A Bronx Dad's Tale.

In this narrative medicine essay, a neonatologist through the complex forces of intensive care physician, son, and ethicist grapples with the impending loss of his father and ultimately understanding his father's demand for autonomy in deciding his care.

Proximal interphalangeal joint arthroplasty: current trends and evidence-based practice.

Arthroplasty of the proximal interphalangeal joint (PIPJ) has evolved since its inception over 60 years ago. This review examines the indications for surgery, highlights the differences in current arthroplasty designs, variances in surgical techniques, clinical controversies, current implant outcomes data and salvage options for the failed implant. Overall, PIPJ implant arthroplasty is a good and reliable option for symptomatic PIPJ degenerative, post-traumatic or inflammatory arthritis given the proper clinical setting. If current techniques for implantation and rehabilitation are followed, predictable pain relief and satisfactory function can be anticipated. The purpose of this review article is to examine the current evidence-based indications for PIPJ arthroplasty and examine the reported, implant-specific outcomes of this procedure. Various techniques and rehabilitation strategies will also be outlined.

Vibration as a New Survey Method for Spiders.

Spiders have important ecological roles as generalist predators, are a significant source of food for many other species, and are bioindicators of environmental health. However, spiders are poorly studied. Given their importance, a comparison of spider survey methods used to determine differences in spider diversity and abundance is required to understand their limitations and biases. A new survey method to attract spiders, based on vibration from an idling diesel tractor, was tested and compared to the traditional methods of pitfall trapping and hand collection of spiders at night. Across the three survey methods, there were, in total, 2294 spiders in 34 families, 138 genera, and 226 species identified. Spider species diversity and richness were significantly greater for spiders collected at night than from the other two methods (spiders collected in pitfall traps and attracted to vibration). The collection of spiders using the night collection and vibration-based methods were very similar in terms of labor required and material costs. Of all spider species identified, 80% were captured during hand collection, 30% through pitfall trapping, and 30% from vibration-based collection. Most species of spiders caught in pitfall traps were species known to be primarily ground-dwelling, whereas both arboreal and ground-dwelling spiders were collected at night and as a result of being attracted and collected using the vibration-based method.

Variability of Care Practices for Extremely Early Deliveries.

OBJECTIVES: Assess temporal changes, intercenter variability, and birthing person (BP) factors relating to interventions for extremely early deliveries. METHODS: Retrospective study of BPs and newborns delivered from 22-24 completed weeks at 13 US centers from 2011-2020. Rates of neonatology consultation, antenatal corticosteroids, cesarean delivery, live birth, attempted resuscitation (AR), and survival were assessed by epoch, center, and gestational age. RESULTS: 2028 BPs delivering 2327 newborns were included. Rates increased in epoch 2-at 22 weeks: neonatology consultation (37.6 vs 64.3%, P < .001), corticosteroids (11.4 vs 29.5%, P < .001), live birth (66.2 vs 78.6%, P < .001), AR (20.1 vs 36.9%, P < .001), overall survival (3.0 vs 8.9%, P = .005); and at 23 weeks: neonatology consultation (73.0 vs 80.5%, P = .02), corticosteroids (63.7 vs 83.7%, P < .001), cesarean delivery (28.0 vs 44.7%, P < .001), live birth (88.1 vs 95.1%, P < .001), AR (67.7 vs 85.2%, P < .001), survival (28.8 vs 41.6%, P < .001). Over time, intercenter variability increased at 22 weeks for corticosteroids (interquartile range 18.0 vs 42.0, P = .014) and decreased at 23 for neonatology consultation (interquartile range 23.0 vs 5.2, P = .045). In BP-level multivariate analysis, AR was associated with increasing gestational age and birth weight, Black BP race, previous premature delivery, and delivery center. CONCLUSIONS: Intervention rates for extremely early newborns increased and intercenter variability changed over time. In BP-level analysis, factors significantly associated with AR included Black BP race, previous premature delivery, and center.

A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.

Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.

Monovalent Pseudo-Natural Product Degraders Supercharge the Native Degradation of IDO1 by KLHDC3.

Targeted protein degradation (TPD) modulates protein function beyond inhibition of enzyme activity or protein-protein interactions. Most degraders function by proximity induction, and directly bridge an E3 ligase with the target to be degraded. However, many proteins might not be addressable via proximity-based degraders, and other challenges, such as resistance acquisition, exist. Here, we identified pseudo-natural products derived from (-)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs induce a unique conformational change and, thereby, boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2KLHDC3, which we identified to also mediate native IDO1 degradation. Therefore, iDegs supercharge the native proteolytic pathway of IDO1, rendering this mechanism of action distinct from traditional degrader approaches involving proteolysis-targeting chimeras (PROTACs) or molecular-glue degraders (MGDs). In contrast to clinically explored IDO1 inhibitors, iDegs reduce formation of kynurenine by both inhibition and induced degradation of the enzyme and should also modulate non-enzymatic functions of IDO1. This unique mechanism of action may open up new therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.

The Ecological Separation of Deer and Domestic, Feral and Native Mammals in Tropical Northern Australia-A Review.

We explored the ecological and historical factors that led to formation of the unique guild of native and introduced mammalian herbivores between 5 and 1000 kg in northern Australia. Following the disappearance of large native herbivores about 46 kya, and until the arrival of Europeans and their livestock, the only herbivorous mammals were mid-sized endemic marsupial macropods, which continued to utilise the same vegetation as their much larger former neighbours. Only one species of contemporary native herbivore has an adult bodyweight approaching 100 kg, and for the past 150-200 years, the total biomass of introduced domestic and wild vertebrate herbivores has massively exceeded that of native herbivorous species. We conclude that the current guild of native and introduced mammalian herbivores differentially utilises the landscape ecologically. However, climate- and anthropogenically related changes due to fire, drought, flooding, predation and introduced weeds are likely to have significant impacts on the trajectory of their relative ecological roles and populations. Given their differing ecological and dietary characteristics, against this backdrop, it is unclear what the potential impact of the dispersal of deer species could have in northern Australia. We hence focus on whether sufficient knowledge exists against which the potential impacts of the range expansion of three deer species can be adequately assessed and have found a dearth of supporting evidence to inform appropriate sustainable management. We identify suitable research required to fill the identified knowledge gaps.

Temperature Dependence of the Mechanical Dissipation of Gallium Bonds for Use in Gravitational Wave Detectors.

The mirror suspensions in gravitational wave detectors demand low mechanical loss jointing to ensure good enough detector performance and to enable the detection of gravitational waves. Hydroxide catalysis bonds have been used in the fused silica suspensions of the GEO600, Advanced LIGO, and Advanced Virgo detectors. Future detectors may use cryogenic cooling of the mirror suspensions and this leads to a potential change of mirror material and suspension design. Other bonding techniques that could replace or be used alongside hydroxide catalysis bonding are of interest. A design that incorporates repair scenarios is highly desirable. Indeed, the mirror suspensions in KAGRA, which is made from sapphire and operated at cryogenic temperatures, have used a combination of hydroxide catalysis bonding and gallium bonding. This Letter presents the first measurements of the mechanical loss of a gallium bond measured between 10 K and 295 K. It is shown that the loss, which decreases with temperature down to the level of (1.8±0.3)×10^{-4} at 10 K, is comparable to that of a hydroxide catalysis bond.

Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.

The yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs of metabolic enzyme substrates. The orthologous higher eukaryotic C-terminal to LisH (CTLH) E3 complex has been proposed to also recognize substrates through an alternative subunit, WDR26, which promotes the formation of supramolecular CTLH E3 assemblies. Here, we discover that human WDR26 binds the metabolic enzyme nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) and mediates its CTLH E3-dependent ubiquitylation independently of canonical GID/CTLH E3-family substrate receptors. The CTLH subunit YPEL5 inhibits NMNAT1 ubiquitylation and cellular turnover by WDR26-CTLH E3, thereby affecting NMNAT1-mediated metabolic activation and cytotoxicity of the prodrug tiazofurin. Cryoelectron microscopy (cryo-EM) structures of NMNAT1- and YPEL5-bound WDR26-CTLH E3 complexes reveal an internal basic degron motif of NMNAT1 essential for targeting by WDR26-CTLH E3 and degron mimicry by YPEL5's N terminus antagonizing substrate binding. Thus, our data provide a mechanistic understanding of how YPEL5-WDR26-CTLH E3 acts as a modulator of NMNAT1-dependent metabolism.

Hand Surgery Fellowship Case Minimums: History and Design.

In the 1960s, the American Society for Surgery of the Hand embarked on an endeavor to improve and standardize the educational experience in hand surgery. By the 1980s, numerous programs existed across the country with the Accreditation Council for Graduate Medical Education formally recognizing orthopedic surgery-based fellowships in 1985 and plastic surgery-based fellowships in 1986. In order to sit for what was then termed the Certificate of Additional Qualification examination, applicants had to demonstrate performance of a specific number of procedures while in practice. Borrowing from this theme, the Accreditation Council for Graduate Medical Education began to analyze programs according to the relative proportion of cases done by fellows at individual institutions compared to national trends. Beginning in 2019 and working collaboratively with the Accreditation Council for Graduate Medical Education, the Hand Fellowship Director's Association has since modified the methods by which programs are evaluated, pivoting away from comparative percentages to the establishment of case minimums. The development of this process has been iterative with the resultant outcome being an evaluation system that focuses on educational quality and technical proficiency over sheer numerical volume.

Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly.

Patients with Skraban-Deardorff syndrome (SKDEAS), a neurodevelopmental syndrome associated with a spectrum of developmental and intellectual delays and disabilities, harbor diverse mutations in WDR26, encoding a subunit of the multiprotein CTLH E3 ubiquitin ligase complex. Structural studies revealed that homodimers of WDR26 bridge two core-CTLH E3 complexes to generate giant, hollow oval-shaped supramolecular CTLH E3 assemblies. Additionally, WDR26 mediates CTLH E3 complex binding to subunit YPEL5 and functions as substrate receptor for the transcriptional repressor HBP1. Here, we mapped SKDEAS-associated mutations on a WDR26 structural model and tested their functionality in complementation studies using genetically engineered human cells lacking CTLH E3 supramolecular assemblies. Despite the diversity of mutations, 15 of 16 tested mutants impaired at least one CTLH E3 complex function contributing to complex assembly and interactions, thus providing first mechanistic insights into SKDEAS pathology.

"COVID-19 - A Perfect Storm": A Qualitative Exploration of Residential Care Facility Managers Perspectives on the Psychosocial Impacts of COVID-19.

Growing evidence highlights the negative impact of managing the COVID-19 pandemic on the wellbeing of the healthcare workforce, including in the aged care sector. We undertook a qualitative study during the pandemic's third year to explore the psychosocial impacts on nine managers of residential care facilities (RCFs) across metropolitan and rural New South Wales, the largest state in Australia. Four themes were identified: (1) Increased pressure on maintaining aged care services, (2) Increased responsibility on RCF managers, (3) Psychosocial impacts due to accumulating pressures, and (4) Experience of beneficial supports. COVID-19 compounded pre-pandemic sector challenges and added new stressors. While resilient and resourceful, RCF managers experienced workplace stress and burnout, which may affect quality of resident care and impact on staff retention. There is a need for more investment to effectively support staff, and research to identify optimal psychosocial and management supports.

Spontaneous Lesions of Endangered Geriatric Julia Creek Dunnarts (Sminthopsis douglasi, Archer 1979) with Emphasis in Reproductive Pathology.

Julia Creek dunnarts are an endangered species of carnivorous marsupials and the focus of multiple conservation strategies involving significant resources such as captive breeding programs. Despite the relevance for conservation, no study to date has focused on evaluating geriatric diseases in dunnarts. This study describes the pathology findings in a group of one wild and thirty-five captive-born, mostly geriatric Julia Creek dunnarts that failed to produce offspring over multiple breeding periods. A total of 20 females and 16 males were submitted for a postmortem examination, with ages ranging from 9 to 42 and 12 to 42 months for females and males, respectively. Of these, 10 had unremarkable findings. The most common condition in females was cystic glandular hyperplasia (n = 8), typical of hormonal dysregulation profiles in senescence, particularly hyperestrogenism. Rarely, cutaneous disease represented by unidentified dermal round cell infiltrates was observed in females (n = 2). Primary reproductive hormonal dysregulation was also suspected in males diagnosed with testicular degeneration, aspermatogenesis and/or atrophy (n = 3). Cutaneous round cell infiltrates, possibly compatible with epitheliotropic lymphomas, were seen in males (n = 3), and 2/3 affected males also had concurrent testicular degeneration or atrophy, indicating male sex could be a predictor for lymphoid neoplasia in aged dunnarts, especially in individuals with concurrent testosterone-luteinizing hormone dysregulation as it occurs in gonadectomized animals. The role of an underlying viral etiology is also explored. This study is the first to describe major spontaneous diseases in endangered aged Julia Creek dunnarts, providing an important understanding of senescence and geriatric diseases within a conservation context.

Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

Implementing recommended COVID-19 public health measures in the era of living with COVID-19: Experiences of residential aged care facility managers in New South Wales, Australia.

OBJECTIVES: To understand residential aged care facility (the facility) managers' perspectives on implementing public health measures (the measures) in their facilities in terms of barriers, facilitators and suggestions for improvement, after three years of the COVID-19 pandemic. METHODS: Nine managers of the facilities without an active COVID-19 outbreak across New South Wales, Australia, representing metropolitan and rural locations, diverse facility size and star quality rating were interviewed (April-June 2023) and data qualitatively analysed. RESULTS: Broader policy context, the need to balance the measures with resident well-being, facility-built infrastructure and mask fatigue were reported as barriers to implementation. Workplace policies, cultural embedding and local innovations were reported as facilitators. Suggested strategies included recommending the measures consistent with temporal COVID-19 risk; government agencies improving communication about the measures; mandatory staff vaccination; and simplified reporting requirements. CONCLUSIONS: We recommend that relevant government agencies develop a single source of formalised, endorsed, up-to-date advice for the sector-specific COVID-19 information and communications; streamline outbreak notification and reporting requirements; and improve consultation with the sector.

Single-Macromolecule Studies of Eukaryotic Genomic Maintenance.

Genomes are self-organized and self-maintained as long, complex macromolecules of chromatin. The inherent heterogeneity, stochasticity, phase separation, and chromatin dynamics of genome operation make it challenging to study genomes using ensemble methods. Various single-molecule force-, fluorescent-, and sequencing-based techniques rooted in different disciplines have been developed to fill critical gaps in the capabilities of bulk measurements, each providing unique, otherwise inaccessible, insights into the structure and maintenance of the genome. Capable of capturing molecular-level details about the organization, conformational changes, and packaging of genetic material, as well as processive and stochastic movements of maintenance factors, a single-molecule toolbox provides an excellent opportunity for collaborative research to understand how genetic material functions in health and malfunctions in disease. In this review, we discuss novel insights brought to genomic sciences by single-molecule techniques and their potential to continue to revolutionize the field-one molecule at a time.

Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE.

Transmembrane E3 ligases play crucial roles in homeostasis. Much protein and organelle quality control, and metabolic regulation, are determined by ER-resident MARCH6 E3 ligases, including Doa10 in yeast. Here, we present Doa10/MARCH6 structural analysis by cryo-EM and AlphaFold predictions, and a structure-based mutagenesis campaign. The majority of Doa10/MARCH6 adopts a unique circular structure within the membrane. This channel is established by a lipid-binding scaffold, and gated by a flexible helical bundle. The ubiquitylation active site is positioned over the channel by connections between the cytosolic E3 ligase RING domain and the membrane-spanning scaffold and gate. Here, by assaying 95 MARCH6 variants for effects on stability of the well-characterized substrate SQLE, which regulates cholesterol levels, we reveal crucial roles of the gated channel and RING domain consistent with AlphaFold-models of substrate-engaged and ubiquitylation complexes. SQLE degradation further depends on connections between the channel and RING domain, and lipid binding sites, revealing how interconnected Doa10/MARCH6 elements could orchestrate metabolic signals, substrate binding, and E3 ligase activity.

Titania Mixed with Silica: A Low Thermal-Noise Coating Material for Gravitational-Wave Detectors.

Coating thermal noise is one of the dominant noise sources in current gravitational wave detectors and ultimately limits their ability to observe weaker or more distant astronomical sources. This Letter presents investigations of TiO_{2} mixed with SiO_{2} (TiO_{2}:SiO_{2}) as a coating material. We find that, after heat treatment for 100 h at 850 °C, thermal noise of a highly reflective coating comprising of TiO_{2}:SiO_{2} and SiO_{2} reduces to 76% of the current levels in the Advanced LIGO and Advanced Virgo detectors-with potential for reaching 45%, if we assume the mechanical loss of state-of-the-art SiO_{2} layers. Furthermore, those coatings show low optical absorption of <1 ppm and optical scattering of ≲5 ppm. Notably, we still observe excellent optical and thermal noise performance following crystallization in the coatings. These results show the potential to meet the parameters required for the next upgrades of the Advanced LIGO and Advanced Virgo detectors.

Activity-based profiling of cullin-RING E3 networks by conformation-specific probes.

The cullin-RING ubiquitin ligase (CRL) network comprises over 300 unique complexes that switch from inactive to activated conformations upon site-specific cullin modification by the ubiquitin-like protein NEDD8. Assessing cellular repertoires of activated CRL complexes is critical for understanding eukaryotic regulation. However, probes surveying networks controlled by site-specific ubiquitin-like protein modifications are lacking. We developed a synthetic antibody recognizing the active conformation of NEDD8-linked cullins. Implementing the probe to profile cellular networks of activated CUL1-, CUL2-, CUL3- and CUL4-containing E3s revealed the complexes responding to stimuli. Profiling several cell types showed their baseline neddylated CRL repertoires vary, and prime efficiency of targeted protein degradation. Our probe also unveiled differential rewiring of CRL networks across distinct primary cell activation pathways. Thus, conformation-specific probes can permit nonenzymatic activity-based profiling across a system of numerous multiprotein complexes, which in the case of neddylated CRLs reveals widespread regulation and could facilitate the development of degrader drugs.