Disruption to de novo uridine biosynthesis alters ß-1,3-glucan masking in Candida albicans.

The uridine derivatives UDP-glucose and UDP-N-acetylglucosamine are important for cell wall construction as they are the precursors for the synthesis of ß-1,3-glucan and chitin, respectively. Previous studies have demonstrated attenuated virulence of uridine auxotrophs in mice, which has been attributed to insufficient uridine levels for growth in the host. We have discovered that uridine deprivation in the uridine auxotroph ura3ΔΔ disrupts cell wall architecture by increasing surface mannans, exposing ß-1,3-glucan and chitin, and decreasing UDP-sugar levels. Cell wall architecture and UDP-sugars can be rescued with uridine supplementation. The cell wall architectural disruptions in the ura3ΔΔ mutant also impact immune activation since the mutant elicited greater TNFα secretion from RAW264.7 macrophages than wild type. To determine if cell wall defects contributed to decreased virulence in the ura3ΔΔ mutant, we used a murine model of systemic infection. Mice infected with the ura3ΔΔ mutant exhibited increased survival and reduced kidney fungal burden compared with mice infected with wild type. However, suppression of the immune response with cyclophosphamide did not rescue virulence in mice infected with the ura3ΔΔ mutant, indicating the attenuation in virulence of uridine auxotrophs can be attributed to decreased growth in the host but not increased exposure of ß-1,3-glucan. Moreover, the ura3ΔΔ mutant is unable to grow on ex vivo kidney agar, which demonstrates its inability to colonize the kidneys due to poor growth. Thus, although uridine auxotrophy elicits changes to cell wall architecture that increase the exposure of immunogenic polymers, metabolic fitness costs more strongly drive the observed virulence attenuation.IMPORTANCECandida albicans is a common cause of bloodstream infections (candidemia). Treatment of these bloodstream infections is made difficult because of increasing antifungal resistance and drug toxicity. Thus, new tactics are needed for antifungal drug development, with immunotherapy being of particular interest. The cell wall of C. albicans is composed of highly immunogenic polymers, particularly ß-1,3-glucan. However, ß-1,3-glucan is naturally masked by an outer layer of mannoproteins, which hampers the detection of the fungus by the host immune system. Alteration in cell wall components has been shown to increase ß-1,3-glucan exposure; however, it is unknown how the inability to synthesize precursors to cell wall components affects unmasking. Here, we demonstrate how cell wall architecture is altered in response to a deficit in precursors for cell wall synthesis and how uridine is a crucial component of these precursors.

Ultrafast photophysics of para-substituted 2,5-bis(arylethynyl) rhodacyclopentadienes: thermally activated intersystem crossing.

2,5-Bis(phenylethynyl) rhodacyclopentadienes (RCPDs), as a type of Rh(iii) complex, exhibit unusually intense fluorescence and slow intersystem crossing (ISC) due to weak metal-ligand interactions. However, details on their ultrafast photophysics and ISC dynamics are limited. In this work, electronic relaxation upon photoexcitation of two substituted RCPDs with two -CO2Me (A-RC-A) or -NMe2/-CO2Me (D-RC-A) end groups are comprehensively investigated using femtosecond transient absorption spectroscopy and theoretical analysis. Upon ultraviolet and visible excitation, dephasing of vibrational coherence, charge transfer, conformation relaxation, and ISC are observed experimentally. By calculating the spin-orbit coupling, reorganization energy, and adiabatic energy gap of plausible ISC channels, semi-classical Marcus theory revealed the dominance of thermally activated ISC (S1 → T2) for both D-RC-A and A-RC-A, while S1 → T1 channels are largely blocked due to high ISC barriers. With weak spin-orbit coupling, such differences in plausible ISC channels are predominately tuned by energetic parameters. Singlet oxygen sensitization studies of A-RC-A provide additional insight into the excited-state behavior of this complex.

Precise Image-level Localization of Intracranial Hemorrhage on Head CT Scans with Deep Learning Models Trained on Study-level Labels.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To develop a highly generalizable weakly supervised model to automatically detect and localize image- level intracranial hemorrhage (ICH) using study-level labels. Materials and Methods In this retrospective study, the proposed model was pretrained on the image-level RSNA dataset and fine-tuned on a local dataset using attention-based bidirectional long-short-term memory networks. This local training dataset included 10,699 noncontrast head CT scans from 7469 patients with ICH study-level labels extracted from radiology reports. Model performance was compared with that of two senior neuroradiologists on 100 random test scans using the McNemar test, and its generalizability was evaluated on an external independent dataset. Results The model achieved a positive predictive value (PPV) of 85.7% (95% CI: [84.0%, 87.4%]) and an AUC of 0.96 (95% CI: [0.96, 0.97]) on the held-out local test set (n = 7243, 3721 female) and 89.3% (95% CI: [87.8%, 90.7%]) and 0.96 (95% CI: [0.96, 0.97]), respectively, on the external test set (n = 491, 178 female). For 100 randomly selected samples, the model achieved performance on par with two neuroradiologists, but with a significantly faster (P < .05) diagnostic time of 5.04 seconds per scan (versus 86 seconds and 22.2 seconds for the two neuroradiologists, respectively). The model's attention weights and heatmaps visually aligned with neuroradiologists' interpretations. Conclusion The proposed model demonstrated high generalizability and high PPVs, offering a valuable tool for expedited ICH detection and prioritization while reducing false-positive interruptions in radiologists' workflows. ©RSNA, 2024.

Pain and Cognition of Breast Cancer Survivors Treated with Chemotherapy: The Mediating Role of Depression.

OBJECTIVES: While chemotherapy is the primary contributor to cancer-related cognitive impairment (CRCI), interindividual differences in CRCI are not well-understood. Studies suggest that breast cancer (BC) survivors who are in pain are more likely to experience depression, which in turn contributes to CRCI, although this hypothesis is not yet tested. Therefore, this study aimed to investigate the relationship between pain and CRCI among BC survivors and the mediation effect of depression on this relationship. METHODS: As a secondary analysis of a descriptive cross-sectional study investigating fatigue and preferred types of fatigue self-management in BC survivors recruited from five tertiary hospitals in South Korea; of the 229 participants, data on 186 who received chemotherapy were analyzed. Study participants were aged between 20 and 69 years, diagnosed with stage I to III, and treated with chemotherapy and/or radiation therapy. Measurement was done with Korean versions of the Cognitive Failure Questionnaire (to assess CRCI), Brief Pain Inventory (for pain severity and interference on daily functioning), and C-ESD (for depression). To assess bivariate relationships between pain, depression, and CRCI, Pearson correlation was used. A mediation analysis was used to examine the effect of depression on CRCI. RESULTS: Significant associations were found among pain, depression, and CRCI (all P < 0.01). Furthermore, a mediation effect of depression was found on the association between pain and CRCI (severity, ß = 1.26, SE = 0.38, 95% confidence intervals [0.60, 2.08]; interference, ß = 1.53, SE = 0.32, 95% confidence intervals [0.95, 2.20]). CONCLUSION: Findings indicate that among BC survivors, those with higher pain tend to show higher depression and consequently had lower cognitive function. IMPLICATION FOR NURSING PRACTICE: Oncology nurses may need to identify BC survivors with higher pain, and screening those survivors could be a strategy to identify those at higher risk for CRCI. Also, nurses should focus on managing depression to prevent and/or treat CRCI in BC survivors.

Synthesis of phenanthrylboroles and formal nitrene insertion to access azaborapyrenes.

Extended conjugation has been introduced into boroles but only on the 2,3- or 4,5-positions of the central BC4 core. In this work we synthesize phenanthrylboroles that also have conjugation on the 3,4-positions and demonstrate their insertion reactivity with azides to furnish B,N-analogues of pyrene.

Central Amygdala Astrocyte Plasticity Underlies GABAergic Dysregulation in Ethanol Dependence.

Dependence is a hallmark of alcohol use disorder characterized by excessive alcohol intake and withdrawal symptoms. The central nucleus of the amygdala (CeA) is a key brain structure underlying the synaptic and behavioral consequences of ethanol dependence. While accumulating evidence suggests that astrocytes regulate synaptic transmission and behavior, there is a limited understanding of the role astrocytes play in ethanol dependence. The present study used a combination of viral labeling, super resolution confocal microscopy, 3D image analysis, and slice electrophysiology to determine the effects of chronic intermittent ethanol (CIE) exposure on astrocyte plasticity in the CeA. During withdrawal from CIE exposure, we observed increased GABA transmission, an upregulation in astrocytic GAT3 levels, and an increased proximity of astrocyte processes near CeA synapses. Furthermore, GAT3 levels and synaptic proximity were positively associated with voluntary ethanol drinking in dependent rats. Slice electrophysiology confirmed that the upregulation in astrocytic GAT3 levels was functional, as CIE exposure unmasked a GAT3-sensitive tonic GABA current in the CeA. A causal role for astrocytic GAT3 in ethanol dependence was assessed using viral-mediated GAT3 overexpression and knockdown approaches. However, GAT3 knockdown or overexpression had no effect on somatic withdrawal symptoms, dependence-escalated ethanol intake, aversion-resistant drinking, or post-dependent ethanol drinking in male or female rats. Moreover, intra-CeA pharmacological inhibition of GAT3 also did not alter dependent ethanol drinking. Together, these findings indicate that ethanol dependence induces GABAergic dysregulation and astrocyte plasticity in the CeA. However, astrocytic GAT3 does not appear necessary for the drinking related phenotypes associated with dependence.

Surface-associated residues in subtilisins contribute to poly-L-lactic acid depolymerization via enzyme adsorption.

Poly-L-lactic acid (PLLA) is currently the most abundant bioplastic; however, limited environmental biodegradability and few recycling options diminish its value as a biodegradable commodity. Enzymatic recycling is one strategy for ensuring circularity of PLLA, but this approach requires a thorough understanding of enzymatic mechanisms and protein engineering strategies to enhance activity. In this study, we engineer PLLA depolymerizing subtilisin enzymes originating from Bacillus species to elucidate the molecular mechanisms dictating their PLLA depolymerization activity and to improve their function. The surface-associated amino acids of two closely related subtilisin homologues originating from Bacillus subtilis (BsAprE) and Bacillus pumilus (BpAprE) were compared, as they were previously engineered to have nearly identical active sites, but still varied greatly in PLLA depolymerizing activity. Further analysis identified several surface-associated amino acids in BpAprE that lead to enhanced PLLA depolymerization activity when engineered into BsAprE. In silico protein modelling demonstrated increased enzyme surface hydrophobicity in engineered BsAprE variants and revealed a structural motif favoured for PLLA depolymerization. Experimental evidence suggests that increases in activity are associated with enhanced polymer binding as opposed to substrate specificity. These data highlight enzyme adsorption as a key factor in PLLA depolymerization by subtilisins.

Synthesis, Photophysical and Electronic Properties of a D-π-A Julolidine-Like Pyrenyl-o-Carborane.

We synthesized 2-(1-1,2-dicarbadodecaboranyl(12))-6,6,12,12-tetramethyl-7,8,11,12-tetrahydro-6H,10H-phenaleno[1,9-fg]pyrido[3,2,1-ij]quinoline (4), a julolidine-like pyrenyl-o-carborane, with pyrene substituted at the 2,7-positions on the HOMO/LUMO nodal plane. Using solid state molecular structures, photophysical data, cyclic voltammetry, DFT and LR-TDDFT calculations, we compare o-carborane and B(Mes)2 (Mes=2,4,6-Me3C6H2) as acceptor groups. Whereas the π-acceptor strength of B(Mes)2 is sufficient to drop the pyrene LUMO+1 below the LUMO, the carborane does not do this. We confirm the π-donor strength of the julolidine-like moiety, however, which raises the pyrene HOMO-1 above the HOMO. In contrast to the analogous pyrene-2-yl-o-carborane, 2-(1-1,2-dicarbadodecaboranyl(12))-pyrene VI, which exhibits dual fluorescence, because the rate of internal conversion between locally-excited (LE) and charge transfer (CT) (from the pyrene to the carborane) states is faster than the radiative decay rate, leading to a thermodynamic equilibrium between the 2 states, 4 shows only single fluorescence, as the CT state involving the carborane as the acceptor moiety in not kinetically accessible, so a more localized CT emission involving the julolidine-like pyrene moiety is observed.

Photoredox/Cu-Catalyzed Decarboxylative C(sp3)-C(sp3) Coupling to Access C(sp3)-Rich gem-Diborylalkanes.

gem-Diborylalkanes are highly valuable building blocks in organic synthesis and pharmaceutical chemistry due to their ability to participate in multi-step cross-coupling transformations, allowing for the rapid generation of molecular complexity. While progress has been made in their synthetic metholodology, the construction of ß-tertiary and C(sp3)-rich gem-diborylalkanes remains a synthetic challenge due to substrate limitations and steric hindrance issues. An approach is presented that utilizes synergistic photoredox and copper catalysis to achieve efficient C(sp3)-C(sp3) cross-coupling of alkyl N-hydroxyphthalimide esters, which can easily be obtained from alkyl carboxylic acids, with diborylmethyl species, providing a series of C(sp3)-rich gem-diborylalkanes with 1°, 2°, and even 3° ß positions. Furthermore, this approach can also be applied to complex medicinal compounds and natural products, offering rapid access to molecular complexity and late-stage functionalization of C(sp3)-rich drug candidates. Mechanistic experiments revealed that diborylmethyl Cu(I) species participated in both the photoredox process and the key C(sp3)-C(sp3) bond-forming step.

Probing Glycerolipid Metabolism using a Caged Clickable Glycerol-3-Phosphate Probe.

In this study, we present the probe SATE-G3P-N3 as a novel tool for metabolic labeling of glycerolipids (GLs) to investigate lipid metabolism in yeast cells. By introducing a clickable azide handle onto the glycerol backbone, this probe enables general labeling of glycerolipids. Additionally, this probe contains a caged phosphate moiety at the glycerol sn-3 position to not only facilitate probe uptake by masking negative charge but also to bypass the phosphorylation step crucial for initiating phospholipid synthesis, thereby enhancing phospholipid labeling. The metabolic labeling activity of the probe was thoroughly assessed through cellular fluorescence microscopy, mass spectrometry (MS), and thin-layer chromatography (TLC) experiments. Fluorescence microscopy analysis demonstrated successful incorporation of the probe into yeast cells, with labeling predominantly localized at the plasma membrane. LCMS analysis confirmed metabolic labeling of various phospholipid species (PC, PS, PA, PI, and PG) and neutral lipids (MAG, DAG, and TAG), and GL labeling was corroborated by TLC. These results showcased the potential of the SATE-G3P-N3 probe in studying GL metabolism, offering a versatile and valuable approach to explore the intricate dynamics of lipids in yeast cells.

The costs of curiosity and creativity: Minimizing the downsides while maximizing the upsides.

The unbridled positivity toward curiosity and creativity may be excessive. Both aid species survival through exploration and advancement. These beneficial effects are well documented. What remains is to understand their optimal levels and contexts for maximal achievement, health, and well-being. Every beneficial element to individuals and groups carries the potential for harm - curiosity and creativity included.

Phosphine-Catalyzed 1,2-cis-Diboration of 1,3-Butadiynes.

Trialkyl phosphines PMe3 and PEt3 catalyze the 1,2-cis-diboration of 1,3-butadiynes to give 1,2-diboryl enynes. The products were utilized to synthesize 1,1,2,4-tetraaryl enynes using a Suzuki-Miyaura protocol and can readily undergo proto-deborylation.

The small molecule CBR-5884 inhibits the Candida albicans phosphatidylserine synthase.

Systemic infections by Candida spp. are associated with high mortality rates, partly due to limitations in current antifungals, highlighting the need for novel drugs and drug targets. The fungal phosphatidylserine synthase, Cho1, from Candida albicans is a logical antifungal drug target due to its importance in virulence, absence in the host, and conservation among fungal pathogens. Inhibitors of Cho1 could serve as lead compounds for drug development, so we developed a target-based screen for inhibitors of purified Cho1. This enzyme condenses serine and cytidyldiphosphate-diacylglycerol (CDP-DAG) into phosphatidylserine (PS) and releases cytidylmonophosphate (CMP). Accordingly, we developed an in vitro nucleotidase-coupled malachite-green-based high throughput assay for purified C. albicans Cho1 that monitors CMP production as a proxy for PS synthesis. Over 7,300 molecules curated from repurposing chemical libraries were interrogated in primary and dose-responsivity assays using this platform. The screen had a promising average Z' score of ~0.8, and seven compounds were identified that inhibit Cho1. Three of these, ebselen, LOC14, and CBR-5884, exhibited antifungal effects against C. albicans cells, with fungicidal inhibition by ebselen and fungistatic inhibition by LOC14 and CBR-5884. Only CBR-5884 showed evidence of disrupting in vivo Cho1 function by inducing phenotypes consistent with the cho1∆∆ mutant, including a reduction of cellular PS levels. Kinetics curves and computational docking indicate that CBR-5884 competes with serine for binding to Cho1 with a Ki of 1,550 ± 245.6 nM. Thus, this compound has the potential for development into an antifungal compound. IMPORTANCE: Fungal phosphatidylserine synthase (Cho1) is a logical antifungal target due to its crucial role in the virulence and viability of various fungal pathogens, and since it is absent in humans, drugs targeted at Cho1 are less likely to cause toxicity in patients. Using fungal Cho1 as a model, there have been two unsuccessful attempts to discover inhibitors for Cho1 homologs in whole-cell screens prior to this study. The compounds identified in these attempts do not act directly on the protein, resulting in the absence of known Cho1 inhibitors. The significance of our research is that we developed a high-throughput target-based assay and identified the first Cho1 inhibitor, CBR-5884, which acts both on the purified protein and its function in the cell. This molecule acts as a competitive inhibitor with a Ki value of 1,550 ± 245.6 nM and, thus, has the potential for development into a new class of antifungals targeting PS synthase.

Applications of Transition Metal-Catalyzed ortho-Fluorine-Directed C-H Functionalization of (Poly)fluoroarenes in Organic Synthesis.

The synthesis of organic compounds efficiently via fewer steps but in higher yields is desirable as this reduces energy and reagent use, waste production, and thus environmental impact as well as cost. The reactivity of C-H bonds ortho to fluorine substituents in (poly)fluoroarenes with metal centers is enhanced relative to meta and para positions. Thus, direct C-H functionalization of (poly)fluoroarenes without prefunctionalization is becoming a significant area of research in organic chemistry. Novel and selective methodologies to functionalize (poly)fluorinated arenes by taking advantage of the reactivity of C-H bonds ortho to C-F bonds are continuously being developed. This review summarizes the reasons for the enhanced reactivity and the consequent developments in the synthesis of valuable (poly)fluoroarene-containing organic compounds.

Genital Surgery Outcomes Using an Individualized Algorithm for Hormone Management in Transfeminine Individuals.

CONTEXT: Transgender and gender diverse (TGD) individuals have greater access to genital surgery (GS) with improved insurance coverage and access to trained surgeons and interdisciplinary gender affirming providers. OBJECTIVE: To determine perioperative medical and behavioral health outcomes in transfeminine (TF) individuals undergoing GS with use of a specific gender-affirming hormone therapy (GAHT) algorithm based on individualized risk factor assessment. DESIGN: Retrospective observational cohort study from 2017-2022. Pre- and post-operative data collected included clinical and biochemical assessment, GAHT regimens, validated behavioral health measures, and post-operative complications. SETTING: Single-center tertiary referral center. PATIENTS: 183 TF individuals, grouped into estradiol continued (Group 1) vs estradiol temporarily discontinued for 2-6 weeks preoperatively (Group 2). MAIN OUTCOME MEASURE(S): Venous thromboembolism (VTE) incidence, non-VTE postoperative complication incidence, and change in behavioral health assessments. RESULTS: The majority of individuals continued estradiol perioperatively [Group 1; 138 (75.4%)]. Individuals who temporarily held estradiol preoperatively [Group 2; 45 (24.6%)] were statistically older (p < 0.01), had higher incidence of cardiometabolic comorbidities (p < 0.01), and higher Caprini scores (p < 0.01). Group 1 was statistically more likely to use oral estradiol (p < 0.01). One episode (0.05%) of VTE occurred (Group 1). There was no significant difference in postoperative complications or behavioral health measures between groups. CONCLUSION: An individualized algorithm for preoperative hormone management for TF GS resulted in perioperative continuation of GAHT for the majority of individuals without significantly increasing the risk for post-operative surgical complications while maintaining stable behavioral health measures perioperatively.

Chemical and linguistic considerations for encoding Chinese characters: an embodiment using chain-end degradable sequence-defined oligourethanes created by consecutive solid phase click chemistry.

Sequence-defined polymers (SDPs) are currently being investigated for use as information storage media. As the number of monomers in the SDPs increases, with a corresponding increase in mathematical base, the use of tandem-MS for de novo sequencing becomes more challenging. In contrast, chain-end degradation routines are truly de novo, potentially allowing very large mathematical bases for encoding. While alphabetic scripts have a few dozen symbols, logographic scripts, such as Chinese, can have several thousand symbols. Using a new in situ consecutive click reaction approach on an oligourethane backbone for writing, and a previously reported chain-end degradation routine for reading, we encoded/decoded a confucius proverb written in Chinese characters using two encoding schemes: Unicode and Zhèng Ma. Unicode is an internationally standardized arbitrary string of hexadecimal (base-16) symbols which efficiently encodes uniquely identifiable symbols but requires complete fidelity of transmission, or context-based inferential strategies to be interpreted. The Zhèng Ma approach encodes with a base-26 system using the visual characteristics and internal composition of Chinese characters themselves, which leads to greater ambiguity of encoded strings, but more robust retrievability of information from partial or corrupted encodings. The application of information-encoded oligourethanes to two different encoding systems allowed us to establish their flexibility and versatility for data storage. We found the oligourethanes immensely adaptable to both encoding schemes for Chinese characters, and we highlight the expected tradeoff between the efficiency and uniqueness of Unicode encoding on the one hand, and the fidelity to a scripts' particular visual characteristics on the other.

Frameshift mutations in peripheral blood as a biomarker for surveillance of Lynch syndrome.

BACKGROUND: Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes, which lead to high microsatellite instability and frameshift mutations at coding mononucleotide repeats in the genome. Recurrent frameshift mutations in these regions are thought to play a central role in the increased risk of various cancers, but no biomarkers are currently available for the surveillance of high microsatellite instability-associated cancers. METHODS: A frameshift mutation-based biomarker panel was developed and validated by targeted next-generation sequencing of supernatant DNA from cultured high microsatellite instability colorectal cancer cells. This panel supported selection of 122 frameshift mutation targets as potential biomarkers. This biomarker panel was then tested using matched tumor, adjacent normal tissue, and buffy coat samples (53 samples) and blood-derived cell-free DNA (cfDNA) (38 samples) obtained from 45 high microsatellite instability and mismatch repair-deficient patients. We also sequenced cfDNA from 84 healthy participants to assess background noise. RESULTS: Recurrent frameshift mutations at coding mononucleotide repeats were detectable not only in tumors but also in cfDNA from high microsatellite instability and mismatch repair-deficient patients, including a Lynch syndrome carrier, with a varying range of target detection (up to 85.2%), whereas they were virtually undetectable in healthy participants. Receiver operating characteristic curve analysis showed high sensitivity and specificity (area under the curve = 0.94) of the investigated panel. CONCLUSIONS: We demonstrated that frameshift mutations can be detected in cfDNA from high microsatellite instability and mismatch repair-deficient patients and asymptomatic carriers. The 122-target frameshift mutation panel described here has promise as a tool for improved surveillance of high microsatellite instability and mismatch repair-deficient patients, with the potential to reduce the frequency of invasive screening methods for this high-cancer-risk cohort.

Innovations in Antifungal Drug Discovery among Cell Envelope Synthesis Enzymes through Structural Insights.

Life-threatening systemic fungal infections occur in immunocompromised patients at an alarming rate. Current antifungal therapies face challenges like drug resistance and patient toxicity, emphasizing the need for new treatments. Membrane-bound enzymes account for a large proportion of current and potential antifungal targets, especially ones that contribute to cell wall and cell membrane biosynthesis. Moreover, structural biology has led to a better understanding of the mechanisms by which these enzymes synthesize their products, as well as the mechanism of action for some antifungals. This review summarizes the structures of several current and potential membrane-bound antifungal targets involved in cell wall and cell membrane biosynthesis and their interactions with known inhibitors or drugs. The proposed mechanisms of action for some molecules, gleaned from detailed inhibitor-protein studeis, are also described, which aids in further rational drug design. Furthermore, some potential membrane-bound antifungal targets with known inhibitors that lack solved structures are discussed, as these might be good enzymes for future structure interrogation.

Critical care nurse leaders' moral distress: A qualitative descriptive study.

BACKGROUND: Unit-based critical care nurse leaders (UBCCNL) play a role in exemplifying ethical leadership, addressing moral distress, and mitigating contributing factors to moral distress on their units. Despite several studies examining the experience of moral distress by bedside nurses, knowledge is limited regarding the UBCCNL's experience. RESEARCH AIM: The aim of this study was to gain a deeper understanding of the lived experiences of Alabama UBCCNLs regarding how they experience, cope with, and address moral distress. RESEARCH DESIGN: A qualitative descriptive design and inductive thematic analysis guided the investigation. A screening and demographics questionnaire and a semi-structured interview protocol were the tools of data collection. PARTICIPANT AND RESEARCH CONTEXT: Data were collected from 10 UBCCNLs from seven hospitals across the state of Alabama from February to July 2023. ETHICAL CONSIDERATIONS: This study was approved by the Institutional Review Board at the University of Alabama in Huntsville. Informed consent was obtained from participants prior to data collection. FINDINGS: UBCCNLs experience moral distress frequently due to a variety of systemic and organizational barriers. Feelings of powerlessness tended to precipitate moral distress among UBCCNLs. Despite moral distress resulting in increased advocacy and empathy, UBCCNLs may experience a variety of negative responses resulting from moral distress. UBCCNLs may utilize internal and external mechanisms to cope with and address moral distress. CONCLUSIONS: The UBCCNL's experience of moral distress is not dissimilar from bedside staff; albeit, moral distress does occur as a result of the responsibilities of leadership and the associated systemic barriers that UBCCNLs are privier to. When organizations allocate resources for addressing moral distress, they should be convenient to leaders and staff. The UBCCNL perspective should be considered in the development of future moral distress measurement tools and interventions. Future research exploring the relationship between empathy and moral distress among nurse leaders is needed.

Vulnerabilities in social anxiety: Integrating intra- and interpersonal perspectives.

What are the major vulnerabilities in people with social anxiety? What are the most promising directions for translational research pertaining to this condition? The present paper provides an integrative summary of basic and applied translational research on social anxiety, emphasizing vulnerability factors. It is divided into two subsections: intrapersonal and interpersonal. The intrapersonal section synthesizes research relating to (a) self-representations and self-referential processes; (b) emotions and their regulation; and (c) cognitive biases: attention, interpretation and judgment, and memory. The interpersonal section summarizes findings regarding the systems of (a) approach and avoidance, (b) affiliation and social rank, and their implications for interpersonal impairments. Our review suggests that the science of social anxiety and, more generally, psychopathology may be advanced by examining processes and their underlying content within broad psychological systems. Increased interaction between basic and applied researchers to diversify and elaborate different perspectives on social anxiety is necessary for progress.