Interprofessional negotiations in biopsychosocial pain rehabilitation: a need for silent bargains.

Communicating effectively, including the ability to negotiate, has been claimed to be key competencies in interprofessional practice. However, these day-to-day contributions to interprofessional teamwork are not yet sufficiently understood. The aim of this article is to explore the day-to-day interprofessional negotiations in biopsychosocial pain rehabilitation. A qualitative design with an ethnographic approach was applied to the overall study. Participant observation of interprofessional encounters and clinical encounters in a pain rehabilitation ward was undertaken in 2016 for a period of 19 weeks. Intermittent interviews with 12 professionals were conducted. Data were analyzed in an abductive process using thematic analysis. We present the results as two themes: 1) Silent conflicting interests in the office, and 2) Silent dissatisfaction with meetings. The study showed that the team members had opportunities to negotiate in interprofessional offices and meetings, while they perceived insufficient time for discussion, and their individual work being interrupted by each other in the offices. They did not discuss their dissatisfaction, but silently bargained on how to spend time together. Professionals can contribute to teamwork through silent bargains that can promote a low level of conflict and thereby preserve a good workflow.

Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG.

The oligosaccharide needed for protein N-glycosylation is assembled on a lipid carrier via a multi-step pathway. Synthesis is initiated on the cytoplasmic face of the endoplasmic reticulum (ER) and completed on the luminal side after transbilayer translocation of a heptasaccharide lipid intermediate. More than 30 Congenital Disorders of Glycosylation (CDGs) are associated with this pathway, including RFT1-CDG which results from defects in the membrane protein Rft1. Rft1 is essential for the viability of yeast and mammalian cells and was proposed as the transporter needed to flip the heptasaccharide lipid intermediate across the ER membrane. However, other studies indicated that Rft1 is not required for heptasaccharide lipid flipping in microsomes or unilamellar vesicles reconstituted with ER membrane proteins, nor is it required for the viability of at least one eukaryote. It is therefore not known what essential role Rft1 plays in N-glycosylation. Here, we present a molecular characterization of human Rft1, using yeast cells as a reporter system. We show that it is a multi-spanning membrane protein located in the ER, with its N and C-termini facing the cytoplasm. It is not N-glycosylated. The majority of RFT1-CDG mutations map to highly conserved regions of the protein. We identify key residues that are important for Rft1's ability to support N-glycosylation and cell viability. Our results provide a necessary platform for future work on this enigmatic protein.

Upper-level inter-disciplinary microbiology CUREs increase student's scientific self-efficacy, scientific identity, and self-assessed skills.

Course-based undergraduate research experiences (CUREs) provide opportunities for undergraduate students to engage in authentic research and generally increase the participation rate of students in research. Students' participation in research has a positive impact on their science identity and self-efficacy, both of which can predict integration of students in Science, Technology, Engineering, and Math (STEM), especially for underrepresented students. The main goal of this study was to investigate instructor-initiated CUREs implemented as upper-level elective courses in the Biomedical Sciences major. We hypothesized that these CUREs would (i) have a positive impact on students' scientific identity and self-efficacy and (ii) result in gains in students' self-assessed skills in laboratory science, research, and science communication. We used Likert-type surveys developed by Estrada et al. (14) under the Tripartite Integration Model of Social Influence to measure scientific identity, self-efficacy, and scientific value orientation. When data from all CUREs were combined, our results indicate that students' self-efficacy and science identity significantly increased after completion. Students' self-assessment of research and lab-related skills was significantly higher after completion of the CUREs. We also observed that prior to participation in the CUREs, students' self-assessment of molecular and bioinformatic skills was low, when compared with microbiological skills. This may indicate strengths and gaps in our curriculum that could be explored further.

The homeobox transcription factor DUXBL controls exit from totipotency.

In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DUX) mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing. We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression. Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the TRIM superfamily involved in gene silencing, and colocalizes with them in nuclear foci upon DUX expression. Importantly, DUXBL overexpression impairs 2C-associated transcription, whereas Duxbl inactivation in mouse embryonic stem cells increases DUX-dependent induction of the 2C-transcriptional program. Consequently, DUXBL deficiency in embryos results in sustained expression of 2C-associated transcripts leading to early developmental arrest. Our study identifies DUXBL as an essential regulator of totipotency exit enabling the first divergence of cell fates.

Cryo-EM structures of amyloid-ß and tau filaments in Down syndrome.

Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-ß (Aß) and tau filaments is unknown. Here we report the structure of Aß and tau filaments from two DS brains. We found two Aß40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aß42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.

Traumatic Self-Inflicted Ventricular Laceration: A Case of Smith-Lemli-Opitz Syndrome in an Adult.

Adults with intellectual and developmental disabilities (IDD) are increasingly living into adulthood, highlighting the need for adult clinicians to expand their familiarity with congenital conditions. Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive inborn error of cholesterol synthesis. SLOS is commonly diagnosed in childhood, but a number of adults with IDD progress into adulthood without a formal diagnosis. We present an 18-year-old male with a history of IDD and altered pain sensation who was hospitalized following a self-inflicted knife injury resulting in a traumatic ventricular septal defect. Over the following 15 years, the patient continued to exhibit self-injurious behaviors. At the age of 33, caregivers consented to further work-up of his intellectual disability, and whole-exome genetic sequencing revealed a diagnosis of SLOS. The clinical course of this patient represents a unique presentation of altered pain sensation, a delayed diagnosis of SLOS into adulthood, and the challenges of providing care to an adult with IDD. The case further highlights the importance of understanding the typical workup and management of genetic and congenital conditions arising in childhood.

Novel delivery systems for controlled release of bacterial therapeutics.

As more is learned about the benefits of microbes, their potential to prevent and treat disease is expanding. Microbial therapeutics are less burdensome and costly to produce than traditional molecular drugs, often with superior efficacy. Yet, as with most medicines, controlled dosing and delivery to the area of need remain key challenges for microbes. Advances in materials to control small-molecule delivery are expected to translate to microbes, enabling similar control with equivalent benefits. In this perspective, recent advances in living biotherapeutics are discussed within the context of new methods for their controlled release. The integration of these advances provides a roadmap for the design, synthesis, and analysis of controlled microbial therapeutic delivery systems.

Environmental Impact of a Direct Laryngoscopy: Opportunities for Pollution Mitigation.

OBJECTIVE: To quantify the environmental impact of standard direct laryngoscopy surgery and model the environmental benefit of three feasible alternative scenarios that meet safe decontamination reprocessing requirements. STUDY DESIGN: This is a life cycle assessment (LCA) modeling study. SETTING: Yale-New Haven Hospital (YNHH), a 1541-bed tertiary medical center in New Haven, Connecticut, USA. METHODS: We performed cradle-to-grave LCA of DLS at Yale New Haven Hospital in 2022, including global warming potential (GWP), water consumption, and fine particulate matter formation. Three alternative scenarios were modeled: disinfecting surgical tools using high-level disinfection rather than steam sterilization, substituting non-sterile for sterile gloves and gowns; and reducing surgical towel and drape sizes by 30%. RESULTS: Changes in disinfection practices would decrease procedure GWP by 11% in each environmental impact category. Substituting non-sterile gowns and gloves reduced GWP by 15%, with nominal changes to water consumption. Linen size reduction resulted in 28% less procedure-related water consumption. Together, a nearly 30% reduction across all environmental impact categories could be achieved. CONCLUSIONS: Not exceeding minimum Center for Disease Control (CDC) decontamination standards for reusable devices and optimizing non-sterile consumable materials could dramatically reduce healthcare-associated emissions without compromising safety, thereby minimizing the negative consequences of hospital operations to environmental and human health. Findings extend to other non-sterile surgical procedures. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3206-3214, 2024.

Dual feed progressive cavity pump extrusion system for functionally graded direct ink write 3D printing.

Material extrusion Additive Manufacturing (AM), is one of the most widely practiced methods of AM. Fused Filament Fabrication (FFF) is what most associate with AM, as it is relatively inexpensive, and highly accessible, involving feeding plastic filament into a hot-end that melts and extrudes from a nozzle as the toolhead moves along the toolpath. Direct Ink Write (DIW) 3D printing falls into this same category of AM, however is primarily practiced in laboratory settings to construct novel parts from flowable feedstock materials. DIW printers are relatively expensive and often depend on custom software to print a part, limiting user-specificity. There have been recent advancements in multi-material and functionally graded DIW, but the systems are highly custom and the methods used to achieve multi-material prints are openly available to the public. The following article outlines the construction and operation method of a DIW system that is capable of printing that can produce compositionally-graded components using a dual feed progressive cavity pump extruder equipped with a dynamic mixer. The extruder and its capabilities to vary material composition while printing are demonstrated using a Prusa i3 MK3S+ desktop fused filament fabrication printer as the gantry system. This provides users ease of operation, and the capability of further tailoring to specific needs.

Alkyl-templated cocrystallization of long-chain 1-bromoalkanes by lipid-like ionic liquids.

The serendipitous discovery of an unorthodox ionic cocrystallization system using 2-mercaptothiazolium-based ionic liquids as a crystallization milieu paves the way for the first report of crystal structures of long-chain 1-bromoalkanes. We used single crystal X-ray diffraction to determine the structures of 1-bromo-hexadecane and 1-octadecane with the aid of ionic liquids with alkyl side chains of equivalent length to the bromoalkane at room temperature. Long alkyl chains in combination with σ-hole interactions from strategically placed sulfur motifs synergistically function to crystallize the 1-bromoalkanes.

YY1 is a transcriptional activator of mouse LINE-1 Tf subfamily.

Long interspersed element type 1 (LINE-1, L1) is an active autonomous transposable element (TE) in the human genome. The first step of L1 replication is transcription, which is controlled by an internal RNA polymerase II promoter in the 5' untranslated region (UTR) of a full-length L1. It has been shown that transcription factor YY1 binds to a conserved sequence motif at the 5' end of the human L1 5'UTR and dictates where transcription initiates but not the level of transcription. Putative YY1-binding motifs have been predicted in the 5'UTRs of two distinct mouse L1 subfamilies, Tf and Gf. Using site-directed mutagenesis, in vitro binding, and gene knockdown assays, we experimentally tested the role of YY1 in mouse L1 transcription. Our results indicate that Tf, but not Gf subfamily, harbors functional YY1-binding sites in its 5'UTR monomers. In contrast to its role in human L1, YY1 functions as a transcriptional activator for the mouse Tf subfamily. Furthermore, YY1-binding motifs are solely responsible for the synergistic interaction between monomers, consistent with a model wherein distant monomers act as enhancers for mouse L1 transcription. The abundance of YY1-binding sites in Tf elements also raise important implications for gene regulation at the genomic level.

Structure-based design, and development of amidinyl, amidoximyl and hydroxamic acid based organic molecules as novel antimalarial drug candidates.

Malaria remains a significant global health concern causing numerous fatalities and the emergence of antimalarial drug resistance highlights the urgent need for novel therapeutic options with innovative mechanisms of action and targets. This study aimed to design potential inhibitors of Plasmodium falciparum 6-pyruvoyltetrahydropterin synthase (PfPTPS), synthesize them, and experimentally validate their efficacy as antimalarial agents. A structure-based approach was employed to design a series of novel derivatives, including amidinyl, amidoximyl and hydroxamic acid analogs (1c, 1d, 2b, and 3b), with a focus on their ability to bind to the Zn2+ present in the active site of PfPTPS. The syntheses of these compounds were accomplished through various multi-step synthetic pathways and their structural identities were confirmed using 1H and 13C NMR spectra, mass spectra, and elemental analysis. The compounds were screened for their antiplasmodial activity against the NF54 strain of P. falciparum and in vitro cytotoxicity testing was performed using L-6 cells. The in vivo acute toxicity of the compounds was evaluated in mice. Docking studies of the compounds with the 3D structure of PfPTPS revealed their strong binding affinities, with compound 3b exhibiting notable metal-acceptor interaction with the Zn2+ in the protein binding pocket thereby positioning it as a lead compound for PfPTPS inhibition. The in vitro antiplasmodial studies revealed moderate efficacies against the Pf NF54 strain, particularly compounds 1d and 3b which displayed IC50 < 0.2 µM. No significant cytotoxicity was noted on the L-6 rat cell line. Moreover, in vivo studies suggested that compound 3b exhibited both safety and efficacy in treating rodent malaria. The identified lead compound in this study represents a possible candidate for antimalarial drug development and can be further explored in the search for alternative antifolate drugs to combat the malaria menace.

Effects of Alzheimer's Diagnosis and Gender on Ageist Attitudes, Aging Anxiety, and Emotional Reactions to Older Adults.

BACKGROUND AND OBJECTIVES: We investigated whether ageist attitudes, aging anxiety, and emotional reactions to older adults differ based on Alzheimer's disease (AD) diagnosis, older adult gender, and participant gender, as well as their interactions. RESEARCH DESIGN AND METHODS: Using an experimental design, 291 participants (176 men, 115 women; 19-55 years) were randomly assigned to read 1 of 4 descriptions of an older adult that varied cognitive health and gender. Measures of ageist attitudes, aging anxiety, and emotional reactions to the older adult were completed online. RESULTS: Relative to a cognitively intact older adult, an older adult with AD evoked less ageist attitudes, less aging anxiety, more compassion, and less emotional distance. A significant interaction between older adult gender and participant gender indicated women felt greater emotional distance from an older adult man than an older adult woman, while men showed no significant difference. DISCUSSION AND IMPLICATIONS: The more positive emotions and less ageist responses to an older adult with AD could present as paternalistic and diminish older adults' agency. Women may prioritize shared gender identity over age, which has implications for caregivers and health professionals working with older adults.

Identifying Specific Gaps in Knowledge of Aging and Examining Its Relation to Biases Toward Older Adults.

Accurate aging knowledge is key to reducing ageist attitudes that impact older adult well-being. We first investigated how aging knowledge and negative and positive age-bias indirectly expressed via aging knowledge responses were related to an explicitly negative ageism measure. We then identified specific gaps in the aging knowledge of emerging adults and middle-aged adults. More negative ageism correlated with less aging knowledge overall and in psychological and social, but not biological, domains. Negative ageism correlated with negative age-bias, but not positive age-bias, expressed via aging knowledge responses. Knowledge of aging was poorest regarding social and psychological aspects of aging and best regarding biological aging. Middle-aged adults had slightly, but significantly, more accurate aging knowledge and less negative age-bias than emerging adults; positive age-bias did not differ by age-group. These results suggest that effectiveness of anti-ageism educational interventions may be enhanced if focused on improving knowledge of social and psychological aging.

Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase.

Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria.

ß-Bracelets: Macrocyclic Cross-ß Epitope Mimics Based on a Tau Conformational Strain.

The aggregation of misfolded tau into neurotoxic fibrils is linked to the progression of Alzheimer's disease (AD) and related tauopathies. Disease-associated conformations of filamentous tau are characterized by hydrophobic interactions between side chains on unique and distant ß-strand modules within each protomer. Here, we report the design and diversity-oriented synthesis of ß-arch peptide macrocycles composed of the aggregation-prone PHF6 hexapeptide of tau and the cross-ß module specific to the AD tau fold. Termed "ß-bracelets", these proteomimetics assemble in a sequence- and macrocycle-dependent fashion, resulting in amyloid-like fibrils that feature in-register parallel ß-sheet structure. Backbone N-amination of a selected ß-bracelet affords soluble inhibitors of tau aggregation. We further demonstrate that the N-aminated macrocycles block the prion-like cellular seeding activity of recombinant tau as well as mature fibrils from AD patient extracts. These studies establish ß-bracelets as a new class of cross-ß epitope mimics and demonstrate their utility in the rational design of molecules targeting amyloid propagation and seeding.

Chronic Exertional Compartment Syndrome Requiring Bilateral Fasciotomy: An Atypical Complication of Familial Stiff Skin Syndrome in a Father and Son.

ABSTRACT: Stiff skin syndrome (SSS) is a rare cutaneous disorder characterized by cutaneous fibrosis resulting in the early onset of thickened and indurated skin, joint mobility restrictions, and contractures. We describe a father and son with familial SSS who presented with bilateral exertional pain and a confirmed diagnosis of chronic exertional compartment syndrome on 4-compartment pressure testing. Patients experienced restored functionality with bilateral 4-compartment fasciotomy. Chronic exertional compartment syndrome should be considered in the differential diagnosis of patients with SSS and chronic pain of the lower limbs.

Screening, isolation and biotechnological potentials of foodborne Lactobacillus fermentum strains MT903311 and MT903312.

Vitamins are an essential food source with excellent roles in the cellular metabolism and other essential nutrients required in food intake but cannot be synthesized by humans. There have been reports of some lactic acid bacteria (LAB) abilities with probiotic activities to produce food-grade vitamins. Our study aimed to investigate lactic acid bacteria (LAB) possessing antimicrobial activities and extracellular production of folate from different Nigerian fermented foods. LAB was assayed for their antimicrobial activities against clinical isolates of Escherichia coli and Salmonella typhimurium and their extracellular production of essential vitamins. Among the 43 isolates of LAB, two strains of Lactobacillus fermentum showed the highest inhibitions against the test bacteria and demonstrated the highest concentrations of extracellular vitamins production. The range of vitamins produced at 24 h was between 12.23 and 801.79 µg/ml, while the highest vitamin production of 801.79 and 310.55 µg/ml was observed for folate and vitamin B12 respectively, the lowest production was for B1+B2. Consistent vitamin production was typical with only L. fermentum MT903311 and L. fermentum MT903312, so were their antimicrobial activities. The L. fermentum strains isolated in this study could be exploited and applied in food products to substitute synthetic vitamin enrichment and fortification.

A Career Preparation Course for Biomedical Science Majors Focused on Skills for Diverse Career Paths.

Training in career preparation is vital for biomedical science, microbiology, and related life science undergraduates to know the types of careers available in the field, to obtain employment after graduation, and to be successful in these careers. This is especially critical for historically marginalized students who have lower science, technology, engineering, and math (STEM) retention and lower STEM employment rates. Thus, we developed a career preparation course aimed for second- and third-year students in biomedical science, microbiology, biology, and related majors. This course introduced students to diverse careers via guest speakers and provided training and practice in key career skills, like writing CVs and cover letters. In this curriculum article, we present our course curriculum and resources, evidence of student achievement of learning objectives, and evidence that this course supported growth in constructs like science networking and confidence in future self, which are known to support student STEM retention and success.

Evaluation of Efflux-Mediated Resistance and Biofilm formation in Virulent Pseudomonas aeruginosa Associated with Healthcare Infections.

Pseudomonas aeruginosa is a significant pathogen identified with healthcare-associated infections. The present study evaluates the role of biofilm and efflux pump activities in influencing high-level resistance in virulent P. aeruginosa strains in clinical infection. Phenotypic resistance in biotyped Pseudomonas aeruginosa (n = 147) from diagnosed disease conditions was classified based on multiple antibiotic resistance (MAR) indices and analysed with logistic regression for risk factors. Efflux pump activity, biofilm formation, and virulence factors were analysed for optimal association in Pseudomonas infection using receiver operation characteristics (ROC). Age-specificity (OR [CI] = 0.986 [0.946-1.027]), gender (OR [CI] = 1.44 [0.211-9.827]) and infection sources (OR [CI] = 0.860 [0.438-1.688]) were risk variables for multidrug resistance (MDR)-P. aeruginosa infection (p < 0.05). Biofilm formers caused 48.2% and 18.5% otorrhea and wound infections (95% CI = 0.820-1.032; p = 0.001) respectively and more than 30% multidrug resistance (MDR) strains demonstrated high-level efflux pump activity (95% CI = 0.762-1.016; p = 0.001), protease (95% CI = 0.112-0.480; p = 0.003), lipase (95% CI = 0.143-0.523; p = 0.001), and hemolysin (95% CI = 1.109-1.780; p = 0.001). Resistance relatedness of more than 80% and 60% to cell wall biosynthesis inhibitors (ceftazidime, ceffproxil, augumentin, ampicillin) and, DNA translational and transcriptional inhibitors (gentamicin, ciprofloxacin, ofloxacin, nitrofurantoin) were observed (p < 0.05). Strong efflux correlation (r = 0.85, p = 0.034) with MDR strains, with high predictive performances in efflux pump activity (ROC-AUC 0.78), biofilm formation (ROC-AUC 0.520), and virulence hierarchical-clustering. Combine activities of the expressed efflux pump and biofilm formation in MDR-P. aeruginosa pose risk to clinical management and infection control.