bluuebunny/crossref_metadata_2025_split huggingface dataset:
-1 Programmed ribosomal frameshifting in Class 2 umbravirus-like RNAs uses multiple long-distance interactions to shift between active and inactive structures and destabilize the frameshift stimulating element
Authors: Mikkelsen Anna A , Gao Feng , Carino Elizabeth , Bera Sayanta , Simon Anne E 
Published: September 2023

Abstract
Plus-strand RNA viruses frequently employ -1 programmed ribosomal frameshifting (-1 PRF) to maximize their coding capacity. Ribosomes can frameshift at a slippery sequence if progression is impeded by a frameshift stimulating element (FSE), which is generally a stable, complex, dynamic structure with multiple conformations that contribute to the efficiency of -1 PRF. As FSE are usually analyzed separate from the viral genome, little is known about cis-acting long-distance interactions. Using full-length genomic RNA of umbravirus-like (ula)RNA citrus yellow vein associated virus (CY1) and translation in wheat germ extracts, six tertiary interactions were found associated with the CY1 FSE that span nearly three-quarters of the 2.7 kb genomic RNA. All six tertiary interactions are conserved in other Class 2 ulaRNAs and two are conserved in all ulaRNAs. Two sets of interactions comprise local and distal pseudoknots that involve overlapping FSE nucleotides and thus are structurally incompatible, suggesting that Class 2 FSEs assume multiple conformations. Importantly, two long-distance interactions connect with sequences on opposite sides of the critical FSE central stem, which would unzip the stem and destabilize the FSE. These latter interactions could allow a frameshifting ribosome to translate through a structurally disrupted upstream FSE that no longer blocks ribosome progression.
Severe recurrent hyponatremia in a 72-year-old patient with undiagnosed partially empty Sella syndrome—a case report
Authors: Dahal Agnimshwor , Chauhan Bhim , Gyawali Jeevan , Thapa Astha , Dhungel Prakash , Yadav Saroj 
Published: September 2023

Abstract
Hyponatremia is one of the most common electrolyte abnormalities encountered in medical practice and is caused by multiple conditions. SIADH is the most common cause of hyponatremia, however, careful workup must be performed on all patients as mere supplementation may cause recurrent hyponatremia and serious side effects. Adrenal insufficiency is a principal culprit that mimics the clinical picture of SIADH and tends to worsen when treated in the line of SIADH. In addition, individuals may have various comorbidities, such as hypothyroidism in our case, which can also cause hyponatremia, making it difficult to determine precise etiology. We present a case of a 72-year-old man with recurrent hyponatremia, who was subsequently diagnosed as partially empty sella syndrome. Given the temporal relationship between the use of corticosteroids and the improvement of his symptoms, low cortisol and ACTH levels, adrenal insufficiency was most likely the cause of the hyponatremia in our patient.
Sugar-Sick Yet Healthy: Changing Concepts of Disease in the Dutch Diabetics Association (1945–1970)
Authors: Haalboom Floor 
Published: September 2023

Summary
Using the journal of the Dutch Diabetics Association (Nederlandse Vereniging van Suikerzieken), the article provides insight into the role of an early patient organisation in conceptualising the chronic disease diabetes and its management in the Netherlands between 1945 and 1970. The dual aims of discipline (steered by health professionals) and independence (steered by diabetics) were reconciled through the concept of balance during the 1940s and 1950s. Organised diabetics played a particularly large role, and independence got particular emphasis as a consequence. This made it possible for organised patients to reconfigure their disease and identity in terms of social health in relation to labour, family and society in the post-war reconstruction period. In the late 1960s, this social concept transformed into a personal concept of health in which the concept of balance lost its prominence, despite a short intermezzo of medicalisation in the early 1960s.
Sleep and circadian influences on blood alcohol concentration
Authors: Miller Mary Beth , Cofresí Roberto U , McCarthy Denis M , Carskadon Mary A 
Published: September 2023

Abstract

Study Objectives
Anecdotally, adults reach higher levels of subjective intoxication on days they are fatigued or sleep-deprived, but sleep is not typically discussed as a predictor of blood alcohol concentration (BAC) in clinical settings. To inform clinical work and future research, this perspective reviews data examining the impact of sleep (process S) and circadian (process C) factors on indicators of BAC in humans and animal models.

Methods
Literature searches of medical and psychological databases were conducted to identify articles that manipulated sleep/circadian factors and reported effects on indicators of alcohol pharmacology (e.g. BAC, alcohol metabolism).

Results
Of the 86 full-text articles reviewed, 21 met inclusion criteria. Studies included manipulations of time of day, circadian phase (evidence for process C), and time in bed (evidence for process S). Evidence for time-of-day effects on alcohol pharmacology was most compelling. Studies also provided evidence for circadian phase effects, but failed to find support for time-in-bed effects. Although results were not uniform across studies, most evidence from human and animal models indicates that peak BACs occur toward the beginning of the biological day, with some studies indicating slower alcohol elimination rates at this time.

Conclusions
Circadian factors likely influence alcohol pharmacokinetics, perhaps due to altered elimination of alcohol from the body. This means that individuals may reach higher BACs if they drink during the morning (when, for most people, circadian alerting is low) versus other times of the day. Alcohol prevention and intervention efforts should highlight sleep/circadian health as a potential contributor to alcohol-related harm.
Sleep-inducing effect of Rhynchophylline in EphA4 knockout mice
Authors: Ballester Roig Maria Neus , Mongrain Valérie 
Published: September 2023

Abstract
We have recently demonstrated that the alkaloid rhynchophylline (RHY; purified from Uncaria plants) induces sleep and modifies electrocorticographic (ECoG) activity throughout the 24-h day in a vigilance state-dependent manner in wild-type mice. We here asked whether this alkaloid impacts wake/sleep variables in the absence of the cell adhesion protein EPHA4, via ECoG recording in EphA4 knockout (KO) mice submitted to the same RHY treatment contemporaneously to the wild-type mice (littermates). We uncover that RHY decreases time spent awake and increases time spent in slow wave sleep in EphA4 KO mice and alters the 24-h time course of ECoG activity during wakefulness and sleep states. These observations are similar to the reported effects of RHY in wild-type littermate animals, which strongly supports that RHY-driven sleep alterations are not dependent on the presence of EPHA4.
Patient perspectives on a proposed pharmacy-based colorectal cancer screening program
Authors: Ferrari Renée M , Atkins Dana L , Wangen Mary , Rohweder Catherine L , Waters Austin R , Correa Sara , Richmond Jennifer , van Rensburg Dillon , Ittes Annika , Odebunmi Olufeyisayo , Issaka Rachel B , Ceballos Rachel , Shah Parth D , Wheeler Stephanie B , Brenner Alison T 
Published: September 2023

Abstract
Colorectal cancer (CRC) is a common and preventable cancer. CRC screening is underutilized, particularly within medically underserved communities. Most interventions aimed at increasing CRC screening are delivered through primary care clinics. Pharmacies are more accessible than traditional primary care settings and may be ideally suited for delivering CRC screening and increasing access. Fecal immunochemical test is an at-home, stool-based CRC screening test that could be distributed through pharmacies. The purpose of our study was to assess patient perspectives on receiving fecal immunochemical test-based CRC screening through pharmacies. We conducted semi-structured interviews with participants residing in North Carolina and Washington. Interviews explored acceptability and intervention design preferences for a pharmacy-based CRC screening program. The interview guide was informed by Andersen’s Healthcare Utilization Model and the Theoretical Domains Framework. Interviews were conducted at the University of North Carolina at Chapel Hill and Fred Hutchinson Cancer Research Center, audio-recorded, and transcribed. Patients perceived a pharmacy-based CRC screening program to be highly acceptable, citing factors such as ease of pharmacy access and avoiding co-pays for an office visit. Some concerns about privacy and coordination with patients’ primary care provider tempered acceptability. Trust and positive relationships with providers and pharmacists as well as seamless care across the CRC screening continuum also were viewed as important. Patients viewed pharmacy-based CRC screening as an acceptable option for CRC screening. To improve programmatic success, it will be important to ensure privacy, determine how communication between the pharmacy and the patient’s provider will take place, and establish closed-loop care, particularly for patients with abnormal results.
Exogenous chelating agents influence growth, physiological characteristics and cell ultrastructure of Robinia pseudoacacia seedlings under lead–cadmium stress
Authors: Zhou Jian , Qi Anguo , Wang Ting , Zhang Songyan , Liu Jinxiu , Lu Yabo 
Published: September 2023

Abstract
Heavy metal pollution of soil, especially by lead (Pb) and cadmium (Cd), is a serious problem worldwide. The application of safe chelating agents, combined with the growing of tolerant trees, constitutes an approach for phytoremediation of heavy-metal-contaminated soil. This study aimed to determine whether the two safe chelators, tetrasodium glutamate diacetate (GLDA) and citric acid (CA), could improve the phytoremediation capacity of black locust (Robinia pseudoacacia L.) in a Pb–Cd-contaminated soil and to find the key factors affecting the biomass accumulation of stressed black locust. In Pb- and Cd-stressed black locust plants, medium- and high-concentration GLDA treatment inhibited the growth, chlorophyll synthesis and maximum photochemical efficiency (Fv/Fm), promoted the absorption of Pb and Cd ions and resulted in the shrinkage of chloroplasts and starch grains when compared with those in Pb- and Cd-stressed plants that were not treated with GLDA. The effects of CA on plant growth, ion absorption, chlorophyll content, chlorophyll fluorescence and organelle size were significantly weaker than those of GLDA. The effect of both agents on Cd absorption was greater than that on Pb absorption in all treatments. The levels of chlorophyll a and plant tissue Cd and rates of starch metabolism were identified as the key factors affecting plant biomass accumulation in GLDA and CA treatments. In the future, GLDA can be combined with functional bacteria and/or growth promoters to promote the growth of Pb- and Cd-stressed plants and to further improve the soil restoration efficiency following pollution by heavy metals. Application of CA combined with the growing of black locust plants has great potential for restoring the Cd-polluted soil. These findings also provide insights into the practical use of GLDA and CA in phytoremediation by R. pseudoacacia and the tolerant mechanisms of R. pseudoacacia to Pb–Cd-contaminated soil.
Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes
Authors: Lai Weiyan , Luo Dan , Li Yin , Li Yuanqing , Wang Qianqian , Hu Zhaoyong , Ye Zengchun , Peng Hui 
Published: September 2023

AbstractMany studies have highlighted the importance of moderate exercise. While it can attenuate diabetic kidney disease, its mechanism has remained unclear. The level of myokine irisin in plasma increases during exercise. We found that irisin was decreased in diabetic patients and was closely related to renal function, proteinuria, and podocyte autophagy injury. Muscle‐specific overexpression of PGC‐1α (mPGC‐1α) in a mouse model is known to increase plasma irisin levels. The mPGC‐1α mice were crossed with db/m mice to obtain db/db mPGC‐1α+ mice in the present study. Compared to db/db mice without mPGC‐1α, plasma irisin was increased, and albuminuria and glomerular pathological damage were both alleviated in db/db mPGC‐1α+ mice. Impaired autophagy in podocytes was restored as well. Irisin inhibited the activation of the PI3K/AKT/mTOR signaling pathway in cultured human podocytes and improved damaged autophagy induced by high glucose levels. Then, db/db mice were treated with recombinant irisin, which had similar beneficial effects on the kidney as those in db/db mPGC‐1α+ mice, with alleviated glomerular injury and albuminuria. Moreover, the autophagy in podocytes was also significantly restored. These results suggest that irisin secreted by skeletal muscles protects the kidney from diabetes mellitus damage. It also restores autophagy in podocytes by inhibiting the abnormal activation of the PI3K/AKT/mTOR signaling pathway. Thus, irisin may become a new drug for the prevention and treatment of diabetic nephropathy.
Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers
Authors: Birnefeld Johan , Petersson Karl , Wåhlin Anders , Eklund Anders , Birnefeld Elin , Qvarlander Sara , Haney Michael , Malm Jan , Zarrinkoob Laleh 
Published: September 2023

Background
Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure.

Methods
Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta.

Results
Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg−1 · h−1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03).

Conclusions
In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

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What This Article Tells Us That Is New
Nail Plate Constructs are Associated with Decreased Rates of Reoperation in Complex Distal Femur Fractures
Authors: Roszman Alexander , Cone Ryan , Chodaba Yvonne , Cichos Kyle , McGwin Gerald , Spitler Clay 
Published: September 2023

Objectives:
To determine if nail plate constructs have lower rates of reoperation to promote bone healing than lateral locking plates in the treatment of distal femur fractures.

Design:
Retrospective Cohort

Setting:
Single Level 1 trauma center
Patients/Participants: 312 consecutive patients treated operatively for native distal femur fractures (OTA/AO 33A or 33C)

Intervention:
Reduction and fixation of distal femur fractures with either a lateral locked plate (LLP) or a nail plus plate construct (NPC)

Main Outcome Measures:
reoperation to promote bone healing at any time after definitive fixation

Results:
279 fractures were treated with LLP and were compared with and 33 fractures treated with NPC constructs. Patient demographics, injury severity score (ISS), and frequency utilization of each construct between different types of OTA/AO classified distal femur fractures were similar. The reoperation rate to promote bone healing was 18.7% (51/273) for LLPs, and 3% (1/33) for NPC constructs. There was no significant difference in surgical site infection (SSI) (p = 0.67).

Conclusions:
Utilization of NPC technique demonstrated a significant decrease in rates of reoperation to promote bone healing compared to LLP alone in the treatment of OTA/AO 33A and 33C distal femur fractures. Augmented fixation with NPCs should be considered to treat complex distal femur fractures as it is associated with lower rates of reoperation to promote bone healing in comparison to LLP.

Level of Evidence:
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Anticholinergic Burden and Xerostomia in Critical Care Settings
Authors: Chung Joohyun , Tjia Jennifer , Zhang Ning , O'Connor Brendan T. 
Published: September 2023

Background
Although previous studies have established the association of medications with anticholinergic adverse effects and xerostomia, anticholinergic burden and xerostomia in critical care settings are poorly characterized. The objective of this study was to determine the impact of medication burdens associated with anticholinergic adverse effects, particularly the occurrence of xerostomia (dry mouth) in a critical care setting. In addition, this study explored the correlation between the timing of the first instance of xerostomia and the administration timing of medication known to have anticholinergic adverse effects.

Methods
A retrospective case-control study was used with the MIMIC (Medical Information Mart for Intensive Care) III database. The MIMIC-III clinical database is a publicly available, deidentified, health-related database with more than 40 000 patients in critical care units from 2001 to 2012. Cases of xerostomia (n = 1344) were selected from clinical notes reporting “dry mouth,” “xerostomia,” or evidence of pharmacological treatment for xerostomia; control (n = 4032) was selected using the propensity analysis with 1:3 matching on covariates (eg, age, sex, race, ethnicity, and length of stay). The anticholinergic burden was quantified as the cumulative effect of anticholinergic activities using the Anticholinergic Burden Scale.

Results
Anticholinergic burden significantly differed between xerostomia patients and control subjects (P = .04). The length of stay was a statistically significant factor in xerostomia. The probability of developing the symptom of xerostomia within 24 hours was .95 (95%) for patients of xerostomia.

Conclusions
Anticholinergic Burden Scale is associated with xerostomia in the critical care setting, particularly within 24 hours after admission. It is crucial to carefully evaluate alternative options for medications that may have potential anticholinergic adverse effects. This evaluation should include assessing the balance between the benefits and harms, considering the probability of withdrawal reactions, and prioritizing deprescribing whenever feasible within the initial 24-hour period.
Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis
Authors: Pratt Henry E. , Wu Tong , Elhajjajy Shaimae , Zhou Jeffrey , Fitzgerald Kate , Fazzio Tom , Weng Zhiping , Pratt Daniel S. 
Published: September 2023

Background:
Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC.

Methods:
Available epigenomic datasets were integrated to build a comprehensive atlas of cell type–specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls.

Results:
Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls.

Conclusions:
Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.
Antihyperalgesic properties of gut microbiota: Parabacteroides distasonis as a new probiotic strategy to alleviate chronic abdominal pain
Authors: Gervason Sandie , Meleine Mathieu , Lolignier Stéphane , Meynier Maëva , Daugey Valentine , Birer Aurélien , Aissouni Youssef , Berthon Jean-Yves , Ardid Denis , Filaire Edith , Carvalho Frédéric Antonio 
Published: September 2023

AbstractThe potential role of gut microbiota in pain modulation is arousing an emerging interest since recent years. This study investigated neuromodulatory properties of gut microbiota to identify next-generation probiotics to propose alternative therapies for visceral pain management. Neuromodulation ability of 10 bacterial strains isolated from a healthy donor was assessed both on ND7/23 immortalized cell line and primary neuronal cells from rat dorsal root ganglia. This screening highlighted the neuroinhibitory property ofParabacteroides distasonis(F1-2) strain, supported both by its intracellular content and membrane fraction, which was further investigated in visceral pain mouse models. Oral administration of F1-2 resulted in a significant decrease of colonic hypersensitivity (CHS) in dextran sulfate sodium (0.5%) model associated with low-grade inflammation and a significant decrease of CHS inCitrobacter rodentiumpostinfectious models. No effect of F1-2 oral administration on CHS was observed in a neonatal maternal separation stress model. Antihyperalgesic effect unlikely involved modulation of inflammatory processes or restoration of intestinal barrier. Exploration of direct dialogue mechanisms between this strain and nervous system, assessed by calcium imaging experiments, revealed that F1-2 interacts directly with nociceptors by reducing activation level on capsaicin, inflammatory soup, and bradykinin stimulations. Our study provides new insights about bacteria–host interaction and placesP distasonisas a potential therapeutic strategy in the treatment of visceral pain observed in leaky gut–associated pathologies.