bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroimaging-based biomarkers for pain: state of the field and current directions
Authors: van der Miesen Maite M. , Lindquist Martin A. , Wager Tor D.
Published: August 2019

Chronic pain is an endemic problem involving both peripheral and brain pathophysiology. Although biomarkers have revolutionized many areas of medicine, biomarkers for pain have remained controversial and relatively underdeveloped. With the realization that biomarkers can reveal pain-causing mechanisms of disease in brain circuits and in the periphery, this situation is poised to change. In particular, brain pathophysiology may be diagnosable with human brain imaging, particularly when imaging is combined with machine learning techniques designed to identify predictive measures embedded in complex data sets. In this review, we explicate the need for brain-based biomarkers for pain, some of their potential uses, and some of the most popular machine learning approaches that have been brought to bear. Then, we evaluate the current state of pain biomarkers developed with several commonly used methods, including structural magnetic resonance imaging, functional magnetic resonance imaging and electroencephalography. The field is in the early stages of biomarker development, but these complementary methodologies have already produced some encouraging predictive models that must be tested more extensively across laboratories and clinical populations.
Applications of dynamic functional connectivity to pain and its modulation
Authors: Necka Elizabeth A. , Lee In-Seon , Kucyi Aaron , Cheng Joshua C. , Yu Qingbao , Atlas Lauren Y.
Published: August 2019

Since early work attempting to characterize the brain's role in pain, it has been clear that pain is not generated by a specific brain region, but rather by coordinated activity across a network of brain regions, the “neuromatrix.” The advent of noninvasive whole-brain neuroimaging, including functional magnetic resonance imaging, has provided insight on coordinated activity in the pain neuromatrix and how correlations in activity between regions, referred to as “functional connectivity,” contribute to pain and its modulation. Initial functional connectivity investigations assumed interregion connectivity remained stable over time, and measured variability across individuals. However, new dynamic functional connectivity (dFC) methods allow researchers to measure how connectivity changes over time within individuals, permitting insights on the dynamic reorganization of the pain neuromatrix in humans. We review how dFC methods have been applied to pain, and insights afforded on how brain connectivity varies across time, either spontaneously or as a function of psychological states, cognitive demands, or the external environment. Specifically, we review psychophysiological interaction, dynamic causal modeling, state-based dynamic community structure, and sliding-window analyses and their use in human functional neuroimaging of acute pain, chronic pain, and pain modulation. We also discuss promising uses of dFC analyses for the investigation of chronic pain conditions and predicting pain treatment efficacy and the relationship between state- and trait-based pain measures. Throughout this review, we provide information regarding the advantages and shortcomings of each approach, and highlight potential future applications of these methodologies for better understanding the brain processes associated with pain.
Outcome of Recurrent Surgery in Dupuytren’s Disease: Comparison with Initial Treatment
Authors: Mendelaar Nienke H. A. , Poelstra Ralph , van Nieuwenhoven Christianne A. , Slijper Harm P. , Feitz Reinier , Hovius Steven E. R. , Selles Ruud W.
Published: August 2019

Background:

There are multiple studies about the effectiveness of primary treatment in Dupuytren’s disease. However, such studies concerning treatment effectiveness of recurrent disease are scarce. Therefore, the primary aim of this study was to compare treatment effectiveness of initial and repeated surgery in patients with Dupuytren’s disease.

Methods:

Patients who underwent both initial and repeated treatment were selected from a prospectively maintained database. Outcome measurements consisted of finger goniometry, the Michigan Hand Outcomes Questionnaire, and complications. Treatment effectiveness was defined as improvement in extension deficit and patient-reported hand function. In addition, measurements at intake of both treatments were compared. Subgroup analyses were performed to evaluate influence of type of surgery of initial treatment on outcomes of repeated treatment.

Results:

One hundred fourteen patients were included in the analyses. Improvement in extension deficit and Michigan Hand Outcomes Questionnaire outcomes was equal for initial and repeated treatments. Extension deficit and Michigan Hand Outcomes Questionnaire scores were worse at intake of repeated treatment compared to these outcomes at intake of initial treatment. In addition, patients who initially underwent needle fasciotomy achieved a better contracture reduction after repeated treatment.

Conclusions:

This study demonstrates that treatment of recurrent Dupuytren’s disease is as effective as initial treatment, despite larger extension deficit and worse self-assessed hand function before undergoing repeated treatment. Complication rates were similar for initial and repeated treatments. Furthermore, needle fasciotomy for initial treatment results in better outcomes of repeated treatment compared to patients who initially underwent limited fasciectomy. These findings can be used for a more evidence-based preoperative counseling with patients with recurrent Dupuytren’s disease.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 Predicts the Changes of Rheumatoid Factor Titers in Rheumatoid Arthritis
Authors: Okahata Akinori , Ito Hiromu , Furu Moritoshi , Ishikawa Masahiro , Fujii Takayuki , Hashimoto Motomu , Tanaka Masao , Morita Yugo , Azukizawa Masayuki , Tomizawa Takuya , Doi Kohei , Nishitani Kohei , Murata Koichi , Yoshitomi Hiroyuki , Mimori Tsuneyo , Matsuda Shuichi
Published: August 2019

Objective

The aim of this longitudinal study was to examine the clinical significance of soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) in patients with rheumatoid arthritis.

Methods

We gathered demographic and clinical data for a large rheumatoid arthritis cohort at 3 time points. Blood samples were collected at each time point; the number of samples was 282 cases in 2012, 431 cases in 2013, and 500 cases in 2014. Plasma sLOX-1 was measured by enzyme-linked immunosorbent assay. Correlations between sLOX-1 and clinical data were analyzed. Predictive factors associated with changes in sLOX-1 and rheumatoid factor (RF) were analyzed by multivariate linear regression.

Results

Plasma sLOX-1 level was significantly correlated with RF titer and other clinical parameters. The longitudinal analyses showed that changes in sLOX-1 were significantly correlated with changes in RF titers and with those at baseline. Multivariate linear regression analysis revealed that changes in RF and baseline RF were predictive factors for changes in sLOX-1. Conversely, the changes in RF were significantly correlated with the changes in sLOX-1 in all years. A stepwise regression analysis showed that the change in sLOX-1 was a predictive factor for the change in RF.

Conclusions

The change in sLOX-1 has predictive value for assessing the change in RF, indicating the usefulness of sLOX-1 in clinical practice.
Hematopoietic Stem Cell Transplantation Improves Functional Outcomes of Systemic Sclerosis Patients
Authors: Costa-Pereira Karla R. , Guimarães Ana Luísa , Moraes Daniela Aparecida , Dias Juliana Bernardes Elias , Garcia Juliana Tomé , de Oliveira-Cardoso Erika Arantes , Zombrilli Andréia , Leopoldo Vanessa , Costa Thalita Melo , Simões Belinda Pinto , Oliveira Maria Carolina
Published: August 2019

Background/Objective

We sought to evaluate if autologous hematopoietic stem cell transplantation (AHSCT) influences the functional status of systemic sclerosis (SSc) patients.

Methods

From 2014 to 2018, a cohort of 27 SSc patients was assessed before, and at 6 and 12 months after AHSCT for modified Rodnan’s skin score (mRSS), mouth opening, hand grip strength, range of motion (ROM), functional ability of upper limbs (DASH questionnaire and Cochin hand function scale—CHFS), 6-minute walk test (6MWT), and quality of life (SF-36 questionnaire). Linear regression models with random effects and Spearman’s test were used for statistical analysis.

Results

At 6 and 12 months after AHSCT, respectively, we observed significant improvement of mRSS (p < 0.01 and p < 0.01), mouth opening (p = 0.02 and p < 0.01), hand function (DASH, p < 0.01 and p < 0.01; CHFS, p < 0.01 and p < 0.01; strength, p < 0.01 and p < 0.01), physical capacity (6MWT, p = 0.02 and p = 0.03) and physical (p < 0.01 and p < 0.01) and mental (ns and p = 0.02) component scores of SF-36. At 12 months after AHSCT, ROM measurements improved (p < 0.05) in five out of six evaluated joints in both hands, compared to baseline. Correlation was significant between physical capacity and quality of life (R = 0.62; p < 0.01), between DASH and quality of life (R = −0.48; p = 0.03), and between skin involvement and wrist ROM measures (dominant hand, R = −0.65, p < 0.01; non-dominant hand, R = −0.59; p < 0.01).

Conclusions

AHSCT enhances the functional status of SSc patients in the first year of follow-up, significantly improving hand function, physical capacity and quality of life. These results are interpreted as positive outcomes of AHSCT for SSc.
Meaningful Patient-centered Outcomes 1 Year Following Cardiac Surgery
Authors: Charles Eric J. , Mehaffey J. Hunter , Hawkins Robert B. , Burks Sandra G. , McMurry Timothy L. , Yarboro Leora T. , Kern John A. , Ailawadi Gorav , Kron Irving L. , Stukenborg George J. , Kozower Benjamin D.
Published: August 2019

Objective:

To evaluate meaningful, patient-centered outcomes including alive-at-home status and patient-reported quality of life 1 year after cardiac surgery.

Background:

Long-term patient-reported quality of life after cardiac surgery is not well understood. Current operative risk models and quality metrics focus on short-term outcomes.

Methods:

In this combined retrospective/prospective study, cardiac surgery patients at an academic institution (2014–2015) were followed to obtain vital status, living location, and patient-reported outcomes (PROs) at 1 year using the NIH Patient-Reported Outcomes Measurement Information System (PROMIS). We assessed the impact of cardiac surgery, discharge location, and Society of Thoracic Surgeons perioperative predicted risk of morbidity or mortality on 1-year outcomes.

Results:

A total of 782 patients were enrolled; 84.1% (658/782) were alive-at-home at 1 year. One-year PROMIS scores were global physical health (GPH) = 48.8 ± 10.2, global mental health (GMH) = 51.2 ± 9.6, and physical functioning (PF) = 45.5 ± 10.2 (general population reference = 50 ± 10). All 3 PROMIS domains at 1 year were significantly higher compared with preoperative scores (GPH: 41.7 ± 8.5, GMH: 46.9 ± 7.9, PF: 39.6 ± 9.0; all P < 0.001). Eighty-two percent of patients discharged to a facility were alive-at-home at 1 year. These patients, however, had significantly lower 1-year scores (difference: GPH = −5.1, GMH = −5.1, PF = −7.9; all P < 0.001). Higher Society of Thoracic Surgeons perioperative predicted risk was associated with significantly lower PRO at 1 year (P < 0.001).

Conclusions:

Cardiac surgery results in improved PROMIS scores at 1 year, whereas discharge to a facility and increasing perioperative risk correlate with worse long-term PRO. One-year alive-at-home status and 1-year PRO are meaningful, patient-centered metrics that help define long-term quality and the benefit of cardiac surgery.
Intraoperative Hypertension and Thrombocytopenia Associated With Intracranial Hemorrhage After Liver Transplantation
Authors: Gao Wei , Li Jun , Nguyen-Buckley Christine , Nguyen-Lee Jennifer , Wray Christopher , Agopian Vatche , Busuttil Ronald W. , Steadman Randolph H. , Xia Victor W.
Published: August 2019

Background.

Intracranial hemorrhage (ICH) is a devastating complication. Although hypertension and thrombocytopenia are well-known risk factors for ICH in the general population, their roles in ICH after liver transplantation (LT) have not been well established.

Methods.

We performed a retrospective study and hypothesized that intraoperative hypertension and thrombocytopenia were associated with posttransplant ICH. New onset of spontaneous hemorrhage in the central nervous system within 30 days after LT were identified by reviewing radiologic reports and medical records. Risk factors were identified by multivariate logistic regression. Receiver operating characteristic analysis and Youden index were used to find the cutoff value with optimal sensitivity and specificity.

Results.

Of 1836 adult patients undergoing LT at University of California, Los Angeles, 36 (2.0%) developed ICH within 30 days after LT. Multivariate logistic regression demonstrated that intraoperative mean arterial pressure ≥105 mm Hg (≥10 min) (odds ratio, 6.5; 95% confidence interval, 2.7-7.7; P < 0.001) and platelet counts ≤30 × 109/L (odds ratio, 3.3; 95% confidence interval, 14-7.7; P = 0.006) were associated with increased risk of postoperative ICH. Preoperative total bilirubin ≥7 mg/dL was also a risk factor. Thirty-day mortality in ICH patients was 48.3%, significantly higher compared with the non-ICH group (3.0%; P < 0.001). Patients with all 3 risk factors had a 16% chance of developing ICH.

Conclusions.

In the current study, postoperative ICH was uncommon but associated with high mortality. Prolonged intraoperative hypertension and severe thrombocytopenia were associated with postoperative ICH. More studies are warranted to confirm our findings and develop a strategy to prevent this devastating posttransplant complication.
Donor-specific B Cell Memory in Alloimmunized Kidney Transplant Recipients: First Clinical Application of a Novel Method
Authors: Wehmeier Caroline , Karahan Gonca E. , Krop Juliette , de Vaal Yvonne , Langerak-Langerak Janneke , Binet Isabelle , Schaub Stefan , Roelen Dave L. , Claas Frans H.J. , Heidt Sebastiaan ,   the Swiss Transplant Cohort Study
Published: August 2019

Background.

HLA-specific memory B cells may contribute to the serum HLA antibody pool upon antigen reexposure. The aim of this pilot study was to investigate the presence of concurrent donor-specific memory B cell–derived HLA antibodies (DSA-M) in renal allograft recipients with pretransplant donor-specific HLA antibodies (DSA) and its association with occurrence of antibody-mediated rejection (AMR) using a recently developed method.

Methods.

Twenty patients with Luminex single antigen bead (SAB) assay-defined DSA but negative complement-dependent cytotoxicity crossmatches were enrolled. Plasma samples and peripheral blood mononuclear cells were collected at 3 timepoints (pretransplant, mo 6, mo 12). We analyzed IgG-purified and concentrated culture supernatants from polyclonally activated peripheral blood mononuclear cells using SAB assays and compared HLA antibody profiles with same day plasma results.

Results.

Plasma SAB analysis revealed 35 DSA in 20 patients pretransplant. DSA-M were detected in 9 of 20 (45%) patients and for 10 of 35 specificities (29%). While median mean fluorescence intensity values of DSA with concurrent DSA-M (5877) were higher than those of DSA without DSA-M (1476), 3 of 6 patients with AMR and low mean fluorescence intensity DSA (<3000) had DSA-M. Overall, pretransplant DSA/DSA-Mpos allograft recipients showed a higher incidence of biopsy-proven (sub)clinical AMR (P = 0.032) and a higher extent (g≥1 + ptc≥1) of microvascular inflammation (67% vs 9%, P = 0.02). In 17 patients (28 DSA) with posttransplant analyses, persisting DSA posttransplant had more often DSA-M (6/12; 50%) than nonpersisting DSA (2/16; 13%).

Conclusions.

Assessment of DSA-M might be a novel tool to supplement serum HLA antibody analysis for pretransplant risk stratification in patients with DSA.
Equity–Efficiency Trade-offs Associated With Alternative Approaches to Deceased Donor Kidney Allocation: A Patient-level Simulation
Authors: Li Bernadette , Cairns John A. , Johnson Rachel J. , Watson Christopher J.E. , Roderick Paul , Oniscu Gabriel C. , Metcalfe Wendy , Bradley J. Andrew , Tomson Charles R. , Draper Heather , Forsythe John L. , Dudley Christopher , Ravanan Rommel
Published: August 2019

Background.

The number of patients waiting to receive a kidney transplant outstrips the supply of donor organs. We sought to quantify trade-offs associated with different approaches to deceased donor kidney allocation in terms of quality-adjusted life years (QALYs), costs, and access to transplantation.

Methods.

An individual patient simulation model was developed to compare 5 different approaches to kidney allocation, including the 2006 UK National Kidney Allocation Scheme (NKAS) and a QALY maximization approach designed to maximize health gains from a limited supply of donor organs. We used various sources of patient-level data to develop multivariable regression models to predict survival, health state utilities, and costs. We simulated the allocation of kidneys from 2200 deceased donors to a waiting list of 5500 patients and produced estimates of total lifetime costs and QALYs for each allocation scheme.

Results.

Among patients who received a transplant, the QALY maximization approach generated 48 045 QALYs and cost £681 million, while the 2006 NKAS generated 44 040 QALYs and cost £625 million. When also taking into consideration outcomes for patients who were not prioritized to receive a transplant, the 2006 NKAS produced higher total QALYs and costs and an incremental cost-effectiveness ratio of £110 741/QALY compared with the QALY maximization approach.

Conclusions.

Compared with the 2006 NKAS, a QALY maximization approach makes more efficient use of deceased donor kidneys but reduces access to transplantation for older patients and results in greater inequity in the distribution of health gains between patients who receive a transplant and patients who remain on the waiting list.
Implications of Fc Neonatal Receptor (FcRn) Manipulations for Transplant Immunotherapeutics
Authors: Jordan Stanley C. , Ammerman Noriko , Vo Ashley
Published: August 2019

Alloimmune injury to allografts is mediated by pathogenic donor-specific alloantibodies, usually of the IgG isotype. Currently, strategies used to reduce donor-specific alloantibodies are collectively called desensitization. Despite successes, these treatments have limited efficacy and can be associated with adverse events, infectious complications, and high cost. Fc neonatal receptor (FcRn) was originally discovered as a transport mechanism for IgG from maternal circulation to fetus. FcRn receptors are now known to be widely distributed in virtually all tissues. IgG and albumin binding to FcRn is pH-dependent, which results in a significant prolongation their half-life. Structural analysis shows FcRn is a nonclassical major histocompatibility complex Class I receptor, which is emerging as a novel target to significantly reduce the half-life of pathogenic antibodies or extend the half-life of therapeutic monoclonals. Manipulation of IgG-Fc/FcRn interactions has implications for treatment of virtually all IgG-mediated diseases. The use of monoclonals directed at the FcRn can rapidly enhance the turnover of total IgG, including pathogenic IgG. In this review, we highlight the aspects of FcRn biology responsible for development of FcRn targeted therapeutics aimed at pathogenic autoantibodies and alloantibodies. We also explore the novel modifications of therapeutic monoclonals that exploit FcRn functions to enhance therapeutic efficacy.
Enlarged and Enhancing Optic Nerves in Advanced Glial Fibrillary Acidic Protein Meningoencephalomyelitis
Authors: White Daniel , Mollan Susan P. , Ramalingam Satheesh , Nagaraju Santhoosh , Hayton Tom , Jacob Saiju
Published: August 2019

A 36-year-old woman presented with intermittent fever, nausea and vomiting, generalized polyarthralgias, and bilateral optic disc swelling. She had a history of difficult-to-control myasthenia gravis since the age of 18 years. Lumbar puncture demonstrated a normal opening pressure; cerebrospinal fluid (CSF) was remarkable for high protein, low glucose, and a mononuclear pleocytosis. Although initial MRI of the brain was normal, a repeat study 8 weeks later revealed enlarged and enhancing bilateral intraorbital and intracranial optic nerves. After a nondiagnostic brain biopsy, a CSF sample tested positive for antibodies to glial fibrillary acidic protein (GFAP). Findings in this case indicate that optic nerve swelling encountered in GFAP meningoencephalomyelitis is more likely due to optic nerve inflammation rather than elevated intracranial pressure.
Time to death and its Predictors among Adult TB/HIV Co-Infected Patients in Mizan Tepi University Teaching Hospital, South West Ethiopia
Authors: Wondimu Wondimagegn , Dube Lamessa , Kabeta Teshome
Published: August 2019

Background

Tuberculosis (TB) and Human Immuno Deficiency Virus (HIV) co-infection represents a complex pathogenic scenario with synergistic effect and leads to about 300,000 HIV-associated TB deaths in the world in 2017. Despite this burden of death, time to death and its predictors among TB-HIV co-infected patient was not adequately studied; and the existing evidences are inconsistent. Therefore, this study was aimed to determine time to death and identify its predictors among adult TB/HIV co-infected patients.

Method

Retrospective cohort study was conducted by reviewing registers of randomly selected 364 TB/HIV co-infected patients enrolled in health care from July 2, 2007 up to July 1, 2017 at Mizan Tepi University Teaching Hospital. The hospital was located in Bench Maji Zone, South West Ethiopia. Data were collected from March 1 through 31, 2018, entered to Epi data 3.1 and exported to SPSS version 21. Each patient was followed from date of TB treatment initiation till death, loss to follow up and treatment completed. On the other hand, events other than death were considered as censored. After checking the proportional hazard model assumption, Cox-regression was used to identify the predictors. In bivariable analyses, P-value≤0.25 was used to identify candidate variables for multivariable analysis. The 95% CI of hazard ratio (HR) with respective P-value <0.05 was used to declare significance in the final model.

Result

All the 364 patients were followed for 1,654 person months. There were 83 (22.8%) deaths and most 38 (45.8%) were occurring within the first two months of anti-TB treatment initiation. The overall incidence rate and median survival time were 5.02 per 100 person months (95% CI: 4.05, 6.22) and 10 months respectively. Statistically significant better survival was observed among patients: with CD4 ≥ 200 cells/mm3 (P<0.001), who had a history of cotrimoxazole preventive therapy (CPT) use (P<0.001), who disclose their HIV status (P<0.001) and with working functional status (P<0.001). Not using CPT (adjusted hazard ratio [AHR] =1.72; P=0.023), bedridden functional status (AHR=2.55; P=0.007), not disclosing HIV status (AHR=4.03; P<0.001) and CD4 < 200 cells/mm3 (AHR=6.05; P<0.001) were predictors of time to death among TB/HIV co-infected patients.

Conclusion

The median survival time was 10 months and poor survival was associated with low CD4 count, not using CPT, not disclosing HIV status and having bedridden functional status. Close monitoring of bedridden and low CD4 count patients, prompt CPT initiation and encouraging HIV status disclosure are recommended.
Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice
Authors: Mukai Jun , Cannavò Enrico , Sun Ziyi , Crabtree Gregg , Diamantopoulou Anastasia , Thakur Pratibha , Chang Chia-Yuan , Cai Yifei , Lomvardas Stavros , Takata Atsushi , Xu Bin , Gogos Joseph A.
Published: August 2019

SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.
Mining the human tonsillar microbiota as autoimmune modulator
Authors: Li Jing , Li Shenghui , Jin Jiayang , Guo Ruochun , Sun Xiaolin , Guo Jianping , Hu Fanlei , Liu Yanying , Jin Yuebo , Zhou Yunshan , Xiao Wenjing , Zhong Yan , Huang Fei , Pan Hudan , Yang Rentao , Zhou Yuanjie , Deng Kaifeng , Wu Lijun , Liu Liang , Qin Junjie , Wang Jun , He Jing , Li Zhanguo
Published: August 2019

Palatine tonsils are important lymphoid organs featuring constant cross-talks between the commensal microorganisms and immune system, and have been implicated as critical autoimmunity origins for immune-related diseases, including rheumatoid arthritis (RA), a common autoimmune disorder. However, there was no evidence to show link between tonsillar microbiota and RA. Here, we identified a significant dysbiosis of RA tonsillar microbiota, with loss of Streptococcus salivarius and its functional molecules salivaricins (a type of antibacterial peptides). Consistent with the niche-preference, S. salivarius and salivaricins administrated intranasally or intraorally conferred prophylactic and therapeutic efficacies against experimental arthritis. Moreover, we demonstrated, for the first time, that S. salivarius and salivaricins exerted immunosuppressive capacities via inhibiting CD4+effector T cell subsets and autoantibody production in mice and human. These results uncover a communication between tonsillar microbiota and host autoimmunity, and identify the active components from tonsillar microbes in modulating immune homeostasis.

One sentence summary

Tonsillar microbiota regulate host autoimmunity via antibacterial peptides
Case studies and mathematical models of ecological speciation. V. Adaptive divergence of whitefish in Fennoscandia
Authors: Thibert-Plante Xavier , Præbel Kim , Østbye Kjartan , Kahilainen Kimmo K. , Amundsen Per-Arne , Gavrilets Sergey
Published: August 2019

Modern speciation theory has greatly benefited from a variety of simple mathematical models focusing on the conditions and patterns of speciation and diversification in the presence of gene flow. Unfortunately the application of general theoretical concepts and tools to specific ecological systems remains a challenge. Here we apply modeling tools to better understand adaptive divergence of whitefish during the postglacial period in lakes of northern Fennoscandia. These lakes harbor up to three different morphs associated with the three major lake habitats: littoral, pelagic, and profundal. Using large-scale individual-based simulations, we aim to identify factors required for in situ emergence of the pelagic and profundal morphs in lakes initially colonized by the littoral morph. The importance of some of the factors we identify and study - sufficiently large levels of initial genetic variation, size- and habitat-specific mating, sufficiently large carrying capacity of the new niche - is already well recognized. In addition, our model also points to two other factors that have been largely disregarded in theoretical studies: fitness-dependent dispersal and strong predator pressure in the ancestral niche coupled with the lack of it in the new niche(s). We use our theoretical results to speculate about the process of diversification of whitefish in Fennoscandia and to identify potentially profitable directions for future empirical research.
Darwinian properties and their trade-offs in autocatalytic RNA reaction networks
Authors: Ameta Sandeep , Arsène Simon , Foulon Sophie , Saudemont Baptiste , Clifton Bryce E. , Griffiths Andrew D. , Nghe Philippe
Published: August 2019

Discovering autocatalytic chemistries that can evolve is a major goal in systems chemistry and a critical step towards understanding the origin of life. Autocatalytic networks have been discovered in various chemistries, but we lack a general understanding of how network topology controls the Darwinian properties of variation, differential reproduction, and heredity, which are mediated by the chemical composition. Using barcoded sequencing and droplet microfluidics, we establish a landscape of thousands of networks of RNAs that catalyze their own formation from fragments, and derive relationships between network topology and chemical composition. We find that strong variations arise from catalytic innovations perturbing weakly connected networks, and that reproduction increases with global connectivity. These rules imply trade-offs between reproduction and variation, and between compositional persistence and variation along trajectories of network complexification. Overall, connectivity in reaction networks provides a lever to balance variation (to explore chemical states) with reproduction and heredity (persistence being necessary for selection to act), as required for chemical evolution.
PulmonDB: a curated lung disease gene expression database
Authors: Villaseñor-Altamirano Ana B. , Moretto Marco , Zayas-Del Moral Alejandra , Maldonado Mariel , Munguía-Reyes Adrián , Romero Yair , García-Sotelo Jair. S. , Aguilar Luis Alberto , Oscar Aldana-Assad , Engelen Kristof , Selman Moisés , Collado-Vides Julio , Balderas-Martínez Yalbi I. , Medina-Rivera Alejandra
Published: August 2019

Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) have contrasting clinical and pathological characteristics, and interesting whole-genome transcriptomic profiles. However, data from public repositories are difficult to reprocess and reanalyze. Here we present PulmonDB, a web-based database (http://pulmondb.liigh.unam.mx/) and R library that facilitates exploration of gene expression profiles for these diseases by integrating transcriptomic data and curated annotation from different sources. We demonstrated the value of this resource by presenting the expression of already well-known genes of COPD and IPF across multiple experiments and the results of two differential expression analyses in which we successfully identified differences and similarities. With this first version of PulmonDB, we create a new hypothesis and compare the two diseases from a transcriptomics perspective.
Post-translational control of PlsB is sufficient to coordinate membrane synthesis with growth inEscherichia coli
Authors: Noga Marek J , Büke Ferhat , van den Broek Niels JF , Imholz Nicole , Scherer Nicole , Yang Flora , Bokinsky Gregory
Published: August 2019

Every cell must produce enough membrane to contain itself. However, the mechanisms by which the rate of membrane synthesis is coupled with the rate of cell growth remain unresolved. By comparing substrate and enzyme concentrations of the fatty acid and phospholipid synthesis pathways ofEscherichia coliacross a 3-fold range of carbon-limited growth rates, we show that the rate of membrane phospholipid synthesis during steady-state growth is determined principally through allosteric control of a single enzyme, PlsB. Due to feedback regulation of the fatty acid pathway, PlsB activity also indirectly controls synthesis of lipopolysaccharide, a major component of the outer membrane synthesized from a fatty acid synthesis intermediate. Surprisingly, concentrations of the enzyme that catalyses the committed step of lipopolysaccharide synthesis (LpxC) do not vary across steady-state growth conditions, suggesting that steady-state lipopolysaccharide synthesis is modulated primarily via indirect control by PlsB. In contrast to steady-state regulation, we find that responses to environmental perturbations are triggered directly via changes in acetyl-CoA concentrations, which enables rapid adaptation. Adaptations are further modulated by ppGpp, which regulates PlsB activity during slow growth and growth arrest. The strong reliance of the membrane synthesis pathway upon post-translational regulation ensures both reliability and responsiveness of membrane synthesis.

Significance

How do bacteria cells grow without breaking their membranes? Although the biochemistry of fatty acid and membrane synthesis is well-known, how membrane synthesis is balanced with growth and metabolism has remained unclear. This is partly due to the many control points that have been discovered within the membrane synthesis pathways. By precisely establishing the contributions of individual pathway enzymes, our results simplify the model of membrane biogenesis in the model bacteria speciesEscherichia coli. Specifically, we find that allosteric control of a single enzyme, PlsB, is sufficient to balance growth with membrane synthesis and to ensure that growingE. coliproduces sufficient membrane. Identifying the signals that activate and deactivate PlsB will answer the question of how membrane synthesis is synchronized with growth.
Emergence and patterning dynamics of mouse definitive endoderm
Authors: Pour Maayan , Kumar Abhishek Sampath , Walther Maria , Wittler Lars , Meissner Alexander , Nachman Iftach
Published: August 2019

The segregation of definitive endoderm (DE) from mesendoderm progenitors leads to the formation of two distinct germ layers. Dissecting DE onset has been challenging as it occurs within a narrow spatio-temporal window in the embryo. Here we employ a dual Bra-GFP, Sox17-RFP reporter cell line to study DE onset dynamics. We find Sox17 starts in a few isolated cellsin vivo. Using 2D and 3Din vitromodels, we show that DE cells emerge from mesendoderm progenitors at a temporally regular, but spatially stochastic pattern, which is subsequently arranged by self-sorting of Sox17+ cells. Self-sorting coincides with up-regulation of E-cadherin but is not necessary for DE differentiation or proliferation. A subpopulation of Bra-high cells commits to a Sox17+ fate independent of external Wnt signal. Ourin vivoandin vitroresults highlight basic rules governing DE onset and patterning through the commonalities and differences between these systems.
Emergence and diversification of a host-parasite RNA ecosystem through Darwinian evolution
Authors: Furubayashi Taro , Ueda Kensuke , Bansho Yohsuke , Motooka Daisuke , Nakamura Shota , Ichihashi Norikazu
Published: August 2019

In the prebiotic evolution, molecular self-replicators are considered to develop into diverse, complex living organisms. The appearance of parasitic replicators is believed inevitable in this process. However, the role of parasitic replicators on prebiotic evolution remains elusive. Here, we demonstrated experimental coevolution of RNA self-replicators (host RNAs) and emerging parasitic replicators (parasitic RNAs) for the first time by using an RNA-protein replication system we had developed. During a long-term replication experiment, a clonal population of the host RNA turned into an evolving host-parasite ecosystem through the continuous emergence of new types of host and parasitic RNAs produced by replication errors. The diversified host and parasitic RNAs exhibited evolutionary arms-race dynamics. The parasitic RNA accumulated unique mutations that the host RNA had never acquired, thus adding a new genetic variation to the whole replicator ensemble. These results provide the first experimental evidence that the coevolutionary interplay between host-parasite molecules play a key role in generating diversity and complexity in prebiotic molecular evolution.
Helicobacter pylori biofilm cells are metabolically distinct, express flagella, and antibiotic tolerant
Authors: Hathroubi Skander , Zerebinski Julia , Ottemann Karen M.
Published: August 2019

Biofilm growth protects bacteria against harsh environments, antimicrobials, and immune responses. Helicobacter pylori is a bacterium that has a robust ability to maintain colonization in a challenging environment. Over the last decade, H. pylori biofilm formation has begun to be characterized, however, there are still gaps in our understanding about how this growth mode is defined and its impact on H. pylori physiology. To provide insights into H. pylori biofilm growth properties, we characterized the antibiotic susceptibility, gene expression, and genes required for biofilm formation of a strong biofilm-producing H. pylori. H. pylori biofilms developed complex 3D structures and were recalcitrant to multiple antibiotics. Disruption of the protein-based matrix decreased this antibiotic tolerance. Using both transcriptomic and genomic approaches, we discovered that biofilm cells demonstrated lower transcripts for TCA cycle enzymes but higher ones for hydrogenase and acetone metabolism. Interestingly, several genes encoding for the natural competence Type IV secretion system 4 (tfs4) were up-regulated during biofilm formation along with several genes encoding for restriction-modification (R-M) systems, suggesting DNA exchange activities in this mode of growth. Flagella genes were also discovered through both approaches, consistent with previous reports about the importance of these filaments in H. pylori biofilm. Together, these data suggest that H. pylori is capable of adjusting its phenotype when grown as biofilm, changing its metabolism and elevating specific surface proteins including those encoding tfs4 and flagella.
Notch signaling coordinates ommatidial rotation in the Drosophila eye via transcriptional regulation of the EGF-Receptor ligand Argos
Authors: Koca Yildiz , Housden Benjamin E. , Gault William J. , Bray Sarah J. , Mlodzik Marek
Published: August 2019

In all metazoans, a small number of evolutionarily conserved signaling pathways are reiteratively used during development to orchestrate critical patterning and morphogenetic processes. Among these, Notch (N) signaling is essential for most aspects of tissue patterning where it mediates the communication between adjacent cells to control cell fate specification. InDrosophila, Notch signaling is required for several features of eye development, including the R3/R4 cell fate choice and R7 specification. Here we show that hypomorphic alleles ofNotch– belonging to theNfacetclass – reveal a novel phenotype: while photoreceptor specification in the mutant ommatidia is largely normal, defects are observed in ommatidial rotation (OR), a planar cell polarity (PCP)-mediated morphogenetic cell motility process. We demonstrate that during OR Notch signaling is specifically required in the R4 photoreceptor to upregulate the transcription ofargos (aos), an inhibitory ligand to the EGFR, to fine-tune the activity of Egfr signaling. Consistently, the loss-of-function defects ofNfacetalleles and EGFR-signaling pathway mutants are largely indistinguishable. A Notch-regulatedaosenhancer confers R4 specific expression arguing thataosis directly regulated by Notch signaling in this context via Su(H)- Mam dependent transcription.
Cas12a-based on-site and rapid nucleic acid detection of African swine fever
Authors: Bai Jing , Lin Haosi , Li Haojian , Zhou Yang , Liu Junshan , Zhong Guorui , Wu Luting , Jiang Weifan , Du Hongli , Yang Jinyi , Xie Qingmei , Huang Lizhen
Published: August 2019

The mortality rate of hemorrhagic African swine fever (ASF), which targets domestic pigs and is caused by African swine fever virus (ASFV), can reach 100%. ASF has been reported in 25 Chinese provinces since August 2018. There is no effective treatment or vaccine for it and the present molecular diagnosis technologies have trade-offs in sensitivity, specificity, cost and speed, and none of them cater perfectly to ASF control. Thus, a technology that overcomes the need for laboratory facilities, is relatively low cost, and rapidly and sensitively detects ASFV would be highly valuable. Here, we describe an RAA-Cas12a-based system that combines recombinase-aided amplification (RAA) and CRISPR/Cas12a for ASFV detection. The fluorescence intensity readout of this system detected ASFV p72 gene levels as low as 10 aM. For on-site ASFV detection, lateral-flow strip readout was introduced for the first time in the RAA-Cas12a based system (named CORDS, Cas12a-based On-site and Rapid Detection System). We used CORDS to detect target DNA highly specifically using the lateral-flow strip readout. CORDS could identify the p72 gene at femtomolar sensitivity in an hour at 37°C, and only requires an incubator. For ease of use, the regents of CORDS was lyophilized to three tubes and remained the same sensitivity when stored at 4 °C for at least 7 days. Thus, CORDS provides a rapid, sensitive and easily operable method for ASFV on-site detection. Lyophilized CORDS can withstand long-term transportation and storage, and is ready for field applications.
Relationship between birth weight and chronic kidney disease: an integrative analysis of observational studies and causal inference through genetic approaches
Authors: Yu Xinghao , Yuan Zhongshang , Chen Haimiao , Yang Jiaji , Gao Yixin , Guan Fengjun , Zeng Ping , Huang Shuiping
Published: August 2019

Objective

Although many observational studies have shown that there was an inverse association between birth weight and chronic kidney disease (CKD) in adults, whether such association is causal remains largely unclear.

Methods

We first conducted a systematic review and meta-analysis to investigate the association between birth weight and CKD. Then using a set of valid instrumental variables for birth weight, we performed a two-sample Mendelian randomization (MR) to evaluate its causal effect on CKD based on summary association statistics available from large scale genome-wide association study (GWAS) (up to 143,677 individuals for birth weight and 118,147 individuals for CKD). We further validated the MR results with extensive sensitive analyses.

Results

The results of meta-analysis showed that individuals with low birth weight have about 76% (95% CI 36∼126%) higher risk of CKD in late life compared with those with normal birth weight. Depending on 26 instrumental variables, the inverse variance weighted MR showed that the odds ratio per one SD increase of birth weight on CKD was estimated to be 0.91 (95% CI 0.72∼1.14, p=0.396). The similar null association between birth weight and CKD is also observed using the weighted median method and maximum likelihood method as well as the Egger regression. Such non-significant association is robust against potential instrumental outliers and pleiotropic effects.

Conclusion

Our study identifies an inverse association between birth weight and adult CKD in observational studies, while it is not supportive of the causal role of birth weight on CKD based on our MR analysis.
A novel stibium phosphate, LiBa(SbO)2(PO4)3: synthesis, crystal structure and RE3+-activated (RE = Tb3+ and Eu3+) fluorescence performance
Authors: Zhang Shi-Rui , Zhao Dan , Zhang Rui-Juan , Shi Lin-Ying , Dai Shao-Jie , Fan Yun-Chang
Published: August 2019

A new stibium phosphate, lithium barium bis(antimony oxide) tris(phosphate), LiBa(SbO)2(PO4)3, was prepared by the molten salt method with LiF as the flux. The crystal structure consists of an original three-dimensional anionic framework of [(SbO)2(PO4)3]∞ built from PO4 tetrahedra sharing their corners with SbO6 octahedra. This framework delimits one-dimensional tunnels where the lithium(I) and barium(II) ions are located. The UV–Vis spectrum shows that LiBa(SbO)2(PO4)3 was transparent from 350 to 800 nm, and is thus suitable as a luminescent host matrix. We then used Tb3+ and Eu3+ activators to test its luminous performance and the purities of the prepared phosphors were studied by powder X-ray diffraction analysis with Rietveld refinements. Photoluminescence (PL) studies reveal that the emission spectra of 1 mol% RE3+-doped (RE = Tb and Eu) samples can be excited by 371 and 394 nm light, emitting green and orange–red light, respectively, for Tb3+ and Eu3+. The CIE coordinates were measured to be (0.295, 0.571) and (0.6027, 0.3967), and the luminescent lifetimes were calculated as 0.178 and 1.159 ms, respectively.
Anderson acceleration for electromagnetic nonlinear problems
Authors: Filippini Mattia , Alotto Piergiorgio , Giust Alessandro
Published: August 2019

Purpose

The purpose of this paper is to implement the Anderson acceleration for different formulations of eletromagnetic nonlinear problems and analyze the method efficiency and strategies to obtain a fast convergence.

Design/methodology/approach

The paper is structured as follows: the general class of fixed point nonlinear problems is shown at first, highlighting the requirements for convergence. The acceleration method is then shown with the associated pseudo-code. Finally, the algorithm is tested on different formulations (finite element, finite element/boundary element) and material properties (nonlinear iron, hysteresis models for laminates). The results in terms of convergence and iterations required are compared to the non-accelerated case.

Findings

The Anderson acceleration provides accelerations up to 75 per cent in the test cases that have been analyzed. For the hysteresis test case, a restart technique is proven to be helpful in analogy to the restarted GMRES technique.

Originality/value

The acceleration that has been suggested in this paper is rarely adopted for the electromagnetic case (it is normally adopted in the electronic simulation case). The procedure is general and works with different magneto-quasi static formulations as shown in the paper. The obtained accelerations allow to reduce the number of iterations required up to 75 per cent in the benchmark cases. The method is also a good candidate in the hysteresis case, where normally the fixed point schemes are preferred to the Newton ones.
Modeling and performance analysis of shunt active filter connected with photovoltaic system based on Z-source inverter
Authors: Teta Ali , Kouzou Abdellah , Rezaoui Mohamed Mounir
Published: August 2019

Purpose

This paper aims to propose a new configuration of a shunt active power filter (SAPF) connected with a photovoltaic (PV) system through a Z-source inverter (ZSI) topology. This topology ensures a single-stage operation and overcomes the limitations of the conventional two-stage operation topologies based on the DC–DC boost converter. The proposed system is designed for the purpose of reducing the total harmonic distortion of the source current by eliminating the current harmonics and exploiting the solar irradiation.

Design/methodology/approach

First, all the main parts of the proposed shunt active power filter are fully described in this paper, and then a PV system based on a Z-source inverter with a maximum power point tracking controller is used to exploit the solar irradiance and solve the problem of discharging of the direct current (DC) capacitor during the filtering process.

Findings

From the extensive simulation tests carried out using MATLAB/Simulink, the obtained results prove that the proposed shunt active power filter performs well despite several operation scenarios, including different load types and under abrupt irradiance.

Originality/value

A new shunt active power filter configuration has been proposed. This configuration benefits from the solar irradiation and overcomes the drawbacks of the conventional configurations by using the Z-source inverter instead of the voltage source inverter and DC–DC boost converter.