bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of the cell-binding component of the
Clostridium difficile
binary toxin reveals a di-heptamer macromolecular assembly
Authors: Xu Xingjian , Godoy-Ruiz Raquel , Adipietro Kaylin A. , Peralta Christopher , Ben-Hail Danya , Varney Kristen M. , Cook Mary E. , Roth Braden M. , Wilder Paul T. , Cleveland Thomas , Grishaev Alexander , Neu Heather M. , Michel Sarah L. J. , Yu Wenbo , Beckett Dorothy , Rustandi Richard R. , Lancaster Catherine , Loughney John W. , Kristopeit Adam , Christanti Sianny , Olson Jessica W. , MacKerell Alexander D. , Georges Amedee des , Pozharski Edwin , Weber David J.
Published: January 2020

Targeting
Clostridium difficile
infection is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent
C. difficile
strains often have a binary toxin termed the
C. difficile
toxin, in addition to the enterotoxins TsdA and TsdB. The
C. difficile
toxin has an enzymatic component, termed CDTa, and a pore-forming or delivery subunit termed CDTb. CDTb was characterized here using a combination of single-particle cryoelectron microscopy, X-ray crystallography, NMR, and other biophysical methods. In the absence of CDTa, 2 di-heptamer structures for activated CDTb (1.0 MDa) were solved at atomic resolution, including a symmetric (
Sym
CDTb; 3.14 Å) and an asymmetric form (
Asym
CDTb; 2.84 Å). Roles played by 2 receptor-binding domains of activated CDTb were of particular interest since the receptor-binding domain 1 lacks sequence homology to any other known toxin, and the receptor-binding domain 2 is completely absent in other well-studied heptameric toxins (i.e., anthrax). For
Asym
CDTb, a Ca
2+
binding site was discovered in the first receptor-binding domain that is important for its stability, and the second receptor-binding domain was found to be critical for host cell toxicity and the di-heptamer fold for both forms of activated CDTb. Together, these studies represent a starting point for developing structure-based drug-design strategies to target the most severe strains of
C. difficile
.
Reconstruction of plasma density profiles by measuring spectra of radiation emitted from oscillating plasma dipoles
Authors: Kylychbekov S , Song H S , Kwon K B , Ra O , Yoon E S , Chung M , Yu K , Yoffe S R , Ersfeld B , Jaroszynski D A , Hur M S
Published: January 2020

We suggest a new method for characterising non-uniform density distributions of plasma by measuring the spectra of radiation emitted from a localised plasma dipole oscillator excited by colliding electromagnetic pulses. The density distribution can be determined by scanning the collision point in space. Two-dimensional particle-in-cell simulations demonstrate the reconstruction of linear and nonlinear density profiles corresponding to laser-produced plasma. The method can be applied to a wide range of plasma, including fusion and low temperature plasmas. It overcomes many of the disadvantages of existing methods that only yield average densities along the path of probe pulses, such as interferometry and spectroscopy.
Bidirectional tactile display driven by electrostatic dielectric elastomer actuator
Authors: Phung Hoa , Nguyen Canh Toan , Jung Hosang , Nguyen Tien Dat , Choi Hyouk Ryeol
Published: January 2020

This paper presents a novel bidirectional tactile display by integrating an antagonistic dielectric elastomer actuator (DEA) with a V-shaped electrostatic actuator (EA), called electrostatic dielectric elastomer actuator (EDEA). Within a simple structure, this device can provide large out-of-plane vibration of the silicone-based DEA membrane. It is noted that, compared to the DEA alone, combining the soft DEA and electrostatic actuator significantly enhances the device performance by about 19.1% in terms of displacement and by about 14%–26% in terms of blocking force. We also analyze the constitutive DEA and EA models to predict the displacement and blocking force behaviors. The simulation results are consistent with the experimental results. The device is successfully fabricated by using 3D printing technology which simplifies the fabrication process and improves the scalability of the system. The tactile display can provide up to 680 μm of displacement and up to 185 mN of blocking force more than the human hand stimulus threshold (displacement/force). By controlling the input voltage and frequency, the device can generate different haptic feelings to the user.
Collective effects of link failures in linear flow networks
Authors: Kaiser Franz , Strake Julius , Witthaut Dirk
Published: January 2020

The reliable operation of supply networks is crucial for the proper functioning of many systems, ranging from biological organisms such as the human blood transport system or plant leaves to man-made systems such as power grids or gas pipelines. Whereas the failure of single transportation links has been analysed thoroughly, the understanding of multiple failures is becoming increasingly important to prevent large scale damages. In this publication, we examine the collective nature of the simultaneous failure of several transportation links. In particular, we focus on the difference between single link failures and the collective failure of several links. We demonstrate that collective effects can amplify or attenuate the impacts of multiple link failures—and even lead to a reversal of flows on certain links. A simple classifier is introduced to predict the overall strength of collective effects that we demonstrate to be generally stronger if the failing links are close to each other. Finally, we establish an analogy between link failures in supply networks and dipole fields in discrete electrostatics by showing that multiple failures may be treated as superpositions of multiple electrical dipoles for lattice-like networks. Our results show that the simultaneous failure of multiple links may lead to unexpected effects that cannot be easily described using the theoretical framework for single link failures.
Resective epilepsy surgery in tuberous sclerosis complex: a nationwide multicentre retrospective study from China
Authors: Liu Shiyong , Yu Tao , Guan Yuguang , Zhang Kai , Ding Ping , Chen Lei , Shan Yongzhi , Guo Qiang , Liu Qingzhu , Yao Yi , Yang Meihua , Zhang Shaohui , Lin Yuanxiang , Zhao Rui , Mao Zhiqi , Zhang Juncheng , Zhang Chunqing , Zhang Rui , Yang Zhiquan , Qian Ruobing , Li Yunlin , Zhang Guangming , Yuan Liu , Yang Weidong , Tian Hong , Zhang Hua , Li Wenling , Zhang Xinwei , Yin Jian , Guo Yanwu , Zou Liping , Qin Jiong , Fang Fang , Wang Xu , Ge Ming , Liang Shuli
Published: January 2020

At least 50% of patients with tuberous sclerosis complex present with intractable epilepsy; for these patients, resective surgery is a treatment option. Here, we report a nationwide multicentre retrospective study and analyse the long-term seizure and neuropsychological outcomes of epilepsy surgery in patients with tuberous sclerosis complex. There were 364 patients who underwent epilepsy surgery in the study. Patients’ clinical data, postoperative seizure outcomes at 1-, 4-, and 10-year follow-ups, preoperative and postoperative intelligence quotients, and quality of life at 1-year follow-up were collected. The patients’ ages at surgery were 10.35 ± 7.70 years (range: 0.5–47). The percentage of postoperative seizure freedom was 71% (258/364) at 1-year, 60% (118/196) at 4-year, and 51% (36/71) at 10-year follow-up. Influence factors of postoperative seizure freedom were the total removal of epileptogenic tubers and the presence of outstanding tuber on MRI at 1- and 4-year follow-ups. Furthermore, monthly seizure (versus daily seizure) was also a positive influence factor for postoperative seizure freedom at 1-year follow-up. The presence of an outstanding tuber on MRI was the only factor influencing seizure freedom at 10-year follow-up. Postoperative quality of life and intelligence quotient improvements were found in 43% (112/262) and 28% (67/242) of patients, respectively. Influence factors of postoperative quality of life and intelligence quotient improvement were postoperative seizure freedom and preoperative low intelligence quotient. The percentage of seizure freedom in the tuberectomy group was significantly lower compared to the tuberectomy plus and lobectomy groups at 1- and 4-year follow-ups. In conclusion, this study, the largest nationwide multi-centre study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient.
High Rates of Influenza-Associated Invasive Pulmonary Aspergillosis May Not Be Universal: A Retrospective Cohort Study from Alberta, Canada
Authors: Schwartz Ilan S , Friedman Daniel Z P , Zapernick Lori , Dingle Tanis C , Lee Nelson , Sligl Wendy , Zelyas Nathan , Smith Stephanie W
Published: January 2020

From 2014–2019, invasive pulmonary aspergillosis complicated 7.2% (0–23.1% in different influenza seasons) of cases of influenza-associated respiratory failure in Edmonton, Alberta. Disease outcomes ranged from survival without therapy to death despite antifungals. Clinician vigilance, longitudinal local surveillance, and refined criteria to identify patients requiring therapy are needed.
The African Green Monkey Model of Pneumonic Plague and US Food and Drug Administration Approval of Antimicrobials Under the Animal Rule
Authors: Hewitt Judith A , Lanning Lynda L , Campbell Joseph L
Published: January 2020

Background

Additional treatment options for pneumonic plague, the most severe form of infection by Yersinia pestis, are needed, as past US Food and Drug Administration (FDA) approvals were not based on clinical trials that meet today’s standards, and multiple drugs are sought to counter resistance or use in special populations. Due to the sporadic nature of outbreaks and the low number of pneumonic cases of disease, we sought FDA approval of antimicrobials for treatment under the Animal Efficacy Rule, where efficacy can be demonstrated in 1 or more well-characterized animal models that sufficiently represent human disease.

Methods

A model was developed in African green monkeys (AGMs) after challenge with a lethal dose of Y. pestis delivered as an aerosol, in 4 independent studies in 3 laboratories. The primary data points were bacteremia (daily), body temperature and heart rate (continuously monitored by telemetry), and survival. In antimicrobial efficacy studies, human-equivalent doses of gentamicin, ciprofloxacin, levofloxacin, and doxycycline were administered upon fever onset for 10 days.

Results

Disease in AGMs was similar to case reports of human disease. Fever was determined to be a reliable sign of disease and selected as a treatment trigger. Gentamicin was 60%–80% effective depending on the dose given to animals. Ciprofloxacin and levofloxacin were found to be >90% efficacious. These data were submitted to FDA and plague indications were approved. Doxycycline was less effective.

Conclusions

The AGM model of pneumonic plague is reproducible, well-characterized, and mimics human disease. It has been used to support plague indications for fluoroquinolones and to test the efficacy of additional antimicrobials.
Measurement of Equilibrium Angiotensin II in the Diagnosis of Primary Aldosteronism
Authors: Guo Zeng , Poglitsch Marko , McWhinney Brett C , Ungerer Jacobus P J , Ahmed Ashraf H , Gordon Richard D , Wolley Martin , Stowasser Michael
Published: January 2020

Background

Many medications (including most antihypertensives) and physiological factors affect the aldosterone/renin ratio (ARR) when screening for primary aldosteronism (PA). We sought to validate a novel equilibrium angiotensin II (eqAngII) assay and compare correlations between the aldosterone/angiotensin II ratio (AA2R) and the current ARR under conditions affecting the renin-angiotensin system.

Methods

Among 78 patients recruited, PA was excluded in 22 and confirmed in 56 by fludrocortisone suppression testing (FST). Peripheral levels of eqAngII, plasma renin activity (PRA) and direct renin concentration (DRC) were measured.

Results

EqAngII showed good consistency with DRC and PRA independent of PA diagnosis, posture, and fludrocortisone administration. EqAngII showed close (P < 0.01) correlations with DRC (r = 0.691) and PRA (r = 0.754) during FST. DRC and PRA were below their assays’ functional sensitivity in 43.9% and 15.1%, respectively, of the total 312 samples compared with only 7.4% for eqAngII (P < 0.01). Bland-Altman analysis revealed an overestimation of PRA and DRC compared with eqAngII in a subset of samples with low renin levels. The AA2R showed not only consistent changes with the ARR but also close (P < 0.01) correlations with the ARR, whether renin was measured by DRC (r = 0.878) or PRA (r = 0.880).

Conclusions

Dynamic changes of eqAngII and the AA2R show good consistency and close correlations with renin and the ARR. The eqAngII assay shows better sensitivity than DRC and PRA assays, especially at low concentrations. Whether the AA2R can reduce the impact of some factors that influence the diagnostic power of the ARR warrants further study.
Debiasing International Economic Law
Authors: Puig Sergio
Published: January 2020

A flourishing number of bodies evaluate the conduct of government officials against broad standards, decide complex questions of scientific probity and calculate the present value of past decisions. The effects of implicit biases (systematic patterns of deviation from rationality in judgment) impact the assessment of these issues, which are central to international economic law. Such effects are well understood by psychologists and increasingly confirmed by experiments involving legal actors, including judges. In this article, I provide three concrete examples of implicit biases affecting international tax, trade and investment adjudication, and I call for the incorporation of mechanisms to overcome such biases as well as their strategic exploitation by litigants. At a conceptual level, I propose a typology to think of ‘debiasing tools’ for international adjudication – mechanisms that can act as a centrepiece of coordination of information rather than mere inoculants of the habits of mind on adjudicators. At a normative level, I pose that biases may impact confidence in dispute settlement systems and that both concerns for sovereignty and a predilection for negotiated solutions make international economic law ripe for testing these interventions.
Role of ethylene response factors (ERFs) in fruit ripening
Authors: Gao Jin , Zhang Yaoxin , Li Zhengguo , Liu Mingchun
Published: January 2020

The ethylene response factors (ERFs) belong to the APETALA2/ethylene response factor (AP2/ERF) superfamily and act downstream of the ethylene signalling pathway to regulate the expression of ethylene responsive genes. In different species, ERFs have been reported to be involved in plant development, flower abscission, fruit ripening, and defense responses. In this review, based on the new progress made by recent studies, we summarize the specific role and mode of action of ERFs in regulating different aspects of ripening in both climacteric and non-climacteric fruits, and provide new insights into the role of ethylene in non-climacteric fruit ripening.
Feigin–Frenkel Image of Witten–Kontsevich Points
Authors: Luu Martin T
Published: January 2020

The Witten–Kontsevich KdV tau function of topological gravity has a generalization to an arbitrary Drinfeld–Sokolov hierarchy associated to a simple complex Lie algebra. Using the Feigin–Frenkel isomorphism we describe the affine opers describing such generalized Witten–Kontsevich functions in terms of Segal–Sugawara operators associated to the Langlands dual Lie algebra. In the case where the Lie algebra is simply laced there is a second role these Segal–Sugawara operators play: their action, in the basic representation of the affine algebra associated to the Lie algebra, singles out the Witten–Kontsevich tau function within the phase space. We show that these two Langlands dual roles of Segal–Sugawara operators correspond to a duality between the first and last operator for a complete set of Segal–Sugawara operators.
Evaluating predictive markers for viral rebound and safety assessment in blood and lumbar fluid during HIV-1 treatment interruption
Authors: De Scheerder Marie-Angélique , Van Hecke Clarissa , Zetterberg Henrik , Fuchs Dietmar , De Langhe Nele , Rutsaert Sofie , Vrancken Bram , Trypsteen Wim , Noppe Ytse , Van Der Gucht Bea , Pelgrom Jolanda , Van Wanzeele Filip , Palmer Sarah , Lemey Philippe , Gisslén Magnus , Vandekerckhove Linos
Published: January 2020

Background

Validated biomarkers to evaluate HIV-1 cure strategies are currently lacking, therefore requiring analytical treatment interruption (ATI) in study participants. Little is known about the safety of ATI and its long-term impact on patient health.

Objectives

ATI safety was assessed and potential biomarkers predicting viral rebound were evaluated.

Methods

PBMCs, plasma and CSF were collected from 11 HIV-1-positive individuals at four different timepoints during ATI (NCT02641756). Total and integrated HIV-1 DNA, cell-associated (CA) HIV-1 RNA transcripts and restriction factor (RF) expression were measured by PCR-based assays. Markers of neuroinflammation and neuronal injury [neurofilament light chain (NFL) and YKL-40 protein] were measured in CSF. Additionally, neopterin, tryptophan and kynurenine were measured, both in plasma and CSF, as markers of immune activation.

Results

Total HIV-1 DNA, integrated HIV-1 DNA and CA viral RNA transcripts did not differ pre- and post-ATI. Similarly, no significant NFL or YKL-40 increases in CSF were observed between baseline and viral rebound. Furthermore, markers of immune activation did not increase during ATI. Interestingly, the RFs SLFN11 and APOBEC3G increased after ATI before viral rebound. Similarly, Tat-Rev transcripts were increased preceding viral rebound after interruption.

Conclusions

ATI did not increase viral reservoir size and it did not reveal signs of increased neuronal injury or inflammation, suggesting that these well-monitored ATIs are safe. Elevation of Tat-Rev transcription and induced expression of the RFs SLFN11 and APOBEC3G after ATI, prior to viral rebound, indicates that these factors could be used as potential biomarkers predicting viral rebound.
Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the treatment of Clostridioides (Clostridium) difficile infection in patients aged 60 years and older in the EXTEND randomized controlled trial
Authors: Guery Benoit , Georgopali Areti , Karas Andreas , Kazeem Gbenga , Michon Ingrid , Wilcox Mark H , Cornely Oliver A
Published: January 2020

Background

Fidaxomicin is a recommended treatment for Clostridioides difficile infection (CDI) and reduces CDI recurrence incidence versus vancomycin. An extended-pulsed fidaxomicin (EPFX) regimen further reduces recurrence frequency. However, the pharmacokinetic profile of fidaxomicin in an EPFX regimen is unknown.

Objectives

To evaluate plasma and stool concentrations of fidaxomicin and its metabolite, OP-1118, after EPFX administration for CDI.

Methods

In the Phase 3b/4 EXTEND trial, patients aged ≥60 years with toxin-confirmed CDI were randomized to receive EPFX (oral fidaxomicin twice daily, Days 1–5; once daily on alternate days, Days 7–25). Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on Days 5 ± 1, 12 ± 1 and 25/26, and post-dose stool samples obtained on Days 5 ± 1, 12 ± 1 and 26 ± 1.

Results

Plasma samples from 14 patients were included in the pharmacokinetic analysis; 12 of these patients provided stool samples. Median (range) plasma concentrations of fidaxomicin on Day 5 ± 1 and Day 25/26 were 0.0252 (0.0038–0.1220) mg/L and 0.0069 (0–0.0887) mg/L, respectively, and those of OP-1118 were 0.0648 (0.0142–0.3250) mg/L and 0.0206 (0–0.3720) mg/L, respectively. Median (range) stool concentrations of fidaxomicin and OP-1118 on Day 26 ± 1 were 272.5 (0–524) mg/kg and 280.5 (0–1120) mg/kg, respectively.

Conclusions

EPFX treatment maintained fidaxomicin stool concentrations above the C. difficile MIC90 until Day 26 ± 1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during treatment.
The potential for developing new antimicrobial resistance from the use of medical devices containing chlorhexidine, minocycline, rifampicin and their combinations: a systematic review
Authors: Reitzel Ruth A , Rosenblatt Joel , Gerges Bahgat Z , Jarjour Andrew , Fernández-Cruz Ana , Raad Issam I
Published: January 2020

Background

Catheter infections remain one of the most persistent adverse events causing significant morbidity, economic impact and mortality. Several strategies have been proposed to reduce these infections including the use of catheters embedded with antibiotics and/or antiseptics. One reoccurring challenge is the fear that antimicrobial medical devices will induce resistance. The aim of this systematic review is to evaluate the evidence for induced antimicrobial resistance caused by exposure to antimicrobial medical devices.

Methods

Four electronic databases [MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus] were screened for studies published between 1983 and 2019 regarding assessment of microbial resistance with use of medical devices containing chlorhexidine, minocycline, rifampicin or combinations thereof. Development of new resistance, selection for tolerant organisms and ‘no change in resistance’ were assessed.

Results

Forty-four publications, grouped by study type and stratified by drug assessed, were included for analyses. The majority of studies found no change in resistance after exposure to antimicrobial medical devices (13 in vitro, 2 in vivo, 20 clinical). Development of new resistance was commonly reported with the use of rifampicin as a single agent and only reported in one study assessing the minocycline/rifampicin combination (M/R); however, the increase in MIC was well below clinical relevance.

Conclusions

Emergence of new resistance to combinations of M/R, minocycline/rifampicin/chlorhexidine (M/R/CH) and chlorhexidine/silver sulfadiazine (CHXSS) was rare. No clinical trials confirmed its occurrence and some refuted it. The risk of development of new resistance to these antimicrobial combinations appears more fear-based than substantiated by clinical and experimental evidence but warrants continued surveillance.
Efficacy of a hydrogel spacer in three-dimensional conformal radiation therapy for prostate cancer
Authors: Ogita Mami , Yamashita Hideomi , Sawayanagi Subaru , Takahashi Wataru , Nakagawa Keiichi
Published: January 2020

Objectives

We aimed to compare the dose constraints fulfillment rate of the three-dimensional conformal radiotherapy treatment plan before and after a hydrogel spacer insertion.

Methods

The planning computed tomography scans of 39 patients who received stereotactic body radiotherapy for prostate cancer were used. All patients inserted a hydrogel spacer and underwent computed tomography scans before and after spacer insertion. The three-dimensional conformal radiotherapy plans according to NCCN classification, low-, intermediate- and high-risk, were made for each patient. Clinical target volume included prostate and seminal vesicle 2 cm for high risk, prostate and seminal vesicle 1 cm for intermediate risk and prostate only for low risk. Three-dimensional conformal radiotherapy including a seven-field conformal technique with 76 Gy in 38 fractions. Dose constraints for rectum and bladder were V70 Gy ≤ 15%, V65 Gy ≤ 30% and V40 Gy ≤ 60%.

Results

Among 39 patients, 35 (90%), 19 (49%) and 13 (33%) and 38 (97%), 38 (97%) and 34 (87%) patients before and after the spacer insertion fulfilled rectum dose constraints for low-, intermediate- and high-risk plans, respectively. A hydrogel spacer significantly reduced rectum dose and improved the rectum dose constraints fulfillment rate in intermediate (P < 0.01) and high (P < 0.01), but no difference was found in low-risk plan (P = 0.25). On multivariate analysis, spacer use was associated with the higher rectum dose constraints fulfillment rate.

Conclusions

A hydrogel spacer reduced rectum dose and improved the dose constraints fulfillment rate in three-dimensional conformal radiotherapy plan. Although IMRT is the standard treatment, 3D-CRT using a hydrogel spacer may be a treatment option.
Constraining the fraction of core-collapse supernovae harbouring choked jets with high-energy neutrinos
Authors: Guetta Dafne , Rahin Roi , Bartos Imre , Della Valle Massimo
Published: January 2020

The joint observation of core-collapse supernovae with gamma-ray bursts shows that jets can be launched in the aftermath of stellar core collapse, likely by a newly formed black hole that accretes matter from the star. Such gamma-ray bursts have only been observed accompanying Type Ibc supernovae, indicating a stellar progenitor that lost its hydrogen envelope before collapse. According to recent hypothesis, it is possible that jets are launched in core-collapse events even when the progenitors still retain their hydrogen envelopes; however, such jets are not able to burrow through the star and will be stalled into the interior of the progenitor star before escaping. These jets are called choked jets. High-energy neutrinos produced by such choked jets could escape the stellar envelope and could be observed. Here, we examine how multimessenger searches for high-energy neutrinos and core-collapse supernovae can detect or limit the fraction of stellar collapses that produce jets. We find that a high fraction of jet production is already limited by previous observational campaigns. We explore possibilities with future observations using Large Synoptic Survey Telescope, IceCube, and Km3NET.
Ancient DNA Evidence from China Reveals the Expansion of Pacific Dogs
Authors: Zhang Ming , Sun Guoping , Ren Lele , Yuan Haibing , Dong Guanghui , Zhang Lizhao , Liu Feng , Cao Peng , Ko Albert Min-Shan , Yang Melinda A , Hu Songmei , Wang Guo-Dong , Fu Qiaomei
Published: January 2020

The ancestral homeland of Australian dingoes and Pacific dogs is proposed to be in South China. However, the location and timing of their dispersal and relationship to dog domestication is unclear. Here, we sequenced 7,000- to 2,000-year-old complete mitochondrial DNA (mtDNA) genomes of 27 ancient canids (one gray wolf and 26 domestic dogs) from the Yellow River and Yangtze River basins (YYRB). These are the first complete ancient mtDNA of Chinese dogs from the cradle of early Chinese civilization. We found that most ancient dogs (18/26) belong to the haplogroup A1b lineage that is found in high frequency in present-day Australian dingoes and precolonial Pacific Island dogs but low frequency in present-day China. Particularly, a 7,000-year-old dog from the Tianluoshan site in Zhejiang province possesses a haplotype basal to the entire haplogroup A1b lineage. We propose that A1b lineage dogs were once widely distributed in the YYRB area. Following their dispersal to South China, and then into Southeast Asia, New Guinea and remote Oceania, they were largely replaced by dogs belonging to other lineages in the last 2,000 years in present-day China, especially North China.
Developmental biology meets toxicology: contributing reproductive mechanisms to build adverse outcome pathways
Authors: Draskau Monica Kam , Spiller Cassy M , Boberg Julie , Bowles Josephine , Svingen Terje
Published: January 2020

An adverse outcome pathway (AOP) is a simplified description of the sequence of mechanistic events that lead to a particular toxicological effect, from initial trigger to adverse outcome. Although designed to inform regulatory risk assessors, the AOP framework also provides a platform for innovative collaborations between experts from relevant research fields and the regulatory community. The underpinning for any AOP is basic knowledge about molecular and developmental processes; such knowledge can only be attained by solid bioscientific research. Starting with this fundamental knowledge, the objective is to devise novel testing strategies that focus on key events in a causative pathway. It is anticipated that such a knowledge-based approach will ultimately alleviate many of the burdens associated with classical chemical testing strategies that typically involve large-scale animal toxicity regimens. This hails from the notion that a solid understanding of the underlying mechanisms will allow the development and use of alternative test methods, including both in vitro and in silico approaches. This review is specifically targeted at professionals working in bioscientific fields, such as developmental and reproductive biology, and aims to (i) inform on the existence of the AOP framework and (ii) encourage new cross-disciplinary collaborations. It is hoped that fundamental biological knowledge can thus be better exploited for applied purposes: firstly, an improved understanding of how our perpetual exposure to environmental chemicals is causing human reproductive disease and, secondly, new approaches to screen for harmful chemicals more efficiently. This is not an instructional manual on how to create AOPs; rather, we discuss how to harness fundamental knowledge from the biosciences to assist regulatory toxicologists in their efforts to protect humans against chemicals that harm human reproductive development and function.
Anticipatory-Vicarious Grief: The Anatomy of a Moral Emotion
Authors: Varga Somogy , Gallagher Shaun
Published: January 2020

Grief is often described as characterized by a particular emotional response to another person’s death. While this is true of paradigm cases, we argue that a broader notion of grief allows accommodating forms of this emotional experience that deviate from the paradigmatic case. The bulk of the paper explores such a nonparadigmatic form of grief, anticipatory-vicarious grief (AV-grief), which is typically triggered by pondering the inevitability of our own death. We argue that AV-grief is a particular moral emotion that serves a unique function and is indissolubly linked to the practical identities of human agents. An agent’s AV-grief is about the harm that occurs to individuals whose practical identities depend on the agent.
rRNA expansion segment 27Lb modulates the factor recruitment capacity of the yeast ribosome and shapes the proteome
Authors: Shankar Vaishnavi , Rauscher Robert , Reuther Julia , Gharib Walid H , Koch Miriam , Polacek Norbert
Published: January 2020

Fine-tuned regulation of protein biosynthesis is crucial for cellular fitness and became even more vital when cellular and organismal complexity increased during the course of evolution. In order to cope with this augmented demand for translation control, eukaryal ribosomes have gained extensions both at the ribosomal protein and rRNA levels. Here we analyze the functional role of ES27L, an rRNA expansion segment in the large ribosomal subunit of Saccharomyces cerevisiae. Deletion of the b-arm of this expansion segment, called ES27Lb, did not hamper growth during optimal conditions, thus demonstrating that this 25S rRNA segment is not inherently crucial for ribosome functioning. However, reductive stress results in retarded growth and rendered unique protein sets prone to aggregation. Lack of ES27Lb negatively affects ribosome-association of known co-translational N-terminal processing enzymes which in turn contributes to the observed protein aggregation. Likely as a compensatory response to these challenges, the truncated ribosomes showed re-adjusted translation of specific sets of mRNAs and thus fine-tune the translatome in order to re-establish proteostasis. Our study gives comprehensive insight into how a highly conserved eukaryal rRNA expansion segment defines ribosomal integrity, co-translational protein maturation events and consequently cellular fitness.
SIRT6 coordinates with CHD4 to promote chromatin relaxation and DNA repair
Authors: Hou Tianyun , Cao Ziyang , Zhang Jun , Tang Ming , Tian Yuan , Li Yinglu , Lu Xiaopeng , Chen Yongcan , Wang Hui , Wei Fu-Zheng , Wang Lina , Yang Yang , Zhao Ying , Wang Zimei , Wang Haiying , Zhu Wei-Guo
Published: January 2020

Genomic instability is an underlying hallmark of cancer and is closely associated with defects in DNA damage repair (DDR). Chromatin relaxation is a prerequisite for DDR, but how chromatin accessibility is regulated remains elusive. Here we report that the histone deacetylase SIRT6 coordinates with the chromatin remodeler CHD4 to promote chromatin relaxation in response to DNA damage. Upon DNA damage, SIRT6 rapidly translocates to DNA damage sites, where it interacts with and recruits CHD4. Once at the damage sites, CHD4 displaces heterochromatin protein 1 (HP1) from histone H3 lysine 9 trimethylation (H3K9me3). Notably, loss of SIRT6 or CHD4 leads to impaired chromatin relaxation and disrupted DNA repair protein recruitment. These molecular changes, in-turn, lead to defective homologous recombination (HR) and cancer cell hypersensitivity to DNA damaging agents. Furthermore, we show that SIRT6-mediated CHD4 recruitment has a specific role in DDR within compacted chromatin by HR in G2 phase, which is an ataxia telangiectasia mutated (ATM)-dependent process. Taken together, our results identify a novel function for SIRT6 in recruiting CHD4 onto DNA double-strand breaks. This newly identified novel molecular mechanism involves CHD4-dependent chromatin relaxation and competitive release of HP1 from H3K9me3 within the damaged chromatin, which are both essential for accurate HR.
Dickkopf 3—a novel biomarker of the ‘kidney injury continuum’
Authors: Schunk Stefan J , Speer Thimoteus , Petrakis Ioannis , Fliser Danilo
Published: January 2020

Chronic kidney disease (CKD) is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, progressive CKD leading to uraemia can be seen as a systemic disease with a critical impact on virtually all organ systems. Therefore, it is of particular importance to identify patients with ongoing CKD progression, which is challenging, because the individual course of CKD is difficult to predict. Patterns of progression in CKD patients include linear and non-linear trajectories of GFR loss, but kidney function can also remain stable for years. Moreover, a substantial GFR decline may occur in the absence of higher-grade albuminuria (non-proteinuric CKD), rendering the measurement of albuminuria less reliable for progression prediction in such individuals. In the present review, we focus on the recently identified glycoprotein Dickkopf-3 (DKK3) as a stress-induced, renal tubular epithelial cell-derived, pro-fibrotic molecule. In experimental CKD models, DKK3 promoted renal tubulointerstitial fibrosis through modulation of the canonical Wnt/β-catenin signalling pathway. In clinical studies, increased urinary DKK3 levels identified patients at high risk for short-term CKD progression, regardless of the cause of kidney disease, baseline kidney function and albuminuria. Moreover, increased urinary DKK3 levels are associated with a high risk for acute kidney injury and the subsequent loss of kidney function after cardiac surgery. These findings highlight DKK3 as a mediator of renal tubular cell damage in kidney injury and short-term progression of kidney disease, with potential therapeutic implications.
Land-surface processes and summer-cloud-precipitation characteristics in the Tibetan Plateau and their effects on downstream weather: a review and perspective
Authors: Fu Yunfei , Ma Yaoming , Zhong Lei , Yang Yuanjian , Guo Xueliang , Wang Chenghai , Xu Xiaofeng , Yang Kun , Xu Xiangde , Liu Liping , Fan Guangzhou , Li Yueqing , Wang Donghai
Published: January 2020

Correct understanding of the land-surface processes and cloud-precipitation processes in the Tibetan Plateau (TP) is an important prerequisite for the study and forecast of the downstream activities of weather systems and one of the key points for understanding the global atmospheric movement. In order to show the achievements that have been made, this paper reviews the progress on the observations for the atmospheric boundary layer, land-surface heat fluxes, cloud-precipitation distributions and vertical structures by using ground- and space-based multiplatform, multisensor instruments and the effect of the cloud system in the TP on the downstream weather. The results show that the form drag related to the topography, land–atmosphere momentum and scalar fluxes is an important part of the parameterization process. The sensible heat flux decreased especially in the central and northern TP caused by the decrease in wind speeds and the differences in the ground-air temperatures. Observations show that the cloud and precipitation over the TP have a strong diurnal variation. Studies also show the compressed-air column in the troposphere by the higher-altitude terrain of the TP makes particles inside clouds vary at a shorter distance in the vertical direction than those in the non-plateau area so that precipitation intensity over the TP is usually small with short duration, and the vertical structure of the convective precipitation over the TP is obviously different from that in other regions. In addition, the influence of the TP on severe weather downstream is preliminarily understood from the mechanism. It is necessary to use model simulations and observation techniques to reveal the difference between cloud precipitation in the TP and non-plateau areas in order to understand the cloud microphysical parameters over the TP and the processes of the land boundary layer affecting cloud, precipitation and weather in the downstream regions.
A Retrospective Analysis and Comparison of the STAM and STAMCO Classification and EAONO/JOS Cholesteatoma Staging System in Predicting Surgical Treatment Outcomes of Middle Ear Cholesteatoma
Authors: van der Toom HFE , van der Schroeff MP , Janssen JMH , Westzaan AM , Pauw RJ
Published: January 2020

Objective:

To evaluate and compare the STAM classification, STAMCO classification and the EAONO/JOS staging system as predictors for cholesteatoma recidivism and postoperative hearing, using a large patient cohort in our tertiary referral center.

Method:

Two hundred thirty-one patients who underwent surgery for primary cholesteatoma between 2003 and December 2012 were included and retrospectively classified and staged according to the STAM classification, STAMCO classification, and EAONO/JOS staging system. Data on cholesteatoma recidivism rates and postoperative hearing were collected. The predictive value of the three instruments for recurrent and residual cholesteatoma was compared by using receiver operating characteristic curves.

Results:

For predicting recurrent cholesteatoma, the STAMCO classification was significantly superior compared to the other two instruments. For predicting residual cholesteatoma, the STAMCO classification was superior to the EANO/JOS Staging system. The postoperative hearing shows a significant increase in ABG with increasing extension of cholesteatoma in the CWU group and a significant decrease in AC threshold level with increasing stage and a significant increase in AC with increasing ossicular chain status in the CWD group.

Conclusion:

Based on our study, the STAMCO classification represents the best available predictor for recurrent cholesteatoma and holds most promise for predicting residual cholesteatoma. Extension of cholesteatoma seems to be linked to postoperative hearing and thus the classifications and staging systems may be able to predict postoperative hearing. More studies are needed to assess the validation of these classifications.
Sensitive detection of tumor mutations from blood and its application to immunotherapy prognosis
Authors: Li Shuo , Noor Zorawar , Zeng Weihua , Ni Xiaohui , Yuan Zuyang , Alber Frank , Li Wenyuan , Garon Edward B. , Zhou Xianghong Jasmine
Published: January 2020

Liquid biopsy using cell-free DNA (cfDNA) is attractive for a wide range of clinical applications, including cancer detection, locating, and monitoring. However, developing these applications requires precise and sensitive calling of somatic single nucleotide variations (SNVs) from cfDNA sequencing data. To date, no SNV caller addresses all the special challenges of cfDNA to provide reliable results. Here we present cfSNV, a revolutionary somatic SNV caller with five innovative techniques to overcome and exploit the unique properties of cfDNA. cfSNV provides hierarchical mutation profiling, thanks to cfDNA’s complete coverage of the clonal landscape, and multi-layer error suppression. In both simulated datasets and real patient data, we demonstrate that cfSNV is superior to existing tools, especially for low-frequency somatic SNVs. We also show how the five novel techniques contribute to its performance. Further, we demonstrate a clinical application using cfSNV to select non-small-cell lung cancer patients for immunotherapy treatment.
FGFR3 is a positive regulator of osteoblast expansion and differentiation during zebrafish skull vault development
Authors: Dambroise Emilie , Ktorza Ivan , Brombin Alessandro , Abdessalem Ghaith , Edouard Joanne , Luka Marine , Fiedler Imke , Binder Olivia , Pelle Olivier , Patton E. Elizabeth , Busse Björn , Menager Mickaël , Sohm Frederic , Legeai-Mallet Laurence
Published: January 2020

Gain- or loss-of-function mutations in fibroblast growth factor receptor 3 (FGFR3) result in cranial vault defects - highlighting the protein’s role in membranous ossification. Zebrafish express high levels offgfr3during skull development; in order to study FGFR3’s role in cranial vault development, we generated the firstfgfr3loss-of-function zebrafish(fgfr3lof/lof). The mutant fish exhibited major changes in the craniofacial skeleton, with a lack of sutures, abnormal frontal and parietal bones, and the presence of ectopic bones. Integrated analyses (in vivoimaging, and single-cell RNA sequencing of the osteoblast lineage) of zebrafishfgfr3lof/lofrevealed a delay in osteoblast expansion and differentiation, together with changes in the extracellular matrix. These findings demonstrate thatfgfr3is a positive regulator of osteogenesis. We hypothesize that changes in the extracellular matrix within growing bone impair cell-cell communication, mineralization, and new osteoblast recruitment.
Improving the informativeness of Mendelian disease-derived pathogenicity scores for common disease
Authors: Kim Samuel S. , Dey Kushal K. , Weissbrod Omer , Marquez-Luna Carla , Gazal Steven , Price Alkes L.
Published: January 2020

Despite considerable progress on pathogenicity scores prioritizing both coding and noncoding variants for Mendelian disease, little is known about the utility of these pathogenicity scores for common disease. Here, we sought to assess the informativeness of Mendelian diseasederived pathogenicity scores for common disease, and to improve upon existing scores. We first applied stratified LD score regression to assess the informativeness of annotations defined by top variants from published Mendelian disease-derived pathogenicity scores across 41 independent common diseases and complex traits (averageN= 320K). Several of the resulting annotations were informative for common disease, even after conditioning on a broad set of coding, conserved, regulatory and LD-related annotations from the baseline-LD model. We then improved upon the published pathogenicity scores by developing AnnotBoost, a gradient boosting-based framework to impute and denoise pathogenicity scores using functional annotations from the baseline-LD model. AnnotBoost substantially increased the informativeness for common disease of both previously uninformative and previously informative pathogenicity scores, implying pervasive variant-level overlap between Mendelian disease and common disease. The boosted scores also produced significant improvements in heritability model fit and in classifying disease-associated, fine-mapped SNPs. Our boosted scores have high potential to improve candidate gene discovery and fine-mapping for common disease.
Hepatic Mitochondrial Remodeling is Mechanistically Linked to Insulin Resistance in Nonalcoholic Fatty Liver Disease
Authors: Shannon Chris E. , Ragavan Mukundan , Palavicini Juan Pablo , Fourcaudot Marcel , Bakewell Terry , Jin Eunsook S. , Madesh Muniswamy , Malloy Craig R. , Han Xianlin , Merritt Matthew E. , Norton Luke
Published: January 2020

Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. We investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation in a rodent model of T2D / NAFLD. Livers from obese, insulin resistant mice displayed augmented mitochondrial content and increased TCA cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both covalent (PDK4 and PDP2) and allosteric (intracellular pyruvate availability) mechanisms. Interestingly, improvements in insulin sensitivity and mitochondrial function were entirely dissociated from changes in hepatic triglycerides, diacylglycerides or fatty acids. Instead, we show that the mitochondrial phospholipid cardiolipin undergoes pathological remodeling in livers from obese mice and that this is reversed by insulin sensitization. Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.
Community lifespan, niche expansion and the evolution of interspecific cooperation
Authors: Rodrigues António M. M. , Estrela Sylvie , Brown Sam P.
Published: January 2020

Natural selection favours individuals who maximise their own reproductive success and that of their close relatives. From this perspective, cooperation that benefits individuals of a different species represents an evolutionary conundrum. The theory of mutualism seeks to resolve this puzzle, and it posits that there must be downstream benefits to cooperators that offset any costs inherently associated with interspecific cooperation. Thus, individuals should only further the survival and fecundity of their interspecific partners if this generates additional return benefits, such as food, shelter or protection. A major challenge for the evolution of mutualism is when the ecological niches of partner species overlap, as this creates a tension between the benefits of exchanging services and the costs of competing for shared resources. Here we study the extent to which niche expansion, in which cooperation augments the common pool of resources, can resolve this problem. We find that niche expansion facilitates the evolution of mutualism, especially when populations are at high densities. Further, we show that niche expansion can promote the evolution of reproductive restraint, in which a focal species adaptively sacrifices its own growth rate to increase the density of partner species. We interpret these results in the context of microbial community interactions, which are often characterized by yield-enhancing exchanges of nutrients, termed ‘cross-feeding’. Our findings suggest that yield-enhancing mutualisms are more prevalent in stable habitats with a constant supply of resources, where populations typically live at high densities, but such mutualisms are particularly vulnerable to the emergence of cheats. In general, our findings highlight the need to integrate both temporal and spatial dynamics in the analysis of mutualisms.