potential terrorist group and male supremacism as a basis for terrorism., (© 2022 London School of Economics and Political Science.)

Despite the recent proliferation of research on aggression in pornography, we still know relatively little about the preferences and perceptions of viewers themselves. In particular, very little research has examined how women who watch pornography feel when encountering aggression toward women. To explore this question, we conducted interviews with 122 regular pornography viewers (61 women, 60 men, and 1 gender-diverse). Quantitative and qualitative analyses of the data show that the majority of both men and women reported that they did not enjoy aggressive content. However, in contrast to common conceptions among most scholars and pundits, it was women, not men, who were more likely to report being aroused by aggression, mainly consensual aggression toward women, which was perceived as pleasurable. Women were also more likely to report actively seeking for aggression and wanting to see more aggression in mainstream pornography. These findings challenge long-held radical feminist views regarding the preferences of both women and men and offer new insights on the relationship between gender and sexual fantasies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

When it comes to detecting volatile chemicals, biological olfactory systems far outperform all artificial chemical detection devices in their versatility, speed, and specificity. Consequently, the use of trained animals for chemical detection in security, defense, healthcare, agriculture, and other applications has grown astronomically. However, the use of animals in this capacity requires extensive training and behavior-based communication. Here we propose an alternative strategy, a bio-electronic nose, that capitalizes on the superior capability of the mammalian olfactory system, but bypasses behavioral output by reading olfactory information directly from the brain. We engineered a brain-computer interface that captures neuronal signals from an early stage of olfactory processing in awake mice combined with machine learning techniques to form a sensitive and selective chemical detector. We chronically implanted a grid electrode array on the surface of the mouse olfactory bulb and systematically recorded responses to a large battery of odorants and odorant mixtures across a wide range of concentrations. The bio-electronic nose has a comparable sensitivity to the trained animal and can detect odors on a variable background. We also introduce a novel genetic engineering approach that modifies the relative abundance of particular olfactory receptors in order to improve the sensitivity of our bio-electronic nose for specific chemical targets. Our recordings were stable over months, providing evidence for robust and stable decoding over time. The system also works in freely moving animals, allowing chemical detection to occur in real-world environments. Our bio-electronic nose outperforms current methods in terms of its stability, specificity, and versatility, setting a new standard for chemical detection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Arrests for acts of violence against women are a common occurrence for professional athletes, including National Basketball Association (NBA) players. Many sports fans, players, and those involved in professional sport believe that arrests for acts of violence against women, whether they result in a conviction or not, are highly detrimental to an athlete's career. We matched all 30 NBA players arrested for acts of violence against women between 2000 and 2016 with similar players who were not arrested and examined the effects of the arrest on postarrest average annual salary and career longevity. We found no significant difference between arrested players' careers and the careers of nonarrested counterparts. From a social learning perspective, this lack of punishment or loss of reward could be an important factor in continued acts of violence against women among NBA athletes.

Candida glabrata is the second leading cause of candidemia in many countries and is one of the most concerning yeast species of nosocomial importance due to its increasing rate of antifungal drug resistance and emerging multidrug-resistant isolates. Application of multilocus sequence typing (MLST) to clinical C. glabrata isolates revealed an association of certain sequence types (STs) with drug resistance and mortality. The current C. glabrata MLST scheme is based on single nucleotide polymorphisms (SNPs) at six loci and is therefore relatively laborious and costly. Furthermore, only a few high-quality C. glabrata reference genomes are available, limiting rapid analysis of clinical isolates by whole genome sequencing. In this study we provide long-read based assemblies for seven additional clinical strains belonging to three different STs and use this information to simplify the C. glabrata MLST scheme. Specifically, a comparison of these genomes identified highly polymorphic loci (HPL) defined by frequent insertions and deletions (indels), two of which proved to be highly resolutive for ST. When challenged with 53 additional isolates, a combination of TRP1 (a component of the current MLST scheme) with either of the two HPL fully recapitulated ST identification. Therefore, our comparative genomic analysis identified a new typing approach combining SNPs and indels and based on only two loci, thus significantly simplifying ST identification in C. glabrata . Because typing tools are instrumental in addressing numerous clinical and biological questions, our new MLST scheme can be used for high throughput typing of C. glabrata in clinical and research settings., (© 2021 Westerdijk Fungal Biodiversity Institute. Production and hosting by ELSEVIER B.V.)

Phytochrome A (phyA) comprises two native types, phyA' and phyA″, with distinct spectroscopic, photochemical, and functional properties, differing at the N-terminal extension, probably, by the state of phosphorylation. To find out if and how protein phosphatases (PP) affect the state of the phyA species in planta, we studied the effect of the non-specific phosphatase inhibitor NaF on etiolated maize seedlings with the use of low-temperature fluorescence spectroscopy and photochemistry. In roots, phosphatase inhibition facilitated photoreceptor destruction in its labile phyA' form and shifted the phyA'/phyA″ ratio towards the more stable phyA″. The effect of NaF was not observed in stems. It was similar, though less pronounced, in comparison to the effects of the serine/threonine PP inhibitors, okadaic and cantharidic acids (OA and CA), which likewise facilitate the destruction of phyA' in etiolated maize stems, not, however, in roots (Sineshchekov et al., Photochem. Photobiol 89:83-96, 2013). The phyA'/phyA″ balance thus depends on the kinase/phosphatase equilibrium in the root cells. The relatively low effect of NaF on phyA in roots, together with the lack of the effect of OA and CA in them, may imply that the mechanism controlling the phyA'/phyA″ balance in roots can be different from that in shoots., (© 2021. The Author(s), under exclusive licence to European Photochemistry Association, European Society for Photobiology.)

Fungal infections cause significant mortality and morbidity worldwide, and the limited existing antifungal reservoir is further weakened by the emergence of strains resistant to echinocandins, a first line of antifungal therapy. Candida glabrata is an opportunistic fungal pathogen that rapidly develops mutations in the echinocandin drug target β-1,3-glucan synthase (GS), which are associated with drug resistance and clinical failure. Although echinocandins are considered fungicidal in Candida sp., a subset of C. glabrata cells survive echinocandin exposure, forming a drug-tolerant cell reservoir, from which resistant mutations are thought to emerge. Despite their importance, the physiology of rare drug-tolerant cells is poorly understood. We used fluorescence-activated cell sorting to enrich for echinocandin-tolerant cells, followed by modified single-cell RNA sequencing to examine their transcriptional landscape. This analysis identified a transcriptional signature distinct from the stereotypical yeast environmental stress response and characterized by upregulation of pathways involved in chromosome structure and DNA topology and downregulation of oxidative stress responses, of which the latter was observed despite increased levels of reactive oxygen species. Further analyses implicated mitochondria in echinocandin tolerance, wherein inhibitors of mitochondrial complexes I and IV reduced echinocandin-mediated cell killing, but mutants lacking various mitochondrial components all showed an echinocandin hypotolerant phenotype. Finally, GS enzyme complexes purified from mitochondrial mutants exhibited normal in vitro inhibition kinetics, indicating that mitochondrial defects influence cell survival downstream of the drug-target interaction. Together, these results provide new insights into the C. glabrata response to echinocandins and reveal a multifactorial role of mitochondria in echinocandin tolerance. IMPORTANCE Echinocandin drugs are a first-line therapy to treat invasive candidiasis, which is a major source of morbidity and mortality worldwide. The opportunistic fungal pathogen Candida glabrata is a prominent bloodstream fungal pathogen, and it is notable for rapidly developing echinocandin-resistant strains associated with clinical failure. Echinocandin resistance is thought to emerge within a small echinocandin-tolerant subset of C. glabrata cells that are not killed by drug exposure, but mechanisms underlying echinocandin tolerance are still unknown. Here, we describe the unique transcriptional signature of echinocandin-tolerant cells and the results of follow-up analyses, which reveal a multifactorial role of mitochondria in C. glabrata echinocandin tolerance. In particular, although chemical inhibition of respiratory chain enzymes increased echinocandin tolerance, deletion of multiple mitochondrial components made C. glabrata cells hypotolerant to echinocandins. Together, these results provide new insights into the C. glabrata response to echinocandins and reveal the involvement of mitochondria in echinocandin tolerance.

Fungal infections are on the rise, and emergence of drug-resistant Candida strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as Candida glabrata . The echinocandins target 1,3-β-glucan synthase (GS), the enzyme responsible for producing 1,3-β-glucans, a major component of the fungal cell wall. Although echinocandins are considered fungicidal, C. glabrata exhibits echinocandin tolerance both in vitro and in vivo , where a subset of the cells survives and facilitates the emergence of echinocandin-resistant mutants, which are responsible for clinical failure. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted in vitro and are thus not able to recapitulate the fungal-host interaction. In this study, we focused on the role of cell wall integrity factors in echinocandin tolerance in C. glabrata. We identified three genes involved in the maintenance of cell wall integrity - YPS1 , YPK2 , and SLT2 - that promote echinocandin tolerance both in vitro and in a mouse model of gastrointestinal (GI) colonization. In particular, we show that mice colonized with strains carrying deletions of these genes were more effectively sterilized by daily caspofungin treatment relative to mice colonized with the wild-type parental strain. Furthermore, consistent with a role of tolerant cells serving as a reservoir for generating resistant mutations, a reduction in tolerance was associated with a reduction in the emergence of resistant strains. Finally, reduced susceptibility in these strains was due both to the well described FKS -dependent mechanisms and as yet unknown, FKS -independent mechanisms. Together, these results shed light on the importance of cell wall integrity maintenance in echinocandin tolerance and emergence of resistance and lay the foundation for future studies of the factors described herein., Competing Interests: DP receives research support and/or serves on advisory boards for Amplyx, Cidara, Scynexis, N8 Medical, Matinas, Merck, Regeneron, and Pfizer. RG-R, RH, AC, KH, and ES declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Garcia-Rubio, Hernandez, Clear, Healey, Shor and Perlin.)