bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of metabolic tumor volume and total lesion glycolysis assessed by 18F-FDG PET/CT in endometrial cancer
Authors: Erdogan Mehmet , Erdemoglu Evrim , Evrimler Şehnaz , Hanedan Candost , Şengül Sevim S.
Published: September 2019

Objective

Surgical staging is the most confidential method for prognosis prediction. However, in which stage the surgery is needed and the treatment management of these patients is controversial. Presentation of new determinant factors with imaging methods for prediction of poor prognosis can provide better disease management. The aim of our study was to demonstrate the ability of metabolic tumor volume and total lesion glycolysis as a prognostic factor to predict the disease-free survival time, necessity of adjuvant radiotherapy–chemotherapy, and the association of these parameters with the clinicopathological features.

Methods

Forty-four endometrial cancer diagnosed patients whose PET/CT scans were performed for treatment planning were included in our study. Metabolic parameters (SUVmax, metabolic tumor volume, total lesion glycolysis) of the primary tumor were calculated. Abdominal hysterectomy was performed for all patients. Histopathologic findings were noted. Patients were followed for 31.4 ± 14.8 months.

Results

Metabolic tumor volume and total lesion glycolysis were significant prognostic factors for disease-free survival, whereas SUVmax did not effect disease-free survival. According to regression analysis, only metabolic tumor volume was found significant for radiotherapy planning (cutoff metabolic tumor volume; 26.30 ml). There was significant association between metabolic tumor volume, total lesion glycolysis and early-stage, myometrial invasion, and lymph node positivity. We observed only weak association between SUVmax and myometrial invasion. ROC curve calculated metabolic tumor volume and total lesion glycolysis cutoff values as 19.6 ml and 90 g for early-stage, 14.3 ml and 173.4 g for myometrial invasion, and 29.7 ml and 283.1 g for lymph node positivity, respectively.

Conclusion

Metabolic tumor volume and total lesion glycolysis may be used as prognostic factors for endometrial cancer. The association between SUVmax and clinical findings, disease-free survival, histopathological features are weak. Further studies are needed for demonstrating the prognostic value of metabolic volumetric parameters.
The effectiveness of a novel cable-driven gait trainer (Robowalk) combined with conventional physiotherapy compared to conventional physiotherapy alone following stroke: a randomised controlled trial
Authors: Stolz Robert , Nayyar Rohini , Louie Julie , Bower Kelly J. , Paul Sanjoy K. , Ng Louisa
Published: September 2019

There is increasing interest in gait training devices to improve walking ability in people following stroke. This randomised controlled trial aimed to compare the effectiveness of the Robowalk, a novel cable-driven gait trainer combined with conventional physiotherapy to conventional physiotherapy alone in improving walking speed, endurance, balance, functional outcomes, and quality of life in people following stroke. Rehabilitation inpatients within 3 months following stroke (n = 40) were randomised to standard care with conventional physiotherapy (‘control,’ n = 20) and cable-driven gait trainer combined with conventional physiotherapy (‘intervention,’ n = 20). All participants received 1 hour of physiotherapy a day, 5 days a week. The control group received conventional physiotherapy only; the intervention group received a combination of 30 minutes of conventional physiotherapy and 30 minutes of cable-driven gait trainer consecutively. Outcome measures were 10-metre walk test (primary outcome), 6-minute walk test, timed up and go, step test, Functional Independence Measure, and EuroQol five-dimension scale. Evaluation timepoints were on admission (T0), discharge (T1), and 4 weeks post discharge (T2). There were no differences between groups at T0, T1, and T2 in all outcome measures although there was a trend towards a larger and more sustained improvement in 10-metre walk test in favour of the intervention group and in Functional Independence Measure motor and self-care in favour of the control group, both at T2. The combination of cable-driven gait trainer with conventional physiotherapy appears as effective as conventional physiotherapy alone in improving gait outcomes in people following a recent stroke. Further studies are required to confirm these findings and determine optimal dosing regimens and long-term outcomes.
Endometrial Gastric (Gastrointestinal)-type Mucinous Lesions
Authors: Wong Richard Wing-Cheuk , Ralte Angela , Grondin Katherine , Talia Karen L. , McCluggage W. Glenn
Published: September 2019

With the recent elucidation of gastric-type lesions in the female genital tract (especially in the cervix), occasional cases of endometrial adenocarcinoma displaying gastric (gastrointestinal) differentiation have been reported, but they are currently not recognized as a distinct pathologic entity. We report 9 cases of endometrial mucinous lesions which exhibit gastric (gastrointestinal)-type features by morphology and immunohistochemistry, including 4 adenocarcinomas and 5 benign mucinous lesions, in patients aged 32 to 85. The adenocarcinomas showed gastric-type morphology in all 4 cases and goblet cells in 1, with a component of benign gastric-type mucinous glands in 1 case. Immunohistochemically, the adenocarcinomas were positive for CK7 (4/4), CEA (4/4), MUC6 (3/3), PAX8 (3/4), CK20 (2/4), CDX2 (2/4), and estrogen receptor (1/4). They were negative for Napsin A (0/3), with mutation-type p53 staining in 2/4 cases, block-type p16 positivity in 1/4, and scattered chromogranin-positive cells in 1/2. Targeted next-generation sequencing revealed nonsense mutation in RB1 gene for the case with block-positive p16. Follow-up was available in all adenocarcinoma cases and indicated aggressive behavior; 2 patients were dead of disease at follow-up of 7 months to 3 years, 1 was alive with progression at 9 months, and 1 was alive without disease at 7 months. The benign mucinous lesions (including the benign component in 1 adenocarcinoma) exhibited gastric-type morphologic features in 5/6 cases, goblet cells in 5/6, and Paneth-like neuroendocrine cells in 1/6. These benign mucinous lesions were associated with an endometrial polyp in 5/6 cases. Cytologic atypia was present in 2/6 cases and a lobular architecture resembling cervical lobular endocervical glandular hyperplasia in 4/6. Immunohistochemically, the benign mucinous lesions were positive for CK7 (5/5), CDX2 (5/6), estrogen receptor (4/5), MUC6 (4/5), CK20 (3/5), PAX8 (3/5), and CEA (2/4), with scattered chromogranin-positive cells in 4/4 cases; in all cases tested Napsin A was negative, p53 was wild-type and p16 was negative. We propose the term “endometrial gastric (gastrointestinal)-type adenocarcinoma” for this distinctive group of rare aggressive endometrial carcinomas. We believe that benign or atypical gastric (gastrointestinal)-type mucinous lesions are putative precursors for these adenocarcinomas, comparable to recognized premalignant gastric-type lesions in the cervix and the vagina. Future recognition and reporting of these gastric-type endometrial mucinous lesions will help delineate their pathogenesis and clinical significance.
Integrative Therapies for Cancer-Related Fatigue
Authors: Arring Noël M. , Barton Debra L. , Brooks Trevor , Zick Suzanna M.
Published: September 2019

Cancer-related fatigue (CRF) is a common symptom for which cancer patients often use integrative and integrative therapies; however, evidence supporting these therapies is limited. The aim of this review is to provide evidence-based recommendations for integrative interventions during and after cancer treatment for CRF. These recommendations are based on a systematic literature review from 1990 through 2019. Cognitive behavior therapy plus hypnosis and American ginseng can be considered during active treatment, and acupressure, mindfulness-based cognitive therapy, and qigong/tai chi easy can be considered during posttreatment. Coenzyme Q10 and l-carnitine are not recommended during active-treatment. All other integrative therapies for CRF had insufficient evidence to make a recommendation. While there is increasing evidence for integrative therapies for CRF, because of lack of rigorous trials and replication, no therapies could be definitively recommended. Further rigorously designed integrative therapy research is needed and should consider implementation and dissemination.
Putting Exercise Into Oncology Practice
Authors: Brown Justin C. , Ligibel Jennifer A.
Published: September 2019

Physical activity provides numerous health benefits for cancer survivors. This review provides a summary of the evidence supporting the efficacy of physical activity to improve patient-reported and physiological outcomes during and after cancer therapy, discusses observational studies that have reported associations of physical activity with cancer outcomes and prognosis, summarizes ongoing phase III randomized trials of physical activity with clinical disease endpoints in cancer survivors, describes randomized trials of physical activity that have examined biomarkers hypothesized to relate to cancer outcomes and prognosis, reviews current guidelines for physical activity promotion among cancer survivors, and provides recommendations for novel strategies to disseminate and implement this evidence into clinical oncology practice to optimize patient outcomes.
Practical Application of “About Herbs” Website
Authors: Hou Yen-Nien , Deng Gary , Mao Jun J.
Published: September 2019

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains About Herbs (www.aboutherbs.com), which provides summaries of research data including purported uses, adverse effects, and herb-drug interactions for about 284 dietary supplements. Using Google Analytics, we found the website registered more than 26,317,000 hits since November 2002. The 10 most searched-for herbs/supplements of 2018 are chaga mushroom, turmeric, ashwagandha, reishi mushroom, graviola, Active Hexose-Correlated Compound, boswellia, dandelion, green tea, and Coriolus versicolor. Here we discuss their safety, herb-drug interactions, and appropriate uses in the oncology setting, based on literature searches in PubMed. Over the past 16 years, the evidence for use of these supplements is based mostly on preclinical findings, with few well-designed studies and limited trials conducted in cancer patients. It is important to familiarize health care professionals about popular supplements, so patients can be informed to make decisions that maximize benefits and minimize risks.
A Consistent, Reliable Landmark to Assist in Placement of Orbital Floor Reconstruction Plates After Blowout Fractures
Authors: Amin Julian D. , Rizzi Christopher J. , Trent Graham , Greywoode Jewel , Grumbine Lawson , Raghavan Prashant , Vakharia Kalpesh T.
Published: September 2019

Objective:

To define a reliable and consistent landmark, the superior posterior wall of the maxillary sinus, and to describe how this landmark can be used when repairing orbital floor fractures.

Methods:

Retrospective chart review. Patients >18 years old diagnosed with unilateral orbital floor and/or zygomaticomaxillary complex fractures.

Main outcomes:

The distance from the inferior orbital rim to the superior posterior wall of the maxillary sinus (landmark distance), and the distance from the landmark to the entrance of the optic canal were reported.

Results:

Eighty patients were included in the study. Each had unilateral isolated orbital floor fractures (n = 46) or unilateral zygomaticomaxillary complex fractures with an orbital floor component (n = 34). The contralateral eye in all patients was uninjured, and was used as an internal control. In orbital floor fractures, the mean landmark distance was 38.8 ± 1.4 mm, with a mean distance on the normal side of 38.8 ± 1.6 mm (P = 0.49). Distance to the optic canal on the injured side in isolated orbital floor fracture patients was 9.0 ± 0.8 mm with the same measurement on the normal side being 8.8 ± 0.7 (P = 0.21). In the setting of zygomaticomaxillary complex fracture, the orbital floor length was 38.2 ± 1.3 mm with a mean normal floor length of 37.8 ± 1.1 mm (P = 0.18). The mean distance from the superior posterior wall to optic canal in zygomaticomaxillary complex fractured orbits was 9.2 ± 1.1 mm with a normal side mean length of 9.5 ± 1.0 mm (P = 0.23). No significant difference was found between the measured distances in the fractured orbit and its normal counterpart for both fracture groups.

Conclusions and Relevance:

The superior posterior wall of the maxillary sinus is a reliable landmark that can be used to assist in placement of an orbital floor reconstructive plate. The landmark is unchanged despite the presence of an orbital floor or zygomaticomaxillary sinus fracture.
Bronchial-arterial-circulation-sparing Lung Preservation: A New Organ Protection Approach for Lung Transplantation
Authors: Tane Shinya , Noda Kentaro , Toyoda Yoshiya , Shigemura Norihisa
Published: September 2019

Background.

Compromised microvasculature resulting from disrupted bronchial arterial circulation appears to trigger chronic lung allograft dysfunction. Maintaining the microvasculature throughout the transplant process could improve the long-term health of transplanted lungs. We recently developed a bronchial-arterial-circulation-sparing (BACS) lung preservation approach and tested whether this approach would decrease microvascular damage and improve allograft function.

Methods.

The lungs of Lewis rats were procured using either the BACS approach, where the bronchial and pulmonary arteries were synchronously perfused; a conventional approach, where only the pulmonary artery was perfused; or a conventional approach with a prostaglandin flush. After 4 hours of cold ischemia, physiologic function and vascular tone of the grafts were evaluated during ex vivo lung perfusion (EVLP), and microvasculature damage was assessed using 2-photon microscopy analysis. Lung function was compared after transplant among the groups.

Results.

After 4 hours of cold ischemia, the BACS group exhibited significantly higher adenosine triphosphate levels and lower expression of phosphorylated myosin light chain, which is essential for vascular smooth muscle contraction. On EVLP, the BACS and prostaglandin groups showed lower pulmonary vascular resistance and less arterial stiffness. BACS attenuated microvasculature damage in the lung grafts when compared with conventional preservation. After transplantation, the lungs preserved with the BACS approach exhibited significantly better graft function and lower expression of phosphorylated myosin light chain.

Conclusions.

Our data suggest that BACS lung preservation protects the dual circulation inherent to the lungs, facilitating robust microvasculature in lung grafts after transplantation, leading to better posttransplant outcomes.
Oral and Inhaled Ribavirin Treatment for Respiratory Syncytial Virus Infection in Lung Transplant Recipients
Authors: Permpalung Nitipong , Thaniyavarn Tany , Saullo Jennifer L. , Arif Sana , Miller Rachel A. , Reynolds John M. , Alexander Barbara D.
Published: September 2019

Background.

Respiratory syncytial virus (RSV) infection in lung transplant recipients (LTRs) causes mortality rates of 10%–20% despite antiviral therapy. Ribavirin (RBV) has been used to treat RSV-infected LTRs with limited data.

Methods.

A retrospective study including all LTRs at Duke Hospital during January 2013–May 2017 with positive RSV polymerase chain reaction respiratory specimens was performed.

Results.

Fifty-six of 70 patients in the oral RBV group and 29 of 32 in the inhaled RBV group had symptomatic RSV infection. One patient receiving oral RBV had to prematurely stop drug due to significant nausea and vomiting. While unadjusted all-cause 1-year mortality was significantly higher in the inhaled RBV group (24.1% versus 7.1% [oral RBV], P = 0.03), adjusted hazard ratio (HR) for death and oral RBV use (compared to inhaled RBV), accounting for oxygen requirement and need for mechanical ventilation, showed the HR for death and oral RBV use was 0.38 ([0.10, 1.46], P = 0.38). The HR for death in patients with supplemental oxygen >2 L/min at diagnosis was 6.18 ([1.33, 26.83], P = 0.02). Kaplan-Meier curves showed patients with forced expiratory volume in 1 second decline ≥5% and ≥10% at 90 days post-RSV infection had a higher 1-year mortality (P = 0.004 and P = 0.001, respectively).

Conclusions.

Oral and inhaled RBV appear to be well tolerated in LTRs, and our data support the use of oral RBV as a safe alternative to inhaled ribavirin in LTRs. Oxygen requirement >2 L/min at diagnosis and forced expiratory volume in 1 second decline ≥5% postinfection may be markers for increased mortality.
Retention of Alzheimer Disease Research Participants
Authors: Grill Joshua D. , Kwon Jimmy , Teylan Merilee A. , Pierce Aimee , Vidoni Eric D. , Burns Jeffrey M. , Lindauer Allison , Quinn Joseph , Kaye Jeff , Gillen Daniel L. , Nan Bin
Published: September 2019

Introduction:

Participant retention is important to maintaining statistical power, minimizing bias, and preventing scientific error in Alzheimer disease and related dementias research.

Methods:

We surveyed representative investigators from NIH-funded Alzheimer’s Disease Research Centers (ADRC), querying their use of retention tactics across 12 strategies. We compared survey results to data from the National Alzheimer’s Coordinating Center for each center. We used a generalized estimating equation with independent working covariance model and empirical standard errors to assess relationships between survey results and rates of retention, controlling for participant characteristics.

Results:

Twenty-five (83%) responding ADRCs employed an average 42 (SD=7) retention tactics. In a multivariable model that accounted for participant characteristics, the number of retention tactics used by a center was associated with participant retention (odds ratio=1.68, 95% confidence interval: 1.42, 1.98; P<0.001 for the middle compared with the lowest tertile survey scores; odds ratio=1.59, 95% confidence interval: 1.30, 1.94; P<0.001 for the highest compared with the lowest tertile survey scores) at the first follow-up visit. Participant characteristics such as normal cognition diagnosis, older age, higher education, and Caucasian race were also associated with higher retention.

Conclusions:

Retention in clinical research is more likely to be achieved by employing a variety of tactics.
Treatment of Catatonia in Frontotemporal Dementia: A Lesson From Zolpidem Test
Authors: Sayadnasiri Mohammad , Rezvani Farzaneh
Published: September 2019

Background

During recent years, zolpidem presents a potential but transient treatment option for a large variety of neurologic conditions. Although most cases had disorders of consciousness or movement disorders, there are few reports of beneficial effects of zolpidem on language function.

Case

We present a case of frontotemporal dementia who developed catatonia during her disease course and her refractory speech problem showed dramatic response to zolpidem.

Conclusions

In dementia patients, different catatonic symptoms may show differential responses to the therapeutic agents and, if verbal symptoms are dominant, it is worthy to try zolpidem in the early stage.
Electromyographic Features in a Chinese Cohort With Hereditary Skeletal Muscle Channelopathies
Authors: Sun Jian , Luo Sushan , Song Jie , Huang Jun , Cai Shuang , Zhu Wenhua , Zhou Lei , Xi Jianying , Lin Jie , Lu Jiahong , Xu Minjie , Dou Tonghai , Zhao Chongbo , Qiao Kai
Published: September 2019

Purpose:

Hereditary skeletal muscle channelopathies are characterized by muscle stiffness and/or periodic muscle weakness because of different gene mutations. The objective of this study was to investigate the clinical and electromyographic phenotypes in Chinese patients with different skeletal ion channel mutations.

Methods:

The electromyographic results of 61 Chinese patients with skeletal muscle channelopathies were retrospectively reviewed and the differential features were characterized.

Results:

Myotonic discharges were in patients with chloride voltage-gated channel 1 and sodium voltage-gated channel alpha subunit 4 mutations. Subclinical myotonia was identified in four patients with hypokalemic periodic paralysis because of sodium voltage-gated channel alpha subunit 4 mutations. Patients with potassium voltage-gated channel subfamily J member 2 mutations had an early decline after exercise (5.7 ± 4.9 minutes) and patients with calcium voltage-gated channel subunit alpha 1S mutations have a relatively lower baseline amplitude (4.6 ± 2 mV). Specific patterns were characterized in patients with Becker disease and paramyotonia congenital after short exercise.

Conclusions:

Myotonic discharges help to discriminate chloride and sodium from other channelopathies. Early decline and low baseline compound motor action potential amplitude in long exercise test are significant in patients with potassium voltage-gated channel subfamily J member 2 and calcium voltage-gated channel subunit alpha 1S mutations, respectively. Electromyographic patterns in the electromyography study and exercise test may help in better providing the comprehensive picture for patients with primary skeletal muscle channelopathies.
Sexual dysfunction in tramadol hydrochloride use disorder male patients: a case-control study
Authors: Hashim Mostafa Ahmad , el Rasheed Amany Haroun , Ismail Ghada Abdel Wahed , Awaad Mona Ibrahim , El Habiby Mahmoud Mamduh , Mohsen Ibrahim Nesreen Mohamed , Abdeen Mai Seifeldin
Published: September 2019

Evidence suggests that opioids can modulate gonadal function, with consequent decreased release of sex hormones. We attempted to investigate the sexual function of males using tramadol hydrochloride (HCL) and its relationship to levels of free testosterone, luteinizing hormone, and follicle stimulating hormone, and to compare them with heroin use disorder patients and healthy controls. Our sample consisted of 60 opiate use disorder patients (assessed by Structured Clinical Interview for DSM-IV Axis I) (30 heroin and 30 tramadol) and 30 healthy controls. Sexual dysfunction was assessed using the International Index of Erectile Function. Free testosterone, follicle stimulating hormone, and luteinizing hormone levels were measured in morning blood samples using enzyme-linked immunosorbent assay (ELISA). Results showed that there was a decrease of luteinizing hormone and free testosterone levels in opiate use disorder patients compared with healthy controls, with heroin-dependent patients having significantly lower levels than those using tramadol. Opiates’ effect on follicle stimulating hormone had mixed results. Opioid-dependent patients (both tramadol HCL and heroin using patients) developed sexual dysfunction more than healthy controls, which was generalized, with erectile dysfunction being the most affected domain. These findings are of ultimate importance, considering the fact that people use opioids to enhance their sexual performance in many countries.
GeneRax: A tool for species tree-aware maximum likelihood based gene family tree inference under gene duplication, transfer, and loss
Authors: Morel Benoit , Kozlov Alexey M. , Stamatakis Alexandros , Szöllősi Gergely J.
Published: September 2019

Inferring phylogenetic trees for individual homologous gene families is difficult because alignments are often too short, and thus contain insufficient signal, while substitution models inevitably fail to capture the complexity of the evolutionary processes. To overcome these challenges species tree-aware methods also leverage information from a putative species tree. However, only few methods are available that implement a full likelihood framework or account for horizontal gene transfers. Furthermore, these methods often require expensive data pre-processing (e.g., computing bootstrap trees), and rely on approximations and heuristics that limit the degree of tree space exploration. Here we present GeneRax, the first maximum likelihood species tree-aware phylogenetic inference software. It simultaneously accounts for substitutions at the sequence level as well as gene level events, such as duplication, transfer, and loss relying on established maximum likelihood optimization algorithms. GeneRax can infer rooted phylogenetic trees for multiple gene families, directly from the per-gene sequence alignments and a rooted, yet undated, species tree. We show that compared to competing tools, on simulated data GeneRax infers trees that are the closest to the true tree in 90% of the simulations in terms of relative Robinson-Foulds distance. On empirical datasets, GeneRax is the fastest among all tested methods when starting from aligned sequences, and it infers trees with the highest likelihood score, based on our model. GeneRax completed tree inferences and reconciliations for 1099 Cyanobacteria families in eight minutes on 512 CPU cores. Thus, its parallelization scheme enables large-scale analyses. GeneRax is available under GNU GPL at https://github.com/BenoitMorel/GeneRax.
Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease
Authors: Nomura Akihiro , Emdin Connor A. , Won Hong Hee , Peloso Gina M. , Natarajan Pradeep , Ardissino Diego , Danesh John , Schunkert Heribert , Correa Adolfo , Bown Matthew J. , Samani Nilesh J. , Erdmann Jeanette , McPherson Ruth , Watkins Hugh , Saleheen Danish , Elosua Roberto , Kawashiri Masa-aki , Tada Hayato , Gupta Namrata , Shah Svati H. , Rader Daniel J. , Gabriel Stacey , Khera Amit V. , Kathiresan Sekar
Published: September 2019

Background

Familial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency – homozygous loss-of-function (LoF) variants — in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes, and have substantially elevated plasma sitosterol and low-density lipoprotein cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8, as occurs in heterozygous carriers of LoF variants, on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

Methods

We first recruited nine sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29,361) versus controls (n=357,326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency less than 0.1% inABCG5orABCG8.

Results

In sitosterolemia families, seven pedigrees harbored causative LoF variants inABCG5and two pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared to non-carriers. Within the large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8were approximately 0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (24.7 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1×10−6), and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 3.35; P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

Conclusions

Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of a LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.
Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals: retained advantage for the transwomen
Authors: Wiik A , Lundberg TR , Rullman E , Andersson DP , Holmberg M , Mandić M , Brismar TB , Dahlqvist Leinhard O , Chanpen S , Flanagan J , Arver S , Gustafsson T
Published: September 2019

Objectives

This study explored the effects of gender-affirming treatment, which includes inhibition of endogenous sex hormones and replacement with cross-sex hormones, on muscle function, size and composition in 11 transwomen (TW) and 12 transmen (TM).

Methods

Isokinetic knee extensor and flexor muscle strength was assessed at baseline (T00), 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement (T0), and 3 (T3) and 11 (T12) months after hormone replacement. In addition, at T00 and T12, we assessed lower-limb muscle volume using MRI, and cross-sectional area (CSA) and radiological density using CT.

Results

Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps CSA (15%) and radiological density (6%). In TW, the corresponding parameters decreased by −5% (muscle volume) and −4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained or slightly increased in strength. Baseline muscle volume correlated highly with strength (R>0.75), yet the relative change in muscle volume and strength correlated only moderately (R=0.65 in TW and R=0.32 in TM). The absolute levels of muscle volume and knee extension strength after the intervention still favored the TW.

Conclusion

Cross-sex hormone treatment markedly affects muscle strength, size and composition in transgender individuals. Despite the robust increases in muscle mass and strength in TM, the TW were still stronger and had more muscle mass following 12 months of treatment. These findings add new knowledge that could be relevant when evaluating transwomen’s eligibility to compete in the women’s category of athletic competitions.
New insights on the ventral attention network: Active suppression and involuntary recruitment during a bimodal task
Authors: Solís-Vivanco Rodolfo , Jensen Ole , Bonnefond Mathilde
Published: September 2019

Reorienting attention to unexpected events is essential in daily life. fMRI studies have revealed the involvement of the ventral attention network (VAN), including the temporo-parietal junction (TPJ), in such process. In this MEG study with 34 participants (17 women) we used a bimodal (visual/auditory) attention task to determine the neuronal dynamics associated with suppression of the activity of the VAN during top-down attention and its recruitment when information from the unattended sensory modality is involuntarily integrated. We observed an anticipatory power increase of alpha/beta (12-20 Hz) oscillations in the VAN following a cue indicating the modality to attend. Stronger VAN power increases predicted better task performance, suggesting that the VAN suppression prevents shifting attention to distractors. Moreover, the TPJ was synchronized with the frontal eye field in that frequency band, suggesting that the dorsal attention network (DAN) might participate in such suppression. Furthermore, we found a 12-20 Hz power decrease, in both the VAN and DAN, when information of both sensory modalities was congruent, suggesting an involvement of these networks for attention capture. Our results show that effective multimodal attentional reorientation includes the modulation of the VAN and DAN through upper-alpha/beta oscillations. Altogether these results indicate that the suppressing role of alpha/beta oscillations might operate beyond sensory regions.

SIGNIFICANCE STATEMENT

Reorienting attention to unexpected events from multiple sensory sources is essential in daily life. We explored the dynamics of the ventral attention network (VAN), a set of brain regions related to attentional reorienting, when relevant information was anticipated (i.e. during top-down attention) and when unexpected congruent information from another sensory modality was presented (involuntary attentional capture). We report that activity in the alpha/beta range (12-20 Hz) within the VAN indexed both top-down and attentional capture processes. Also, the VAN was synchronized with the dorsal attention network in this frequency band, suggesting an integrated role of both networks for attentional regulation. Our results shed light on the neurophysiological mechanisms that the brain carry out for reorienting attention to relevant environmental stimuli.
RNF144A shapes the hierarchy of cytokine signaling to provide protective immunity against influenza
Authors: Afzali B. , Kim S. , West E. , Nova-Lamperti E. , Cheru N. , Nagashima H. , Yan B. , Freiwald T , Merle N. , Chauss D. , Bijlmakers M. , Weitsman G. , Yu Z. , Jankovic D. , Mitra S. , Villarino A. , Kemper C. , Laurence A. , Kazemian M. , O’Shea J.J. , John S.
Published: September 2019

Cytokine-induced signaling pathways are tightly regulated and self-limiting, as their dysregulation causes immune disorders and cancer. The precise mechanisms that fine-tune these responses are incompletely understood. We show that the E3 ubiquitin ligaseRNF144Ais an IL-2/STAT5-induced gene in T cells and critically orchestrates the hierarchy of IL-2R signaling to promote STAT5 activation and limit RAF-ERK-MAPK output from the IL-2R. Mechanistically, RNF144A increased the interaction between IL-2Rβ and STAT5 and polyubiquitinated RAF1, enhancing its proteasomal degradation and preventing the formation of the potent RAF1/BRAF kinase complex. CD8+T cells fromRnf144a–/–mice had impaired IL-2-induction of effector genes, includingTnfand granzymes, and these mice demonstrated increased susceptibility to influenza. Reduced RNF144A expression was associated with more severe influenza in humans and its expression in patients was a biomarker distinguishing moderate from severe disease. These studies reveal a vital physiological role for RNF144A in maintaining the fidelity of IL-2R signaling in CTLs to prevent severe inflammation in response to infection.

One Sentence Summary

RNF144A promotes anti-viral immunity by regulating the hierarchy of cytokine signal output
COPO: a metadata platform for brokering FAIR data in the life sciences
Authors: Etuk Anthony , Shaw Felix , Gonzalez-Beltran Alejandra , Johnson David , Laporte Marie-Angélique , Rocca-Serra Philippe , Arnaud Elizabeth , Devare Medha , Kersey Paul J , Sansone Susanna-Assunta , Davey Robert P
Published: September 2019

Scientific innovation is increasingly reliant on data and computational resources. Much of today’s life science research involves generating, processing, and reusing heterogeneous datasets that are growing exponentially in size. Demand for technical experts (data scientists and bioinformaticians) to process these data is at an all-time high, but these are not typically trained in good data management practices. That said, we have come a long way in the last decade, with funders, publishers, and researchers themselves making the case for open, interoperable data as a key component of an open science philosophy. In response, recognition of the FAIR Principles (that data should be Findable, Accessible, Interoperable and Reusable) has become commonplace. However, both technical and cultural challenges for the implementation of these principles still exist when storing, managing, analysing and disseminating both legacy and new data.

COPO is a computational system that attempts to address some of these challenges by enabling scientists to describe their research objects (raw or processed data, publications, samples, images, etc.) using community-sanctioned metadata sets and vocabularies, and then use public or institutional repositories to share it with the wider scientific community. COPO encourages data generators to adhere to appropriate metadata standards when publishing research objects, using semantic terms to add meaning to them and specify relationships between them. This allows data consumers, be they people or machines, to find, aggregate, and analyse data which would otherwise be private or invisible. Building upon existing standards to push the state of the art in scientific data dissemination whilst minimising the burden of data publication and sharing.

Availability

COPO is entirely open source and freely available on GitHub athttps://github.com/collaborative-open-plant-omics. A public instance of the platform for use by the community, as well as more information, can be found atcopo-project.org.
LAX28 is required for assembly of the inner dynein arm l1 and tether/tether head complex in the Leishmania flagellum
Authors: Beneke Tom , Banecki Katherine , Fochler Sophia , Gluenz Eva
Published: September 2019

Motile eukaryotic flagella beat through coordinated activity of dynein motor proteins yet the mechanisms of dynein coordination and regulation are incompletely understood. The inner dynein arm IDA f/I1 complex and the tether/tether head (T/TH) complex are thought to be key regulators but, unlike IDA f/I1, T/TH proteins show limited conservation across flagellates. Here we characterised T/TH-associated proteins in the protist Leishmania mexicana. Proteome analysis of ΔCFAP44 mutant axonemes showed that they lacked IDA f/I1 protein IC140 and a novel 28-kDA axonemal protein, LAX28. Sequence analysis identified similarities between LAX28 and the uncharacterised human sperm tail protein TEX47, sharing features with sensory BLUF-domain proteins. Leishmania lacking LAX28, CFAP44 or IC140 retained some motility albeit with reduced swimming speed and directionality and a propensity for flagellar curling. Expression of tagged proteins in different null mutant backgrounds showed that the axonemal localisation of LAX28 requires CFAP44 and IC140, and the axonemal localisations of CFAP44 and IC140 both depend on LAX28. These data demonstrate a role for LAX28 in motility and show mutual dependencies of IDA f/1I and T/TH-associated proteins for axonemal assembly in Leishmania.

Summary Statement

The inner dynein arm f/l1 complex is required for coordinating flagellar motility. Here we show that LAX28 is needed for its function and localization in the flagellum of Leishmania mexicana.
Single-cell time-series mapping of cell fate trajectories reveals an expanded developmental potential for human PSC-derived distal lung progenitors
Authors: Hurley Killian , Ding Jun , Villacorta-Martin Carlos , Herriges Michael J. , Jacob Anjali , Vedaie Marall , Alysandratos Konstantinos D. , Sun Yuliang L. , Lin Chieh , Werder Rhiannon B. , Wilson Andrew A. , Mithal Aditya , Mostoslavsky Gustavo , Caballero Ignacio S. , Guttentag Susan H. , Ahangari Farida , Kaminski Naftali , Rodriguez-Fraticelli Alejo , Camargo Fernando , Bar-Joseph Ziv , Kotton Darrell N
Published: September 2019

Alveolar epithelial type 2 cells (AEC2s) are the facultative progenitors responsible for maintaining lung alveoli throughout life, yet are difficult to access from patients for biomedical research or lung regeneration applications. Here we engineer AEC2s from human induced pluripotent stem cells (iPSCs) in vitro and use single cell RNA sequencing (scRNA-seq) to profile the detailed kinetics of their differentiation over time. We focus on both the desired target cells as well as those that appear to diverge to alternative endodermal fates. By combining scRNA-seq with lentiviral barcoding to trace differentiating clones, we reveal the bifurcating cell fate trajectories followed as primordial lung progenitors differentiate into mature AEC2s. We define the global transcriptomic signatures of primary developing human AEC2s from fetal through adult stages in order to identify the subset of in vitro differentiating cells that appear to recapitulate the path of in vivo development. In addition, we develop computational methods based on Continuous State Hidden Markov Models (CSHMM) to identify the precise timing and type of signals, such as over-exuberant Wnt responses, that induce some early multipotent NKX2-1+ progenitors to lose lung fate as they clonally diverge into a variety of non-lung endodermal lineages. Finally, we find that this initial developmental plasticity is regulatable via Wnt modulation, and subsides over time, ultimately resulting in iPSC-derived AEC2s that exhibit a stable phenotype and nearly limitless self-renewal capacity in vitro. Our methods and computational approaches can be widely applied to study and control directed differentiation, producing an inexhaustible supply of mature lineages, exemplified here by the generation of AEC2s.
Detection of anomalous high frequency events in human intracranial EEG
Authors: Charupanit Krit , Sen-Gupta Indranil , Lin Jack J , Lopour Beth A
Published: September 2019

Objective

High-frequency oscillations (HFOs) are a promising biomarker for the epileptogenic zone. However, no physiological definition of an HFO has been established, so detection relies on the empirical definition of an HFO derived from visual observation. This can bias estimates of HFO features such as amplitude and duration, thereby hindering their utility as biomarkers. Therefore, we set out to develop an algorithm that detects high frequency events in the intracranial EEG that stand out from the background and does not require assumptions about event amplitude or morphology.

Method

We propose the anomaly detection algorithm (ADA), which integrates several unsupervised machine learning techniques to identify segments of data that are distinct from the background. We apply ADA and a standard HFO detector using a root-mean-square amplitude threshold to intracranial EEG from 11 patients undergoing evaluation for epilepsy surgery. The rate, amplitude, and duration of the detected events and the percent overlap between the two detectors are compared.

Result

In the seizure onset zone (SOZ), ADA detected a subset of conventional HFOs. In non-SOZ channels, ADA detected at least twice as many events as the standard approach, including some conventional HFOs; however, ADA also identified many low and intermediate amplitude events missed by the standard amplitude-based method. The rate of ADA events was similar across all channels; however, the amplitude of ADA events was significantly higher in SOZ channels, and the threshold between SOZ and non-SOZ channels was relatively consistent across patients.

Significance

ADA does not require human supervision, parameter optimization, or prior assumptions about event shape, amplitude, or duration. It provides an unbiased estimate of HFO features, and our results suggest that amplitude may differentiate SOZ and non-SOZ channels. Further studies will examine the utility of HFO amplitude as a biomarker for epilepsy surgical outcome.
Molecular Determinants of Substrate Selectivity of a Pneumococcal Rgg-regulated Peptidase-Containing ABC Transporter
Authors: Wang Charles Y , Medlin Jennifer S. , Nguyen Don R. , Disbennett W. Miguel , Dawid Suzanne
Published: September 2019

Peptidase-containing ABC transporters (PCATs) are a widely distributed family of transporters which secrete double-glycine (GG) peptides. In the opportunistic pathogenStreptococcus pneumoniae(pneumococcus), the PCATs ComAB and BlpAB have been shown to secrete quorum-sensing pheromones and bacteriocins related to the competence and pneumocin pathways. Here, we describe another pneumococcal PCAT, RtgAB, encoded by thertglocus and found intact in 17% of strains. The Rgg/SHP-like quorum sensing system RtgR/S, which uses a peptide pheromone with a distinctive Trp-X-Trp motif, regulates expression of thertglocus and provides a competitive fitness advantage in a mouse model of nasopharyngeal colonization. RtgAB secretes a set of co-regulatedrtgGG peptides. ComAB and BlpAB, which share a substrate pool with each other, do not secrete thertgGG peptides. Similarly, RtgAB does not efficiently secrete ComAB/BlpAB substrates. We examined the molecular determinants of substrate selectivity between ComAB, BlpAB, and RtgAB and found that the GG peptide signal sequences contain all the information necessary to direct secretion through specific transporters. Secretion through ComAB and BlpAB depends largely on the identity of four conserved hydrophobic signal sequence residues previously implicated in substrate recognition by PCATs. In contrast, a motif situated at the N-terminal end of the signal sequence, found only inrtgGG peptides, directs secretion through RtgAB. These findings illustrate the complexity in predicting substrate-PCAT pairings by demonstrating specificity that is not dictated solely by signal sequence residues previously implicated in substrate recognition.

Importance

The export of peptides from the cell is a fundamental process carried out by all bacteria. One method of bacterial peptide export relies on a family of transporters called peptidase-containing ABC transporters (PCATs). PCATs export so-called GG peptides which carry out diverse functions, including cell-to-cell communication and inter-bacterial competition. In this work, we describe a PCAT-encoding genetic locus,rtg, in the pathogenStreptococcus pneumoniae(pneumococcus). Thertglocus is linked to increased competitive fitness advantage in a mouse model of nasopharyngeal colonization. We also describe how thertgPCAT preferentially secretes a set of co-regulated GG peptides but not GG peptides secreted by other pneumococcal PCATs. These findings illuminate a relatively understudied part of PCAT biology: how these transporters discriminate between different subsets of GG peptides. Ultimately, expanding our knowledge of PCATs will advance our understanding of the many microbial processes dependent on these transporters.
A dynamic pattern of local auxin sources is required for root regeneration
Authors: Matosevich Rotem , Cohen Itay , Gil-Yarom Naama , Modrego Abelardo , Verna Carla , Scarpella Enrico , Efroni Idan
Published: September 2019

Following removal of its stem cell niche, the root meristem can regenerate by recruitment of remnant cells from the stump. Regeneration is initiated by rapid accumulation of auxin near the injury site but the source of this auxin is unknown. Here, we show that auxin accumulation arises from the activity of multiple auxin biosynthetic sources that are newly specified near the cut site and that their continuous activity is required for the regeneration process. Auxin synthesis is highly localized and PIN-mediate transport is dispensable for auxin accumulation and tip regeneration. Roots lacking the activity of the regeneration competence factorERF115, or that are dissected at a zone of low-regeneration potential, fail to activate local auxin sources. Remarkably, restoring auxin supply is sufficient to confer regeneration capacity to these recalcitrant tissues. We suggest that regeneration competence relies on the ability to specify new local auxin sources in a precise spatio-temporal pattern.