bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polycystic ovary rat model exposure to 150 kHz intermediate frequency: hypothalamic-pituitary-ovarian axis at the receptor, cellular, tissue, and hormone levels
Authors: Mohammed Stephanie , Sundaram Venkatesan , Adidam Venkata Chalapathi R. , Zyuzikov Nikolay 
Published: December 2021

Abstract
Introduction
The hypothalamic-pituitary-ovarian (HPO) axis is the principal regulator of the reproductive system. The neurons in the arcuate nucleus of the hypothalamus signal the basophilic cells of the anterior pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), which bind to the granulosa and theca cells of a follicle in the ovary to promote healthy follicular development. Disruption of this process at any time can lead to polycystic ovaries and, if left untreated, can lead to Polycystic Ovarian Syndrome (PCOS), one of the leading causes of infertility. A novel treatment option using 150 kHz Intermediate Frequency (IF) Electromagnetic Radiation (EMR) has been proposed to monitor the effect of this frequency during cystic development.

Methods
To prove this, an experiment was conducted to study the effect of whole-body exposure to 150 kHz EMR for 8 weeks at receptor, cellular, tissue and hormonal levels on the HPO axis of 25 young cyclic female rats.

Results
The results showed that 150 kHz EMR did not affect the histoarchitecture of neurons of arcuate nucleus of the hypothalamus of PCO-induced rats. It was also found that the number of basophilic cells of the pituitary gland was increased and the immunoreactivity of LH and FSH secretion increased. This EMR field also decreased the development of follicular cysts in the ovary and possibly increased the immunoreactivity of the LH and FSH receptors as well on the theca and granulosa cells of follicles in the ovary.

Conclusion
There are still many limitations to this study. If properly evaluated, the results of this experiment could help develop a new non-invasive treatment option for women with PCOS in the near future.
Early-life exposures and age at thelarche in the Sister Study cohort
Authors: Goldberg Mandy , D’Aloisio Aimee A. , O’Brien Katie M. , Zhao Shanshan , Sandler Dale P. 
Published: December 2021

Abstract
Background
Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974.

Methods
Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11–13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood.

Results
Early thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09–1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04–1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13–1.27), young maternal age (OR 1.30, 95% CI 1.16–1.47 for < 20 vs. 25–29 years), and being firstborn (OR = 1.25, 95% CI 1.17–1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche.

Conclusions
Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.
The ELSA trial: single versus combinatory effects of non-prohibited beta-2 agonists on skeletal muscle metabolism, cardio-pulmonary function and endurance performance—study protocol for a randomized 4-way balanced cross-over trial
Authors: Zügel Martina , Bizjak Daniel A. , Nussbaumer Dorle , Winkert Kay , Takabayashi Kensuke , Kirsten Johannes , Washington Mickel , Treff Gunnar , Dreyhaupt Jens , Steeb Luise , Diel Patrick , Parr Maria Kristina , Steinacker Jürgen M. , Persch Hasema 
Published: December 2021

Abstract
Background
Asthma and/or airway hyper-responsiveness (AHR) are common in elite endurance athletes with a high prevalence rate of beta-2 adrenoreceptor (beta-2) agonists use. Nevertheless, there are data on dose-dependent ergogenic effects of beta-2 agonists suggesting increased muscle strength, endurance and neuromuscular performance. Therefore, most beta-2 agonists belong to the World Anti Doping Agency (WADA) list of prohibited substances and it is tempting to speculate that illegitimate use of beta-2 agonists might be a common practice to boost performance in competitive sports. It is currently unknown whether or not inhaled beta-2 agonists enhance performance by stimulatory effects in skeletal and cardiac muscle.

Methods
The ELSA trial is a double-blinded, placebo-controlled, randomized, balanced, four-way cross-over study. Study participants (n=24, 12 ♀, 12 ♂) complete four study arms (i.e. periods with treatment A, placebo; B, salbutamol; C, formoterol; D, formoterol + salbutamol) in random order after an initial preliminary testing session. Participants inhale the study medication 20 min before the 10-min time trial (TT; exercise performance test), where participants cycle 10 min at the highest possible workload. Cardiac output is measured continuously. A skeletal muscle biopsy is collected 3 h after the TT. Study endpoints include measures of skeletal muscle expression of nuclear receptors, hormones and cytokine levels, urinary and plasma concentrations of salbutamol and formoterol, circulating cardiac markers, cardiopulmonary function and exercise performance (average power and peak power during the TT). Blood and urine are collected and respiratory testing is performed 24 h post TT.

Summary/conclusions
This clinical trial evaluates the potential performance-enhancing effects of non-prohibited, not medically indicated inhaled short- and long-acting beta-2 agonists on skeletal muscle gene expression, endocrine regulation, cardiac biomarkers, cardiopulmonary function and acute endurance exercise performance. These data will be used by WADA to adapt the annually published list of prohibited substances (WADA 2021) and will be published in scientific journals.

Trial registration
The trial is registered at the European Clinical Trials Database (Eudra CT) with the number: 2015-005598-19 as well as at the German register for clinical studies (DRKS number 00010574).
TIMELAPSE study—efficacy of low-dose amitriptyline versus cognitive behavioral therapy for chronic insomnia in patients with medical comorbidity: study protocol of a randomized controlled multicenter non-inferiority trial
Authors: Rauwerda Nynke L. , Knoop Hans , Pot Irene , van Straten Annemieke , Rikkert Marian E. , Zondervan Anouk , Timmerhuis Thom P. J. , Braamse Annemarie M. J. , Boss H. Myrthe 
Published: December 2021

Abstract
Background
Insomnia is common in people with long-term medical conditions and is related to increased mortality and morbidity. Cognitive behavioral therapy for insomnia (CBT-I) is first choice treatment and effective for people with insomnia and comorbid long-term medical conditions. However, CBT-I has some limitations as it might not always be available or appeal to patients with medical conditions. Furthermore, a small proportion of patients do not respond to CBT-I. Preliminary evidence and clinical experience suggest that low-dose amitriptyline (AM) might be an effective alternative to treat insomnia in patients with medical comorbidity. In this randomized controlled trial, we will determine whether AM is non-inferior to the first choice treatment for insomnia, CBT-I.

Methods/design
This study will test if treatment with low-dose amitriptyline for insomnia in patients with medical comorbidity is non-inferior to CBT-I in a multicenter randomized controlled non-inferiority trial. Participants will be 190 adults with a long-term medical condition and insomnia. Participants will be randomly allocated to one of two intervention arms: 12 weeks AM (starting with 10 mg per day, and if ineffective at 3 weeks, doubling this dose) or 12 weeks of CBT-I consisting of 6 weekly sessions and a follow-up session 6 weeks later. The primary outcome is subjective insomnia severity, measured with the Insomnia Severity Index (ISI). The primary endpoint is at 12 weeks. Secondary outcomes include sleep quality (e.g., sleep efficiency), questionnaires on daytime functioning (physical functioning and impairment of functioning), and symptoms (e.g., fatigue, pain, anxiety) at 12 weeks and 12 months post treatment and relapse of insomnia until 12 months after treatment.

Discussion
Irrespective of the outcome, this study will be a much-needed contribution to evidence based clinical guidelines on the treatment of insomnia in patients with medical comorbidity.

Trial registration
Dutch Trial Register NTR NL7971. Registered on 18 August 2019
Evaluation of the Intensive Treatment and Rehabilitation Program for Residential Treatment and Rehabilitation Centers (INTREPRET) in the Philippines: a study protocol for a randomized controlled trial
Authors: Harada Takayuki , Baba Toshiaki , Shirasaka Tomohiro , Kanamori Shogo 
Published: December 2021

Abstract
Background
The Philippines has been severely affected by the methamphetamine crisis. The government has launched a policy war against drug use, although the severe sanctions imposed on drug users have been criticized internationally. To help implement a more effective and humane approach to drug use, this study aimed to introduce a comprehensive treatment program for methamphetamine users based on cognitive-behavioral therapy (CBT) whose effectiveness will be evaluated through a randomized controlled trial.

Methods
Methamphetamine users admitted into government-run rehabilitation facilities are recruited and randomly assigned to either a CBT-based treatment program or existing therapeutic community (TC)-based treatment. The CBT treatment program was developed based on the Matrix Model that considers cultural and social factors in the Philippines. After 6 months of treatment, there will be a three-month follow-up, when the participants’ drug use (tested through urine testing) and other psychological variables, including craving, coping skills, and well-being, will be compared. Potential participants are given a summary of the study and a consent form. The consent form is signed and dated by participants prior to their study participation. Ethical approval was obtained prior to the commencement of the study.

Discussion
This is the first randomized controlled trial to compare the residential CBT program and the TC model for methamphetamine users in the Philippines. The study aims to fill the current knowledge and capacity gaps by introducing a CBT-based treatment program to improve the psychosocial well-being of drug users in the Philippines. Moreover, if the effectiveness of the treatment program is demonstrated, anti-drug campaigns and severe sanctions against drug users may be reconsidered.

Trial registration
UMIN Clinical Trials Registry JPRN-UMIN000038597. Registered on 15 November 2019. Protocol version October 17, 2021 ver.2
Genetic diversity of Anopheles stephensi in Ethiopia provides insight into patterns of spread
Authors: Carter Tamar E. , Yared Solomon , Getachew Dejene , Spear Joseph , Choi Sae Hee , Samake Jeanne N. , Mumba Peter , Dengela Dereje , Yohannes Gedeon , Chibsa Sheleme , Murphy Matthew , Dissanayake Gunawardena , Flately Cecilia , Lopez Karen , Janies Daniel , Zohdy Sarah , Irish Seth R. , Balkew Meshesha 
Published: December 2021

Abstract
Background
The recent detection of the South Asian malaria vector Anopheles stephensi in the Horn of Africa (HOA) raises concerns about the impact of this mosquito on malaria transmission in the region. Analysis of An. stephensi genetic diversity and population structure can provide insight into the history of the mosquito in the HOA to improve predictions of future spread. We investigated the genetic diversity of An. stephensi in eastern Ethiopia, where detection suggests a range expansion into this region, in order to understand the history of this invasive population.

Methods
We sequenced the cytochrome oxidase subunit I (COI) and cytochrome B gene (CytB) in 187 An. stephensi collected from 10 sites in Ethiopia in 2018. Population genetic, phylogenetic, and minimum spanning network analyses were conducted for Ethiopian sequences. Molecular identification of blood meal sources was also performed using universal vertebrate CytB sequencing.

Results
Six An. stephensi COI-CytB haplotypes were observed, with the highest number of haplotypes in the northeastern sites (Semera, Bati, and Gewana towns) relative to the southeastern sites (Kebridehar, Godey, and Degehabur) in eastern Ethiopia. We observed population differentiation, with the highest differentiation between the northeastern sites compared to central sites (Erer Gota, Dire Dawa, and Awash Sebat Kilo) and the southeastern sites. Phylogenetic and network analysis revealed that the HOA An. stephensi are more genetically similar to An. stephensi from southern Asia than from the Arabian Peninsula. Finally, molecular blood meal analysis revealed evidence of feeding on cows, goats, dogs, and humans, as well as evidence of multiple (mixed) blood meals.

Conclusion
We show that An. stephensi is genetically diverse in Ethiopia and with evidence of geographical structure. Variation in the level of diversity supports the hypothesis for a more recent introduction of An. stephensi into southeastern Ethiopia relative to the northeastern region. We also find evidence that supports the hypothesis that HOA An. stephensi populations originate from South Asia rather than the Arabian Peninsula. The evidence of both zoophagic and anthropophagic feeding support the need for additional investigation into the potential for livestock movement to play a role in vector spread in this region.

Graphical Abstract
Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue
Authors: Chakraborti Soumyananda , Chhibber-Goel Jyoti , Sharma Amit 
Published: December 2021

Abstract
Background
Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure–function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored.

Methods
We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database (https://vectorbase.org/vectorbase/app) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases—were generated using the I-TASSER and Phyre protein modeling servers.

Results
Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%.

Conclusions
Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.
Semi-field evaluation of novel chemical lures for Aedes aegypti, Culex quinquefasciatus, and Anopheles minimus (Diptera: Culicidae) in Thailand
Authors: Kim Dae-Yun , Leepasert Theerachart , Bangs Michael J. , Chareonviriyaphap Theeraphap 
Published: December 2021

Abstract
Background
Entomological surveillance is an important means of assessing the efficacy of insect vector management programs and estimating disease transmission thresholds. Among baited traps, Biogents’ BG-Sentinel (BGS) trap baited with BG-Lure is considered to have the most similar outcome to, and be a possible replacement for, human-landing catches for the epidemiologically relevant monitoring of adult Aedes aegypti and Culex quinquefasciatus. In contrast to the BGS trap, the Black Hole ultraviolet (UV) light trap, which is widely used to catch nocturnal flying insects, is not baited with synthetic human odor-mimicking lures.

Methods
We evaluated the l-lactic acid-based Kasetsart University (KU)-lures nos. 1–6 as novel candidate chemical lures for the diurnal species Ae. aegypti and the nocturnal species Cx. quinquefasciatus using two commercial traps (the BGS trap and the Black Hole UV light trap) in a semi-field screen (SFS) house. Firstly, we optimized the dose of each KU-lure in an SFS house (140 m3). Secondly, six different candidate KU-lures were screened by comparing their percent attraction using a single discriminating dose (0.5 g). Finally, we evaluated the synergism of the KU-lures selected in this way with commercially available traps.

Results
BGS traps baited with KU-lure no. 1 exhibited the greatest percent attraction for Ae. aegypti (29.5% ± 14.3%), whereas those baited with KU-lure no. 6 most strongly attracted Cx. quinquefasciatus (33.3% ± 10.7%). Interestingly, BGS traps treated with 10 g BG-Lure did not significantly attract more Ae. aegypti or Cx. quinquefasciatus than the untreated BGS traps. CO2 at a flow rate of 250 ml/min most strongly attracted both Ae. aegypti and Cx. quinquefasciatus (42.2% ± 14.2% and 75.1% ± 16.9%, respectively). BGS and Black Hole UV light traps with KU-lure no. 6 exhibited a stronger attraction for Cx. quinquefasciatus than untreated traps, and the percent attraction did not differ between the treated traps.

Conclusions
Synergistic effects of KU-lures nos. 1 and 6 with the mosquito traps were demonstrated for both the diurnal and nocturnal species in the SFS house assays. However, further studies are urgently needed for the development of species-specific lures to increase trap efficacy in the field for local vector mosquitoes in Thailand.

Graphical Abstract
Imaging pheochromocytoma in small animals: preclinical models to improve diagnosis and treatment
Authors: Mohr Hermine , Foscarini Alessia , Steiger Katja , Ballke Simone , Rischpler Christoph , Schilling Franz , Pellegata Natalia S. 
Published: December 2021

AbstractPheochromocytomas (PCCs) and paragangliomas (PGLs), together referred to as PPGLs, are rare chromaffin cell-derived tumors. They require timely diagnosis as this is the only way to achieve a cure through surgery and because of the potentially serious cardiovascular complications and sometimes life-threatening comorbidities that can occur if left untreated. The biochemical diagnosis of PPGLs has improved over the last decades, and the knowledge of the underlying genetics has dramatically increased. In addition to conventional anatomical imaging by CT and MRI for PPGL detection, new functional imaging modalities have emerged as very useful for patient surveillance and stratification for therapy. The availability of validated and predictive animal models of cancer is essential for translating molecular, imaging and therapy response findings from the bench to the bedside. This is especially true for rare tumors, such as PPGLs, for which access to large cohorts of patients is limited. There are few animal models of PPGLs that have been instrumental in refining imaging modalities for early tumor detection, as well as in identifying and evaluating novel imaging tracers holding promise for the detection and/or treatment of human PPGLs. The in vivo PPGL models mainly include xenografts/allografts generated by engrafting rat or mouse cell lines, as no representative human cell line is available. In addition, there is a model of endogenous PCCs (i.e., MENX rats) that was characterized in our laboratory. In this review, we will summarize the contribution that various representative models of PPGL have given to the visualization of these tumors in vivo and we present an example of a tracer first evaluated in MENX rats, and then translated to the detection of these tumors in human patients. In addition, we will illustrate briefly the potential of ex vivo biological imaging of intact adrenal glands in MENX rats.
Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation
Authors: Zajíčková Markéta , Prchal Lukáš , Navrátilová Martina , Vodvárková Nikola , Matoušková Petra , Vokřál Ivan , Nguyen Linh Thuy , Skálová Lenka 
Published: December 2021

AbstractHaemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.