bluuebunny/crossref_metadata_2025_split huggingface dataset:
Audit of enuresis referrals on the waiting list for a tertiary hospital outpatient clinic
Authors: Eiselen Carl , Trajanovska Misel , Griffith Andrew , Phan Tracey , Goldfeld Sharon , Gibb Susan , King Sebastian K 
Published: May 2021

AimEnuresis, defined as intermittent incontinence occurring exclusively during sleep, affects 4–19% of children, but can be effectively treated using education and alarm‐bell therapies. However, delays in treatment are likely to impact upon the quality of life of the child, parents and carers. Poor quality and incomplete referrals are thought to be a major driver of inefficiencies. The aim of this study was to explore characteristics of enuresis referrals on the waiting list for a general medicine clinic at a tertiary paediatric hospital.MethodsAn audit was conducted to examine all enuresis referrals on the general medicine outpatient clinic waiting list in February 2019 at The Royal Children's Hospital, Melbourne. Enuresis referrals with an organic cause and those for children less than 5 years of age were excluded.ResultsOf the 2613 referrals on the general medicine waiting list, 486 of 2613 (19%) were related to enuresis. The median age of patients on the waiting list was 8 years and 65% (315/486) were male. Sufficient detail was provided to determine temporal and disease stratification in 45% (218/486) of referrals; primary versus secondary enuresis, and monosymptomatic versus non‐monosymptomatic enuresis. The mean number of days on the waiting list calculated at the time of data extraction (13 February 2019) was 226 (±179) days.ConclusionsThe findings from this study suggest that there are long waiting times for enuresis services and referrals often do not contain complete information.
The status of Florida pompano, Trachinotus carolinus, as a commercially ready species for U.S. marine aquaculture
Authors: Weirich Charles R. , Riley Kenneth L. , Riche Marty , Main Kevan L. , Wills Paul S. , Illán Gonzalo , Cerino David S. , Pfeiffer Timothy J. 
Published: May 2021

AbstractOwing to their high value, in the 1950s researchers and commercial ventures began investigating the potential of Florida pompano, Trachinotus carolinus, for aquaculture; however, initial efforts did not result in commercialization. In the early 2000s, a renewed interest in pompano as a candidate for aquaculture occurred, and over the last two decades, protocols have been developed that have allowed commercialization of pompano aquaculture. Florida pompano broodstock can be readily conditioned to spawn (26–28°C) to produce large numbers of fertilized eggs year‐round via hormonally induced volitional tank spawning. Larval rearing is straight forward using a standard feeding regime of rotifers, then Artemia, followed by co‐feeding and weaning to microparticulate diets with metamorphosis occurring at approximately 18–25 days post hatch. Pompano readily consume formulated diets and growout of juveniles to produce marketable fish for consumption is fairly rapid (<12 months) and has been achieved mainly via recirculating aquaculture system technologies and ocean net pens. To expand industry development, there is an ongoing need for research directed towards topics including broodstock domestication, selective breeding, and genetic improvement; delayed maturation; diet development and refinement; disease management; economics and business planning; and marketing strategies.
LAZY2 controls rice tiller angle through regulating starch biosynthesis in gravity‐sensing cells
Authors: Huang Linzhou , Wang Wenguang , Zhang Ning , Cai Yueyue , Liang Yan , Meng Xiangbing , Yuan Yundong , Li Jiayang , Wu Dianxing , Wang Yonghong 
Published: May 2021

Summary

Rice (Oryza sativa) tiller angle is a key component for achieving ideal plant architecture and higher grain yield. However, the molecular mechanism underlying rice tiller angle remains elusive.

We characterized a novel rice tiller angle mutant lazy2 (la2) and isolated the causative gene LA2 through map‐based cloning. Biochemical, molecular and genetic studies were conducted to elucidate the LA2‐involved tiller angle regulatory mechanism.

The la2 mutant shows large tiller angle with impaired shoot gravitropism and defective asymmetric distribution of auxin. We found that starch granules in amyloplasts are completely lost in the gravity‐sensing leaf sheath base cells of la2, whereas the seed development is not affected. LA2 encodes a novel chloroplastic protein that can interact with the starch biosynthetic enzyme Oryza sativa plastidic phosphoglucomutase (OspPGM) to regulate starch biosynthesis in rice shoot gravity‐sensing cells. Genetic analysis showed that LA2 regulates shoot gravitropism and tiller angle by acting upstream of LA1 to mediate lateral auxin transport.

Our studies revealed that LA2 acts as a novel regulator of rice tiller angle by specifically regulating starch biosynthesis in gravity‐sensing cells, and established the framework of the starch‐statolith‐dependent rice tiller angle regulatory pathway, providing new insights into the rice tiller angle regulatory network.
Direct and indirect effects of a massive piped water expansion on child‐related outcomes
Authors: Chong Alberto , Galdo Virgilio 
Published: May 2021

AbstractWe explore the effects of a massive water supply and sanitation expansion on child mortality, schooling, and child labor in Ecuador. We combine census data with project administrative information to identify treated dwellings. A matching differences‐in‐differences estimator is used to identify treatment effects. We find a child mortality reduction of about 8.1%, an increase in children formal schooling of 1.3%, and a reduction in child labor of 13.7%, all attributable to the intervention. We also find heterogeneous treatment effects suggesting that those in the poorest quartiles benefit the least from the intervention. However, even in the latter case, if a woman had at least primary education, the household may still enjoy benefits.
Assessment of Intravertebral Mechanical Strains and Cancellous Bone Texture Under Load Using a Clinically Available Digital Tomosynthesis Modality
Authors: Oravec Daniel , Drost Joshua , Zauel Roger , Flynn Michael J. , Yeni Yener N. 
Published: May 2021

AbstractVertebral fractures are the most common osteoporotic fractures, but clinical means for assessment of vertebral bone integrity are limited in accuracy, as they typically use surrogate measures that are indirectly related to mechanics. The objective of this study was to examine the extent to which intravertebral strain distributions and changes in cancellous bone texture generated by a load of physiological magnitude can be characterized using a clinically available imaging modality. We hypothesized that digital tomosynthesis-based digital volume correlation (DTS-DVC) and image texture-based metrics of cancellous bone microstructure can detect development of mechanical strains under load. Isolated cadaveric T11 vertebrae and L2–L4 vertebral segments were DTS imaged in a nonloaded state and under physiological load levels. Axial strain, maximum principal strain, maximum compressive and tensile principal strains, and von Mises equivalent strain were calculated using the DVC technique. The change in textural parameters (line fraction deviation, anisotropy, and fractal parameters) under load was calculated within the cancellous centrum. The effect of load on measured strains and texture variables was tested using mixed model analysis of variance, and relationships of strain and texture variables with donor age, bone density parameters, and bone size were examined using regression models. Magnitudes and heterogeneity of intravertebral strain measures correlated with applied loading and were significantly different from background noise. Image texture parameters were found to change with applied loading, but these changes were not observed in the second experiment testing L2–L4 segments. DTS-DVC-derived strains correlated with age more strongly than did bone mineral density (BMD) for T11.
An In Vitro Study to Investigate Biomechanical Responses of Peripheral Nerves in Hypoxic Neonatal Piglets
Authors: Singh Anita , Magee Rachel , Balasubramanian Sriram 
Published: May 2021

Abstract
Despite occurrence of neonatal hypoxia and peripheral nerve injuries in complicated birthing scenarios, the effect of hypoxia on the biomechanical responses of neonatal peripheral nerves is not studied. In this study, neonatal brachial plexus (BP) and tibial nerves, obtained from eight normal and eight hypoxic 3–5-day-old piglets, were tested in uniaxial tension until failure at a rate of 0.01 mm/s or 10 mm/s. Failure load, stress, and modulus of elasticity were reported to be significantly lower in hypoxic neonatal BP and tibial nerves than respective normal tissue at both 0.01 and 10 mm/s rates. Failure strain was significantly lower in the hypoxic neonatal BP nerves only at 10 mm/s rate when compared to normal BP nerve. This is the first available data that indicate weaker mechanical behavior of hypoxic neonatal peripheral nerves as compared to normal tissue and offer an understanding of the biomechanical responses of peripheral nerves of hypoxic neonatal piglets.
The Effects of an Acute “Train-Low” Nutritional Protocol on Markers of Recovery Optimization in Endurance-Trained Male Athletes
Authors: Russo Isabella , Della Gatta Paul A. , Garnham Andrew , Porter Judi , Burke Louise M. , Costa Ricardo J.S. 
Published: May 2021

Purpose:This study aimed to determine the effects of an acute “train-low” nutritional protocol on markers of recovery optimization compared to standard recovery nutrition protocol.Methods:After completing a 2-hour high-intensity interval running protocol, 8 male endurance athletes consumed a standard dairy milk recovery beverage (CHO; 1.2 g/kg body mass [BM] of carbohydrate and 0.4 g/kg BM of protein) and a low-carbohydrate (L-CHO; isovolumetric with 0.35 g/kg BM of carbohydrate and 0.5 g/kg BM of protein) dairy milk beverage in a double-blind randomized crossover design. Venous blood and breath samples, nude BM, body water, and gastrointestinal symptom measurements were collected preexercise and during recovery. Muscle biopsy was performed at 0 hour and 2 hours of recovery. Participants returned to the laboratory the following morning to measure energy substrate oxidation and perform a 1-hour distance test.Results:The exercise protocol resulted in depletion of muscle glycogen stores (250 mmol/kg dry weight) and mild body-water losses (BM loss = 1.8%). Neither recovery beverage replenished muscle glycogen stores (279 mmol/kg dry weight) or prevented a decrease in bacterially stimulated neutrophil function (−21%). Both recovery beverages increased phosphorylation of mTORSer2448(main effect of time = P < .001) and returned hydration status to baseline. A greater fold increase in p-GSK-3βSer9/total-GSK-3β occurred on CHO (P = .012). Blood glucose (P = .005) and insulin (P = .012) responses were significantly greater on CHO (618 mmol/L per 2 h and 3507 μIU/mL per 2 h, respectively) compared to L-CHO (559 mmol/L per 2 h and 1147 μIU/mL per 2 h, respectively). Rates of total fat oxidation were greater on CHO, but performance was not affected.Conclusion:A lower-carbohydrate recovery beverage consumed after exercise in a “train-low” nutritional protocol does not negatively impact recovery optimization outcomes.
Neurodevelopmental outcome following hypoxic ischaemic encephalopathy and therapeutic hypothermia is related to right ventricular performance at 24-hour postnatal age
Authors: Giesinger Regan E , El Shahed Amr I , Castaldo Michael P , Bischoff Adrianne R , Chau Vann , Whyte Hilary E A , El-Khuffash Afif Faisal , Mertens Luc , McNamara Patrick J 
Published: May 2021

ObjectiveOur aim was to determine whether right ventricular (RV) dysfunction at 24-hour postnatal age predicts adverse developmental outcome among patients with hypoxic ischaemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH).DesignNeonates≥35 weeks with HIE/TH were enrolled in a physiological study in the neonatal period (n=46) and either died or underwent neurodevelopmental follow-up at 18 months (n=43). The primary outcome was a composite of death, diagnosis of cerebral palsy or any component of the Bayley Scores of Infant Development III<70. We hypothesised that tricuspid annulus plane systolic excursion (TAPSE) <6 mm and/or RV fractional area change (RV-FAC) <0.29 would predict adverse outcome.ResultsNine patients died and 34 patients were followed up at a mean age of 18.9±1.4 months. Both indices of RV systolic performance were abnormal in 15 (35%) patients, TAPSE <6 mm only was abnormal in 4 (9%) patients and RV-FAC <0.29 only was abnormal in 5 (12%) patients (19 had with normal RV function). Although similar at admission, neonates with RV dysfunction had higher cardiovascular and neurological illness severity by 24 hours than those without and severe MRI abnormalities (70% vs 53%, p=0.01) were more common. On logistic regression, TAPSE <6 mm (OR 3.6, 95% CI 1.2 to 10.1; p=0.017) and abnormal brain MRI [OR 21.7, 95% CI 1.4 to 336; p=0.028) were independently associated with adverse outcome. TAPSE <6 mm predicted outcome with a 91% sensitivity and 81% specificity.ConclusionsThe role of postnatal cardiovascular function on neurological outcomes among patients with HIE who receive TH merits further study. Quantitative measurement of RV function at 24 hours may provide an additional neurological prognostic tool.
Where to go to in chlamydia control? From infection control towards infectious disease control
Authors: van Bergen Jan E A M , Hoenderboom Bernice Maria , David Silke , Deug Febe , Heijne Janneke C M , van Aar Fleur , Hoebe Christian J P A , Bos Hanna , Dukers-Muijrers Nicole H T M , Götz Hannelore M , Low Nicola , Morré Servaas Antonie , Herrmann Bjőrn , van der Sande Marianne A B , de Vries Henry J C , Ward Helen , van Benthem Birgit H B 
Published: May 2021

ObjectivesThe clinical and public health relevance of widespread case finding by testing for asymptomatic chlamydia infections is under debate. We wanted to explore future directions for chlamydia control and generate insights that might guide for evidence-based strategies. In particular, we wanted to know the extent to which we should pursue testing for asymptomatic infections at both genital and extragenital sites.MethodsWe synthesised findings from published literature and from discussions among national and international chlamydia experts during an invitational workshop. We described changing perceptions in chlamydia control to inform the development of recommendations for future avenues for chlamydia control in the Netherlands.ResultsDespite implementing a range of interventions to control chlamydia, there is no practice-based evidence that population prevalence can be reduced by screening programmes or widespread opportunistic testing. There is limited evidence about the beneficial effect of testing on pelvic inflammatory disease prevention. The risk of tubal factor infertility resulting from chlamydia infection is low and evidence on the preventable fraction remains uncertain. Overdiagnosis and overtreatment with antibiotics for self-limiting and non-viable infections have contributed to antimicrobial resistance in other pathogens and may affect oral, anal and genital microbiota. These changing insights could affect the outcome of previous cost–effectiveness analysis.ConclusionThe balance between benefits and harms of widespread testing to detect asymptomatic chlamydia infections is changing. The opinion of our expert group deviates from the existing paradigm of ‘test and treat’ and suggests that future strategies should reduce, rather than expand, the role of widespread testing for asymptomatic chlamydia infections.
NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis
Authors: Zhao Zhenjun , Gad Helge , Benitez-Buelga Carlos , Sanjiv Kumar , Xiangwei Hua , Kang He , Feng Mingxuan , Zhao Zhicong , Berglund Ulrika Warpman , Xia Qiang , Helleday Thomas 
Published: May 2021

AbstractPatients with hepatocellular carcinoma (HCC) suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for nontransformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and polymerase beta (POLB)-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC.Significance:This study describes compartmentalization of base excision repair during mitosis that is dependent on NEIL3, APE1, and POLB to repair oxidative damage accumulating at telomeres in hepatocellular carcinoma.
Evaluation of the Small-molecule BRD4 Degrader CFT-2718 in Small-cell Lung Cancer and Pancreatic Cancer Models
Authors: Sun Danlin , Nikonova Anna S. , Zhang Peishan , Deneka Alexander Y. , Fitzgerald Mark E. , Michael Ryan E. , Lee Linda , Lilly Anna C. , Fisher Stewart L. , Phillips Andrew J. , Nasveschuk Christopher G. , Proia David A. , Tu Zhigang , Golemis Erica A. 
Published: May 2021

Abstract
Targeted, catalytic degradation of oncoproteins using heterobifunctional small molecules is an attractive modality, particularly for hematologic malignancies, which are often initiated by aberrant transcription factors and are challenging to drug with inhibitors. BRD4, a member of the bromodomain and extraterminal family, is a core transcriptional and epigenetic regulator that recruits the P-TEFb complex, which includes Cdk9 and cyclin T, to RNA polymerase II (pol II). Together, BRD4 and CDK9 phosphorylate serine 2 (pSer2) of heptad repeats in the C-terminal domain of RPB1, the large subunit of pol II, promote transcriptional elongation. Small-molecule degraders of BRD4 have shown encouraging efficacy in preclinical models for several tumor types but less efficacy in other cancers including small-cell lung cancer (SCLC) and pancreatic cancer. Here, we evaluated CFT-2718, a new BRD4-targeting degrader with enhanced catalytic activity and in vivo properties. In vivo, CFT-2718 has significantly greater efficacy than the CDK9 inhibitor dinaciclib in reducing growth of the LX-36 SCLC patient-derived xenograft (PDX) model and performed comparably to dinaciclib in limiting growth of the PNX-001 pancreatic PDX model. In vitro, CFT-2718 reduced cell viability in four SCLC and two pancreatic cancer models. In SCLC models, this activity significantly exceeded that of dinaciclib; furthermore, CFT-2718 selectively increased the expression of cleaved PARP, an indicator of apoptosis. CFT-2718 caused rapid BRD4 degradation and reduced levels of total and pSer2 RPB1 protein. These and other findings suggest that BRD-mediated transcriptional suppression merits further exploration in the setting of SCLC.
Silylation of Deoxynucleotide Analog Yields an Orally Available Drug with Antileukemia Effects
Authors: Ureshino Hiroshi , Kurahashi Yuki , Watanabe Tatsuro , Yamashita Satoshi , Kamachi Kazuharu , Yamamoto Yuta , Fukuda-Kurahashi Yuki , Yoshida-Sakai Nao , Hattori Naoko , Hayashi Yoshihiro , Kawaguchi Atsushi , Tohyama Kaoru , Okada Seiji , Harada Hironori , Ushijima Toshikazu , Kimura Shinya 
Published: May 2021

Abstract
DNA methyltransferase inhibitors have improved the prognosis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, because these agents are easily degraded by cytidine deaminase (CDA), they must be administered intravenously or subcutaneously. Recently, two orally bioavailable DNA methyltransferase inhibitors, CC-486 and ASTX727, were approved. In previous work, we developed 5-O-trialkylsilylated decitabines that resist degradation by CDA. However, the effects of silylation of a deoxynucleotide analog and enzymatic cleavage of silylation have not been fully elucidated. Enteric administration of OR21 in a cynomolgus monkey model led to high plasma concentrations and hypomethylation, and in a mouse model, oral administration of enteric-coated OR21 led to high plasma concentrations. The drug became biologically active after release of decitabine (DAC) from OR21 following removal of the 5′-O-trisilylate substituent. Toxicities were tolerable and lower than those of DAC. Transcriptome and methylome analysis of MDS and AML cell lines revealed that OR21 increased expression of genes associated with tumor suppression, cell differentiation, and immune system processes by altering regional promoter methylation, indicating that these pathways play pivotal roles in the action of hypomethylating agents. OR21 induced cell differentiation via upregulation of the late cell differentiation drivers CEBPE and GATA-1. Thus, silylation of a deoxynucleotide analog can confer oral bioavailability without new toxicities. Both in vivo and in vitro, OR21 exerted antileukemia effects, and had a better safety profile than DAC. Together, our findings indicate that OR21 is a promising candidate drug for phase I study as an alternative to azacitidine or decitabine.
Cytidine Deaminase APOBEC3A Regulates PD-L1 Expression in Cancer Cells in a JNK/c-JUN-Dependent Manner
Authors: Zhao Kailiang , Zhang Qiang , Flanagan Sheryl A. , Lang Xueting , Jiang Long , Parsels Leslie A. , Parsels Joshua D. , Zou Weiping , Lawrence Theodore S. , Buisson Rémi , Green Michael D. , Morgan Meredith A. 
Published: May 2021

Abstract

Programmed death-ligand 1 (PD-L1) promotes tumor immune evasion by engaging the PD-1 receptor and inhibiting T-cell activity. While the regulation of PD-L1 expression is not fully understood, its expression is associated with tumor mutational burden and response to immune checkpoint therapy. Here, we report that Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) is an important regulator of PD-L1 expression. Using an APOBEC3A inducible expression system as well as siRNA against endogenous APOBEC3A, we found that APOBEC3A regulates PD-L1 mRNA and protein levels as well as PD-L1 cell surface expression in cancer. Mechanistically, APOBEC3A-induced PD-L1 expression was dependent on APOBEC3A catalytic activity as catalytically dead APOBEC3A mutant (E72A) failed to induce PD-L1 expression. Furthermore, APOBEC3A-induced PD-L1 expression was dependent on replication-associated DNA damage and JNK/c-JUN signaling but not interferon signaling. In addition, we confirmed the relevance of these finding in patient tumors as APOBEC3A expression and mutational signature correlated with PD-L1 expression in multiple patient cancer types. These data provide a novel link between APOBEC3A, its DNA mutagenic activity and PD-L1-mediated antitumoral immunity. This work nominates APOBEC3A as a mechanism of immune evasion and a potential biomarker for the therapeutic efficacy of immune checkpoint blockade.

Implications:
APOBEC3A catalytic activity induces replication-associated DNA damage to promote PD-L1 expression implying that APOBEC3A-driven mutagenesis represents both a mechanism of tumor immune evasion and a therapeutically targetable vulnerability in cancer cells.