bluuebunny/crossref_metadata_2025 huggingface dataset:
Necrotizing fasciitis associated with malignancy
Authors: Chen Leon L. , Tayban Kate , Caravanos Christopher , Shaz David , Halpern Neil A.
Published: August 2019

Necrotizing fasciitis (NF) is a rare soft-tissue condition with a high mortality rate even with treatment. Diagnosis is challenging due to an absence of specific symptoms at the early stages of clinical presentation. NF is typically associated with traumatic injuries, superficial skin breakdown, and surgical procedures. Diabetes mellitus and immunosuppression also increase the risk of developing NF. NF predominantly occurs in the lower extremities, the peritoneum, and the perineum. Treatments include antimicrobials, supportive care, and surgical source control. It is important for clinicians to recognize the association of spontaneous atraumatic NF caused by Clostridium septicum with malignancy, so they can maintain a high index of suspicion and provide timely interventions to optimize patient outcomes.
Optimal and responsible use of antibiotics
Authors: Depuydt Pieter , De Waele Jan J.
Published: August 2019

Purpose of review

In this review, we focus on the dual face of antibiotic therapy in the critically ill that must harmonize the need for early, appropriate and adequate antibiotic therapy in the individual-infected patient with the obligation to limit antibiotic selection pressure as much as possible to preserve its future potential.

Recent findings

Recent articles have highlighted and detailed the various aspects, which determine antibiotic efficacy, and have identified adjunctive treatments, such as source control, which impact outcome. In addition, settings and indications where antibiotics do not improve outcome and may cause harm have been identified.

Reconciling antibiotic efficacy with the limitations of their use is feasible but requires a dedicated and sustained effort throughout the whole process of clinical decision-making, from initial suspicion of sepsis to its definitive treatment.
How “Age” Shapes Health Care
Authors: Powell Suzanne K.
Published: August 2019

Age plays a role in health care: both the age of the case management population and the age of the consumers. The Advisory Group surveyed consumers of 4 different age groups, and differences in health care priorities and wishes are detailed.
Craniosynostosis Treatment Using Distraction Devices
Authors: Katahira Jiro , Hasaegawa Masahiro , Aihara Yasuo , Sakurai Hiroyuki , Kure Robert Katsuhiro , Isago Tsukasa
Published: August 2019

Background:

The authors report on surgical treatment for 20 patients with craniosynostosis in Japan in collaboration with neurosurgery department since 2007. They could safely expand the skull using distraction devices.

Methods:

Total number of patients with craniosynostosis joint surgery was 20 (23 surgeries) at the time of this report. All patients were referred from the neurosurgery department. Neurosurgeons decided the patient selection and the surgical indications, and performed osteotomy, intraoperative measurement of intracranial pressure, and perioperative management. The plastic and reconstructive surgeons set in bone models and simulate bone cutting line preoperatively, and performed skin incisions with flap, set bone distractors or bone absorption plate fitted with flap closure during surgery. Postoperative systemic management was undertaken in the neurosurgery intensive care unit. In the plastic and reconstructive surgery department, postoperative wound care and bone lengthening, and removal of the bone distractors were done.

Results:

All patients showed good bone forms, and there were no patients of serious complications such as meningitis.

Conclusion:

With these roles shared, safe surgery and perioperative management could be performed. Use of the craniosynostosis distraction devices is safe and excellent way, and the authors will continue to explore that direction further.
Surgical Management of Lateral Orbital Contour Following Le Fort III Distraction
Authors: Margulies Ilana G. , Greenberg Alex M. , Taub Peter J.
Published: August 2019

Le Fort III distraction is indicated for the management of skeletal malocclusions, midface hypoplasia, and exorbitism and has been found to be a safe procedure with predictable results. Although variation in the placement of the lateral orbital osteotomy has been described, the classic osteotomy divides the zygomatic arch, crosses the lateral orbital rim, transverses the orbital floor, and ends in the midline. Distraction of this segment may lead to a palpable, and sometimes visible, step deformity between the lower and upper segments of the lateral orbital wall. The authors present a novel approach to the management of the lateral orbital wall step deformity following Le Fort III distraction.
The Use of Dehydrated Human Amniotic Membrane Versus Amniotic/Chorionic Membrane Allografts to Treat Partial Thickness Facial Burns
Authors: Puyana Salomon , Ruiz Samuel , Elkbuli Adel , Bernal Eileen , McKenney Mark , Askari Morad , Lim Rizal , Mir Haaris
Published: August 2019

Background:

Facial burns have significant physical and psychologic effects on patients. Human dehydrated amniotic membrane represents novel technology, yet its outcome has not been sufficiently studied to guide practice. The objective of our study is to compare the benefits of amniotic membrane (DHAM) to amniotic/chorionic membrane (DHACM) skin substitutes to treat partial thickness facial burns.

Methods:

Retrospective review of data collected from our institutional burn registry from 2012 to 2016. Demographic characteristics including age, total body surface area (TBSA) burn and injury severity scores were collected and outcome measures were compared between the 2 groups. Paired sample t-test and Chi-squared were used with significance defined as P < 0.05.

Results:

A total of 77 adult patients with partial thickness facial burns who received DHAM and DHACM skin substitutes were included in the analysis. The mean age for the DHAM group was 39.8 compared to 41.4 for the DHACM. Mean TBSA was similar, with 10.9% in the DHAM group compared to 8.3% in the DHACM. Patients receiving DHAM had higher requirement for skin substitute surgical reapplications as compared to the DHACM group (23.7% versus 5.1%, P ≤ 0.05). Remaining morbidities remained low and not significantly different between patients receiving DHAM and DHACM substitutes (P > 0.05).

Conclusion:

The DHAM and DHACM skin substitutes are valid and safe alternatives in the treatment of adult partial thickness facial burns.
Significance of Hepatectomy in Patients Diagnosed With T2 Gallbladder Cancer
Authors: Li GuangYi , Kim Ji Hun , Jung Woohyun , Hwang Jae Chul , Yang Min Jae , Kim Jin Hong , Yoo Byung Moo , Kim Wook Hwan
Published: August 2019

Background:

A radical surgery is mandatory for advanced gallbladder cancer. However, the appropriate surgical procedure for T2 gallbladder cancer remains controversial because of the difficulty associated with accurate preoperative diagnosis. The aims of the study were to analyze the clinicopathologic features of patients diagnosed with T2 gallbladder cancer and to identify the survival benefit of hepatectomy for such cases.

Methods:

Eighty-four patients, who were diagnosed with pT2 gallbladder cancer from January 1995 to December 2012, were included in this study. Patients were divided into nonhepatectomy and hepatectomy groups.

Results:

Partial hepatectomies were performed in 36 of 84 patients (42.9%). A significant difference in age was observed between the nonhepatectomy and hepatectomy groups (P=0.027). However, no significant differences were observed in sex, tumor size, or pathologic outcome between the 2 groups. No significant difference in survival rate was observed between the 2 groups (5-year survival rate, 60.4% vs. 66.6%). Of the 23 patients who underwent cholecystectomy, 11 (47.8%) were treated with extended surgery as a second operation with curative intent. No remnant tumor was detected at the hepatectomy site in any patient. However, the second operation revealed lymph node metastasis in 2 patients (18.2%). In terms of recurrence, 8 patients (34.7%) had hepatic metastasis. However, the metastatic tumor was away from the resection margin. No significant difference in survival rate was found between the peritoneal and the hepatic side groups (5-year survival rate, 62.5% vs. 73.0%).

Conclusions:

Hepatectomy is not associated with a better survival rate after surgery for T2 gallbladder cancer. Moreover, no recurrence near the gallbladder fossa is observed. In case of T2 gallbladder cancer confirmed by first operation, however, a second operation should be recommended on the basis of accurate nodal staging and additional therapy.
IL-17A Contributes to Lung Fibrosis in a Model of Chronic Pulmonary Graft-versus-host Disease
Authors: Martinu Tereza , McManigle William C. , Kelly Francine L. , Nelson Margaret E. , Sun Jesse , Zhang Helen L. , Kolls Jay K. , Gowdy Kymberly M. , Palmer Scott M.
Published: August 2019

Background.

Chronic pulmonary graft-versus-host disease (cpGVHD) after hematopoietic cell transplant (HCT) manifests as progressive airway and parenchymal lung fibrosis. On the basis of our prior data, mice that undergo allogeneic HCT with Tbet-knockout donors (AlloTbet−/−) have increased lung Th17 cells and IL-17A and develop fibrosis resembling human cpGVHD. The role of IL-17A in posttransplant pulmonary fibrosis remains incompletely understood. We hypothesized that IL-17A is necessary for development of murine cpGVHD in this model.

Methods.

AlloTbet−/− mice received weekly intraperitoneal anti-IL-17A or IgG (200 μg/mouse) starting 2 weeks post-HCT and were sacrificed after week 5. Histologic airway and parenchymal fibrosis were semiquantitatively graded in a blinded fashion. Lung cells and proteins were measured by flow cytometry, ELISA, and multicytokine assays.

Results.

Anti-IL-17A modestly decreased airway and parenchymal lung fibrosis, along with a striking reduction in pulmonary neutrophilia, IL-6, MIP-1α, MIP-1β, CXCL1, and CXCL5 in AlloTbet−/− mice. Additionally, anti-IL-17A decreased CCL2, inflammatory monocytes and macrophages, and Th17 cells.

Conclusions.

In the setting of murine AlloHCT with Tbet−/− donors, IL-17A blockade decreases fibrotic features of cpGVHD. This may be mediated by the observed reduction in neutrophils or specific lung monocyte and macrophage populations or alternatively via a direct effect on fibroblasts. Collectively, our results further suggest that anti-IL-17A strategies could prove useful in preventing alloimmune-driven fibrotic lung diseases.
The Comparable Efficacy of Lung Donation After Circulatory Death and Brain Death: A Systematic Review and Meta-analysis
Authors: Zhou Jian , Chen Boran , Liao Hu , Wang Zihuai , Lyu Mengyuan , Man Shulei , Pu Qiang , Liu Lunxu
Published: August 2019

Background.

Lung transplantations (LTx) have become an effective lifesaving treatment for patients with end-stage lung diseases. While the shortage of lung donor pool and severe posttransplantation complications exaggerate the obstacle of LTx. This meta-analysis aimed to evaluate the efficacy of donation after circulatory death (DCD) in LTx for patients with end-stage lung diseases.

Methods.

PubMed, EmBase, and Web of Science were systematically searched for all relevant studies comparing the efficacy of DCD and conventional donation after brain death (DBD). The relative risk (RR) value as well as the weighted mean difference with a 95% confidence interval (CI) were pooled for dichotomous and continuous outcomes, respectively. The heterogeneity across the included studies was also assessed carefully.

Results.

Overall, 17 studies with 995 DCD recipients and 38 579 DBD recipients were included. The pooled analysis showed comparable 1-year overall survival between the 2 cohorts (RR 0.89, 95% CI, 0.74-1.07, P = 0.536, I
2 = 0%). The airway anastomotic complications rate in DCD cohort was higher than that in DBD cohorts (RR 2.00; 95% CI, 1.29-3.11, P = 0.002, I

2
= 0%). There was no significant difference between DCD and DBD regarding the occurrence of primary graft dysfunction grade 2/3, bronchiolitis obliterans syndrome, acute transplantation rejection, and length of stay. The stability of the included studies was strong.

Conclusions.

Evidence of this meta-analysis indicated that the use of lungs from DCD donors could effectively and safely expand the donor pool and therefore alleviate the crisis of organ shortage.
Rapid improvement of obsessive-compulsive disorder associated with schizophrenia with cariprazine add-on in a subject under paliperidone long-acting injection: a case report
Authors: De Berardis Domenico , Vellante Federica , Fornaro Michele , Orsolini Laura , Valchera Alessandro , Baroni Gaia , Kim Yong-Ku , Martinotti Giovanni , Di Giannantonio Massimo
Published: August 2019

Obsessive-compulsive disorder is often associated with schizophrenia and may represent a significant challenge in the treatment as this comorbidity may not respond properly to antipsychotic medication and usually require a pharmacological and psychotherapeutic add-on. In the present case report, we present the case of a 26-year-old male blue-collar subject who developed obsessive-compulsive disorder after a year of complete remission of schizophrenia symptoms under paliperidone long-acting injection that rapidly resolved after low-dosage cariprazine add-on. No adverse effects were reported due to cariprazine- paliperidone long-acting injection combination.
Patient Benefit and Risk in Anticancer Drug Development: A Systematic Review of the Ixabepilone Trial Portfolio
Authors: Carlisle Benjamin , Mattina James , Zheng Tiger , Kimmelman Jonathan
Published: August 2019

OBJECTIVE

To describe the patient burden and benefit, and the dynamics of trial success in the development of ixabepilone—a drug that was approved in the US but not in Europe.

DATA SOURCES

Trials were captured by searching Embase and MEDLINE on July 27, 2015.

STUDY SELECTION

Inclusion: 1) primary trial reports, 2) interventional trials, 3) human subjects, 4) phase 1 to phase 3, 5) trials of ixabepilone in monotherapy or combination therapy of 6) pre-licensure cancer indications. Exclusion: 1) secondary reports, 2) interim results, 3) meta-analyses, 4) retrospective/observational studies, 5) laboratory analyses (ex vivo tissues), 6) reviews, 7) letters, editorials, guidelines, interviews, abstract-only and poster presentations.

DATA EXTRACTION AND SYNTHESIS

Data were independently double-extracted and differences between coders were reconciled by discussion.

MAIN OUTCOMES AND MEASURES

We measured risk using the number of drug-related adverse events that were grade 3 or higher, benefit by objective response rate and trial outcomes by whether studies met their primary endpoint with acceptable safety.

RESULTS

We identified 39 publications of ixabepilone monotherapy and 23 primary publications of combination therapy, representing 5615 patients and 1598 patient-years of involvement over 11 years and involving 17 different malignancies. In total, 830 patients receiving ixabepilone experienced objective tumour response (16%, 95% CI 12.5%–20.1%), and 74 died from drug-related toxicites (2.2%, 95% CI 1.6%–2.9%). Responding indications and combinations were identified very quickly; thereafter, the search for additional responding indications or combinations did not lead to labelling additions. A total of 11 “uninformative” trials were found, representing 27% of studies testing efficacy, 208 grade 3–4 events and 226 patient-years of involvement (21% and 26% of the portfolio total, respectively). After the European Medicines Agency rejected ixabepilone for licensing, all further trial activity involving ixabepilone was pursued outside of Europe.

DISCUSSION

Risk/benefit for patients who enrolled in trials of non-approved indications of ixabepilone did not improve over the course of the drug’s development. Clinical value was discovered very quickly; however, a large fraction of trials were uninformative.
A metabolic reconstruction ofLactobacillus reuteriJCM 1112 and analysis of its potential as a cell factory
Authors: Kristjansdottir Thordis , Bosma Elleke F. , Santos Filipe Branco dos , Özdemir Emre , Herrgård Markus J. , França Lucas , Ferreira Bruno Sommer , Nielsen Alex T. , Gudmundsson Steinn
Published: August 2019

Background

Lactobacillus reuteriis a heterofermentative Lactic Acid Bacterium (LAB) that is commonly used for food fermentations and probiotic purposes. Due to its robust properties, it is also increasingly considered for use as a cell factory. It produces several industrially important compounds such as 1,3-propanediol and reuterin natively, but for cell factory purposes, developing improved strategies for engineering and fermentation optimization is crucial. Genome-scale metabolic models can be highly beneficial in guiding rational metabolic engineering. Reconstructing a reliable and a quantitatively accurate metabolic model requires extensive manual curation and incorporation of experimental data.

Results

A genome-scale metabolic model ofL. reuteriJCM 1112Twas reconstructed and the resulting model, Lreuteri_530, was validated and tested with experimental data. Several knowledge gaps in the metabolism were identified and resolved during this process, including presence/absence of glycolytic genes. Flux distribution between the two glycolytic pathways, the phosphoketolase and Embden-Meyerhof-Parnas pathways, varies considerably between LAB species and strains. As these pathways result in different energy yields, it is important to include strain-specific utilization of these pathways in the model. We determined experimentally that the Embden-Meyerhof-Parnas pathway carried at most 7% of the total glycolytic flux. Predicted growth rates from Lreuteri_530 were in good agreement with experimentally determined values. To further validate the prediction accuracy of Lreuteri_530, the predicted effects of glycerol addition andadhEgene knock-out, which results in impaired ethanol production, were compared toin vivodata. Examination of both growth rates and uptake- and secretion rates of the main metabolites in central metabolism demonstrated that the model was able to accurately predict the experimentally observed effects. Lastly, the potential ofL. reuterias a cell factory was investigated, resulting in a number of general metabolic engineering strategies.

Conclusion

We have constructed a manually curated genome-scale metabolic model ofL. reuteriJCM 1112Tthat has been experimentally parameterized and validated and can accurately predict metabolic behavior of this important platform cell factory.
Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201
Authors: Amoroso Francesca , Glass Kimberley , Liberal Francisco , Steele Rebecca E. , Maguire Sarah , Tarapore Rohinton , Allen Joshua E. , Van Schaeybroeck Sandra , Butterworth Karl T. , Prise Kevin , O’Sullivan Joe M. , Jain Suneil , Waugh David J. , Mills Ian G.
Published: August 2019

Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. Localised disease is mostly treated with surgery or radiotherapy. As PCa develops and treatment resistance emerges, the unfolded protein response (UPR) arises as an important adaptive biology co-amplifying with key cancer drivers [1]. The UPR can be cytoprotective but when acutely activated can lead to cell death. In this study we sought to enhance the acute activation of the UPR using radiation and ONC201, previously reported to be an UPR activator [2]. We found that treating PCa cells with ONC201 quickly increases the expression of components in all arms of the UPR – ATF4, ATF6 and IRE1-XBP1 – culminating in the subsequent cell death. During this time window between UPR activation and cell death we tested the priming effect of short-term administration of ONC201 on radiation responses. Pre-treatment with ONC201 for 24 hours prior to irradiation led to enhanced cytotoxicity compared to radiation alone assessed by cell viability and clonogenic assays. With priming, RNA-Seq analysis showed a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways. Phenotypically this was reflected in enhanced cell cycle arrest and induction of necrosis and apoptosis. Furthermore, we demonstrated that short-term administration of inhibitors of cell cycle regulators (Dinaciclib and BI2536), could replicate this priming effect. Thus, we propose future studies to assess the impact of the short-term administration of drugs targeting the UPR and cell cycle regulation to enhance radiotherapy response.
Deep microbial community profiling along the fermentation process of pulque, a major biocultural resource of Mexico
Authors: Rocha-Arriaga Carolina , Espinal-Centeno Annie , Martinez-Sanchez Shamayim , Caballero-Pérez Juan , Alcaraz Luis D. , Cruz-Ramirez Alfredo
Published: August 2019

Some of the biggest non-three plants endemic to Mexico were called metl in the Nahua culture. During colonial times they were renamed with the antillan word maguey. This was changed again by Carl von Linné who called them Agave (a greco-latin voice for admirable). For several Mexican prehispanic cultures, Agave species were not only considered as crops, but also part of their biocultural resources and cosmovision. Among the major products obtained from some Agave spp since pre-hispanic times is the alcoholic beverage called pulque or octli. This beverage represents a precolumbian biotechnological development obtained by the natural fermentation of the mead (aguamiel) from such plants. The pulque played a central role in mexican prehispanic cultures, mainly the Mexica and the Tolteca, where it was considered as sacred. For modern Mexicans, pulque is still part of their heritage and, in recent times, there has been a renewed interest in this ancient beverage, due to its high content in nutrients such as essential amino acids. We focus this study in the microbial diversity involved in pulque fermentation process, specially because it is still produced using classic antique technologies,. In this work, we report the microbiome of pulque fermentation stages, using massive sequencing of the 16S rRNA gene and the internal transcribed spacer (ITS) for describing bacterial and fungal diversity and dynamics along pulque production. In this study, we are providing the most diverse catalogue of microbes during pulque production with 57 identified bacterial genus and 94 fungal species, these findings allowed us to identify core microbes resilient during pulque production which point to be potential biomarkers exclusive to each fermentation stage.

Our approach allowed the identification of a broader microbial diversity in Pulque

We increased 4.4 times bacteria genera and 40 times fungal species detected in mead.

Newly reported bacteria genera and fungal species associated to Pulque fermentation
The two-step chemosensory system underlying the oligophagy of silkworm larvae
Authors: Tsuneto Kana , Endo Haruka , Shii Fumika , Sasaki Ken , Nagata Shinji , Sato Ryoichi
Published: August 2019

Oligophagous insect herbivores specifically identify host-plant leaves using their keen sense of taste1. Plant secondary metabolites and sugars are key chemical cues for insects to identify host plants and evaluate their nutritional value, respectively2. However, it is poorly understood how the insect chemosensory system integrates the information from various gustatory inputs. Here we report that a two-step chemosensory system is responsible for host acceptance by larvae of the silkworm Bombyx mori, a specialist for several mulberry species. The first step controlled by a gustatory organ, the maxillary palp (MP), is host-plant recognition during palpation at the leaf edge. Surprisingly, MP detects chlorogenic acid, quercetin glycosides, and β-sitosterol, which stimulate feeding by the silkworm3–6, with ultra-sensitivity (thresholds of aM to fM). Detecting a mixture of these compounds triggers test biting. The second step is evaluation of the sugar content in the leaf sap exuded by test biting. Low-sensitivity chemosensory neurons in another gustatory organ, the maxillary galea (MG), mainly detect sucrose in the leaf sap exuded by test biting, allowing larvae to accept the leaf and proceed to persistent biting. Our present work shows the behavioral and neuronal basis of host acceptance in the silkworm, mainly driven by six phytochemicals. It also reveals that the ultra-sensitive gustation via MP strictly limits initiation of feeding in the silkworm unless it detects a certain combination of host compounds, suggesting an essential role of MP in host-plant selection. The two-step chemosensory system reported herein may commonly underlie stereotyped feeding behavior in phytophagous insects and determine their feeding habits.
Microbial degradation of plastic in aqueous solutions demonstrated by CO2 evolution and quantification
Authors: Rose Ruth-Sarah , Richardson Katherine H. , Latvanen Elmeri Johannes , Hanson China A. , Resmini Marina , Sanders Ian A.
Published: August 2019

The environmental accumulation of plastics worldwide is a consequence of the durability of the material. Alternative polymers, marketed as biodegradable, present a potential solution to mitigate their ecological damage. However, understanding of biodegradability has been hindered by a lack of reproducible testing methods. Here, we present a new approach to assess biodegradability by monitoring bacterial respiration, in an aqueous media supplemented with a polymer as a single carbon source. Rhodococcus rhodochrous and Alcanivorax borkumensis are good model organisms for soil and marine systems respectively, allowing simulations of plastic biodegradation in these key environments. We demonstrate that polymer molecular weight reduction is the critical factor in the biodegradability of low-density polyethylene. Additionally, we tested a wide variety of plastics, including environmentally weathered and laboratory aged samples, using the same method allowing direct comparisons of the relative biodegradability of various polymers.
Network-based functional prediction augments genetic association to predict candidate genes for histamine hypersensitivity in mice
Authors: Tyler Anna L. , Raza Abbas , Krementsov Dimitry N. , Case Laure K. , Huang Rui , Ma Runlin Z. , Blankenhorn Elizabeth P. , Teuscher Cory , Mahoney J. Matthew
Published: August 2019

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is oftenad hocand biased by previous findings. Here we present a technique for computationally prioritizing positional candidates based on computationally inferred gene function. Our method uses machine learning with functional genomic networks, whose links encode functional associations among genes, to identify network-based signatures of functional association to a trait of interest. We demonstrate the method by functionally ranking positional candidates in a large locus on mouse Chr 6 (45.9 Mb to 127.8 Mb) associated with histamine hypersensitivity (Hhs). Hhs is characterized by systemic vascular leakage and edema in response to histamine challenge, which can lead to multiple organ failure and death. Although Hhs risk is strongly influenced by genetics, little is known about its underlying molecular or genetic causes, due to genetic and physiological complexity of the trait. To dissect this complexity, we ranked genes in theHhslocus by predicting functional association with multiple Hhs-related processes. We integrated these predictions with new single nucleotide polymorphism (SNP) association data derived from a survey of 23 inbred mouse strains and congenic mapping data. The top-ranked genes includedCxcl12, Ret, Cacna1c, andCntn3, all of which had strong functional associations and were proximal to SNPs segregating with Hhs. These results demonstrate the power of network-based computational methods to nominate highly plausible quantitative trait genes even in highly challenging cases involving large QTLs and extreme trait complexity.
Vimentin provides the mechanical resilience required for amoeboid migration and protection of the nucleus
Authors: Stankevicins Luiza Da Cunha , Urbanska Marta , Flormann Daniel AD. , Terriac Emmanuel , Mostajeran Zahra , Gad Annica K.B. , Cheng Fang , Eriksson John E. , Lautenschläger Franziska
Published: August 2019

Dendritic cells use amoeboid migration through constricted passages to reach the lymph nodes, and this homing function is crucial for immune responses. Amoeboid migration requires mechanical resilience, however, the underlying molecular mechanisms for this type of migration remain unknown. Because vimentin intermediate filaments (IFs) and microfilaments regulate adhesion-dependent migration in a bidirectional manner, we analyzed if they exert a similar control on amoeboid migration. Vimentin was required for cellular resilience, via a joint interaction between vimentin IFs and F-actin. Reduced actin mobility in the cell cortex of vimentin-reduced cells indicated that vimentin promotes Factin subunit exchange and dynamics. These mechano-dynamic alterations in vimentin-deficient dendritic cells impaired amoeboid migration in confined environments in vitro and blocked lymph node homing in mouse experiments in vivo. Correct nuclear positioning is important in confined amoeboid migration both to minimize resistance and to avoid DNA damage. Vimentin-deficiency also led to DNA double strand breaks in the compressed dendritic cells, pointing to a role of vimentin in nuclear positioning. Together, these observations show that vimentin IF-microfilament interactions provide both the specific mechano-dynamics required for dendritic cell migration and the protection the genome needs in compressed spaces.

Summary statement

Vimentin — in joint action with actin — mediates the mechanical stiffness of cells required for amoeboid cell migration through confined spaces and protects the nucleus from DNA damage.
Noninvasive Prenatal Diagnosis for Duchenne Muscular Dystrophy Based on the Direct Haplotype Phasing
Authors: Chen Min , Chen Chao , Huang Xiaoyan , Sun Jun , Jiang Lu , Li Yingting , Zhu Yaping , Tian Changgeng , Li Yufan , Lu Zhe , Wang Yaoshen , Zeng Fanwei , Yang Yun , Peng Zhiyu , Yin Chenghong , Chen Dunjin
Published: August 2019

Objective

We aimed to investigate the validity of noninvasive prenatal diagnosis (NIPD) based on direct haplotype phasing without the proband and its feasibility for clinical application in the case of Duchenne Muscular Dystrophy (DMD).

Methods

Thirteen singleton-pregnancy families affected by DMD were recruited. Firstly, we resolved maternal haplotypes for each family by performing targeted linked-read sequencing of their high molecular weight DNA, respectively. Then, we identified SNPs of the DMD gene in all carrier mothers and inferred the DMD gene mutation status of all fetuses. Finally, the fetal genotypes were further validated by using chorionic villus sampling.

Results

The method of directly resolving maternal haplotype through targeted linked-read sequencing was smoothly performed in all participated families. The predicted mutational status of 13 fetuses was correct, which had been confirmed by invasive prenatal diagnosis.

Conclusion

Direct haplotyping of NIPD based on linked-read sequencing for DMD is accurate.
Ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling
Authors: Constable Sandii , Long Alyssa B. , Floyd Katharine A. , Schurmans Stéphane , Caspary Tamara
Published: August 2019

Sonic hedgehog (Shh) signal transduction specifies ventral cell fates in the neural tube and is mediated by the Gli transcription factors that play both activator (GliA) and repressor (GliR) roles. Cilia are essential for Shh signal transduction and the ciliary phosphatidylinositol phosphatase, Inpp5e, is linked to Shh regulation. In the course of a forward genetic screen for recessive mouse mutants, we identified a functional null allele ofInpp5e,ridge top (rdg), with expanded ventral neural cell fates at E10.5. By E12.5,Inpp5erdg/rdgembryos displayed normal neural patterning and this correction over time required Gli3, the predominant repressor in neural patterning.Inpp5erdgfunction largely depended on the presence of cilia and on Smoothened, the obligate transducer of Shh signaling, indicating Inpp5e functions within the cilium to regulate the pathway. These data indicate that Inpp5e plays a more complicated role in Shh signaling than previously appreciated. We propose that Inpp5e attenuates Shh signaling in the neural tube through regulation of the relative timing of GliA and GliR production, which is important in understanding how duration of Shh signaling regulates neural tube patterning.

Summary statement

Inpp5e attenuates Sonic hedgehog signal transduction through a combination of positive and negative regulatory roles that likely control the relative timing of Gli processing.
Genetic analysis ofAegilops tauschii-derived seedling resistance to leaf rust in synthetic hexaploid wheat
Authors: Mohler Volker , Schmolke Michael , Zeller Friedrich J. , Hsam Sai L.K.
Published: August 2019

Seedling resistance to leaf rust available in the synthetic hexaploid wheat line Syn137 was characterized by means of cytogenetic and linkage mapping. Monosomic analysis located a single dominant gene for leaf rust resistance on chromosome 5D. Molecular mapping not only confirmed this location but also positioned the gene to the distal part of the long arm of chromosome 5D. A test of allelism showed that the gene, tentatively namedLrSyn137, is independent but closely linked toLr1. It appears that Syn137 is occasionally heterogeneous forLr1since the analysis of theLr1-specific marker RGA567-5 in the mapping population indicated the presence ofLr1. Syn137 represents another source of genetic variation that can be useful for the diversification of leaf rust resistance in wheat cultivars.
Host-specific subtelomere: Genomic architecture of pathogen emergence in asexual filamentous fungi
Authors: Huang Xiaoqiu
Published: August 2019

Several asexual species of filamentous fungal pathogens contain supernumerary chromosomes carrying secondary metabolite (SM) or pathogenicity genes. Supernumerary chromosomes have been shown inin vitroexperiments to transfer from pathogenic isolates to non-pathogenic ones and between isolates whose fusion can result in vegetative or heterokaryon incompatibility (HET). However, much is still unknown about the acquisition and maintenance of SM/pathogenicity gene clusters in the adaptation of these asexual pathogens to their hosts. We investigated several asexual fungal pathogens for genomic elements involved in maintaining telomeres for supernumerary and core chromosomes during vegetative reproduction. We found that in vegetative species or lineages with a nearly complete telomere-to-telomere genome assembly (e.g.Fusarium equisetiand fiveformae specialesof theF. oxysporumspecies complex), core and super-numerary chromosomes were flanked by highly similar subtelomeric sequences on the 3’ side and by their reverse complements on the 5’ side. This subtelomere sequence structure was preserved in isolates from the same species or from polyphyletic lineages in the sameforma specialis(f.sp.) of theF. oxysporumspecies complex. Moreover, between some isolates withinF. oxysporumf.sp.lycopersici, the mean rate of single nucleotide polymorphisms (SNPs) in a supernumerary chromosome was at least 300 times lower than those in core chromosomes. And a large number of HET domain genes were located in SM/pathogenicity gene clusters, with a potential role in maintaining these gene clusters during vegetative reproduction.
Molecular Basis of the Activation and Dissociation of Dimeric PYL2 Receptor in Abscisic Acid Signaling
Authors: Zhao Chuankai , Shukla Diwakar
Published: August 2019

Phytohormone abscisic acid (ABA) is essential for plant responses to biotic and abiotic stresses. Dimeric receptors are a class of ABA receptors that are important for various ABA responses. While extensive experimental and computational studies have investigated these receptors, it remains not fully understood how ABA leads to their activation and dissociation for interaction with downstream phosphatase. Here, we study the activation and the homodimeric association processes of PYL2 receptor as well as its heterodimeric association with the phosphatase HAB1 using molecular dynamics simulations. Free energy landscapes from ~223 μs simulations show that dimerization substantially constrains PYL2 conformational plasticity and stabilizes inactive state, resulting in lower ABA affinity. Also, we establish the thermodynamic model for competitive binding between homodimeric PYL2 association and heterodimeric PYL2-HAB1 association in the absence and presence of ABA. Our results suggest that the binding of ABA destabilizes PYL2 complex and further stabilizes PYL2-HAB1 association, thereby promoting PYL2 dissociation. Overall, this study explains several key aspects on activation of dimeric ABA receptors, which provide new avenues for selective regulation of these receptors.
Systematic assessment of blood-borne microRNAs highlights molecular profiles of endurance sport and carbohydrate uptake
Authors: Kern Fabian , Ludwig Nicole , Backes Christina , Maldener Esther , Fehlmann Tobias , Suleymanov Artur , Meese Eckart , Hecksteden Anne , Keller Andreas , Meyer Tim
Published: August 2019

Multiple studies endorsed the positive effect of regular exercising on mental and physical health. However, the molecular mechanisms underlying training-induced fitness in combination with personal life-style remain largely unexplored. Circulating biomarkers such as microRNAs (miRNAs) offer themselves for studying systemic and cellular changes since they can be collected from the bloodstream in a low-invasive manner. In Homo sapiens miRNAs are known to regulate a substantial number of protein-coding genes in a post-transcriptional manner and hence are of great interest to understand differential gene expression profiles, offering a cost-effective mechanism to study molecular training adaption, and connecting the dots from genomics to observed phenotypes.

Here, we investigated molecular expression patterns of 2, 549 miRNAs in whole-blood samples from 23 healthy and untrained adult participants of a cross-over study, consisting of 8 weeks of endurance training, with several sessions per week, followed by 8 weeks of washout and another 8 weeks of running, using microarrays. Participants were randomly assigned to one of the two study groups, one of which administered carbohydrates before each session in the first training period, switching the treatment group for the second training period. During running sessions clinical parameters as heartbeat frequency were recorded. This information was extended with four measurements of maximum oxygen uptake (VO2 max) for each participant.

We observed that multiple circulating miRNAs show expression changes after endurance training, leveraging the capability to separate the blood samples by training status. To this end, we demon-strate that most of the variance in miRNA expression can be explained by both common and known biological and technical factors. Our findings highlight six distinct clusters of miRNAs, each exhibiting an oscillating expression profile across the four study timepoints, that can effectively be utilized to predict phenotypic VO2 max levels. In addition, we identified miR-532-5p as a candidate marker to determine personal alterations in physical training performance on a case-by-case analysis taking the influence of a carbohydrate-rich nutrition into account. In literature, miR-532-5p is known as a common down-regulated miRNA in diabetes and obesity, possibly providing a molecular link between cellular homeostasis, personal fitness levels, and health in aging.

We conclude that circulating miRNAs expression can be altered due to regular endurance training, independent of the carbohydrate availability in the timeframe around training. Further validation studies are required to confirm the role of exercise-affected miRNAs and the extraordinary function of miR-532-5p in modulating the metabolic response to a high availability of glucose.
Three-fluorophore FRET enables the analysis of ternary protein association in living plant cells
Authors: Glöckner Nina , Oven-Krockhaus Sven zur , Rohr Leander , Wackenhut Frank , Burmeister Moritz , Wanke Friederike , Holzwart Eleonore , Meixner Alfred J. , Wolf Sebastian , Harter Klaus
Published: August 2019

Protein-protein interaction studies provide valuable insights into cellular signaling. The well-studied brassinosteroid (BR) signaling is initiated by the hormone-binding receptor Brassinosteroid Insensitive 1 (BRI1) and its co-receptor BRI1 Associated Kinase 1 (BAK1). BRI1 and BAK1 were shown to interact independently with the Receptor-Like Protein 44 (RLP44), which is implicated in BRI1/BAK1-dependent cell wall integrity perception. To demonstrate the proposed complex formation of BRI1, BAK1 and RLP44, we established three-fluorophore intensity-based spectral Förster resonance energy transfer (FRET) and FRET-fluorescence lifetime imaging microscopy (FLIM) for living plant cells. Our evidence indicates that RLP44, BRI1 and BAK1 form a ternary complex in a distinct plasma membrane nanodomain. In contrast, although the immune receptor Flagellin Sensing 2 (FLS2) also forms a heteromer with BAK1, the FLS2/BAK1 complexes are localized in other nanodomains. In general, our three-fluorophore FRET approaches provide a feasible basis for studying the interaction and sub-compartmentalization of proteins in great detail.
Predicting coral adaptation to global warming in the Indo-West-Pacific
Authors: Matz Mikhail V. , Treml Eric , Haller Benjamin C.
Published: August 2019

The potential of reef-building corals to adapt to increasing sea surface temperatures is often speculated about but has rarely been comprehensively modeled on a region-wide scale. Here, we used individual-based simulations to model adaptation to warming in a coral metapopulation comprising 680 reefs and representing the whole of the Central Indo-West Pacific. We find that in the first century of warming (approximately from 50 years ago to 50 years in the future) corals adapt rapidly by redistributing pre-existing adaptive alleles among populations (“genetic rescue”). In this way, some coral populations - most notably, Vietnam, Japan, Taiwan, New Caledonia, and the southern half of the Great Barrier Reef - appear to be able to maintain their fitness even under the worst warming scenarios (at least in theory, assuming the rate of evolution is the only limitation to local coral recovery). Still, survival of the majority of reefs in the region critically depends on the warming rate, underscoring the urgent need to curb carbon emissions. Conveniently, corals’ adaptive potential was largely independent of poorly known genetic parameters and could be predicted based on a simple metric derived from the biophysical connectivity model: the proportion of recruits immigrating from warmer locations. We have confirmed that this metric correlates with actual coral cover changes throughout the region, based on published reef survey data from the 1970s to early 2000s. The new metric allows planning assisted gene flow interventions to facilitate adaptation of specific coral populations.
The tropical coral Pocillopora acuta has a mosaic DNA methylome, an unusual chromatin structure and shows histone H3 clipping
Authors: Roquis David , Picart Picolo Ariadna , Raffalli Kelly Brener , Romans Pascal , Masanet Patrick , Cosseau Céline , Mitta Guillaume , Grunau Christoph , Vidal-Dupiol Jeremie
Published: August 2019

Pocillopora acuta is a hermatypic coral with a worldwide distribution and a strong ecological importance. Anthropogenic disturbances and global warming threaten it. Thermal stress can induce coral bleaching, a phenomenon in which the mutualistic symbiosis between the coral polyps host and its endosymbiotic unicellular algae is disrupted, and can lead to the death of entire colonies. Previous works have shown that soma clonal colonies display different levels of survival depending on the environmental conditions they previously faced. Epigenetic mechanisms are good candidates to explain this phenomenon. The clonal nature of a colony and the possibility of generating genetically identical colonies through propagation make corals an attractive model to study the impact of the environment on the epigenome. However, until now, no work had been published on the P. acuta epigenome. One of the main problems is caused by the intracellular location of Symbiodinium, which makes it complicated to isolate coral chromatin free of contamination by endiosymbiotic biological material. Here, (i) we describe a simple method to purify P. acuta chromatin, (ii) we provide the first description of a coral methylome, with a mosaic pattern of cytosine methylation principally in a CpG context (4% of all CpG), and (iii) we show that P. acuta, but not all corals, has an unusual chromatin structure, and displays histone H3 clipping.
Direction-Averaged Diffusion-Weighted MRI Signal using different Axisymmetric B-tensor Encoding Schemes “Submitted to Magnetic Resonance in Medicine”
Authors: Afzali Maryam , Aja-Fernández Santiago , Jones Derek K
Published: August 2019

Purpose

It has been shown previously that for the conventional Stejskal-Tanner pulsed gradient, or linear tensor encoding (LTE), as well as planar tensor encoding (PTE) and in tissue in which diffusion exhibits a ‘stick-like’ geometry, the diffusion-weighted MRI signal at extremely high b-values follows a power-law. Specifically, the signal decays as a in LTE and 1/b in PTE. Here, the direction-averaged signal for arbitrary diffusion encoding waveforms is considered to establish whether power-law behaviors occur with other encoding wave-forms and for other (non-stick-like) diffusion geometries.

Methods

We consider the signal decay for high b-values for encoding geometries ranging from 2-dimensional planar tensor encoding (PTE), through isotropic or spherical tensor encoding (STE) to linear tensor encoding. When a power-law behavior was suggested, this was tested using in-silico simulations and in-vivo using an ultra-strong gradient (300 mT/m) Connectom scanner.

Results

The results show that using an axisymmetric b-tensor a power-law only exists for two scenarios: For stick-like geometries, (i) the already-discovered LTE case; and (ii) for pure planar encoding. In this latter case, to first order, the signal decays as 1/b. Our in-silico and in-vivo experiments confirm this 1/b relationship.

Conclusion

A complete analysis of the power-law dependencies of the diffusion-weighted signal at high b-values has been performed. Only two forms of encoding result in a power-law dependency, pure linear and pure planar tensor encoding and when the diffusion geometry is ‘stick-like’. The different exponents of these encodings could be used to provide independent validation of the presence of stick-like geometries in-vivo.