Ccr4-Not ubiquitin ligase signaling regulates ribosomal protein homeostasis and inhibits 40S ribosomal autophagy.

The Ccr4-Not complex contains the poorly understood Not4 ubiquitin ligase that functions in transcription, mRNA decay, translation, proteostasis, and endolysosomal nutrient signaling. To gain further insight into the in vivo functions of the ligase, we performed quantitative proteomics in Saccharomyces cerevisiae using yeast cells lacking Not4, or cells overexpressing wild-type Not4 or an inactive Not4 mutant. Herein, we provide evidence that balanced Not4 activity maintains ribosomal protein (RP) homeostasis independent of changes to RP mRNA or known Not4 ribosomal substrates. Intriguingly, we also find that Not4 loss activates 40S ribosomal autophagy independently of canonical Atg7-dependent macroautophagy, indicating that microautophagy is responsible. We previously demonstrated that Ccr4-Not stimulates target of rapamycin complex 1 (TORC1) signaling, which activates RP expression and inhibits autophagy, by maintaining vacuole V-ATPase H+ pump activity. Importantly, combining Not4 deficient cells with a mutant that blocks vacuole H+ export fully restores RP expression and increases 40S RP autophagy efficiency. In contrast, restoring TORC1 activity alone fails to rescue either process, indicating that Not4 loss disrupts additional endolysosomal functions that regulate RP expression and 40S autophagy. Analysis of the Not4 regulated proteome reveals increases in endolysosomal and autophagy-related factors that functionally interact with Not4 to control RP expression and affect 40S autophagy. Collectively, our data indicate that balanced Ccr4-Not ubiquitin ligase signaling maintains RP homeostasis and inhibits 40S autophagy via the ligase's emerging role as an endolysosomal regulator.

Analysis of the privacy-performance tradeoff of reference testing in Forensic Investigative Genetic Genealogy.

During an investigation using Forensic Investigative Genetic Genealogy, which is a novel approach for solving violent crimes and identifying human remains, reference testing-when law enforcement requests a DNA sample from a person in a partially constructed family tree-is sometimes used when an investigation has stalled. Because the people considered for a reference test have not opted in to allow law enforcement to use their DNA profile in this way, reference testing is viewed by many as an invasion of privacy and by some as unethical. We generalize an existing mathematical optimization model of the genealogy process by incorporating the option of reference testing. Using simulated versions of 17 DNA Doe Project cases, we find that reference testing can solve cases more quickly (although many reference tests are required to substantially hasten the investigative process), but only rarely (<1%) solves cases that cannot otherwise be solved. Through a mixture of mathematical and computational analysis, we find that the most desirable people to test are at the bottom of a path descending from an ancestral couple that is most likely to be related to the target. We also characterize the rare cases where reference testing is necessary for solving the case: when there is only one descending path from an ancestral couple, which precludes the possibility of identifying an intersection (e.g., marriage) between two descendants of two different ancestral couples.

Inequality in high-cost borrowing and unemployment insurance generosity in US states during the COVID-19 pandemic.

US consumers may turn to the private market for credit when income and government benefits fall short. The most vulnerable consumers have access only to the highest-cost loans. Prior research on trade-offs of credit with government welfare support cannot distinguish between distinct forms of unsecured credit due to data limitations. Here we provide insight on credit-welfare state trade-offs vis-à-vis unemployment insurance generosity by leveraging a large sample of credit data that allow us to separate credit cards, personal loans and alternative financial services loans and to analyse heterogeneity in credit use by household income. We find that more generous state unemployment insurance benefits were associated with a lower probability of high-cost credit use during the first seven quarters of the coronavirus disease 2019 (COVID-19) pandemic. This inverse association was concentrated among consumers living in low-income households. Our results support theories that public benefits are inversely associated with the use of costly credit.

Granulomatosis With Polyangiitis as an Etiology of Silent Sinus Syndrome: A Case Report.

Silent sinus syndrome (SSS) is a rare condition characterized by the collapse of the maxillary sinus and the sinking of the eye socket (enophthalmos). Only around 100 cases of SSS have been reported so far. The underlying cause of this condition is the chronic obstruction of the osteomeatal complex, which leads to sinus contraction. In this case, we present a novel finding linking SSS with granulomatosis with polyangiitis (GPA). The patient described is a 39-year-old male who was diagnosed with SSS after a prolonged period of sinus pressure, headaches, epistaxis, and generalized congestion. Additionally, the patient reported a significant autoimmune history, including a previous occurrence of ANCA-mediated glomerulonephritis. Surgical intervention revealed the presence of significant granulation tissue, while histopathological examination identified areas of necrosis, vasculitis, and multinucleated giant cells consistent with GPA. This finding was further supported by the detection of positive blood c-ANCA. This case is particularly noteworthy as it is the first reported instance of GPA causing SSS. It serves as an excellent example to illustrate the underlying pathophysiology of SSS.

Suspect screening of per-and polyfluoroalkyl substances in paper by selective and non-selective extraction with UHPLC-Q orbitrap MS.

Non-targeted analysis and suspect screening of per- and polyfluoroalkyl substances (PFAS) in various matrices have gained traction with advancements in accurate mass analytical instruments. This study employed ultra-high performance liquid chromatography coupled to quadrupole orbitrap high-resolution mass spectrometry for PFAS suspect screening of paper grades used in the paper recycling chain. The samples were prepared using two extraction techniques; selective accelerated solvent extraction with weak anionic exchange solid-phase extraction and non-selective ultrasonic-assisted extraction. A suspect screening protocol was established to tentatively identify suspected PFAS against spectral databases using a systematic approach of peak filtering and study-specific thresholds for reporting, linked to a confidence level. The possible prevalence of previously unreported PFAS in several paper materials across the various collection sites in the paper recycling chain was inferred by the common detection of short-chain polyfluoroalkyl ketones and diketones in the paper recycling chain. The suspect screening tentatively identified 41 unique PFAS, with 3 common to both pre-treatment techniques. The detection of unique PFAS by the two sample pre-treatment techniques highlighted the significance of both selective and non-selective extraction in PFAS screening endeavours. Further, it showed the importance of understanding the acquisition mechanisms employed in mass spectrometry where data-dependent acquisition triggered fragmentation in certain identified compounds, and not in others. The tentatively identified PFAS indicated that there were several previously unreported PFAS in the paper recycling chain and that additional studies were required to investigate their abundance, possible persistence, bioaccumulation and toxicity, in relation to their functional groups and carbon chains.

Stochastic resonance in the sensory systems and its applications in neural prosthetics.

Noise is generally considered to be detrimental. In the right conditions, however, noise can improve signal detection or information transmission. This counterintuitive phenomenon is called stochastic resonance (SR). SR has generated significant interdisciplinary interest, particularly in physics, engineering, and medical and environmental sciences. In this review, we discuss a growing empirical literature that suggests that noise at the right intensity may improve the detection and processing of auditory, sensorimotor, and visual stimuli. We focus particularly on applications of SR in sensory biology and investigate whether SR-based technologies present a pathway to improve outcomes for individuals living with sensory impairments. We conclude that there is considerable evidence supporting the application of SR in developing sensory prosthetics. However, the progression of SR-based technologies is variable across the sensory modalities. We suggest opportunities for further advancements in each modality, considering the best approaches to maximise benefits and capitalise on progress already made. Overall, SR can offer opportunities to improve existing technologies or to motivate innovations.

Phase 1 study of the pharmacokinetics and clinical proof-of-concept activity of a biofilm-disrupting human monoclonal antibody in patients with chronic prosthetic joint infection of the knee or hip.

We report the results of a first-in-human phase 1 clinical study to evaluate TRL1068, a native human monoclonal antibody that disrupts bacterial biofilms with broad-spectrum activity against both Gram-positive and Gram-negative species. The study population consisted of patients with chronic periprosthetic joint infections (PJIs) of the knee or hip, including both monomicrobial and polymicrobial infections, that are highly resistant to antibiotics due to biofilm formation. TRL1068 was administered via a single pre-surgical intravenous infusion in three sequentially ascending dose groups (6, 15, and 30 mg/kg). Concomitant perioperative antibiotics were pathogen-targeted as prescribed by the treating physician. In this double-blinded study, 4 patients were randomized to receive placebo and 11 patients to receive TRL1068 on day 1, as well as targeted antibiotics for 7 days prior to the scheduled removal of the infected implant and placement of an antibiotic-eluting spacer as the first stage of the standard of care two-stage exchange arthroplasty. No adverse events attributable to TRL1068 were reported. TRL1068 serum half-life was 15-18 days. At day 8, the concentration in synovial fluid was approximately 60% of the blood level and thus at least 15-fold above the threshold for biofilm-disrupting activity in vitro. Explanted prostheses were sonicated to release adherent bacteria for culture, with elimination of the implant bacteria observed in 3 of the 11 patients who received TRL1068, which compares favorably to prior PJI treatments. None of the patients who received TRL1068 had a relapse of the original infection by the end of the study (day 169). CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04763759.

Perceptions of metabolic syndrome management utilization in relation to patient experience and health-related quality of life.

Background: One factor for the poor health outcomes among adult people with metabolic syndrome (MetS) is poor utilization of disease management resources, which may be attributable to prior experience with pharmacists (PEwP) and perceptions of disease management resource utilization (PMU). Therefore, understanding patients' experience could be critical to improving their perceptions and promoting health outcomes. Objectives: The study explored the influence of PEwP and PMU on the health-related quality of life (HRQoL) of people with MetS. Methods: Data on perceptions of healthcare, medication, and pharmacy services utilization, PEwP, and HRQoL were collected using validated tools via an electronic survey. Chi-square and ordinal regression tests were used to predict the association between PMU, PEwP, and HRQoL. Also, mediation analysis through Haye's model 4 explored the direct and indirect relationship of PMU and PEwP on HRQoL. Results: A total of 706 completed surveys were collected and used for analyses. On average, respondents reported three comorbidities. Of the respondents, 72.0% had good PEwP, while 32.6% had good PMU. Comparatively, 38.4% of those with good PEwP had good PMU, compared to 17.3% of those with poor PEwP. Also, 47.0% of those with good PMU had good HRQoL compared to 35.3% with poor PMU. The odds of having fair or good PMU were nearly triple (OR = 2.97, p < 0.001) among those with good PEwP compared to those with poor PEwP. Also, respondents with good PMU had 58% (OR = 1.58, p = 0.008) higher odds of having fair or good HRQoL. Analysis through bootstrap indicated a significant relationship (BootCI = -0.072, -0.022) between PEwP and HRQoL via respondents' PMU. Conclusions: MetS individuals with good experience and PMU were more likely to have good HRQoL. Prior experience with pharmacists influenced PMU and indirectly impacted HRQoL. Therefore, pharmacists must consider patients' experience and management utilization perceptions to promote health outcome among people with MetS, while implementing interventions.

Learning About Sex from Different Sources: Implications for Sexual Attitudes, Sexual Knowledge, and Risky Sexual Behavior Among U.S. College Students.

This exploratory cross-sectional study, guided by primary socialization theory, examined relations between four primary socialization agents of sexual learning (i.e., mothers, fathers, friends/peers, and online media) and sexual attitudes, sexual knowledge, and risky sexual behavior. Latent-variable structural equation models were tested using self-report data obtained from 515 emerging adults who had spent at least 6 months attending in-person college classes. Results showed that learning about sex from mothers was associated with more conservative sexual attitudes and lower risky sexual behavior. Sexual learning from friends/peers was linked to liberal sexual attitudes and greater sexual knowledge. Learning from online media was associated with increased sexual knowledge. To account for a shift in sexual learning patterns from before to after entry to college, we created algebraic difference scores for each source of sexual information. Greater reliance on sexual learning from friends/peers in the past 6 months of college relative to before college was associated with liberal sexual attitudes and greater sexual knowledge. Additional analyses revealed different effects of learning about sex from mothers more during college than before college between those living on campus vs. commuters living at home. The discussion emphasizes the different role that each of the primary socialization agents plays for emerging adults' sexual development, including the protective role of mothers against risky sexual behavior, the impact of friends and peers on sexual attitudes and knowledge, and the shifting dynamics of socialization processes during college.

Taxonomic revision of the Southeast Asian brook barb genus Poropuntius Smith, 1931 (Teleostei, Cyprinidae) with description of a new species from Vietnam.

Molecular data from samples encompassing 22 nominal species of Poropuntius indicate that the species-level diversity in the genus has been vastly overestimated, likely due to inadequate taxon and geographic sampling and reliance on morphological characters that vary intra-specifically. The latter includes discrete mouth morphologies related to alternate feeding strategies (ecomorphs) within populations. One new species is described, Poropuntiusanlaoensis Hoàng, Pham & Tran, sp. nov., and 17 synonyms of six valid species names of Poropuntius, P.krempfi, P.alloiopleurus, P.huangchuchieni, P.laoensis, P.kontumensis, and P.deauratus, are recognised. Additional taxonomic changes in this widespread and generally poorly known genus are likely as more molecular and morphological data become available.

Genetic Risk For Depression and Quality of Life in Patients With Head and Neck Cancer.

Importance: Although patients with head and neck cancer (HNC) have been shown to experience high distress, few longitudinal studies include a comprehensive evaluation of biopsychosocial factors affecting quality of life (QoL), including genetic risk for depression. Objective: To identify factors at the time of cancer diagnosis associated with QoL scores at 3 months after treatment in patients newly diagnosed with a first occurrence of HNC. Design, Setting, and Participants: This prospective longitudinal study of 1464 participants with a 3-month follow-up, including structured clinical interviews and self-administered measures was carried out at the Department of Otolaryngology Head and Neck Surgery at 2 tertiary care McGill University Affiliated Hospitals, McGill University Health Centre, and Jewish General Hospital. Eligible patients were adults newly diagnosed within 2 weeks with a primary first occurrence of HNC, had a Karnofsky Performance Scale score higher than 60, and an expected survival of more than 6 months. Two hundred and twenty-three patients (72%) consented to participate and completed the baseline questionnaire, and 71% completed the 3-month follow-up measures. Exposures: An a priori conceptual model including sociodemographics, medical variables, psychosocial risk factors, and a polygenic risk score for depression (PRS-D) was tested. Main outcomes and measures: The Functional Assessment of Cancer Therapy-Head and Neck measured QoL at baseline and at 3 months. Results: Participants were mostly men (68.7%), with a mean (range) age of 62.9 (31-92) years, 36.6% having a university degree, 35.6% living alone, and 71.4% diagnosed with advanced HNC with mostly cancers being of the oropharynx (42.2%), oral cavity (17%), and larynx (16.3%). QoL at 3 months after HNC diagnosis was associated with higher PRS-D (B = -4.71; 95% CI, -9.18 to -0.23), and a diagnosis of major depressive disorder within 2 weeks of an HNC diagnosis (B = -32.24; 95% CI, -51.47 to 13.02), lifetime suicidal ideation (B = -22.39; 95% CI, -36.14 to -8.65), living with someone (B = 12.48; 95% CI, 3.43-21.52), having smoked cigarettes in the past 30 days pre-HNC diagnosis (B = -15.50; 95% CI, -26.07 to -4.93), chemotherapy type (B = -11.13; 95% CI, -21.23 to -1.02), and total radiotherapy dose (Gy) (B = -0.008; 95% CI, -0.01 to -0.002). Conclusions and relevance: This study identified the predictive value of a genetic predisposition to depression on QoL and function immediately after oncologic treatments. These findings highlight the potential importance of genetic profiling pretreatment to identify those most susceptible to experience QoL and functional compromise. Depression is a clear area of public health concern and should be a central focus in the treatment of patients with HNC.

Whole-body magnetic resonance neurography in patients with chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: Whole-body magnetic resonance neurography (MRN) is an imaging modality that shows peripheral nerve signal change in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We aimed to explore the diagnostic potential of whole-body MRN and its potential as a monitoring tool after immunotherapy in treatment-naïve CIDP patients. METHODS: Whole-body MRN using coronal 3-dimensional short tau inversion recovery (STIR) sampling perfection with application-optimized contrasts by using different flip angle evolution (SPACE) techniques was performed in patients being investigated for CIDP and in healthy controls. Baseline clinical neuropathy scales and electrophysiologic parameters were collected, and MRN findings were compared before and after CIDP treatment. RESULTS: We found highly concordant symmetrical thickening and increased T2 signal intensities in the brachial/lumbosacral plexus, femoral, or sciatic nerves in five of the eight patients with a final diagnosis of CIDP and none of the healthy controls. There were no treatment-related imaging changes in five patients with CIDP who completed a follow-up study. Diffuse, symmetrical thickening, and increased T2 signal in root, plexus, and peripheral nerves were found in two patients ultimately excluded due to a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome in addition to signal changes in the muscles, bony lesions, organomegaly, and lymphadenopathy. DISCUSSION: Whole-body MRN imaging shows promise in detecting abnormalities in proximal nerve segments in patients with CIDP. Future studies evaluating the role of MRN in assessing treatment response should consider follow-up scans after treatment durations of more than 4 months.

Feasibility and optimization of19F MRI on a clinical 3T with a large field-of-view torso coil.

Objective.The objective of this work is to: (1) demonstrate fluorine-19 (19F) MRI on a 3T clinical system with a large field of view (FOV) multi-channel torso coil (2) demonstrate an example parameter selection optimization for a19F agent to maximize the signal-to-noise ratio (SNR)-efficiency for spoiled gradient echo (SPGR), balanced steady-state free precession (bSSFP), and phase-cycled bSSFP (bSSFP-C), and (3) validate detection feasibility inex vivotissues.Approach.Measurements were conducted on a 3.0T Discovery MR750w MRI (GE Healthcare, USA) with an 8-channel1H/19F torso coil (MRI Tools, Germany). Numerical simulations were conducted for perfluoropolyether to determine the theoretical parameters to maximize SNR-efficiency for the sequences. Theoretical parameters were experimentally verified, and the sensitivity of the sequences was compared with a 10 min acquisition time with a 3.125 × 3.125 × 3 mm3in-plane resolution. Feasibility of a bSSFP-C was also demonstrated in phantom andex vivotissues.Main Results. Flip angles (FAs) of 12 and 64° maximized the signal for SPGR and bSSFP, and validation of optimal FA and receiver bandwidth showed close agreement with numerical simulations. Sensitivities of 2.47, 5.81, and 4.44ms-0.5mM-1 and empirical detection limits of 20.3, 1.5, and 6.2 mM were achieved for SPGR, bSSFP, and bSSFP-C, respectively. bSSFP and bSSFP-C achieved 1.8-fold greater sensitivity over SPGR (p< 0.01).Significance.bSSFP-C was able to improve sensitivity relative to simple SPGR and reduce both bSSFP banding effects and imaging time. The sequence was used to demonstrate the feasibility of19F MRI at clinical FOVs and field strengths withinex-vivotissues.

Antinociceptive effects of fentanyl and nonopioid drugs in methocinnamox-treated rats.

BACKGROUND: A single administration of the opioid receptor antagonist methocinnamox (MCAM) antagonizes the antinociceptive effects of µ-opioid receptor agonists for 2 weeks or longer. Such a long duration of antagonism could necessitate the use of nonopioid drugs for treating pain in patients receiving MCAM for opioid use disorder (OUD). METHODS: The antinociceptive effects of fentanyl and nonopioid drugs were assessed in 24 male Sprague Dawley rats using a complete Freund's adjuvant (CFA) model of inflammatory pain. Twelve rats received 10mg/kg MCAM and 12 received vehicle; half (n=6) of the animals from each treatment group were treated (intraplantar) with CFA or saline. Hypersensitivity to mechanical stimulation was measured using a von Frey anesthesiometer. Fentanyl (0.01-0.1mg/kg), ketamine (17.8-56mg/kg), gabapentin (32-100mg/kg), meloxicam (3.2-10mg/kg), and ∆9-tetrahydrocannabinol (THC, 1-10mg/kg) were administered intraperitoneally and tested every 3 days in a pseudorandom order. Next, the same drugs were studied for effects on motor performance using a rotarod apparatus. RESULTS: CFA-induced hypersensitivity was attenuated by fentanyl in vehicle- but not MCAM-treated rats. THC, ketamine, and gabapentin attenuated (up to 82, 66, and 46 %, respectively) CFA-evoked mechanical hypersensitivity in both MCAM- and vehicle-treated rats. Meloxicam failed to alter CFA-evoked mechanical hypersensitivity in either group. Fentanyl, THC, gabapentin, and meloxicam did not affect motor performance in either group whereas ketamine impaired motor performance in both groups (up to 71 % reduction in latency to fall). CONCLUSIONS: These data suggest that ketamine, gabapentin, and THC could be effective for treating inflammatory pain under conditions of long term µ-opioid receptor antagonism.

New record of Gracilariaphuquocensis (Gracilariaceae, Rhodophyta) in the Philippines.

While reliance on morphology has been at the expense of clearly distinguishing gracilarioid species, molecular data have proven to be more reliable in discriminating between taxa. Gracilariaphuquocensis was originally described, based on materials collected from Vietnam. Since it was described in 2020, there have been no further reports of this species. Meanwhile, a question has been raised as to whether the identity of a rhodophyte gracilarioid alga collected from the Philippines that has been referred to as an unidentified species of Gracilaria, could be G.phuquocensis. Based on comparative morpho-anatomical features and a molecular phylogeny based on rbcL gene sequences, establishing the identity of the Philippine material has led to the finding of the new record of G.phuquocensis outside its type locality. In addition to the discovery of G.phuquocensis in the Philippines, the species here is also identified as a newly-reported host for the adelphoparasite resembling Gracilariababae.

Prenatal opioid exposure by likelihood of exposure and risk to prenatal development: Medicaid-covered births in Wisconsin, 2010-2019.

Prenatal opioid exposure is an established public health problem, in particular among Medicaid-covered births. Yet, existing prevalence rates are plausibly underestimated. We leverage extensive linked longitudinal administrative data for all Medicaid-covered live births in Wisconsin from 2010 to 2019 to estimate a range of prevalence rates using an innovative strategy that jointly accounts for both likelihood of exposure and potential risk to prenatal development. We find that 20.8% of infants may have been prenatally exposed to opioids, with 1.7% diagnosed with neonatal abstinence syndrome and an additional 1.2% having a high combined likelihood of exposure and potential risk to prenatal development, 2.6% a moderate combined likelihood and risk, and 15.3% a low or uncertain combined likelihood and risk. We assess improvements in prevalence estimates based on our nuanced classification relative to those of prior studies. Our strategy could be broadly used to quantify the scope of the opioid crisis for pregnant populations, target interventions, and promote child health and development.