Aquatic connectivity: challenges and solutions in a changing climate.

The challenge of managing aquatic connectivity in a changing climate is exacerbated in the presence of additional anthropogenic stressors, social factors, and economic drivers. Here we discuss these issues in the context of structural and functional connectivity for aquatic biodiversity, specifically fish, in both the freshwater and marine realms. We posit that adaptive management strategies that consider shifting baselines and the socio-ecological implications of climate change will be required to achieve management objectives. The role of renewable energy expansion, particularly hydropower, is critically examined for its impact on connectivity. We advocate for strategic spatial planning that incorporates nature-positive solutions, ensuring climate mitigation efforts are harmonized with biodiversity conservation. We underscore the urgency of integrating robust scientific modelling with stakeholder values to define clear, adaptive management objectives. Finally, we call for innovative monitoring and predictive decision-making tools to navigate the uncertainties inherent in a changing climate, with the goal of ensuring the resilience and sustainability of aquatic ecosystems.

Mandibular Advancement vs CPAP for Blood Pressure Reduction in Patients With Obstructive Sleep Apnea.

BACKGROUND: Hypertension guidelines recommend diagnosis and treatment of obstructive sleep apnea (OSA) in patients with hypertension. The mandibular advancement device (MAD) is an oral appliance therapy for patients who decline or cannot tolerate continuous positive airway pressure (CPAP). OBJECTIVES: We compared the relative effectiveness of MAD vs CPAP in reducing 24-hour ambulatory blood pressure (BP). METHODS: In an investigator-initiated, randomized, noninferiority trial (prespecified margin 1.5 mm Hg), 321 participants aged ≥40 years with hypertension and increased cardiovascular risk were recruited at 3 public hospitals for polysomnography. Of these, 220 participants with moderate-to-severe OSA (apnea-hypopnea index ≥15 events per hour) were randomized to either MAD or CPAP (1:1). The primary outcome was the difference between the 24-hour mean arterial BP at baseline and 6 months. RESULTS: Compared with baseline, the 24-hour mean arterial BP decreased by 2.5 mm Hg (P = 0.003) at 6 months in the MAD group, whereas no change was observed in the CPAP group (P = 0.374). The between-group difference was -1.6 mm Hg (95% CI: -3.51 to 0.24, noninferiority P < 0.001). The MAD group demonstrated a larger between-group reduction in all secondary ambulatory BP parameters compared with the CPAP group, with the most pronounced effects observed in the asleep BP parameters. Both the MAD and CPAP improved daytime sleepiness, with the between-group difference similar (P = 0.384). There were no between-group differences in cardiovascular biomarkers. CONCLUSIONS: MAD is noninferior to CPAP for reducing 24-hour mean arterial BP in participants with hypertension and increased cardiovascular risk. (Cardiosleep Research Program on Obstructive Sleep Apnea, Blood Pressure Control and Maladaptive Myocardial Remodeling-Non-inferiority Trial [CRESCENT]; NCT04119999).

Tunable 2D Conjugated Porous Organic Polymer Films for Precise Molecular Nanofiltration and Optoelectronics.

Structural design of 2D conjugated porous organic polymer films (2D CPOPs), by tuning linkage chemistries and pore sizes, provides great adaptability for various applications, including membrane separation. Here, four free-standing 2D CPOP films of imine- or hydrazone-linked polymers (ILP/HLP) in combination with benzene (B-ILP/HLP) and triphenylbenzene (TPB-ILP/HLP) aromatic cores are synthesized. The anisotropic disordered films, composed of polymeric layered structures, can be exfoliated into ultrathin 2D-nanosheets with layer-dependent electrical properties. The bulk CPOP films exhibit structure-dependent optical properties, triboelectric nanogenerator output, and robust mechanical properties, rivaling previously reported 2D polymers and porous materials. The exfoliation energies of the 2D CPOPs and their mechanical behavior at the molecular level are investigated using density function theory (DFT) and molecular dynamics (MD) simulations, respectively. Exploiting the structural tunability, the comparative organic solvent nanofiltration (OSN) performance of six membranes having different pore sizes and linkages to yield valuable trends in molecular weight selectivity is investigated. Interestingly, the OSN performances follow the predicted transport modeling values based on theoretical pore size calculations, signifying the existence of permanent porosity in these materials. The membranes exhibit excellent stability in organic solvents at high pressures devoid of any structural deformations, revealing their potential in practical OSN applications.

RNA Binding Proteins that Mediate LPS-induced Alternative Splicing of the MyD88 Innate Immune Regulator.

Inflammation driven by Toll-like receptor (TLR) signaling pathways is required to combat infection. However, inflammation can damage host tissues; thus it is essential that TLR signaling ultimately is terminated to prevent chronic inflammatory disorders. One mechanism that terminates persistent TLR signaling is alternative splicing of the MyD88 signaling adaptor, which functions in multiple TLR signaling pathways. While the canonical long isoform of MyD88 (MyD88-L) mediates TLR signaling and promotes inflammation, an alternatively-spliced shorter isoform of MyD88 (MyD88-S) produces a dominant negative inhibitor of TLR signaling. MyD88-S production is induced by inflammatory agonists including lipopolysaccharide (LPS), and thus MyD88-S induction is thought to act as a negative feedback loop that prevents chronic inflammation. Despite the potential role that MyD88-S production plays in inflammatory disorders, the mechanisms controlling MyD88 alternative splicing remain unclear. Here, we identify two RNA binding proteins, SRSF1 and HNRNPU, that regulate LPS-induced alternative splicing of MyD88.

Hypoxia Inducible Factor pathway proteins in high-altitude mammals.

Humans and other mammals inhabit hypoxic high-altitude locales. In many of these species, genes under positive selection include ones in the Hypoxia Inducible Factor (HIF) pathway. One is PHD2 (EGLN1), which encodes for a key oxygen sensor. Another is HIF2A (EPAS1), which encodes for a PHD2-regulated transcription factor. Recent studies have provided insights into mechanisms for these high-altitude alleles. These studies have (i) shown that selection can occur on nonconserved, unstructured regions of proteins, (ii) revealed that high altitude-associated amino acid substitutions can have differential effects on protein-protein interactions, (iii) provided evidence for convergent evolution by different molecular mechanisms, and (iv) suggested that mutations in different genes can complement one another to produce a set of adaptive phenotypes.

Stimulant Use Associated With Psychosocial Factors, HIV Risk, and Concurrent Hazardous Alcohol Use Among US Adults: Exploratory Cross-Sectional Questionnaire Study.

BACKGROUND: Stimulant use is a major public health problem that contributes to morbidity and mortality among men who have sex with men (MSM) in the United States. To reduce the harms associated with stimulant use, there is a need to identify the factors associated with stimulant use to inform interventions. Additionally, there is a need to use large crowdsourcing platforms like Amazon Mechanical Turk (MTurk) to engage more individuals who use substances across the United States. OBJECTIVE: We identified the correlates of stimulant use among people who use alcohol or stimulants in the United States recruited using MTurk. METHODS: Participants who were aged ≥18 years in the United States and reported alcohol or stimulant (ie, cocaine, crack cocaine, and methamphetamine) use were deemed eligible and recruited via the web platform MTurk. Participants completed a baseline survey, which assessed sociodemographics, psychosocial (ie, depression, affect, self-esteem, and stress) factors, substance use, and sexual behaviors. Data were collected and analyzed with STATA (version 17; StataCorp). Stratifying by MSM status, bivariate and multivariable logistic regression models were built in STATA to examine the correlates of stimulant use. Multivariable models controlled for age, race, health insurance, and relationship status. RESULTS: Of 272 participants, 201 (73.9%) identified as male, 134 (49.2%) were MSM, 52 (19.1%) were from racial and ethnic minoritized communities, and 158 (58%) were in a relationship. The mean age was 36.10 (SD 10.3) years. A total of 40 (14.7%) participants reported stimulant use in the past 6 months. Factors significantly associated with stimulant use were being MSM (adjusted odds ratio [aOR] 4.61, 95% CI 1.97-10.81), a higher Alcohol Use Disorders Identification Test-Concise score (aOR 1.24, 95% CI 1.08-1.42), more intense cravings for alcohol in the past 24 hours (aOR 1.03, 95% CI 1.01-1.04), a higher depression score (aOR 1.06, 95% CI 1.01-1.12), a greater number of male partners in the last 6 months (aOR 1.32, 95% CI 1.08-1.61), a greater number of female partners in the last 6 months (aOR 1.42, 95% CI 1.04-1.92), and being diagnosed with a sexually transmitted infection (eg, syphilis, gonorrhea, chlamydia, herpes simplex virus, human papillomavirus, and other) in the last 6 months (aOR 14.61, 95% CI 3.45-61.87). Additionally, there was a significant additive interaction between MSM status and negative affect, such that the impact of negative affect on stimulant use was significantly greater among MSM compared with non-MSM (relative excess risk due to interaction 0.085, 95% CI 0.037-0.13). CONCLUSIONS: Interventions that address stimulant use should use evidence-based approaches that reduce negative affect, depression, and cravings for alcohol. Additionally, interventions should be customized for MSM populations.

Myelodysplastic neoplasm-associated U2AF1 mutations induce host defense defects by compromising neutrophil chemotaxis.

Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients. To determine the molecular underpinnings of the host defense defects in MDS patients, we investigated the MDS-associated spliceosome mutation U2AF1-S34F using a transgenic mouse model that expresses this mutant gene. We found that U2AF1-S34F causes a profound host defense defect in these mice, likely by inducing a significant neutrophil chemotaxis defect. Studies in human neutrophils suggest that this effect of U2AF1-S34F likely extends to MDS patients as well. RNA-seq analysis suggests that the expression of multiple genes that mediate cell migration are affected by this spliceosome mutation and therefore are likely drivers of this neutrophil dysfunction.

An atypical basement membrane forms a midline barrier in left-right asymmetric gut development.

Correct intestinal morphogenesis depends on the early embryonic process of gut rotation, an evolutionarily conserved program in which a straight gut tube elongates and forms into its first loops. However, the gut tube requires guidance to loop in a reproducible manner. The dorsal mesentery (DM) connects the gut tube to the body and directs the lengthening gut into stereotypical loops via left-right (LR) asymmetric cellular and extracellular behavior. The LR asymmetry of the DM also governs blood and lymphatic vessel formation for the digestive tract, which is essential for prenatal organ development and postnatal vital functions including nutrient absorption. Although the genetic LR asymmetry of the DM has been extensively studied, a divider between the left and right DM has yet to be identified. Setting up LR asymmetry for the entire body requires a Lefty1+ midline barrier to separate the two sides of the embryo-without it, embryos have lethal or congenital LR patterning defects. Individual organs including the brain, heart, and gut also have LR asymmetry, and while the consequences of left and right signals mixing are severe or even lethal, organ-specific mechanisms for separating these signals are not well understood. Here, we uncover a midline structure composed of a transient double basement membrane, which separates the left and right halves of the embryonic chick DM during the establishment of intestinal and vascular asymmetries. Unlike other basement membranes of the DM, the midline is resistant to disruption by intercalation of Netrin4 (Ntn4). We propose that this atypical midline forms the boundary between left and right sides and functions as a barrier necessary to establish and protect organ asymmetry.

Cauchy-type integral method for solving the linearized one-dimensional Vlasov-Poisson equation.

We present a method for solving the linearized Vlasov-Poisson equation, based on analyticity properties of the equilibrium and initial condition through Cauchy-type integrals, that produces algebraic expressions for the distribution and field, i.e., the solution is expressed without integrals. Standard extant approaches involve deformations of the Bromwich contour that give erroneous results for certain physically reasonable configurations or eigenfunction expansions that are misleading as to the temporal structure of the solution. Our method is more transparent, lacks these defects, and predicts previously unrecognized behavior.

High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.

Three-dimensional analysis of the interchangeability of a semiadjustable articulator system in service over time.

STATEMENT OF PROBLEM: Some contemporary articulator systems claim to be highly precise in their interchangeability, with tolerances below 10 µm in vertical error; however, the claims have not been independently verified. PURPOSE: The purpose of this study was to investigate the interchangeability of calibrated semiadjustable articulators in service over time. MATERIAL AND METHODS: A calibrated mounting articulator served as the master articulator, while the test groups were used articulators with a minimum of 1-year use by predoctoral dental students (n=10); used articulators with a minimum of 1-year use by prosthodontic residents (n=10); and new articulators (n=10). One set of mounted maxillary and mandibular master models was positioned in the master and test articulators. High-precision reference markers on the master models were used to determine interarch 3D distance distortions (dRR, dRC, and dRL), interocclusal 3D distance distortion (dRM), interocclusal 2D distance distortions (dxM, dyM, and dzM), and interocclusal angular distortion (dθM) relative to the master articulator. All measurements were conducted three times using a coordinate measuring machine and then averaged to derive the final data set. RESULTS: For interarch 3D distance distortion, the mean dRR ranged from 4.6 ±21.6 µm for new articulators to 56.3 ±47.6 µm for articulators used by prosthodontic residents; mean dRC ranged from 65 ±48.6 µm for new articulators to 119.0 ±58.8 µm for articulators used by prosthodontic residents; and mean dRL ranged from 12.7 ±39.7 µm for articulators used by prosthodontic residents to 62.8 ±75.2 µm for new articulators. For interocclusal 3D distance distortion, the mean dRM ranged from 21.5 ±49.8 µm for new articulators to 68.6 ±64.9 µm for articulators used by predoctoral dental students. For the 2D distance distortions, the mean dxM ranged from -17.9 ±43.4 µm for articulators used by predoctoral dental students to -61.9 ±48.3 µm for articulators used by prosthodontic residents; mean dyM ranged from 18.1 ±59.4 µm for new articulators to 69.3 ±115.1 µm for articulators used by prosthodontic residents; and mean dzM ranged from 29.5 ±20.2 µm for new articulators to 70.1 ±37.8 µm for articulators used by prosthodontic residents. Mean dθM ranged from -0.018 ±0.289 degree for new articulators to 0.141 ±0.267 degree for articulators used by prosthodontic residents. One-way ANOVA by articulator type revealed statistically significant differences among the test groups for dRR (P=.007) and dzM (P=.011) only, where articulators used by prosthodontic residents fared significantly poorer than the other test groups. CONCLUSIONS: The new and used articulators tested did not fulfill the manufacturer's claim of accuracy of up to 10 µm in the vertical dimension. Up to 1 year of time in service, none of the investigated test groups fulfilled the criterion for articulator interchangeability, even if the more lenient threshold of 166 µm were accepted.

Localised strain and doping of 2D materials.

There is a growing interest in 2D materials-based devices as the replacement for established materials, such as silicon and metal oxides in microelectronics and sensing, respectively. However, the atomically thin nature of 2D materials makes them susceptible to slight variations caused by their immediate environment, inducing doping and strain, which can vary between, and even microscopically within, devices. One of the misapprehensions for using 2D materials is the consideration of unanimous intrinsic properties over different support surfaces. The interfacial interaction, intrinsic structural disorder and external strain modulate the properties of 2D materials and govern the device performance. The understanding, measurement and control of these factors are thus one of the significant challenges for the adoption of 2D materials in industrial electronics, sensing, and polymer composites. This topical review provides a comprehensive overview of the effect of strain-induced lattice deformation and its relationship with physical and electronic properties. Using the example of graphene and MoS2 (as the prototypical 2D semiconductor), we rationalise the importance of scanning probe techniques and Raman spectroscopy to elucidate strain and doping in 2D materials. These effects can be directly and accurately characterised through Raman shifts in a non-destructive manner. A generalised model has been presented that deconvolutes the intertwined relationship between strain and doping in graphene and MoS2 that could apply to other members of the 2D materials family. The emerging field of straintronics is presented, where the controlled application of strain over 2D materials induces tuneable physical and electronic properties. These perspectives highlight practical considerations for strain engineering and related microelectromechanical applications.

Unravelling the room temperature growth of two-dimensional h-BN nanosheets for multifunctional applications.

The room temperature growth of two-dimensional van der Waals (2D-vdW) materials is indispensable for state-of-the-art nanotechnology. Low temperature growth supersedes the requirement of elevated growth temperatures accompanied with high thermal budgets. Moreover, for electronic applications, low or room temperature growth reduces the possibility of intrinsic film-substrate interfacial thermal diffusion related deterioration of the functional properties and the consequent deterioration of the device performance. Here, we demonstrated the growth of ultrawide-bandgap boron nitride (BN) at room temperature by using the pulsed laser deposition (PLD) process, which exhibited various functional properties for potential applications. Comprehensive chemical, spectroscopic and microscopic characterizations confirmed the growth of ordered nanosheet-like hexagonal BN (h-BN). Functionally, the nanosheets show hydrophobicity, high lubricity (low coefficient of friction), and a low refractive index within the visible to near-infrared wavelength range, and room temperature single-photon quantum emission. Our work unveils an important step that brings a plethora of potential applications for these room temperature grown h-BN nanosheets as the synthesis can be feasible on any given substrate, thus creating a scenario for "h-BN on demand" under a frugal thermal budget.

Distinct Energy-Coupling Factor Transporter Subunits Enable Flavin Acquisition and Extracytosolic Trafficking for Extracellular Electron Transfer in Listeria monocytogenes.

A variety of electron transfer mechanisms link bacterial cytosolic electron pools with functionally diverse redox activities in the cell envelope and extracellular space. In Listeria monocytogenes, the ApbE-like enzyme FmnB catalyzes extracytosolic protein flavinylation, covalently linking a flavin cofactor to proteins that transfer electrons to extracellular acceptors. L. monocytogenes uses an energy-coupling factor (ECF) transporter complex that contains distinct substrate-binding, transmembrane, ATPase A, and ATPase A' subunits (RibU, EcfT, EcfA, and EcfA') to import environmental flavins, but the basis of extracytosolic flavin trafficking for FmnB flavinylation remains poorly defined. In this study, we show that the EetB and FmnA proteins are related to ECF transporter substrate-binding and transmembrane subunits, respectively, and are essential for exporting flavins from the cytosol for flavinylation. Comparisons of the flavin import versus export capabilities of L. monocytogenes strains lacking different ECF transporter subunits demonstrate a strict directionality of substrate-binding subunit transport but partial functional redundancy of transmembrane and ATPase subunits. Based on these results, we propose that ECF transporter complexes with different subunit compositions execute directional flavin import/export through a broadly conserved mechanism. Finally, we present genomic context analyses that show that related ECF exporter genes are distributed across members of the phylum Firmicutes and frequently colocalize with genes encoding flavinylated extracytosolic proteins. These findings clarify the basis of ECF transporter export and extracytosolic flavin cofactor trafficking in Firmicutes. IMPORTANCE Bacteria import vitamins and other essential compounds from their surroundings but also traffic related compounds from the cytosol to the cell envelope where they serve various functions. Studying the foodborne pathogen Listeria monocytogenes, we find that the modular use of subunits from a prominent class of bacterial transporters enables the import of environmental vitamin B2 cofactors and the extracytosolic trafficking of a vitamin B2-derived cofactor that facilitates redox reactions in the cell envelope. These studies clarify the basis of bidirectional small-molecule transport across the cytoplasmic membrane and the assembly of redox-active proteins within the cell envelope and extracellular space.

Serum amyloid P component (SAP) modulates antidepressant effects through promoting membrane insertion of the serotonin transporter.

Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer's disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [11C]DASB. We also investigated the effect of SAP on treatment response to escitalopram in mice with the forced swim test (FST), a classical behaviour paradigm to assess antidepressant effects. SAP reduced [11C]DASB binding as an index of SERT levels, consistent with Western blots showing decreased total SAP protein because of increased protein degradation. In conjunction with the global decrease in SERT levels, SAP also promotes VAMP-2 mediated SERT membrane insertion. SAP levels are correlated with behavioural despair and SSRI treatment response in mice with FST. In MDD patients, the SAP and membrane SERT levels are correlated with response to SSRI treatment. SAP has complex effects on SERT levels and localization, thereby modulating the effect of SSRIs, which could partially explain clinical variability in antidepressant treatment response. These results add to our understanding of the mechanism for antidepressant drug action, and with further work could be of clinical utility.

Single Cell RNA-Sequence Analyses Reveal Uniquely Expressed Genes and Heterogeneous Immune Cell Involvement in the Rat Model of Intervertebral Disc Degeneration.

Intervertebral disc (IVD) degeneration is characterized by a loss of cellularity, and changes in cell-mediated activity that drives anatomic changes to IVD structure. In this study, we used single-cell RNA-sequencing analysis of degenerating tissues of the rat IVD following lumbar disc puncture. Two control, uninjured IVDs (L2-3, L3-4) and two degenerated, injured IVDs (L4-5, L5-6) from each animal were examined either at the two- or eight-week post-operative time points. The cells from these IVDs were extracted and transcriptionally profiled at the single-cell resolution. Unsupervised cluster analysis revealed the presence of four known cell types in both non-degenerative and degenerated IVDs based on previously established gene markers: IVD cells, endothelial cells, myeloid cells, and lymphoid cells. As a majority of cells were associated with the IVD cell cluster, sub-clustering was used to further identify the cell populations of the nucleus pulposus, inner and outer annulus fibrosus. The most notable difference between control and degenerated IVDs was the increase of myeloid and lymphoid cells in degenerated samples at two- and eight-weeks post-surgery. Differential gene expression analysis revealed multiple distinct cell types from the myeloid and lymphoid lineages, most notably macrophages and B lymphocytes, and demonstrated a high degree of immune specificity during degeneration. In addition to the heterogenous infiltrating immune cell populations in the degenerating IVD, the increased number of cells in the AF sub-cluster expressing Ngf and Ngfr, encoding for p75NTR, suggest that NGF signaling may be one of the key mediators of the IVD crosstalk between immune and neuronal cell populations. These findings provide the basis for future work to understand the involvement of select subsets of non-resident cells in IVD degeneration.

Alternative pre-mRNA splicing as a mechanism for terminating Toll-like Receptor signaling.

While inflammation induced by Toll-like receptor (TLR) signaling is required to combat infection, persistent inflammation can damage host tissues and contribute to a myriad of acute and chronic inflammatory disorders. Thus, it is essential not only that TLR signaling be activated in the presence of pathogens but that TLR signaling is ultimately terminated. One mechanism that limits persistent TLR signaling is alternative pre-mRNA splicing. In addition to encoding the canonical mRNAs that produce proteins that promote inflammation, many genes in the TLR signaling pathway also encode alternative mRNAs that produce proteins that are dominant negative inhibitors of signaling. Many of these negative regulators are induced by immune challenge, so production of these alternative isoforms represents a negative feedback loop that limits persistent inflammation. While these alternative splicing events have been investigated on a gene by gene basis, there has been limited systemic analysis of this mechanism that terminates TLR signaling. Here we review what is known about the production of negatively acting alternative isoforms in the TLR signaling pathway including how these inhibitors function, how they are produced, and what role they may play in inflammatory disease.

The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α.

Prolyl hydroxylase domain protein 2 (PHD2)-catalyzed modification of hypoxia-inducible factor (HIF)-α is a key event in oxygen sensing. We previously showed that the zinc finger of PHD2 binds to a Pro-Xaa-Leu-Glu (PXLE) motif. Here, we show that the zinc finger binds to this motif in the ribosomal chaperone nascent polypeptide complex-α (NACA). This recruits PHD2 to the translation machinery to cotranslationally modify HIF-α. Importantly, this cotranslational modification is enhanced by a translational pause sequence in HIF-α. Mice with a knock-in Naca gene mutation that abolishes the PXLE motif display erythrocytosis, a reflection of HIF pathway dysregulation. In addition, human erythrocytosis-associated mutations in the zinc finger of PHD2 ablate interaction with NACA. Tibetans, who have adapted to the hypoxia of high altitude, harbor a PHD2 variant that we previously showed displays a defect in zinc finger binding to p23, a PXLE-containing HSP90 cochaperone. We show here that Tibetan PHD2 maintains interaction with NACA, thereby showing differential interactions with PXLE-containing proteins and providing an explanation for why Tibetans are not predisposed to erythrocytosis.

Rotational Load Fatigue Performance of Titanium vs Titanium-Zirconium Implant-Abutment Connections.

PURPOSE: Titanium-zirconium (Ti-Zr) alloy has been developed to strengthen the implant body, but clinically relevant information is still limited. The aim of this in vitro study was to compare the rotational load fatigue performance of implant-abutment connections in narrow-diameter (3.3-mm) and regular-diameter (4.1-mm) implants made with commercially pure grade 4 titanium alloy (CPTi-G4) and Ti-Zr. MATERIALS AND METHODS: Narrow-diameter (N) and regular-diameter (R) implants with CPTi-G4 (Ti) or Ti-Zr (Tz) materials were tested. This resulted in four test groups: NTi, NTz, RTi and RTz. Five specimens were made for each group (n = 5). Abutments used were milled from titanium-aluminum-niobium alloy abutment blanks. A rotational load fatigue machine applied a sinusoidally varying load at an angle of 45 degrees to produce an effective bending moment of 35 Ncm at a frequency of 14 Hz in air at 20°C. The number of cycles to failure was recorded. The upper limit was set as 5 million cycles. Results were evaluated using analysis of variance (ANOVA) and Tukey post hoc tests. Failure locations and patterns were evaluated with scanning electron microscope (SEM). RESULTS: All regular-diameter test groups reached the upper limit of 5 million cycles without failure. All narrow-diameter test groups failed within the range of 402,530 cycles to 3,374,353 cycles. It could be observed that NTz showed a higher mean cycle count as compared to NTi. NTi test group recorded two implants damaged, one implant fracture, five abutment fractures, and four screw fractures. NTz test group showed only abutment fractures at the level of implant platform, with no damage to the implant bodies. Significant difference was found between implants of different diameters. There was no significant difference between implants of different materials. CONCLUSION: Regular-diameter implants performed significantly better than narrow-diameter implants, regardless of material, while no significant difference in cyclic load to failure was found between groups of different alloys. All NTz failures were at the abutment only, without damage to the implant. This failure pattern can potentially be clinically advantageous in terms of retrieval and subsequent replacement of a failed prosthesis.

Technique for Reconstruction of Midcarpal Instability Associated with Lunotriquetral Coalition.

Carpal coalition is a rare congenital presentation of 2 or more fused carpal bones due to a failure of apoptotic segmentation during development. The most common subtype is lunotriquetral coalition (LTC). Most cases are asymptomatic and found incidentally on imaging; however, a few symptomatic cases requiring treatment have been reported. Surgical intervention of arthrodesis and proximal row carpectomy in adults have been reported where conservative management of splinting, physiotherapy, anti-inflammatory medication, or steroid injections have failed. We report a unique case of Minnaar type 2 LTC in a 20-year-old man with a 6-year history of daily right wrist pain and symptomatic wrist instability whose previous conservative therapies failed. Midcarpal instability and volar intercalated segment instability-volar flexion of the lunate-were present. A novel technique using the palmaris longus tendon to reconstruct the triquetrohamate, triquetrocapitate, and dorsal radiolunate ligaments was performed. The graft was secured dorsally to the hamate, triquetrum, and capitate. An additional graft from the lunate to distal radius acted as a biomechanical checkrein. There were no complications. Temporary Kirschner wires were removed 2 months postoperatively, followed by occupational hand therapy. At 1-year follow-up, the patient no longer reported pain or lunotriquetral tenderness. Midcarpal instability and volar intercalated segment instability resolved. Postoperative right wrist flexion and extension were 40 and 75 degrees, respectively. We discuss the successful outcome of this novel technique as an alternative to arthrodesis in the surgical management of LTC.