bluuebunny/crossref_metadata_2025_split huggingface dataset:
The implementation and public health impacts of cannabis legalization in Canada: a systematic review
Authors: Hall Wayne , Stjepanović Daniel , Dawson Danielle , Leung Janni 
Published: June 2023

AbstractAimsWe provide a narrative summary of research on changes in cannabis arrests, cannabis products and prices, cannabis use and cannabis‐related harm since legalization.MethodsWe systematically searched for research on the impacts of cannabis legalization in Canada in PubMed, Embase, Statistics Canada and government websites and Google Scholar, published between 2006 and 2021.ResultsCannabis legalization in Canada has been followed by substantial reductions in cannabis‐related arrests and cannabis prices. It has also increased adults’ access to a diverse range of cannabis products, including edibles and extracts. The prevalence of cannabis use among young adults has increased, but there have been no marked increases or decreases in use among high school students or changes in the prevalence of daily or near‐daily use. Legalization has been associated with increased adult hospital attendances for psychiatric distress and vomiting, unintentional ingestion of edible cannabis products by children and hospitalizations for cannabis use disorders in adults. There is conflicting evidence on whether cannabis‐impaired driving has increased since legalization. There is suggestive evidence that presentations to emergency departments with psychoses and cannabis use disorders may have increased since legalization.ConclusionsLegalization of cannabis in Canada appears to have reduced cannabis arrests and increased access to a variety of more potent cannabis products at lower prices. Since 2019, recent cannabis use in Canada has modestly increased among adults but not among adolescents. There is evidence of increased acute adverse effects of cannabis among adults and children.
Significant association of mutations close to LCORL gene with growth performance in Zhedong white geese (Anser cygnoides)
Authors: Yang Yunzhou , Wang Cui , Li Guangquan , Wang Xianze , Qiu Songyin , Liu Yi , Wang Huiying , He Daqian 
Published: June 2023

AbstractThis study aimed to investigate the role of the LCORL gene in regulating the growth performance of Zhedong white (ZDW) geese, belonging to the swan geese (Anser cygnoides), and identify possible selective signatures in diverse goose breeds. Single nucleotide polymorphisms around LCORL were genotyped, and their associations with body‐size‐related (BSR) traits were estimated. The results showed that the genotyped loci upstream of LCORL were significantly related to the body weight and breast width of ZDW geese aged 10 weeks (p < 0.05). A genome scan comparing expected heterozygosity among different breeds identified a ~150 kb long genomic region with extremely low heterozygosity downstream of LCORL among swan geese. Further, significant associations of variants within the low heterozygosity region among ZDW geese with BSR traits, including body weight, body length and breast width (p < 0.05) were also detected. Overall, mutations adjacent to LCORL were related to the growth performance of swan geese, and the significant effects of variants in a low‐heterozygosity region on BSR traits provided valuable insights into the molecular mechanism of artificial selection reshaping body stature in swan geese.
Opioid analgesic effects on subjective well‐being in the operating theatre*
Authors: Eikemo M. , Meier I. M. , Løseth G. E. , Trøstheim M. , Ørstavik N. , Jensen E. N. , Garland E. L. , Berna C. , Ernst G. , Leknes S. 
Published: June 2023

SummaryExposure to opioid analgesics due to surgery increases the risk of new persistent opioid use. A mechanistic hypothesis for opioids' abuse liability rests on the belief that, in addition to pain relief, acute opioid treatment improves well‐being (e.g. via euphoria) and relieves anxiety. However, opioids do not consistently improve mood in laboratory studies of healthy non‐opioid users. This observational study determined how two commonly used opioid analgesics affected patients' subjective well‐being in standard clinical practice. Day surgery patients rated how good and how anxious they felt before and after an open‐label infusion of remifentanil (n = 159) or oxycodone (n = 110) in the operating theatre before general anaesthesia. One minute after drug injection, patients reported feeling intoxicated (> 6/10 points). Anxiety was reduced after opioids, but this anxiolytic effect was modest (remifentanil Cohen's d = 0.21; oxycodone d = 0.31). There was moderate to strong evidence against a concurrent improvement in well‐being (Bayes factors > 6). After remifentanil, ratings of ‘feeling good’ were significantly reduced from pre‐drug ratings (d = 0.28). After oxycodone, one in three participants felt better than pre‐drug. Exploratory ordered logistic regressions revealed a link between previous opioid exposure and opioid effects on well‐being, as only 14 of the 80 opioid‐naïve patients reported feeling better after opioid injection. The odds of improved well‐being ratings after opioids were higher in patients with previous opioid exposure and highest in patients with > 2 weeks previous opioid use (adjusted OR = 4.4). These data suggest that opioid‐induced improvement of well‐being is infrequent in opioid‐naïve patients. We speculate that peri‐operative exposure could increase risk of persistent use by rendering subsequent positive opioid effects on well‐being more likely.
On Interquantile Smoothness of Censored Quantile Regression with Induced Smoothing
Authors: Cai Zexi , Sit Tony 
Published: June 2023

Abstract
Quantile regression has emerged as a useful and effective tool in modeling survival data, especially for cases where noises demonstrate heterogeneity. Despite recent advancements, non-smooth components involved in censored quantile regression estimators may often yield numerically unstable results, which, in turn, lead to potentially self-contradicting conclusions. We propose an estimating equation-based approach to obtain consistent estimators of the regression coefficients of interest via the induced smoothing technique to circumvent the difficulty. Our proposed estimator can be shown to be asymptotically equivalent to its original unsmoothed version, whose consistency and asymptotic normality can be readily established. Extensions to handle functional covariate data and recurrent event data are also discussed. To alleviate the heavy computational burden of bootstrap-based variance estimation, we also propose an efficient resampling procedure that reduces the computational time considerably. Our numerical studies demonstrate that our proposed estimator provides substantially smoother model parameter estimates across different quantile levels and can achieve better statistical efficiency compared to a plain estimator under various finite-sample settings. The proposed method is also illustrated via four survival datasets, including the HMO (health maintenance organizations) HIV (human immunodeficiency virus) data, the primary biliary cirrhosis (PBC) data, and so forth.
Therapeutic role of mesenchymal stem cell‐derived extracellular vesicles in neuroinflammation and cognitive dysfunctions induced by binge‐like ethanol treatment in adolescent mice
Authors: Mellado Susana , Cuesta Carlos M. , Montagud Sandra , Rodríguez‐Arias Marta , Moreno‐Manzano Victoria , Guerri Consuelo , Pascual María 
Published: June 2023

AbstractBackgroundExtracellular vesicles (EVs) are heterogeneous membrane vesicles secreted by cells in extracellular spaces that play an important role in intercellular communication under both normal and pathological conditions. Mesenchymal stem cells (MSC) are anti‐inflammatory and immunoregulatory cells capable of secreting EVs, which are considered promising molecules for treating immune, inflammatory, and degenerative diseases. Our previous studies demonstrate that, by activating innate immune receptors TLR4 (Toll‐like receptor 4), binge‐like ethanol exposure in adolescence causes neuroinflammation and neural damage.AimsTo evaluate whether the intravenous administration of MSC‐derived EVs is capable of reducing neuroinflammation, myelin and synaptic alterations, and the cognitive dysfunction induced by binge‐like ethanol treatment in adolescent mice.Materials & MethodsMSC–derived EVs obtained from adipose tissue were administered in the tail vein (50 microg/dose, one weekly dose) to female WT adolescent mice treated intermittently with ethanol (3.0 g/kg) during two weeks.ResultsMSC‐derived EVs from adipose tissue ameliorate ethanol‐induced up‐regulation of inflammatory genes (e.g., COX‐2, iNOS, MIP‐1α, NF‐κB, CX3CL1, and MCP‐1) in the prefrontal cortex of adolescent mice. Notably, MSC‐derived EVs also restore the myelin and synaptic derangements, and the memory and learning impairments, induced by ethanol treatment. Using cortical astroglial cells in culture, our results further confirm that MSC‐derived EVs decrease inflammatory genes in ethanol‐treated astroglial cells. This, in turn, confirms in vivo findings.ConclusionTaken together, these results provide the first evidence for the therapeutic potential of the MSC‐derived EVs in the neuroimmune response and cognitive dysfunction induced by binge alcohol drinking in adolescence.
Functional analysis of two SLC9A6 frameshift variants in lymphoblastoid cells from patients with Christianson syndrome
Authors: He Hailan , Zhang Huiwen , Chen Hui , He Fang , Yin Fei , Stauber Tobias , Zou Xiaomin , Peng Jing 
Published: June 2023

AbstractBackgroundChristianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by global developmental delay, epilepsy, hyperkinesis, ataxia, microcephaly, and behavioral disorder. However, the molecular mechanism by which these SLC9A6 mutations cause CS in humans is not entirely understood, and there is no objective method to determine the pathogenicity of single SLC9A6 variants.MethodsTrio‐based whole exome sequencing (WES) was carried out on two individuals with suspicion of CS. qRT‐PCR, western blot analysis, filipin staining, lysosomal enzymatic assays, and electron microscopy examination, using EBV‐LCLs established from the two patients, were performed.ResultsTrio‐based WES identified a hemizygous SLC9A6 c.1560dupT, p.T521Yfs*23 variant in proband 1 and a hemizygous SLC9A6 c.608delA, p.H203Lfs*10 variant in proband 2. Both children exhibited typical phenotypes associated with CS. Expression analysis in EBV‐LCLs derived from the two patients showed a significant decrease in mRNA levels and no detectable normal NHE6 protein. EBV‐LCLs showed a statistically significant increase in unesterified cholesterol in patient 1, but only non‐significant increase in patient 2 when stained with filipin. Activities of lysosomal enzymes (β‐hexosaminidase A, β‐hexosaminidase A + B, β‐galactosidase, galactocerebrosidase, arylsulfatase A) of EBV‐LCLs did not significantly differ between the two patients and six controls. Importantly, by electron microscopy we detected an accumulation of lamellated membrane structures, deformed mitochondria, and lipid droplets in the patients' EBV‐LCLs.ConclusionsThe SLC9A6 p.T521Yfs*23 and p.H203Lfs*10 variants in our patients result in loss of NHE6. Alterations of mitochondria and lipid metabolism may play a role in the pathogenesis of CS. Moreover, the combination of filipin staining with electron microscopy examination of patient lymphoblastoid cells can serve as a useful complementary diagnostic method for CS.
Baseline determinants of remission of type 2 diabetes in response to short‐term insulin‐based therapy: The pivotal role of beta‐cell function
Authors: Retnakaran Ravi , Pu Jiajie , Emery Alexandra , Kramer Caroline K. , Zinman Bernard 
Published: June 2023

AbstractAimTo identify baseline determinants of diabetes remission in response to short‐term insulin‐based therapy.MethodsIn this study, adult patients with type 2 diabetes (T2D) of less than 7 years duration were randomized to 8 weeks of treatment with (a) insulin glargine, (b) glargine + thrice‐daily lispro, or (c) glargine + twice‐daily exenatide, followed by 12 weeks of washout that enabled assessment of remission (defined as HbA1c < 6.5% after ≥ 3 months without glucose‐lowering therapy). At baseline, 8 weeks and washout, beta‐cell function was assessed with four measures: Insulin Secretion‐Sensitivity Index‐2 (ISSI‐2), insulinogenic index/Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR), ΔC‐peptide0‐120/Δglucose0‐120 × Matsuda and Δinsulin secretion rate (ISR)0‐120/Δgluc0‐120 × Matsuda.ResultsDiabetes remission was achieved in 31 of 90 participants (34.4%). Compared with their peers, those who went on to remission had lower HbA1c (P < .001) and better beta‐cell function at baseline (all four measures P ≤ .01). The non‐remission and remission groups did not otherwise differ in baseline insulin sensitivity/resistance (Matsuda, HOMA‐IR), body mass index, duration of diabetes, pretrial diabetes medications or allocated insulin‐based therapy during the trial. On logistic regression analyses, each baseline measure of beta‐cell function emerged as a significant predictor of remission (log ISSI‐2: adjusted OR 4.41 [95% CI: 1.71‐11.34]; log insulinogenic index/HOMA‐IR: 2.21 [1.26‐3.89]; log ΔC‐peptide0‐120/Δglucose0‐120 × Matsuda: 1.62 [1.00‐2.64]; log ΔISR0‐120/Δgluc0‐120 × Matsuda: 1.87 [1.09‐3.23]). Similarly, higher baseline ISSI‐2 tertile predicted longer time to glycaemic relapse after cessation of the insulin‐based therapy (log‐rank P = .029).ConclusionBeta‐cell function is the dominant baseline pathophysiological determinant of the likelihood of achieving remission of diabetes in response to short‐term insulin‐based therapy.
Brain transcriptome of gobies inhabiting natural CO2 seeps reveal acclimation strategies to long‐term acidification
Authors: Suresh Sneha , Mirasole Alice , Ravasi Timothy , Vizzini Salvatrice , Schunter Celia 
Published: June 2023

AbstractOcean acidification (OA) is known to affect the physiology, survival, behaviour and fitness of various fish species with repercussions at the population, community and ecosystem levels. Some fish species, however, seem to acclimate rapidly to OA conditions and even thrive in acidified environments. The molecular mechanisms that enable species to successfully inhabit high CO2 environments have not been fully elucidated especially in wild fish populations. Here, we used the natural CO2 seep in Vulcano Island, Italy to study the effects of elevated CO2 exposure on the brain transcriptome of the anemone goby, a species with high population density in the CO2 seep and investigate their potential for acclimation. Compared to fish from environments with ambient CO2, gobies living in the CO2 seep showed differences in the expression of transcripts involved in ion transport and pH homeostasis, cellular stress, immune response, circadian rhythm and metabolism. We also found evidence of potential adaptive mechanisms to restore the functioning of GABAergic pathways, whose activity can be affected by exposure to elevated CO2 levels. Our findings indicate that gobies living in the CO2 seep may be capable of mitigating CO2‐induced oxidative stress and maintaining physiological pH while meeting the consequent increased energetic costs. The conspicuous difference in the expression of core circadian rhythm transcripts could provide an adaptive advantage by increasing the flexibility of physiological processes in elevated CO2 conditions thereby facilitating acclimation. Our results show potential molecular processes of acclimation to elevated CO2 in gobies enabling them to thrive in the acidified waters of Vulcano Island.
Dilemma between yield and quality: Multigenerational effect of elevated CO2 and nitrogen supply on wheat cultivars
Authors: Wang Xizi , Yang Xin , Li Shenglan , Li Xiangnan , Liang Kehao , Liu Fulai 
Published: June 2023

AbstractStudying the long‐term effect of elevated atmospheric CO2 concentration (e[CO2]) on wheat (Triticum aestivum L.) over multiple generations has received increasing attention. Here, five wheat cultivars were grown under ambient CO2 concentration (a[CO2], 400 ppm) and e[CO2] (800 ppm), respectively, for three consecutive generations (G1 to G3) under two nitrogen (N) levels (1N and 2N). Compared to plants grown under a[CO2], e[CO2] increased shoot biomass and grain yield (GY) over three generations and the enhancement was greater in G3 than in G1. However, plant N concentration was lowered by e[CO2] and the reduction was not mitigated by higher N supply. The carbon (C) concentration significantly increased in leaf and stem but decreased in grain, indicating an inhibited C translocation to grain under e[CO2]. Most importantly, these negative impacts were exacerbated in G3. Concentrations of mineral nutrients in grain were significantly lowered by e[CO2] with larger reduction in G3 than in G1 in some micronutrients such as Zn, Cu and Fe. These findings suggest that long‐term exposure to e[CO2] sustained the positive effects on plant growth and production but aggravated the reduction of grain quality over multiple generations. Among the five cultivars, 325Jimai showed the greatest increase in shoot biomass and GY, and a greater sink capacity compared with the other cultivars, indicating its potential for future breeding strategies.
Pharmacokinetic disposition of marbofloxacin after intramuscular administration in estuarine crocodiles (Crocodylus porosus)
Authors: Yalong Mona , Poapolathep Saranya , Giorgi Mario , Khidkhan Kraisiri , Klangkaew Narumol , Phaochoosak Napasorn , Chaiyabutr Narongsak , Wongwaipairoj Tara , Poapolathep Amnart 
Published: June 2023

AbstractTo date, the pharmacokinetics of fluoroquinolones in estuarine crocodiles (Crocodylus porosus) have been reported for enrofloxacin but not for marbofloxacin (MBF), which is a broad‐spectrum antibiotic used only in veterinary medicine. This study investigated the pharmacokinetics of MBF after intramuscular administration at two difference dosages (2 and 4 mg/kg body weight) in estuarine crocodiles and estimated pharmacokinetic/pharmacodynamic (PK/PD) surrogate parameters for the optimization of dosage regimens. Ten treated estuarine crocodiles were divided into two groups (n = 5) using a randomization procedure according to a parallel study design. Blood samples were collected at assigned times up to 168 h. MBF plasma samples were cleaned up using liquid–liquid extraction and analyzed using a validated high‐performance liquid chromatography method with fluorescence detection. A non‐compartment approach was used to fit the plasma concentration of MBF vs time curve for each crocodile. The plasma concentrations of MBF were quantifiable for up to 168 h in both groups. The elimination half‐life values of MBF were long (33.99 and 39.28 h for 2 and 4 mg/kg, respectively) with no significant differences between the groups. The average plasma protein binding of MBF was 30.85%. According to the surrogated PK/PD parameter (AUC0–24‐to‐MIC ratio >100–125), the 2 and 4 mg/kg dosing rates should be effective for bacteria with MIC values lower than 0.125 μg/mL and 0.35 μg/mL, respectively.
Protective effects of statins on the incidence of NAFLD–related decompensated cirrhosis in T2DM
Authors: Wu Szu‐Yuan , Chen Wan‐Ming , Chiang Ming‐Feng , Lo Hung‐Chieh , Wu Ming‐Shun , Lee Ming‐Che , Soong Ruey‐Shyang 
Published: June 2023

AbstractBackground and AimsNon‐alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and poses a significant threat to patients with type 2 diabetes mellitus (T2DM) and metabolic dysregulation. Statins exert anti‐inflammatory, antioxidative and antithrombotic effects that target mechanisms underlying NAFLD. However, the protective effects of the different doses, intensities and types of statins on the incidence of NAFLD‐related decompensated liver cirrhosis (DLC) in patients with T2DM remain unclear.MethodsThis study used the data of patients with T2DM who were non‐HBV and non‐HCV carriers from a national population database to examine the protective effects of statin use on DLC incidence through propensity score matching. The incidence rate (IR) and incidence rate ratios (IRRs) of DLC in patients with T2DM with or without statin use were calculated.ResultsA higher cumulative dose and specific types of statins, namely rosuvastatin, pravastatin, atorvastatin, simvastatin and fluvastatin, reduced the risk of DLC in patients with T2DM. Statin use was associated with a significant reduction in the risk of DLC (HR: .65, 95% CI: .61–.70). The optimal daily intensity of statin use with the lowest risk of DLC was .88 defined daily dose (DDD).ConclusionsThe results revealed the protective effects of specific types of statins on DLC risk in patients with T2DM and indicated a dose–response relationship. Additional studies are warranted to understand the specific mechanisms of action of different types of statins and their effect on DLC risk in patients with T2DM.
Cumulative absolute velocity prediction for earthquake early warning with deep learning
Authors: Wang Yanwei , Zhao Qingxu , Qian Kai , Wang Zifa , Cao Zhenzhong , Wang Jianming 
Published: June 2023

AbstractA rapid and accurate estimate of earthquake damage is a key component in a successful earthquake early warning (EEW) system. The cumulative absolute velocity (CAV) is an important and widely used parameter to measure ground motion intensity, but it cannot be correctly estimated via the traditional approach with the limited information available in typical EEW systems. Therefore, current EEW systems cannot effectively use CAV to predict earthquake damage. Herein, a CAV prediction model (DLcav) based on convolutional neural networks was proposed for EEW systems. DLcav is an end‐to‐end solution to continuously predict CAV using arriving seismic waves of increasing length and supplemented with additional auxiliary information. The effectiveness of DLcav to predict CAV was tested based on Japanese ground motion records, and the generalization ability of DLcav was assessed using the ground motion records from Chile. The results demonstrate that DLcav can rapidly predict CAV with good accuracy, which will help better estimate earthquake damage in EEW systems.
Tomato geranylgeranyl diphosphate synthase isoform 1 is involved in the stress‐triggered production of diterpenes in leaves and strigolactones in roots
Authors: Ezquerro Miguel , Li Changsheng , Pérez‐Pérez Julia , Burbano‐Erazo Esteban , Barja M. Victoria , Wang Yanting , Dong Lemeng , Lisón Purificación , López‐Gresa M. Pilar , Bouwmeester Harro J. , Rodríguez‐Concepción Manuel 
Published: June 2023

Summary
Carotenoids are photoprotectant pigments and precursors of hormones such as strigolactones (SL). Carotenoids are produced in plastids from geranylgeranyl diphosphate (GGPP), which is diverted to the carotenoid pathway by phytoene synthase (PSY). In tomato (Solanum lycopersicum), three genes encode plastid‐targeted GGPP synthases (SlG1 to SlG3) and three genes encode PSY isoforms (PSY1 to PSY3).
Here, we investigated the function of SlG1 by generating loss‐of‐function lines and combining their metabolic and physiological phenotyping with gene co‐expression and co‐immunoprecipitation analyses.
Leaves and fruits of slg1 lines showed a wild‐type phenotype in terms of carotenoid accumulation, photosynthesis, and development under normal growth conditions. In response to bacterial infection, however, slg1 leaves produced lower levels of defensive GGPP‐derived diterpenoids. In roots, SlG1 was co‐expressed with PSY3 and other genes involved in SL production, and slg1 lines grown under phosphate starvation exuded less SLs. However, slg1 plants did not display the branched shoot phenotype observed in other SL‐defective mutants. At the protein level, SlG1 physically interacted with the root‐specific PSY3 isoform but not with PSY1 and PSY2.
Our results confirm specific roles for SlG1 in producing GGPP for defensive diterpenoids in leaves and carotenoid‐derived SLs (in combination with PSY3) in roots.