Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

Overcoming Understaging and Undergrading in Upper Tract Urothelial Carcinoma. Comment on Ghoreifi et al. Modern Kidney-Sparing Management of Upper Tract Urothelial Carcinoma. Cancers 2023, 15, 4495.

Kidney-sparing management for upper tract urothelial carcinoma (UTUC) has become more common but is still most limited by inaccurate histopathologic diagnosis [...].

Myopia control: Seeing beyond efficacy.

SIGNIFICANCE: The availability of a range of effective myopia control modalities enables the clinician to exercise judgment when discussing the treatment plan with the patient and their parents. This article outlines important considerations beyond efficacy.Clinically meaningful myopia control may be attained with some spectacle lenses, select soft contact lenses, some concentrations of atropine, and overnight orthokeratology. Given that satisfactory efficacy can be achieved with a range of modalities, other factors should be considered when deciding upon the best intervention for a given child. Four key factors-compliance, quality of vision, quality of life, and safety-are discussed in this review. Compliance directly impacts efficacy regardless of the modality and is the most important consideration, as it is influenced by quality of vision and comfort. Daily disposal myopia control contact lenses and overnight orthokeratology are generally associated with high compliance, provide better vision-related quality of life than spectacles, and carry a very low risk when used appropriately. A further benefit of overnight orthokeratology is the elimination of a need for optical correction during the day.

Outcomes of Short and Long Tibial Stems for Primary Total Knee Arthroplasty in a Population of Obese Patients at Two-Year Follow-Up: A Clinical and Biomechanical Study.

BACKGROUND: Obesity can be a source of higher failure rates and inferior clinical outcomes after total knee arthroplasty (TKA). The aim of this study was to compare outcomes, failure rates, and stress distributions of TKA in obese patients using a short, long, or no tibial stem. METHODS: A matching process based on the type of stem used and the age allowed included 180 patients who had a body mass index (BMI) > 30 and underwent a TKA between January 2010 and December 2019, with a minimum follow-up of 2 years. They were classified as moderately obese (MO: 30 < BMI < 35, N = 90) and severely obese (SO: BMI > 35, N = 90). For each, 3 subgroups were defined: thirty patients received a 30 mm short stem (SS), thirty received a 100 mm long stem (LS), and thirty received no stem (NS). Patients were assessed preoperatively and postoperatively using the Knee Society Score (KSS). A finite element model was developed to evaluate the biomechanical effects of the tibial stem on stress distribution in the subchondral bone based on BMI. RESULTS: The SS patients had significantly higher postoperative KSS knee score [MO: 88.9 (SS) versus 79 (LS) versus 80.6 (NS); SO: 84.5 versus 72.4 versus 78.2] (P < .0001) and function score [MO: 90.4 (SS) versus 78.4 (LS) versus 68.5 (NS); SO: 85.5 versus 73 versus 61.8] (P < .0001) compared to LS and NS patients. The biomechanical study demonstrated a BMI-dependent increase in stress in the subchondral bone in contact with the tibial components. These stresses were mainly distributed at the tibial cut for NS and along the stem for SS and LS. CONCLUSIONS: A short, cemented tibial stem offers better functional outcomes without increasing failure rates compared to a longer stem during primary TKA in a population of obese patients at two-year follow-up. A short tibial stem does not lead to increased stress compared to an LS, at least for certain BMI categories.

New examples of ferroelectric nematic materials showing evidence for the antiferroelectric smectic-Z phase.

We present a new ferroelectric nematic material, 4-((4'-((trans)-5-ethyloxan-2-yl)-2',3,5,6'-tetrafluoro-[1,1'-biphenyl]-4-yl)difluoromethoxy)-2,6-difluorobenzonitrile (AUUQU-2-N) and its higher homologues, the molecular structures of which include fluorinated building blocks, an oxane ring, and a terminal cyano group, all contributing to a large molecular dipole moment of about 12.5 D. We observed that AUUQU-2-N has three distinct liquid crystal phases, two of which were found to be polar phases with a spontaneous electric polarization Ps of up to 6 µC cm-2. The highest temperature phase is a common enantiotropic nematic (N) exhibiting only field-induced polarization. The lowest-temperature, monotropic phase proved to be a new example of the ferroelectric nematic phase (NF), evidenced by a single-peak polarization reversal current response, a giant imaginary dielectric permittivity on the order of 103, and the absence of any smectic layer X-ray diffraction peaks. The ordinary nematic phase N and the ferroelectric nematic phase NF are separated by an antiferroelectric liquid crystal phase which has low permittivity and a polarization reversal current exhibiting a characteristic double-peak response. In the polarizing light microscope, this antiferroelectric phase shows characteristic zig-zag defects, evidence of a layered structure. These observations suggest that this is another example of the recently discovered smectic ZA (SmZA) phase, having smectic layers with the molecular director parallel to the layer planes. The diffraction peaks from the smectic layering have not been observed to date but detailed 2D X-ray studies indicate the presence of additional short-range structures including smectic C-type correlations in all three phases-N, SmZA and NF-which may shed new light on the understanding of polar and antipolar order in these phases.

Juvenile-onset myopia-who to treat and how to evaluate success.

The risk of eye diseases such as myopic macular degeneration increases with the level of myopia, but there is no safe level of myopia and the burden of lower degrees of myopia remains considerable. Effective treatments are available that slow progression and thus limit the final degree of myopia. In this review, the rationale for slowing progression is summarized, and a case made for treating all myopic children. Measurement of refractive error and axial length is reviewed, stressing the precision of optical biometry, but also the need for cycloplegic autorefraction. The factors influencing progression are considered and the available tools for interpretation of progression rate are discussed. Finally, the need to set attainable treatment goals is emphasized.

PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer.

PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

PIM1 drives lipid droplet accumulation to promote proliferation and survival in prostate cancer.

Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed that LDs promote cell survival by providing an energy source during energy deprivation. However, the precise mechanisms controlling LD accumulation and utilization in prostate cancer are not well known. Here, we show peroxisome proliferator-activated receptor α (PPARα) acts downstream of PIM1 kinase to accelerate LD accumulation and promote cell proliferation in prostate cancer. Mechanistically, PIM1 inactivates glycogen synthase kinase 3 beta (GSK3ß) via serine 9 phosphorylation. GSK3ß inhibition stabilizes PPARα and enhances the transcription of genes linked to peroxisomal biogenesis (PEX3 and PEX5) and LD growth (Tip47). The effects of PIM1 on LD accumulation are abrogated with GW6471, a specific inhibitor for PPARα. Notably, LD accumulation downstream of PIM1 provides a significant survival advantage for prostate cancer cells during nutrient stress, such as glucose depletion. Inhibiting PIM reduces LD accumulation in vivo alongside slow tumor growth and proliferation. Furthermore, TKO mice, lacking PIM isoforms, exhibit suppression in circulating triglycerides. Overall, our findings establish PIM1 as an important regulator of LD accumulation through GSK3ß-PPARα signaling axis to promote cell proliferation and survival during nutrient stress.

Reduced strength and increased variability of extinction selectivity during mass extinctions.

Two of the traits most often observed to correlate with extinction risk in marine animals are geographical range and body size. However, the relative effects of these two traits on extinction risk have not been investigated systematically for either background times or during mass extinctions. To close this knowledge gap, we measure and compare extinction selectivity of geographical range and body size of genera within five classes of benthic marine animals across the Phanerozoic using capture-mark-recapture models. During background intervals, narrow geographical range is strongly associated with greater extinction probability, whereas smaller body size is more weakly associated with greater extinction probability. During mass extinctions, the association between geographical range and extinction probability is reduced in every class and fully eliminated in some, whereas the association between body size and extinction probability varies in strength and direction across classes. While geographical range is universally the stronger predictor of survival during background intervals, variation among classes during mass extinction suggests a fundamental shift in extinction processes during these global catastrophes.

The underestimated role of myopia in uncorrectable visual impairment in the United States.

We estimate the US prevalence of uncorrectable visual impairment in 2050 accounting for the changing distribution of both age and myopia. Age projections of the US population (from an estimated total of 379 million in 2050), were taken from the US census website. The distribution of myopia, by severity, was calculated from literature-derived prevalence estimates of 58.4% (≤ - 0.50 D, 2050 projection) and 33.1% (≤ - 1.00 D, 1999-2004 estimate) to provide predicted and conservative estimates, respectively. Uncorrectable visual impairment as a function of age and refractive error was modelled by multiple linear regression. Finally, the likely number of individuals in the US with visual impairment in 2050 was calculated. For a projected myopia prevalence of 58.4%, 222 million are projected to be myopic and 48 million will have high myopia (- 5 D or worse). The projected total number with uncorrectable visual impairment is 11.4 million of which 4.9 million cases (43%) of visual impairment will be directly attributed to increased risk of eye disease associated with myopia. For a projected myopia prevalence of 33.1%, 8.9 million are projected to have uncorrectable visual impairment of which 2.4 million cases (27%) will be directly attributed to myopia. It is predicted that between 27 and 43% of uncorrectable visual impairment in the US population in 2050 will be directly attributable to myopia. Failure to account for the increasing prevalence of myopia among the aging population leads to a substantial underestimate of the prevalence of visual impairment.

Relational sanctification, communal coping, and depression among African American couples.

Despite the common use of religious buffers, African Americans are disproportionately affected by depressive symptoms. Communal coping may serve as one factor in helping religious African American couples alleviate the symptoms of depression. This study examines the association between relational sanctification and depressive symptoms as mediated by the communal coping of 467 African American married and cohabiting couples. Data from the sampled couples were analyzed using a common fate model, and analyses revealed higher scores on the measure of sanctification were associated with more communal coping; more communal coping was associated with fewer depressive symptoms among women and men, and communal coping acted as a mediator between relational sanctification and depressive symptoms in both partners. Findings from this study underscore the importance of considering how the religiosity and cooperative action of African American couples relate to depressive symptoms.

Topological defect coarsening in quenched smectic-C films analyzed using artificial neural networks.

Mechanically quenching a thin film of smectic-C liquid crystal results in the formation of a dense array of thousands of topological defects in the director field. The subsequent rapid coarsening of the film texture by the mutual annihilation of defects of opposite sign has been captured using high-speed, polarized light video microscopy. The temporal evolution of the texture has been characterized using an object-detection convolutional neural network to determine the defect locations, and a binary classification network customized to evaluate the brush orientation dynamics around the defects in order to determine their topological signs. At early times following the quench, inherent limits on the spatial resolution result in undercounting of the defects and deviations from expected behavior. At intermediate to late times, the observed annihilation dynamics scale in agreement with theoretical predictions and simulations of the 2D XY model.

PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion.

Distinguishing key factors that drive the switch from indolent to invasive disease will make a significant impact on guiding the treatment of prostate cancer (PCa) patients. Here, we identify a novel signaling pathway linking hypoxia and PIM1 kinase to the actin cytoskeleton and cell motility. An unbiased proteomic screen identified Abl-interactor 2 (ABI2), an integral member of the wave regulatory complex (WRC), as a PIM1 substrate. Phosphorylation of ABI2 at Ser183 by PIM1 increased ABI2 protein levels and enhanced WRC formation, resulting in increased protrusive activity and cell motility. Cell protrusion induced by hypoxia and/or PIM1 was dependent on ABI2. In vivo smooth muscle invasion assays showed that overexpression of PIM1 significantly increased the depth of tumor cell invasion, and treatment with PIM inhibitors significantly reduced intramuscular PCa invasion. This research uncovers a HIF-1-independent signaling axis that is critical for hypoxia-induced invasion and establishes a novel role for PIM1 as a key regulator of the actin cytoskeleton.

Applications of Genomics and Transcriptomics in Precision Medicine for Myopia Control or Prevention.

Myopia is a globally emerging concern accompanied by multiple medical and socio-economic burdens with no well-established causal treatment to control thus far. The study of the genomics and transcriptomics of myopia treatment is crucial to delineate disease pathways and provide valuable insights for the design of precise and effective therapeutics. A strong understanding of altered biochemical pathways and underlying pathogenesis leading to myopia may facilitate early diagnosis and treatment of myopia, ultimately leading to the development of more effective preventive and therapeutic measures. In this review, we summarize current data about the genomics and transcriptomics of myopia in human and animal models. We also discuss the potential applicability of these findings to precision medicine for myopia treatment.

The future of clinical trials of myopia control.

In the field of myopia control, effective optical or pharmaceutical therapies are now available to patients in many markets. This creates challenges for the conduct of placebo-controlled, randomised clinical trials, including ethics, recruitment, retention, selective loss of faster progressors and non-protocol treatments: Ethics: It is valid to question whether withholding treatment in control subjects is ethical. Recruitment: Availability of treatments is making recruitment into clinical trials more difficult. Retention: If masking is not possible, parents may immediately withdraw their child if randomised to no treatment. Selective loss: Withdrawal of fast progressors in the control group leading to a control group biased towards low progression. Non-protocol treatment: Parents may access other myopia treatments in addition to those within the trial. We propose that future trials may adopt one of the following designs: Non-inferiority trials using an approved drug or device as the control. The choice will depend on whether a regulatory agency has approved the drug or device. Short conventional efficacy trials where data are subsequently entered into a model created from previous clinical trials, which allows robust prediction of long-term treatment efficacy from the initial efficacy. Virtual control group trials based on data relating to axial elongation, myopia progression or both, accounting for subject's age and race. Short-term control data from a cohort, for example, 1 year or less, and applying an appropriate, proportional annual reduction in axial elongation to that population and extrapolating to subsequent years. Time-to-treatment-failure trials using survival analysis; once a treated or control subject progresses or elongates by a given amount, they exit the study and can be offered treatment. In summary, the future development of new treatments in myopia control will be hampered if significant changes are not made to the design of clinical trials in this area.

A Duration-Dependent Interaction Between High-Intensity Light and Unrestricted Vision in the Drive for Myopia Control.

Purpose: To evaluate the duration-dependent and synergetic impact of high-intensity light (HL) and unrestricted vision (UnV) on lens-induced myopia (LIM) development in chickens. Methods: Myopia was induced in one eye in chicks (10 groups, n = 126) from day 1 posthatching (D1) until day 8 (D8) using -10 diopter (D) lenses. Fellow eyes remained uncovered as controls. Nine groups were exposed daily to 2, 4, or 6 hours of HL (15,000 lux), UnV (removal of -10 D lens), or both (HL + UnV). One group served as the LIM group without any interventions. Ocular axial length (AL), refractive error, and choroidal thickness were measured on D1, D4, and D8. Outcome measures are expressed as interocular difference (IOD = experimental eye - control eye) ± SEM. Results: By D8, LIM increased AL (0.36 ± 0.04 mm), myopic refraction (-9.02 ± 0.37 D), and choroidal thinning (-90.27 ± 16.44 µm) in the LIM group (all, P < 0.001). Compared to the LIM group, exposure to 2, 4, or 6 hours of HL, UnV, or HL + UnV reduced myopic refraction in a duration-dependent manner, with UnV being more effective than HL (P < 0.05). Only 6 hours of HL + UnV (not 2 or 4 hours) prevented LIM and was more effective than UnV (P = 0.004) or HL (P < 0.001) in reducing myopic refraction and more effective than HL (P < 0.001) in reducing axial elongation. Conclusions: Daily exposure to 2, 4, or 6 hours of HL, UnV, or HL + UnV reduced lens-induced myopic refraction in a duration-dependent manner in chickens. Only 6 hours of HL + UnV completely stopped LIM development. The synergetic effect of HL and UnV is dependent on the duration of the interventions.

The smectic ZA phase: Antiferroelectric smectic order as a prelude to the ferroelectric nematic.

We have structurally characterized the liquid crystal (LC) phase that can appear as an intermediate state when a dielectric nematic, having polar disorder of its molecular dipoles, transitions to the almost perfectly polar-ordered ferroelectric nematic. This intermediate phase, which fills a 100-y-old void in the taxonomy of smectic LCs and which we term the "smectic ZA," is antiferroelectric, with the nematic director and polarization oriented parallel to smectic layer planes, and the polarization alternating in sign from layer to layer with a 180 Å period. A Landau free energy, originally derived from the Ising model of ferromagnetic ordering of spins in the presence of dipole-dipole interactions, and applied to model incommensurate antiferroelectricity in crystals, describes the key features of the nematic-SmZA-ferroelectric nematic phase sequence.

Upper Tract Tumor En Bloc Enucleation: A Novel Approach to the Diagnosis and Management of Upper Tract Urothelial Carcinoma.

OBJECTIVES: To describe and demonstrate our novel en bloc enucleation technique for the endoscopic diagnosis and treatment of upper tract tumors. METHODS: We detail the instruments required for this procedure, as well as the surgical technique to perform an en bloc enucleation and specimen removal. Endoscopic video of a 2 cm renal pelvis tumor demonstrates all aspects of the technique, and histopathologic slides illustrate the diagnostic information obtained. RESULTS: A ureteral access sheath is inserted distal to the upper tract tumor, and a flexible ureteroscope is used to visualize the extent of upper tract disease and tumor characteristics. A 200 µm thulium fiber laser partially ablates the tumor surface to create an edge for tissue biopsy and post-ablation urine cytology. The tumor base is identified and the sub epithelial connective tissue is carefully entered with low ablation laser settings. The correct tissue plane is extended by maintaining the ureteroscope in the subepithelial connective tissue and continuing the dissection along the entire width of the tumor base. Once the tumor is enucleated, a Nitinol stone retrieval basket is used to remove the specimen(s) and a ureteral stent is placed. CONCLUSIONS: En bloc enucleation may provide extensive histopathologic information in upper tract urothelial carcinoma. In cases where complete enucleation is not feasible, this procedure may afford a mechanism for large caliber biopsies.