bluuebunny/crossref_metadata_2025 huggingface dataset:
Phytate degradation cascade in pigs as affected by phytase supplementation and rapeseed cake inclusion in corn–soybean meal-based diets
Authors: Rosenfelder-Kuon Pia , Klein Nicolas , Zegowitz Benedikt , Schollenberger Margit , Kühn Imke , Thuringer Lucia , Seifert Jana , Rodehutscord Markus
Published: February 2020

Two experiments (Exp.) with ileally cannulated growing barrows were conducted. The concentrations of positional inositol phosphate (InsP) isomers in ileal digesta and feces were determined, as well as the prececal and total tract phytate (InsP6) hydrolysis, and digestibility of dry matter, P, Ca, nitrogen, and gross energy. Prececal amino acid (AA) digestibility and digestive enzyme activities in ileal digesta were also studied. In both Exp., pigs had an initial body weight (BW) of 28 kg and were completely randomized to a Double Latin Square Design with eight pigs, four diets, and three periods of 12 d each. Feces and ileal digesta were collected for 5 d and 2 d, respectively. Pigs were housed individually in stainless steel metabolic units. Water was available ad libitum and feed was provided two times daily at an amount of 4% of mean BW. In Exp. 1, pigs received a corn–soybean meal (SBM)-based diet that was supplemented with 0, 750, 1,500, or 3,000 FTU of a microbial phytase/kg diet. In Exp. 2, pigs were allotted to a 2 × 2 arrangement of diets based on corn and SBM or an SBM-rapeseed cake (RSC) mix and phytase supplementation at 0 or 1,500 FTU/kg of diet. In ileal digesta of pigs fed without the phytase supplement, the dominating InsP isomers beside InsP6 were InsP5 isomers. The InsP pattern in ileal digesta changed with the inclusion of microbial phytase in both Exp., as there was a remarkable increase in Ins(1,2,5,6)P4 concentration (P < 0.001). In both Exp., the myo-inositol concentration in ileal digesta was greater upon phytase addition (P < 0.001). Without phytase supplementation, prececal and total tract P digestibility were low, whereas hardly any InsP6 was excreted in feces. There was no difference between prececal and total tract P digestibility values. For most AA studied in Exp. 2, prececal digestibility was lower (P < 0.01) when the diet contained RSC. However, phytase supplementation did not significantly affect prececal AA digestibility in both Exp. The present study showed that InsP6 disappearance by the end of the ileum can be increased up to around 90% in SBM- and SBM–RSC-based diets when microbial phytase is supplemented, but prececal P digestibility hardly exceeded 60%. The study confirms that pigs cannot benefit from a remarkable InsP6 degradation in the hindgut.
History of Japan Clinical Oncology Group (JCOG) Lung Cancer Study Group
Authors: Horinouchi Hidehito , Ohe Yuichiro
Published: February 2020

The Japan Clinical Oncology Group Lung Cancer Study Group has been carrying out clinical studies, exploring new strategies of treatment, supportive therapies (antiemetics, etc.), etc., for a variety of cancers, including not only small cell lung cancer and non-small cell lung cancer but also rare chest tumours (represented by thymoma) and cancer-associated conditions (cancerous pericarditis, cancerous pleuritis, etc.). In this review, an overview of all studies conducted from 1985 to 2019 is provided.
Between National Interests and Global Business: China’s Possible Reservations to the Hague Convention on Choice of Court Agreements
Authors: Cai Wei , Kolieb Jonathan
Published: February 2020

In September 2017, China signed the Hague Convention on Choice of Court Agreements. There are no obstacles preventing China from ratifying the Convention. However, the possible reservations China may declare appear to be a key concern for the success of the Convention. This article identifies the key conflicts between the Convention and Chinese law and practice, and analyses the pros and cons of some possible reservations the Chinese authorities may consider when ratifying the Convention. China’s ratification of the Convention would have a positive impact on the global recognition and enforcement of foreign civil and commercial judgments. Although China may have some specific concerns (e.g. national security) in its recognition and enforcement of particular foreign judgments, it is desirable that China adopts a pragmatic approach and minimize the number and extent of its reservations to the Convention.
Bayesian phylolinguistics infers the internal structure and the time-depth of the Turkic language family
Authors: Savelyev Alexander , Robbeets Martine
Published: February 2020

Despite more than 200 years of research, the internal structure of the Turkic language family remains subject to debate. Classifications of Turkic so far are based on both classical historical–comparative linguistic and distance-based quantitative approaches. Although these studies yield an internal structure of the Turkic family, they cannot give us an understanding of the statistical robustness of the proposed branches, nor are they capable of reliably inferring absolute divergence dates, without assuming constant rates of change. Here we use computational Bayesian phylogenetic methods to build a phylogeny of the Turkic languages, express the reliability of the proposed branches in terms of probability, and estimate the time-depth of the family within credibility intervals. To this end, we collect a new dataset of 254 basic vocabulary items for thirty-two Turkic language varieties based on the recently introduced Leipzig–Jakarta list. Our application of Bayesian phylogenetic inference on lexical data of the Turkic languages is unprecedented. The resulting phylogenetic tree supports a binary structure for Turkic and replicates most of the conventional sub-branches in the Common Turkic branch. We calculate the robustness of the inferences for subgroups and individual languages whose position in the tree seems to be debatable. We infer the time-depth of the Turkic family at around 2100 years before present, thus providing a reliable quantitative basis for previous estimates based on classical historical linguistics and lexicostatistics.
ETHYLENE RESPONSE FACTOR39–MYB8 complex regulates low-temperature-induced lignification of loquat fruit
Authors: Zhang Jing , Yin Xue-ren , Li Heng , Xu Meng , Zhang Meng-xue , Li Shao-jia , Liu Xiao-fen , Shi Yan-na , Grierson Donald , Chen Kun-song
Published: February 2020

Flesh lignification is a specific chilling response that causes deterioration in the quality of stored red-fleshed loquat fruit (Eribotrya japonica) and is one aspect of wider chilling injury. APETALA2/ETHLENE RESPONSIVE FACTOR (AP2/ERF) transcription factors are important regulators of plant low-temperature responses and lignin biosynthesis. In this study, the expression and action of 27 AP2/ERF genes from the red-fleshed loquat cultivar ‘Luoyangqing’ were investigated in order to identify transcription factors regulating low-temperature-induced lignification. EjERF27, EjERF30, EjERF36, and EjERF39 were significantly induced by storage at 0 °C but inhibited by a low-temperature conditioning treatment (pre-storage at 5 °C for 6 days before storage at 0 °C, which reduces low-temperature-induced lignification), and their transcript levels positively correlated with flesh lignification. A dual-luciferase assay indicated that EjERF39 could transactivate the promoter of the lignin biosynthetic gene Ej4CL1, and an electrophoretic mobility shift assay confirmed that EjERF39 recognizes the DRE element in the promoter region of Ej4CL1. Furthermore, the combination of EjERF39 and the previously characterized EjMYB8 synergistically transactivated the Ej4CL1 promoter, and both transcription factors showed expression patterns correlated with lignification in postharvest treatments and red-fleshed ‘Luoyangqing’ and white-fleshed ‘Ninghaibai’ cultivars with different lignification responses. Bimolecular fluorescence complementation and luciferase complementation imaging assays confirmed direct protein–protein interaction between EjERF39 and EjMYB8. These data indicate that EjERF39 is a novel cold-responsive transcriptional activator of Ej4CL1 that forms a synergistic activator complex with EjMYB8 and contributes to loquat fruit lignification at low temperatures.
CDF transcription factors: plant regulators to deal with extreme environmental conditions
Authors: Renau-Morata Begoña , Carrillo Laura , Dominguez-Figueroa Jose , Vicente-Carbajosa Jesús , Molina Rosa V , Nebauer Sergio G , Medina Joaquín
Published: February 2020

In terrestrial environments, water and nutrient availabilities and temperature conditions are highly variable, and especially in extreme environments limit survival, growth, and reproduction of plants. To sustain growth and maintain cell integrity under unfavourable environmental conditions, plants have developed a variety of biochemical and physiological mechanisms, orchestrated by a large set of stress-responsive genes and a complex network of transcription factors. Recently, cycling DOF factors (CDFs), a group of plant-specific transcription factors (TFs), were identified as components of the transcriptional regulatory networks involved in the control of abiotic stress responses. The majority of the members of this TF family are activated in response to a wide range of adverse environmental conditions in different plant species. CDFs regulate different aspects of plant growth and development such as photoperiodic flowering-time control and root and shoot growth. While most of the functional characterization of CDFs has been reported in Arabidopsis, recent data suggest that their diverse roles extend to other plant species. In this review, we integrate information related to structure and functions of CDFs in plants, with special emphasis on their role in plant responses to adverse environmental conditions.
Hydrogen sulfide: a multi-tasking signal molecule in the regulation of oxidative stress responses
Authors: Chen Tao , Tian Mimi , Han Yi
Published: February 2020

Accumulating evidence suggests that hydrogen sulfide (H2S) is an important signaling molecule in plant environmental interactions. The consensus view amongst plant scientists is that environmental stress leads to enhanced production and accumulation of reactive oxygen species (ROS). H2S interacts with the ROS-mediated oxidative stress response network at multiple levels, including the regulation of ROS-processing systems by transcriptional or post-translational modifications. H2S–ROS crosstalk also involves other interacting factors, including nitric oxide, and can affect key cellular processes like autophagy. While H2S often functions to prevent ROS accumulation, it can also act synergistically with ROS signals in processes such as stomatal closure. In this review, we summarize the mechanisms of H2S action and the multifaceted roles of this molecule in plant stress responses. Emphasis is placed on the interactions between H2S, ROS, and the redox signaling network that is crucial for plant defense against environmental threats.
Implications of vocabulary density for poetry: Reading T. S. Eliot’s poetry through computational methods
Authors: Kim Seonghoon , Tak Jin-young , Kwak Eun Joo , Lim Tae Yun , Lee Shin Haeng
Published: February 2020

By incorporating computational methods into reading literary texts, this study examines the literary implications of the ‘vocabulary density’ and frequency of nouns and adjectives in T. S. Eliot’s poetry. This study analyzes 4,689,655 words from forty-seven poets available on Project Gutenberg, a catalog spanning from the eighteenth century to the early twentieth century. The data illustrate both the continuity and discontinuity found in English and American poetry dependent on conventional divisions between literary movements: eighteenth century, Romanticism, Imagism, and Modernism. The findings shed light on the similarities and differences between Eliot’s poetry and others’, particularly in terms of Franco Moretti’s concept of ‘modern epic’ and his methodology of ‘distant reading’. Through this combined quantitative and qualitative research, this article ultimately upholds the notion that the linguistic distinction of Eliot’s high modernist poetry lies, by and large, in his use of invented and equivocal words that reflects and represents an artistic response to modern human, cultural, social conditions, and experiment with poetic diction and polyphonic voice in the early twentieth century.
Cardiorespiratory Fitness Is Associated With Better Cardiometabolic Health and Lower PTSD Severity in Post-9/11 Veterans
Authors: Whitworth James W , Hayes Scott M , Andrews Ryan J , Fonda Jennifer R , Beck Brigitta M , Hanlon Lilly B , Fortier Catherine B , Milberg William P , McGlinchey Regina E
Published: February 2020

Introduction

Post-traumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular and metabolic diseases and physical inactivity. Cardiorespiratory fitness (CRF), which is modifiable by physical activity, is a strong independent predictor of cardiometabolic health. However, the relationship between CRF and cardiometabolic health in veterans with PTSD is unknown. Thus, this study aimed to explore the cross-sectional relationships among CRF, indices of cardiometabolic health (ie, HbA1c, blood lipids, blood pressure, waist-hip ratio, and body mass index), and PTSD severity in veterans with PTSD.

Materials and Methods

This study was approved by the local Institutional Review Board. All participants were informed of the study risks and provided consent prior to participation. Participants (n = 13) completed a cardiopulmonary exercise test, a fasting blood draw, and the Clinician Administered PTSD Scale. Correlations between CRF and cardiometabolic health were examined with Spearman’s rank correlations, and differences in PTSD symptom severity were explored as a function of CRF (ie, low-to-moderate vs. high CRF), using multiple linear regression.

Results

Peak oxygen uptake ($\dot{\mathrm{V}}$O2peak) was correlated with high-density lipoproteins rho = 0.60, P = 0.04 and diastolic blood pressure rho = −0.56, P = 0.05. Ventilatory threshold was correlated with HbA1c rho = −0.61, P = 0.03 and diastolic blood pressure rho = −0.56, P = 0.05. Higher CRF was associated with lower total PTSD severity standardized β = −0.84, P = 0.01, adjusted R2 = 0.47, total Cluster C symptoms (avoidance/numbing) β = −0.71, P = 0.02, adjusted R2 = 0.49, and total Cluster D symptoms (hyperarousal) β = −0.89, P = 0.01, adjusted R2 = 0.41, while adjusting for age and smoking status.

Conclusions

These preliminary findings suggest that CRF and by proxy physical activity may be important factors in understanding the increased risk of cardiovascular and metabolic disease associated with PTSD.
Remote Access Therapy for Veterans With Psychological Problems: Current State of the Art
Authors: Fleuty Kristina , Almond Michael K
Published: February 2020

Introduction

The past decade has seen both an increase in use and research into ways in which psychological therapy might be delivered remotely. Remote access therapy uses technology to deliver talking therapies. It is important to understand how remote technologies are being used as part of the therapeutic process and consider what effect this has on the success of therapeutic interventions. This review discusses what is currently known about the use of remote access therapy with a veteran population. Moreover, the review summarizes potential benefits and barriers to conducting therapy remotely.

Materials and Methods

This review was conducted to explore the use of remote access therapies with veterans. All available literature identified for this review focused on veteran cohorts from the US and UK. To meet search criteria, studies had to include veteran participants engaging with any form of talking therapy delivered remotely. A total of 15 studies met the inclusion criteria: two from the UK and 13 from the US. Searches were carried out during June and July 2019.

Results

A number of potential benefits to remote therapy delivery were observed in the research reviewed, including improved accessibility to therapy for people living in remote locations (providing infrastructure existed to facilitate the remote access technologies), increased flexibility of timing, and being able to undergo therapy alongside other life commitments. The studies also suggested that those involved in remote therapy found the technology accessible and easy to operate. Digital technologies could generally be relied upon and although there were some technical difficulties reported that these were generally not seen as a barrier to the use of remote technologies as a whole. Some limitations to using remote therapies were observed, such as the acceptability of remote therapy, particularly in the UK, and the willingness of practitioners to engage with digital technologies to facilitate remote therapy. There was also caution raised that the apparent cost effectiveness of delivering therapy remotely needs to be further investigated, particularly in relation to costs involved in enabling remote access technologies in locations where poor infrastructure exists.

Conclusions

Overall, studies reported largely positive outcomes for veterans undergoing remote access therapy and in general participants did not find the therapeutic process compromised by remote delivery. Studies showed that remote access therapy is being conducted successfully in both the US and UK. There is, however, a need for more research into the use of remote access therapies to treat a wider range of psychological difficulties in veterans.
Post-9/11 Veteran Satisfaction With the VA eScreening Program
Authors: Almklov Erin , Afari Niloofar , Floto Elizabeth , Lindamer Laurie , Hurst Samantha , Pittman James O E
Published: February 2020

Introduction

eScreening is a mobile health technology resource for veterans and staff to support Veterans Health Administration initiatives such as early identification of health problems, shared decision-making, and measurement-based care.

Methods

We conducted an exploratory mixed methods retrospective study with newly enrolling post-9/11 veterans to (1) understand eScreening user experience and obtain practical feedback on the technology to guide improvements, (2) assess veteran satisfaction with eScreening following improvements to the technology, and (3) examine veteran characteristics associated with eScreening satisfaction. Focus group data were collected on user experience with eScreening from a sample of veterans who participated in an eScreening pilot. Guided by a user-centered design approach, findings informed improvements to the technology. Survey data were subsequently collected from a large cohort of veterans to assess satisfaction with the improved program. Questionnaire data were also collected to examine variables associated with eScreening satisfaction. Qualitative focus group data were analyzed using content analysis. Descriptive statistics were used to characterize sociodemographic variables, questionnaires, and satisfaction ratings. Correlations were run to examine the relationship between certain veteran characteristics (eg, age, resiliency, anxiety, insomnia, post-traumatic stress disorder, somatic symptoms, depression, pain) and satisfaction with eScreening. All research activities were conducted at VA San Diego Healthcare System and approved by the Institutional Review Board.

Results

Focus group data revealed that veterans were largely satisfied with eScreening, but they suggested some improvements (eg, to interface functionality), which were integrated into an updated version of eScreening. Following these changes, survey data revealed that veterans were highly satisfied with eScreening, including its usability, information security, and impact on health services. There were statistically significant, though not clinically meaningful relationships between health-related characteristics and satisfaction with eScreening. However, millennials showed significantly higher satisfaction ratings compared with non-millennials.

Conclusions

These findings support the use of patient experiences and feedback to aide product development. In addition, post-9/11 veterans support the use of eScreening to assist health screening. However, evaluating the eScreening program in more diverse veteran groups and Veterans Affairs settings is needed to improve the generalizability of these findings to the larger veteran population.
Gravitational waves from in-spirals of compact objects in binary common-envelope evolution
Authors: Ginat Yonadav Barry , Glanz Hila , Perets Hagai B , Grishin Evgeni , Desjacques Vincent
Published: February 2020

Detection of gravitational-wave (GW) sources enables the characterization of binary compact objects (COs) and of their in-spiral. However, other dissipative processes can affect the in-spiral. Here, we show that the in-spiral of COs through a gaseous common envelope (CE) arising from an evolved stellar companion produces a novel type of GW sources, whose evolution is dominated by the dissipative gas dynamical friction effects from the CE, rather than the GW emission itself. The evolution and properties of the GW signals differ from those of isolated gas-poor mergers significantly. We find characteristic strains of ∼10−23–10−21 ($10\, {\rm kpc}/{D}$) for such sources – observable by next-generation space-based GW detectors (at rates of once per a few centuries for LISA, and about once a year for BBO). The evolution of the GW signal can serve as a probe of the interior regions of the evolved star, and the final stages of CE evolution, otherwise inaccessible through other observational means. Moreover, such CE mergers are frequently followed by observable explosive electromagnetic counterparts and/or the formation of exotic stars.
The genome of Shaw’s sea snake (Hydrophis curtus) reveals secondary adaptation to its marine environment
Authors: Peng Changjun , Ren Jin-Long , Deng Cao , Jiang Dechun , Wang Jichao , Qu Jiangyong , Chang Jiang , Yan Chaochao , Jiang Ke , Murphy Robert W , Wu Dong-Dong , Li Jia-Tang
Published: February 2020

The transition of terrestrial snakes to marine life approximately 10 million years ago (Ma) is ideal for exploring adaptive evolution. Sea snakes possess phenotype specializations including laterally compressed bodies, paddle-shaped tails, valvular nostrils, cutaneous respiration, elongated lungs and salt glands yet knowledge on the genetic underpinnings of the transition remain limited. Herein, we report the first genome of Shaw’s sea snake (Hydrophis curtus) and use it to investigate sea snake secondary marine adaptation. A hybrid assembly strategy obtains a high quality genome. Gene family analyses date a pulsed coding-gene expansion to about 20 Ma, and these genes associate strongly with adaptations to marine environments. Analyses of selection pressure and convergent evolution discover the rapid evolution of protein-coding genes, and some convergent features. Additionally, 108 conserved non-coding elements appear to have evolved quickly, and these may underpin the phenotypic changes. Transposon elements may contribute to adaptive specializations by inserting into genomic regions around functionally related coding genes. The integration of genomic and transcriptomic analyses indicates independent origins and different components in sea snake and terrestrial snake venom; the venom gland of the sea snake harbours the highest PLA2 (17.23%) expression in selected elapids and these genes may organize tandemly in the genome. These analyses provide insights into the genetic mechanisms that underlay the secondary adaptation to marine and venom production of this sea snake.
Dynamic Evolution of De Novo DNA Methyltransferases in Rodent and Primate Genomes
Authors: Molaro Antoine , Malik Harmit S , Bourc’his Deborah
Published: February 2020

Transcriptional silencing of retrotransposons via DNA methylation is paramount for mammalian fertility and reproductive fitness. During germ cell development, most mammalian species utilize the de novo DNA methyltransferases DNMT3A and DNMT3B to establish DNA methylation patterns. However, many rodent species deploy a third enzyme, DNMT3C, to selectively methylate the promoters of young retrotransposon insertions in their germline. The evolutionary forces that shaped DNMT3C’s unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred ∼60 Ma in the last common ancestor of muroid rodents. Importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds have undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has instead evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result of an ongoing evolutionary arms race with young retrotransposon lineages in muroid genomes. Interestingly, although primates lack DNMT3C, we find that the N-terminus of DNMT3A has also evolved under diversifying selection. Thus, the N-termini of two independent de novo methylation enzymes have evolved under diversifying selection in rodents and primates. We hypothesize that repression of young retrotransposons might be driving the recurrent innovation of a functional domain in the N-termini on germline DNMT3s in mammals.
Practical Speedup of Bayesian Inference of Species Phylogenies by Restricting the Space of Gene Trees
Authors: Wang Yaxuan , Ogilvie Huw A , Nakhleh Luay
Published: February 2020

Species tree inference from multilocus data has emerged as a powerful paradigm in the postgenomic era, both in terms of the accuracy of the species tree it produces as well as in terms of elucidating the processes that shaped the evolutionary history. Bayesian methods for species tree inference are desirable in this area as they have been shown not only to yield accurate estimates, but also to naturally provide measures of confidence in those estimates. However, the heavy computational requirements of Bayesian inference have limited the applicability of such methods to very small data sets. In this article, we show that the computational efficiency of Bayesian inference under the multispecies coalescent can be improved in practice by restricting the space of the gene trees explored during the random walk, without sacrificing accuracy as measured by various metrics. The idea is to first infer constraints on the trees of the individual loci in the form of unresolved gene trees, and then to restrict the sampler to consider only resolutions of the constrained trees. We demonstrate the improvements gained by such an approach on both simulated and biological data.
Using miRNAs as diagnostic biomarkers for male infertility: opportunities and challenges
Authors: Vashisht A , Gahlay G K
Published: February 2020

The non-coding genome has been extensively studied for its role in human development and diseases. MicroRNAs (miRNAs) are small non-coding RNAs, which can regulate the expression of hundreds of genes at the post-transcriptional level. Therefore, any defects in miRNA biogenesis or processing can affect the genes and have been linked to several diseases. Male infertility is a clinical disorder with a significant number of cases being idiopathic. Problems in spermatogenesis and epididymal maturation, testicular development, sperm maturation or migration contribute to male infertility, and many of these idiopathic cases are related to issues with the miRNAs which tightly regulate these processes. This review summarizes the recent research on various such miRNAs and puts together the candidate miRNAs that may be used as biomarkers for diagnosis. The development of strategies for male infertility treatment using anti-miRs or miRNA mimics is also discussed. Although promising, the development of miRNA diagnostics and therapeutics is challenging, and ways to overcome some of these challenges are also reviewed.
Quantitative comparison of within-sample heterogeneity scores for DNA methylation data
Authors: Scherer Michael , Nebel Almut , Franke Andre , Walter Jörn , Lengauer Thomas , Bock Christoph , Müller Fabian , List Markus
Published: February 2020

DNA methylation is an epigenetic mark with important regulatory roles in cellular identity and can be quantified at base resolution using bisulfite sequencing. Most studies are limited to the average DNA methylation levels of individual CpGs and thus neglect heterogeneity within the profiled cell populations. To assess this within-sample heterogeneity (WSH) several window-based scores that quantify variability in DNA methylation in sequencing reads have been proposed. We performed the first systematic comparison of four published WSH scores based on simulated and publicly available datasets. Moreover, we propose two new scores and provide guidelines for selecting appropriate scores to address cell-type heterogeneity, cellular contamination and allele-specific methylation. Most of the measures were sensitive in detecting DNA methylation heterogeneity in these scenarios, while we detected differences in susceptibility to technical bias. Using recently published DNA methylation profiles of Ewing sarcoma samples, we show that DNA methylation heterogeneity provides information complementary to the DNA methylation level. WSH scores are powerful tools for estimating variance in DNA methylation patterns and have the potential for detecting novel disease-associated genomic loci not captured by established statistics. We provide an R-package implementing the WSH scores for integration into analysis workflows.
Real-world Effectiveness of Sofosbuvir/Velpatasvir for Treatment of Chronic Hepatitis C in British Columbia, Canada: A Population-Based Cohort Study
Authors: Wilton James , Wong Stanley , Yu Amanda , Ramji Alnoor , Cook Darrel , Butt Zahid A , Alvarez Maria , Binka Mawuena , Darvishian Maryam , Jeong Dahn , Bartlett Sofia R , Pearce Margo E , Adu Prince A , Yoshida Eric M , Krajden Mel , Janjua Naveed Z
Published: February 2020

Background

Clinical trials show high efficacy of sofosbuvir/velpatasvir (SOF/VEL), but there are limited data from “real-world” settings. We aimed to evaluate SOF/VEL effectiveness for all hepatitis C virus (HCV) genotypes (GTs) in British Columbia (BC), Canada.

Methods

We used the BC Hepatitis Testers Cohort, which includes all HCV cases in the province (1990–2015) linked to administrative databases, including prescriptions to end of 2018. We measured sustained virologic response (SVR; negative RNA ≥10 weeks after treatment end) and identified characteristics associated with non-SVR. Conservatively, we excluded individuals with no assessment for SVR if their last RNA test after treatment initiation was negative (but included if positive).

Results

Of 2821 eligible participants, most were infected with GT1 (1076, 38.1%) or GT3 (1072, 38.0%), and a minority (278, 9.9%) were treated with RBV. SVR was 94.6% (2670/2821) overall and 94.5% (1017/1076) for GT1, 96.4% (512/531) for GT2, and 93.7% (1004/1072) for GT3. When disaggregated by GT, treatment regimen, and cirrhosis/treatment experience, SVR was lowest (30/40, 75.0%) among treatment-experienced GT3 individuals treated with RBV. Characteristics associated with non-SVR in multivariable analysis included younger age, RBV addition, and being a person with HIV (PWH) or who injects/injected drugs (PWID). When treatment regimen (±RBV) was removed from multivariable model, treatment experience was associated with non-SVR for GT3. Of 151 non-SVR individuals, 56.3% were nonvirological failures (treatment incomplete/no assessment for SVR) and 43.7% were virological failures (nonresponse/relapse). A disproportionately high percentage of non-SVR among PWID was due to nonvirological failure.

Conclusions

SOF/VEL was highly effective in this “real-world” population-based cohort. Additional support is required for PWID/PWH to reach SVR.
The Role of Healthcare Worker-Mediated Contact Networks in the Transmission of Vancomycin-Resistant Enterococci
Authors: Klein Eili Y , Tseng Katie K , Hinson Jeremiah , Goodman Katherine E , Smith Aria , Toerper Matt , Amoah Joe , Tamma Pranita D , Levin Scott R , Milstone Aaron M
Published: February 2020

Background

User- and time-stamped data from hospital electronic health records (EHRs) present opportunities to evaluate how healthcare worker (HCW)-mediated contact networks impact transmission of multidrug-resistant pathogens, such as vancomycin-resistant enterococci (VRE).

Methods

This is a retrospective analysis of incident acquisitions of VRE between July 1, 2016 and June 30, 2018. Clinical and demographic patient data were extracted from the hospital EHR system, including all recorded HCW contacts with patients. Contacts by an HCW with 2 different patients within 1 hour was considered a “connection”. Incident VRE acquisition was determined by positive clinical or surveillance cultures collected ≥72 hours after a negative surveillance culture.

Results

There were 2952 hospitalizations by 2364 patients who had ≥2 VRE surveillance swabs, 112 (4.7%) patients of which had incident nosocomial acquisitions. Patients had a median of 24 (interquartile range [IQR], 18–33) recorded HCW contacts per day, 9 (IQR, 5–16) of which, or approximately 40%, were connections that occurred <1 hour after another patient contact. Patients that acquired VRE had a higher average number of daily connections to VRE-positive patients (3.1 [standard deviation {SD}, 2.4] versus 2.0 [SD, 2.1]). Controlling for other risk factors, connection to a VRE-positive patient was associated with increased odds of acquiring VRE (odds ratio, 1.64; 95% confidence interval, 1.39–1.92).

Conclusions

We demonstrated that EHR data can be used to quantify the impact of HCW-mediated patient connections on transmission of VRE in the hospital. Defining incident acquisition risk of multidrug-resistant organisms through HCWs connections from EHR data in real-time may aid implementation and evaluation of interventions to contain their spread.
Issues and Perspectives in Designing Clinical Trials for Negative Symptoms in Schizophrenia: Consensus Statements
Authors: Marder Stephen R , Davidson Michael , Zaragoza Silvia , Kott Alan , Khan Anzalee , Wang Xingmei , Velligan Dawn I , Umbricht Daniel , Luthringer Remy , Daniel David
Published: February 2020

Individuals from academia, the pharmaceutical industry, and regulators reevaluated earlier recommendations for the design of clinical trials for negative symptoms based on data from recent large trials. A session in February, 2018 at the International Society of CNS Clinical Trails and Methodology (ISCTM) annual meeting reviewed results from selected trials that reported findings between 2013 and 2018. The group reached a consensus on prior recommendations that should be reconsidered in future trials which included: (1) How can placebo effects be minimized? (2) Should global measures of negative symptoms be included? (3) Should a new drug targeting negative symptoms be tested in a monotherapy design or in an add-on design? (4) Can new information from negative symptom trials inform the selection of clinical outcome assessments (COA’s) for future trials? For each of these issues new data was evaluated, discussed by the group, and in some cases the earlier recommendations were revised.
A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys
Authors: Mitra Mayur S , Lancaster Karla , Adedeji Adeyemi O , Palanisamy Gopinath S , Dave Rutwij A , Zhong Fiona , Holdren Matthew S , Turley Shannon J , Liang Wei-Ching , Wu Yan , Meng Y Gloria , Vernes Jean-Michel , Schutten Melissa M
Published: February 2020

Transforming growth factor β (TGFβ) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGFβ therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFβ signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGFβ receptor and not considered to be a liability associated with pan-TGFβ neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGFβ neutralizing mAb (pan-TGFβ mAb; neutralizes TGFβ1, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100 mg/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at ≥ 30 mg/kg and prolonged menstruation in female monkeys at 100 mg/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGFβ signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGFβ inhibiting mAb.
Hide-and-seek with hoverflies: Merodon aureus – a species, a complex or a subgroup?
Authors: Vujić Ante , Šašić Zorić Ljiljana , Ačanski Jelena , Likov Laura , Radenković Snežana , Djan Mihajla , Milić Dubravka , Šebić Anja , Ranković Milica , Khaghaninia Samad
Published: February 2020

In order to disentangle the currently confused interpretations and nomenclature of Merodon aureus and M. aeneus, we have reviewed all existing type material and species names known to us as assigned synonyms of these taxa. We resolve M. aeneus as being a junior synonym of M. aureus. We designate a lectotype for M. aureus and a neotype for M. aeneus. Additionally, we provide evidence that M. aureus, together with two newly discovered taxa (M. calidus sp. nov. and M. ortus sp. nov.), represent a complex of cryptic species named the M. aureus species complex. This complex, together with the M. unicolor species complex and the species M. pumilus, is part of the M. aureus subgroup. The M. unicolor species complex comprises two cryptic species: M. unicolor and M. albidus sp. nov. The new species are described by applying an integrative taxonomic approach using several data types (COI and 28S rRNA genes, geometric morphometry of the wings, ecological and distributional data). Based on the COI gene sequence analysis and distributional data, the pupa previously described as an immature stage of the species M. aureus is redefined as an immature stage of the new species M. calidus. Speciation within the M. aureus subgroup is discussed in the context of the phylogeographic history in the studied region.
STAT1-dependent tolerance of intestinal viral infection
Authors: Filyk Heather A , Sharon Andrew J , Fonseca Nicolette M , Simister Rachel L , Yuen Wallace , Hardman Blair K , Robinson Hannah G , Seo Jung Hee , Rocha-Pereira Joana , Welch Ian , Neyts Johan , Crowe Sean A , Osborne Lisa C
Published: February 2020

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that maintain tolerance to the virome remain largely unknown. Here, we use colonization with the model commensal murine norovirus (MNV CR6) to interrogate host-directed mechanisms of viral tolerance, and show that STAT1 is a central coordinator of tolerance following CR6 colonization. STAT1 restricts CR6 replication to the intestinal tract, prevents systemic viral-induced tissue damage and disease, and regulates antiviral CD4+and CD8+T cell responses. In contrast to systemic viral pathogens that drive T cell mediated immunopathology in STAT1-deficient mice, our data indicates that loss of CD4+or CD8+T cells and their associated effector functions has no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound to limit viral replication prevented viral-induced tissue damage and death despite ongoing dysregulated antiviral T cell responses. Collectively, our data uncouple the requirement for STAT1-mediated regulation of antiviral T cell responses from innate immune-mediated restriction of viral replication that is necessary for intestinal viral tolerance.
Dopaminergic modulation of human inter-temporal choice: a diffusion model analysis using the D2-receptor-antagonist haloperidol
Authors: Wagner Ben , Clos Mareike , Sommer Tobias , Peters Jan
Published: February 2020

The neurotransmitter dopamine is implicated in diverse functions, including reward processing, reinforcement learning and cognitive control. The tendency to discount future rewards in value over time has long been discussed in the context of potential dopaminergic modulation. Here we examined the effect of a single dose of the D2 receptor antagonist Haloperidol (2mg) on temporal discounting. Our approach extends previous human pharmacological studies in two ways. First, we applied state-of-the-art computational modeling based on the drift diffusion model to comprehensively examine choice dynamics. Second, we examined dopaminergic modulation of reward magnitude effects on temporal discounting. Drift diffusion modeling revealed reduced temporal discounting and substantially faster non-decision times under Haloperidol. Temporal discounting was substantially increased for low vs. high reward magnitudes, but this magnitude effect was largely unaffected by Haloperidol. These results were corroborated by model-free analyses as well as modeling via more standard approaches using softmax action selection. We previously reported elevated caudate activation under Haloperidol in this sample of participants, supporting the idea that Haloperidol elevated dopamine neurotransmission, e.g. by blocking inhibitory feedback via presynaptic D2 autoreceptors. The present modeling results show that during inter-temporal choice, this leads to attenuated temporal discounting and increased response vigor (shorter non-decision times).
Gut-resident microorganisms and their genes are associated with cognition and neuroanatomy in children
Authors: Bonham Kevin S , Bottino Guilherme Fahur , McCann Shelley Hoeft , Beauchemin Jennifer , Weisse Elizabeth , Barry Fatoumata , Cano-Lorente Rosa ,   RESONANCE Consortium, Huttenhower Curtis , Bruchhage Muriel M.K. , D'Sa Viren , Deoni Sean , Klepac-Ceraj Vanja
Published: February 2020

The gastrointestinal tract, its resident microorganisms, and the central nervous system are connected by biochemical signaling, also known as "microbiome-gut-brain-axis." Both the human brain and the gut microbiome have critical developmental windows in the first years of life, raising the possibility that their development is co-occurring and likely co-dependent. Emerging evidence implicates gut microorganisms and microbiota composition in cognitive outcomes and neurodevelopmental disorders (e.g., autism and anxiety), but the influence of gut microbial metabolism on typical neurodevelopment has not been explored in detail. We investigated the relationship of the microbiome with the neuroanatomy and cognitive function of 361 healthy children, demonstrating that differences in gut microbial taxa and gene functions are associated with overall cognitive function and with differences in the size of multiple brain regions. Using a combination of multivariate linear and machine learning (ML) models, we showed that many species, including Gordonibacter pamelae and Blautia wexlerae, were significantly associated with higher cognitive function, while some species such as Ruminococcus gnavus were more commonly found in children with low cognitive scores after controlling for sociodemographic factors. Microbial genes for enzymes involved in the metabolism of neuroactive compounds, particularly short-chain fatty acids such as acetate and propionate, were also associated with cognitive function. In addition, ML models were able to use microbial taxa to predict the volume of brain regions, and many taxa that were identified as important in predicting cognitive function also dominated the feature importance metric for individual brain regions. For example, B. wexlerae was the most important species in models predicting the size of the parahippocampal region in both the left and right hemispheres, while several species from the phylum Bacteroidetes, including GABA-producing B. ovatus, were important for predicting the size of the left accumbens area, but not the right. These findings provide potential biomarkers of neurocognition and brain development and may lead to the future development of targets for early detection and early intervention.
RNA binding protein hnRNP-U is required for physiological hypertrophy of skeletal muscle
Authors: Bagchi Debalina , Mason Benjamin D , Baldino Kodilichi , Li Bin , Lee Eun-Joo , Zhang Yuteng , Chu Linh Khanh , el Raheb Sherif , Sinha Indranil , Neppl Ronald L
Published: February 2020

Skeletal muscle has the remarkable ability to modulate its mass in response to physiological changes associated with nutritional input, functional utilization, systemic disease, and age. A decreased responsiveness to anabolic stimuli is thought to contribute significantly to the loss of skeletal muscle mass and strength associated with sarcopenia, however the molecular mechanisms precipitating this are unclear. The signal transduction pathways that control the relative balance between anabolic and catabolic processes are tightly regulated at the transcriptional and post-transcriptional levels. Alternative splicing produces multiple protein isoforms from a single gene in a cell-type-specific manner and in response to environmental cues. We show that sustained activation of Akt1 inHnrnpudeficient mice leads to premature muscle wasting, in part, through impaired autophagy while providing mechanistic insights into the development of anabolic resistance.
Amphibians in the Brazilian Cerrado: diversity, research effort and conservation
Authors: Alves Enne Gomes , Pelicice Fernando Mayer
Published: February 2020

In order to investigate the relationship among amphibian diversity, research effort and conservation status across the Brazilian Cerrado, we carried out a scientometric analysis. Scientific publications were searched in international databases, totaling 72 studies, with 177 taxa recorded. Most studies occurred in the Southeast and Midwest regions of the country, followed by Northeast and North. The first two regions summed almost all taxa; controlling for sampling effort, however, northern regions appeared more diverse. Moreover, northern regions still preserve much of the original vegetation, while savanna in Southeast and Midwest regions has been significantly suppressed. These differences indicate particular geographical needs: immediate conservation efforts to protect diversity and restore savannas in Southeast and Midwest regions; and basic research effort (inventory) to uncover biodiversity in northern Cerrado areas.
Gut bacterial deamination of residual levodopa medication for Parkinson’s disease
Authors: van Kessel Sebastiaan P. , de Jong Hiltje R. , Winkel Simon L. , van Leeuwen Sander S. , Nelemans Sieger A. , Permentier Hjalmar , Keshavarzian Ali , Aidy Sahar El
Published: February 2020

Aromatic bacterial metabolites are attracting considerable attention due to their impact on gut homeostasis and host’s physiology.Clostridium sporogenesis a key contributor to the production of these bioactive metabolites in the human gut. Here, we show thatC. sporogenesdeaminates levodopa, the main treatment in Parkinson’s disease, and identify the aromatic aminotransferase responsible for the initiation of the deamination pathway. The deaminated metabolite from levodopa, 3-(3,4-dihydroxyphenyl)propionic acid, elicits an inhibitory effect on ileal motility in anex vivomodel. 3-(3,4-dihydroxyphenyl)propionic acid is detected in fecal samples of Parkinson’s disease patients on levodopa medication. Our data are of significant impact to the treatment of Parkinson’s disease, where constipation is reported as the most common gastrointestinal symptom. Overall, this study underpins the importance of the metabolic pathways of the gut microbiome involved in drug metabolism not only to preserve drug effectiveness, but also to avoid potential side effects of bacterial breakdown products of the unabsorbed residue of medication.