bluuebunny/crossref_metadata_2025 huggingface dataset:
N-acetyl cysteine inhibits lipopolysaccharide-mediated synthesis of interleukin-1β and tumor necrosis factor-α in human periodontal ligament fibroblast cells through nuclear factor-kappa B signaling
Authors: Zheng Rui , Tan Yujie , Gu Mengqin , Kang Ting , Zhang Hui , Guo Ling
Published: October 2019

Background:

The aim of this study was to investigate the role of n-acetyl cysteine (NAC) in the lipopolysaccharide (LPS)-mediated induction of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) synthesis by human periodontal ligament fibroblast cells (hPDLFs). In addition, we aimed to determine the involvement of the nuclear factor-kappa B (NF-κB) pathway in any changes in IL-1β and TNF-α expression observed in response to LPS and NAC.

Methods:

HPDLFs were obtained by primary culture. The culture medium used in this experiment was Dulbecco's Modified Eagle Medium (DMEM low-glucose). Cells were stimulated with various concentrations of NAC or LPS. Cell proliferation was measured at various time-points with the cell Counting Kit 8 (CCK-8) assay. mRNA levels of IL-1β and TNF-α were determined by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Protein levels of IL-1β and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expression levels of NF-κB were measured by western blot and RT-qPCR.

Results:

The results showed that LPS treatment in hPDLFs induced mRNA and protein expression of IL-1β, TNF-α, and NF-κB. However, these effects were eliminated by pretreatment with NAC. Pretreatment with both NAC (1 mmol/L) and BAY11-7082 (10 μmol/L) significantly inhibited the NF-κB activity induced by LPS.

Conclusion:

NAC inhibits the LPS-mediated synthesis of tumor TNF-α and IL-1β in hPDLFs, through the NF-κB pathway.
Gitelman syndrome combined with growth hormone deficiency
Authors: Huang Ke , Dai Yang-Li , Zhang Jian-Wei , Zhang Li , Wu Wei , Dong Guan-Ping , Ullah Rahim , Fei Yue , Fu Jun-Fen
Published: October 2019

Rationale:

Gitelman syndrome (GS) is a rare autosomal recessive hereditary salt-losing tubulopathy caused by loss-of-function mutations in the SLC12A3 gene. It is usually characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. There are only a few reports on GS combined with growth hormone deficiency (GHD).

Patient concerns:

Three patients presented with weakness, spasm, and growth retardation, respectively.

Diagnoses:

GS was diagnosed based on the clinical symptoms, laboratory test results, and genetic analysis. GH stimulation tests were performed when the magnesium level returned to normal under magnesium oxide (MgO) therapy.

Interventions:

Initially, all patients received oral replacement of MgO and potassium chloride, and 2 of them received simultaneous spironolactone therapy. Recombinant human growth hormone (rhGH) therapy was initiated after they were diagnosed with GHD.

Outcomes:

All 3 patients exhibited satisfactory growth velocity and normal serum magnesium level, although the potassium level was still slightly lower than normal.

Lessons:

We suggest that all GS patients should undergo genetic evaluation, especially regarding SLC12A3 gene mutation. GHD should be considered if these patients have short stature. rhGH therapy is useful for stimulating the patients’ growth, and it may increase the serum magnesium level.
Prognostic significance of long non-coding RNAs in clear cell renal cell carcinoma
Authors: Wang Yan , Li Zhan , Li Wei , Zhou Le , Jiang Yuehua
Published: October 2019

Background:

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults, and patients with advanced ccRCC have a 5-year survival rate of <30%. The poor prognosis of ccRCC is closely related to its lacking of potential therapeutic and prognostic biomarkers. This meta-analysis aimed to elucidate the precise prognostic value of long non-coding RNAs (lncRNAs) in patients with ccRCC.

Methods:

A literature search was performed in related databases up to January 31, 2019. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated to explore the relationship between special lncRNAs expression and survival in patients with ccRCC.

Results:

After literature researching, a total of 16 studies, including 13 lncRNAs were identified. The data from studies that investigated the association between lncRNA expression and survival outcomes in patients with ccRCC were extracted. Results revealed that lncRNAs expression was significantly associated with poor overall survival (OS) outcome in patients with ccRCC (HR = 1.71, 95%CI = 1.40–2.01 in up-regulated subgroup; HR = 0.53, 95% CI = 0.25–0.80 in down-regulated subgroup). The overexpression of PVT1 was significantly associated with poor OS in ccRCC (HR = 1.51, 95% CI = 1.02–2.00). Meanwhile, up-regulation of LUCAT1 was significantly related to worse OS in ccRCC patients (HR = 1.51, 95% CI = 1.01–2.00).

Conclusions:

These results suggest that lncRNAs could be used to predict unfavorable prognosis and function as potential prognostic biomarkers in ccRCC.
Large tumor size is a poor prognostic factor of gastric cancer with signet ring cell
Authors: Zhou Liyuan , Li Weihua , Cai Shaoxin , Yang Changshun , Liu Yi , Lin Zhizun
Published: October 2019

There has been a steady increase in the incidence of signet ring cell (SRC) carcinoma, a distinct histological type with cells containing abundant intracytoplasmic mucin. We aimed to analyze the clinicopathological characteristics and prognostic value of patients with SRC gastric cancer (GC) who underwent gastrectomy.

Clinical data of 10,312 GC patients who underwent D2 radical gastrectomy were obtained from the Surveillance, Epidemiology, and End Results database and were retrospectively analyzed. X-tile plots were constructed to illustrate the optimal cut-off points using the minimum P-value from the log-rank Chi-squared test. The Kaplan–Meier method was used for the analysis of the overall cumulative probability of survival. Their differences were evaluated using the log-rank test. The Cox multiple factors analysis was performed using the logistic regression method.

In total, 946 (9.17%) SRC GC patients with pT1a-4bN0-3bM0 stage cancer were recruited. The optimal cut-off point for size was 49 mm. The 3-year overall survival (OS) rates of the SRC GC, large-size, and small-size groups were 35.89%, 30.63%, and 44.96%, respectively (P < .05). Cox multivariate analysis showed that tumor size (odds ratio [OR] = 2.032), T3 category (OR = 1.324), T4a category (OR = 1.945), and T4b category (OR = 2.163) were independent hazard prognostic factors.

SRC GC has a distinct biological behavior, presents as a large-sized tumor (≥49 mm), and is associated with worse outcomes. SRC GC patients have 2.032 times risk of mortality. SRC patients with larger tumors are at higher risk for infiltrative growth, lymph node metastasis, and distant metastasis.
The impact of iron chelation therapy on patients with lower/intermediate IPSS MDS and the prognostic role of elevated serum ferritin in patients with MDS and AML
Authors: Yang Yuan , Tang Zengwei , An Tianli , Zhao Li
Published: October 2019

Serum ferritin (SF) has been identified as a potential prognostic factor for patients undergoing stem cell transplantation, but the prognostic value of SF in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients and the impact of iron chelation therapy (ICT) on MDS patients are controversial. The present meta-analysis aimed to better elucidate these relationships.

Three electronic databases were searched systematically to identify reports on the prognostic role of SF in MDS and AML patients, and those investigating the impact of ICT on prognosis of MDS patients. The hazard ratios (HRs) and its 95% confidence interval (95%CI) were extracted from the identified studies using Cox proportional hazard regression model for overall survival (OS) and progression of MDS to AML.

Twenty reports including 1066 AML patients and 4054 MDS patients were included in present study. The overall pooled HRs for OS of AML and MDS patients with elevated SF prior to transplantation was 1.73 (1.40–2.14), subgroup analyses stratified by the cut-off value of SF ≥1400/1000 ng/mL showed that the pooled HRs were 1.45 (0.98–2.15) and 1.65 (1.30–2.10), respectively. The pooled HRs for ICT in MDS patients was 0.30 (0.23–0.40). For ICT, the pooled HRs for the progression of MDS to AML was 0.84 (0.61–1.61).

SF has a negative impact on the OS of AML and MDS patients when it is higher than 1000 ng/mL. ICT can improve the OS of MDS patients with iron overload but it is not associated with the progression of MDS to AML.
Hand-off bundle implementation associated with decreased medical errors and preventable adverse events on an academic family medicine in-patient unit
Authors: Dewar Zachary Ewan , Yurkonis Theresa , Attia Maximos
Published: October 2019

To determine the impact of the implementation of a hand-off bundle on medical errors at an inpatient unit of an academic community teaching hospital. Our secondary objective was to determine the research utility of the use of an all-electronic data collection system for medical errors.

A retrospective review was conducted of 1290 admissions 6 months before and after implementation of an improved computerized hand-off tool and training bundle. The study took place at an academic community teaching hospital on a Family Medicine inpatient service caring for patients of all ages. The comparison focused on preventable and non-preventable adverse events.

A significant decrease in medical errors was noted. Medical error rate dropped from 6.0 (95% CI, 4.2–8.3) to 2.2 (95% CI, 1.2–3.7) per 100 admissions (P < .001). Preventable medical errors dropped from 0.65 (95% CI, 0.18–1.67) to 0.15 (95% CI, 0.03–0.82) per 100 admissions (P = .194). Non-intercepted potential adverse events dropped from 1.30 (95% CI, 0.56–2.57) to 0.44 (95% CI, 0.09–1.30) per 100 admissions (P = .131). Intercepted potential adverse events dropped from 0.98 (95% CI 0.36–2.13) to 0.74 (95% CI 0.24–1.7) per 100 admissions (P = .766) and errors with little potential for harm dropped from 2.77 (95% CI 1.61–4.43) to 0.74 (95% CI 0.24–1.7) per 100 admissions (P = .009).

Implementation of a standardized hand-off bundle was associated with a reduction in medical errors despite a low overall event rate. Further studies are warranted to determine the generalizability of this finding, to examine the overall epidemiology of medical errors and the reporting of such events within general medical teaching units.
Common carotid artery puncture in anterior circulation thrombectomy in patients with unfavorable vascular anatomy
Authors: Yuan Zhengzhou , Li Jinglun , Zhou Muke , Zheng Hongbo , Luo Hua , Chen Xiu , Li Zuoxiao , He Li
Published: October 2019

The objective of this study was to compare clinical outcomes in patients who with unfavorable vascular anatomy underwent mechanical thrombectomy (MT) by common carotid artery access versus transfemoral approach.

A retrospective review was performed in our hospital database to identify patients with challenging vascular anatomy who underwent MT for anterior circulation large vessel occlusion (LVO) between August 2015 and November 2018. Transcarotid and transfemoral cohorts were compared. Patient characteristics, procedural techniques, clinical outcomes were recorded.

A total of 52 patients were included, 16 (31%) underwent MT via transcarotid access. There were no significant differences in patient characteristics, intravenously recombinant tissue plasminogen activator therapy, clot location, or carotid tortuosity and presence of aortic arch type. There were significant differences in clinical outcomes between the 2 cohorts, including mean access-to-reperfusion time (84 vs 44 minutes; P = .000), poor clinical outcome (modified Rankin scale >2) at 90 days follow-up (37.5% vs 63.9%; P = .034). But there were no significant differences in successful revascularization rates (thrombolysis in cerebral infarction score ≥2b 87.5% vs 80.6%; P = .541), post-thrombectomy symptomatic intracranial hemorrhage (12.5% vs 13.9%; P = .892), and mortality (12.5% vs 22.2%; P = .412) were similar between transcarotid and transfemoral cohorts.

Our results demonstrate that transcarotid access for MT of anterior circulation LVO in patients with unfavorable vascular anatomy may be considerable. Transcarotid access may be better than transfemoral access in well-selected unfavorable vascular anatomy patients undergoing MT.
Lipid management in people with peripheral artery disease
Authors: Golledge Jonathan , Ward Natalie C. , Watts Gerald F.
Published: October 2019

Purpose of review

To summarize recent data on the role of dyslipidaemia and the benefit from managing this in people with disease of the abdominal aorta and its peripheral branches (peripheral artery disease, PAD).

Recent findings

Findings from the Further Cardiovascular Outcomes Research with Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition in Subjects with Elevated Risk (FOURIER) trial demonstrate the benefit of intensely lowering low-density lipoprotein-cholesterol (LDL-c) in people with PAD to substantially reduce the incidence of major cardiovascular events (MACE; myocardial infarction, stroke or cardiovascular death) and major adverse limb events (MALE). Despite the evidence of substantial benefits from lowering LDL-c, the uptake of drug therapies to lower LDL-c remains sub-optimal in people with PAD.

Effective methods to educate physicians and patients on best medical management are needed. Further research is needed to examine the benefit of LDL-c lowering and other lipid therapies for PAD-specific problems like abdominal aortic aneurysm progression and walking impairment. Other novel lipid therapies, such as those that lower lipoprotein (a), maybe particularly beneficial to people with PAD given the evidence indicating high concentrations in this population and the high incidence of MACE in these individuals.
Is proteomics of value in cardiovascular risk assessment?
Authors: Arnold Natalie , Koenig Wolfgang
Published: October 2019

Purpose of review

To briefly summarize recently published evidence in the field of cardiovascular proteomics, focusing on its ability to improve cardiovascular risk stratification and critically discussing still open and burning issues and future perspectives of proteomics research.

Recent findings

Several epidemiological studies have demonstrated an improvement in cardiovascular risk prediction beyond traditional risk factors by adding novel biomarkers, identified by both discovery and targeted proteomics. However, only a moderate improvement in risk discrimination over clinical variables was observed. Moreover, despite different outcomes there was also a strong overlap of identified candidates, with several of them being already well established cardiovascular risk markers such as growth differentiation factor 15, natriuretic peptides, C-reactive protein, interleukins, and metalloproteases.

Although proteomics plays a crucial role in biomarker discovery, the modest discriminative ability of this technique raises the possibility that there are still hidden mechanisms in protein regulatory networks, which urgently need to be evaluated to improve a cardiovascular risk assessment to a clinically significant extent.
SPPARM alpha: the Lazarus effect
Authors: Fruchart Jean-Charles , Santos Raul D.
Published: October 2019

Purpose of review

Atherogenic dyslipidaemia, characterized by high plasma triglycerides (a surrogate for triglyceride-rich remnant lipoproteins) and low high-density lipoprotein cholesterol (HDL-C), is prevalent in patients with type 2 diabetes mellitus (T2DM) and contributes to a high modifiable residual cardiovascular risk. Fibrates are effective in managing hypertriglyceridaemia but lack consistent cardiovascular benefit in clinical trials and exhibit pharmacokinetic interaction with statins (gemfibrozil) and renal and hepatic safety issues (fenofibrate). The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm offers potential for improving potency, selectivity and the benefit-risk profile.

Recent findings

The present review discusses evidence for the novel SPPARMα agonist, pemafibrate. Clinical trials showed robust lowering of triglyceride-rich lipoproteins, elevation in HDL-C and nonlipid beneficial effects including anti-inflammatory activity. There was a favourable safety profile, with no increase in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT is critical to confirming the SPPARMα concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety.

SPPARMα offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMα, pemafibrate, as a novel therapeutic class distinct from current fibrates.
Giving Meaning to Differences in BREAST-Q Scores: Minimal Important Difference for Breast Reconstruction Patients
Authors: Voineskos Sophocles H. , Klassen Anne F. , Cano Stefan J. , Pusic Andrea L. , Gibbons Christopher J.
Published: October 2019

Background:

The reconstruction module of the BREAST-Q patient-reported outcome measure is frequently used by investigators and in clinical practice. A minimal important difference establishes the smallest change in outcome measure score that patients perceive to be important. To enhance interpretability of the BREAST-Q reconstruction module, the authors determined minimal important difference estimates using distribution-based methods.

Methods:

An analysis of prospectively collected data from 3052 Mastectomy Reconstruction Outcomes Consortium patients was performed. The authors used distribution-based methods to investigate the minimal important difference for the entire patient sample and three clinically relevant groups. The authors used both 0.2 SD units (effect size) and the standardized response mean value of 0.2 as distribution-based criteria. Clinical experience was used to guide and assess appropriateness of results.

Results:

A total of 3052 patients had BREAST-Q data available for analysis. The average age and body mass index were 49.5 and 26.8, respectively. The minimal important difference estimates for each domain were 4 (Satisfaction with Breasts), 4 (Psychosocial Well-being), 3 (Physical Well-being), and 4 (Sexual Well-being). The minimal important difference estimates for each domain were similar when compared within the three clinically relevant groups.

Conclusions:

The authors propose that a minimal important difference score of 4 points on the transformed 0 to 100 scale is clinically useful when assessing an individual patient’s outcome using the reconstruction module of the BREAST-Q. When designing research studies, investigators should use the minimal important difference estimate for their domain of interest when calculating sample size. The authors acknowledge that distribution-based minimal important differences are estimates and may vary based on patient population and context.
Liver Transplantation for Hepatic Epithelioid Hemangioendothelioma Is Facilitated by Exception Points With Acceptable Long-term Outcomes
Authors: Brahmbhatt Mihir , Prenner Stacey , Bittermann Therese
Published: October 2019

Background.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular tumor with a high mortality rate. HEHE is now a formally recognized indication for exception point priority in the United States under the new National Liver Review Board. The role of liver transplantation (LT) and exception point waitlist priority in the United States for patients with HEHE remains understudied.

Methods.

This was a retrospective cohort study using the United Network for Organ Sharing transplant database. From February 27, 2002 to January 31, 2018, 131 adults waitlisted for LT with HEHE were identified by free-text entry.

Results.

Exception point applications were submitted for 91.6% (120/131) of patients. All patients with fully reviewed applications received exception points at least once during waitlisting, and 85% (103/120) upon first submission. Among the 88 patients transplanted, median model for end-stage liver disease score at LT was 7 ((interquartile range [IQR]: 6–11) and waiting time 78.5 days (IQR: 29.5–237.5). Unadjusted post-LT survival of HEHE recipients at 1-, 3-, and 5-years from LT was 88.6%, 78.9%, and 77.2%. Unadjusted post-LT patient and graft survival of HEHE patients was not different from patients with hepatocellular carcinoma within Milan receiving exception point priority (P = 0.08). An increased rate of graft failure due to hepatic artery thrombosis ≤14 days from initial LT was observed in HEHE versus non-HEHE patients (4.6% versus 0.5%).

Conclusions.

The majority of HEHE recipients receive exception points at a universal approval rate allowing prompt access to deceased donor LT.
Influence of image segmentation on one-dimensional fluid dynamics predictions in the mouse pulmonary arteries
Authors: Colebank Mitchel J. , Paun L. Mihaela , Qureshi M. Umar , Chesler Naomi , Husmeier Dirk , Olufsen Mette S. , Fix Laura Ellwein
Published: October 2019

Computational fluid dynamics (CFD) models are emerging tools for assisting in diagnostic assessment of cardiovascular disease. Recent advances in image segmentation have made subject-specific modelling of the cardiovascular system a feasible task, which is particularly important in the case of pulmonary hypertension, requiring a combination of invasive and non-invasive procedures for diagnosis. Uncertainty in image segmentation propagates to CFD model predictions, making the quantification of segmentation-induced uncertainty crucial for subject-specific models. This study quantifies the variability of one-dimensional CFD predictions by propagating the uncertainty of network geometry and connectivity to blood pressure and flow predictions. We analyse multiple segmentations of a single, excised mouse lung using different pre-segmentation parameters. A custom algorithm extracts vessel length, vessel radii and network connectivity for each segmented pulmonary network. Probability density functions are computed for vessel radius and length and then sampled to propagate uncertainties to haemodynamic predictions in a fixed network. In addition, we compute the uncertainty of model predictions to changes in network size and connectivity. Results show that variation in network connectivity is a larger contributor to haemodynamic uncertainty than vessel radius and length.
Load-dependent adaptation near zero load in the bacterial flagellar motor
Authors: Nirody Jasmine A. , Nord Ashley L. , Berry Richard M.
Published: October 2019

The bacterial flagellar motor is an ion-powered transmembrane protein complex which drives swimming in many bacterial species. The motor consists of a cytoplasmic ‘rotor’ ring and a number of ‘stator’ units, which are bound to the cell wall of the bacterium. Recently, it has been shown that the number of functional torque-generating stator units in the motor depends on the external load, and suggested that mechanosensing in the flagellar motor is driven via a ‘catch bond’ mechanism in the motor’s stator units. We present a method that allows us to measure—on a single motor—stator unit dynamics across a large range of external loads, including near the zero-torque limit. By attaching superparamagnetic beads to the flagellar hook, we can control the motor’s speed via a rotating magnetic field. We manipulate the motor to four different speed levels in two different ion-motive force (IMF) conditions. This framework allows for a deeper exploration into the mechanism behind load-dependent remodelling by separating out motor properties, such as rotation speed and energy availability in the form of IMF, that affect the motor torque.
Fatiguing effects of indirect vibration stimulation in upper limb muscles: pre, post and during isometric contractions superimposed on upper limb vibration
Authors: Pujari Amit N. , Neilson Richard D. , Cardinale Marco
Published: October 2019

Whole-body vibration and upper limb vibration (ULV) continue to gain popularity as exercise intervention for rehabilitation and sports applications. However, the fatiguing effects of indirect vibration stimulation are not yet fully understood. We investigated the effects of ULV stimulation superimposed on fatiguing isometric contractions using a purpose developed upper limb stimulation device. Thirteen healthy volunteers were exposed to both ULV superimposed to fatiguing isometric contractions (V) and isometric contractions alone Control (C). Both Vibration (V) and Control (C) exercises were performed at 80% of the maximum voluntary contractions. The stimulation used was 30 Hz frequency of 0.4 mm amplitude. Surface-electromyographic (EMG) activity of the Biceps Brachii, Triceps Brachii and Flexor Carpi Radialis were measured. EMG amplitude (EMGrms) and mean frequency (MEF) were computed to quantify muscle activity and fatigue levels. All muscles displayed significantly higher reduction in MEFs and a corresponding significant increase in EMGrms with the V than the Control, during fatiguing contractions (
p
< 0.05). Post vibration, all muscles showed higher levels of MEFs after recovery compared to the control. Our results show that near-maximal isometric fatiguing contractions superimposed on vibration stimulation lead to a higher rate of fatigue development compared to the isometric contraction alone in the upper limb muscles. Results also show higher manifestation of mechanical fatigue post treatment with vibration compared to the control. Vibration superimposed on isometric contraction not only seems to alter the neuromuscular function during fatiguing efforts by inducing higher neuromuscular load but also post vibration treatment.
Not a limitless resource: ethics and guidelines for destructive sampling of archaeofaunal remains
Authors: Pálsdóttir Albína Hulda , Bläuer Auli , Rannamäe Eve , Boessenkool Sanne , Hallsson Jón Hallsteinn
Published: October 2019

With the advent of ancient DNA, as well as other methods such as isotope analysis, destructive sampling of archaeofaunal remains has increased much faster than the effort to collect and curate them. While there has been considerable discussion regarding the ethics of destructive sampling and analysis of human remains, this dialogue has not extended to archaeofaunal material. Here we address this gap and discuss the ethical challenges surrounding destructive sampling of materials from archaeofaunal collections. We suggest ways of mitigating the negative aspects of destructive sampling and present step-by-step guidelines aimed at relevant stakeholders, including scientists, holding institutions and scientific journals. Our suggestions are in most cases easily implemented without significant increases in project costs, but with clear long-term benefits in the preservation and use of zooarchaeological material.
Developing an integrated understanding of the evolution of arthropod segmentation using fossils and evo-devo
Authors: Chipman Ariel D. , Edgecombe Gregory D.
Published: October 2019

Segmentation is fundamental to the arthropod body plan. Understanding the evolutionary steps by which arthropods became segmented is being transformed by the integration of data from evolutionary developmental biology (evo-devo), Cambrian fossils that allow the stepwise acquisition of segmental characters to be traced in the arthropod stem-group, and the incorporation of fossils into an increasingly well-supported phylogenetic framework for extant arthropods based on genomic-scale datasets. Both evo-devo and palaeontology make novel predictions about the evolution of segmentation that serve as testable hypotheses for the other, complementary data source. Fossils underpin such hypotheses as arthropodization originating in a frontal appendage and then being co-opted into other segments, and segmentation of the endodermal midgut in the arthropod stem-group. Insights from development, such as tagmatization being associated with different modes of segment generation in different body regions, and a distinct patterning of the anterior head segments, are complemented by palaeontological evidence for the pattern of tagmatization during ontogeny of exceptionally preserved fossils. Fossil and developmental data together provide evidence for a short head in stem-group arthropods and the mechanism of its formation and retention. Future breakthroughs are expected from identification of molecular signatures of developmental innovations within a phylogenetic framework, and from a focus on later developmental stages to identify the differentiation of repeated units of different systems within segmental precursors.
Clinical and laboratory characteristics of clozapine treated schizophrenia patients referred to a national immunodeficiency clinic reveals a B-cell signature resembling CVID
Authors: Ponsford M.J. , Steven R. , Bramhall K. , Burgess M , Wijetilleka S , Carne E. , McGuire F , Price C. , Moody M. , Zouwail S , Tahir T , Farewell D. , El-Shanawany T. , Jolles S.
Published: October 2019

Purpose

An association between antibody deficiency and clozapine use in individuals with Schizophrenia has recently been reported. We hypothesized that if clozapine-associated hypogammaglobulinaemia was clinically relevant this would manifest in referral patterns.

Methods

Retrospective case note review of patients referred and assessed by Immunology Centre for Wales (ICW) between January 2005 and July 2018 with extraction of clinical and immunologic features for individuals with diagnosis of schizophrenia-like illness.

Results

1791 adult patients were assessed at ICW during this period; 23 patients had a psychiatric diagnosis of schizophrenia or schizo-affective disorder. Principal indications for referral were findings of low calculated globulin and immunoglobulins. Clozapine was the single most commonly prescribed antipsychotic (17/23), disproportionately increased relative to reported use in the general schizophrenia population (OR 6.48, 95% CI: 1.79 to 23.5). Clozapine therapy was noted in 6/7 (86%) of patients subsequently requiring immunoglobulin replacement therapy (IgRT). Marked reduction of class-switched memory B-cells (CSMB) and plasmablasts were observed in clozapine-treated individuals relative to healthy age-matched controls. Clozapine duration is associated with CSMB decline. One patient discontinued clozapine, with gradual recovery of IgG levels without use of IgRT.

Conclusion

Our findings are consistent with enrichment of clozapine-treatment within schizophrenic individuals referred for ICW assessment over the last 13 years. These individuals displayed clinical patterns closely resembling the primary immunodeficiency CVID, however appears reversible upon drug cessation. This has diagnostic, monitoring and treatment implications for psychiatry and immunology teams and directs prospective studies to address causality and the wider implications for this patient group.
Technical artifact drives apparent deviation from Hardy-Weinberg equilibrium at CCR5-Δ32 and other variants in gnomAD
Authors: Karczewski Konrad J. , Gauthier Laura D. , Daly Mark J.
Published: October 2019

Following an earlier report suggesting increased mortality due to homozygosity at the CCR5-Δ32 allele1, Wei and Nielsen recently suggested a deviation from Hardy-Weinberg Equilibrium (HWE) observed in public variant databases as additional supporting evidence for this hypothesis2. Here, we present a re-analysis of the primary data underlying this variant database and identify a pervasive genotyping artifact, especially present at long insertion and deletion polymorphisms. Specifically, very low levels of contamination can affect the variant calling likelihood models, leading to the misidentification of homozygous individuals as heterozygous, and thereby creating an apparent depletion of homozygous calls, which is especially prominent at large insertions and deletions. The deviation from HWE observed at CCR5-Δ32 is a consequence of this specific genotyping error mode rather than a signature of selective pressure at this locus.
Pulmonary acini exhibit complex changes during postnatal rat lung development
Authors: Haberthür David , Yao Eveline , Barré Sébastien F. , Cremona Tiziana P. , Tschanz Stefan A. , Schittny Johannes C.
Published: October 2019

Pulmonary acini represent the functional gas-exchanging units of the lung. Due to technical limitations, individual acini cannot be identified on microscopic lung sections. To overcome these limitations, we imaged the right lower lobes of instillation-fixed rat lungs from postnatal days P4, P10, P21, and P60 at the TOMCAT beamline of the Swiss Light Source synchrotron facility at a voxel size of 1.48 μm. Individual acini were segmented from the three-dimensional data by closing the airways at the transition from conducting to gas exchanging airways. For a subset of acini (N=268), we followed the acinar development by stereologically assessing their volume and their number of alveoli. We found that the mean volume of the acini increases 23 times during the observed time-frame. The coeffcients of variation dropped from 1.26 to 0.49 and the difference between the mean volumes of the fraction of the 20 % smallest to the 20 % largest acini decreased from a factor of 27.26 (day 4) to a factor of 4.07 (day 60), i.e. shows a smaller dispersion at later time points. The acinar volumes show a very large variation early in lung development and homogenize during maturation of the lung by reducing their size distribution by a factor of 7 until adulthood. The homogenization of the acinar sizes hints at an optimization of the gas-exchange region in the lungs of adult animals and that acini of different size are not evenly distributed in the lungs. This likely leads to more homogeneous ventilation at later stages in lung development.
A general principle of dendritic constancy – a neuron’s size and shape invariant excitability
Authors: Cuntz Hermann , Bird Alexander D , Beining Marcel , Schneider Marius , Mediavilla Laura , Hoffmann Felix Z , Deller Thomas , Jedlicka Peter
Published: October 2019

Reducing neuronal size results in less cell membrane and therefore lower input conductance. Smaller neurons are thus more excitable as seen in their voltage responses to current injections in the soma. However, the impact of a neuron’s size and shape on its voltage responses to synaptic activation in dendrites is much less understood. Here we use analytical cable theory to predict voltage responses to distributed synaptic inputs and show that these are entirely independent of dendritic length. For a given synaptic density, a neuron’s response depends only on the average dendritic diameter and its intrinsic conductivity. These results remain true for the entire range of possible dendritic morphologies irrespective of any particular arborisation complexity. Also, spiking models result in morphology invariant numbers of action potentials that encode the percentage of active synapses. Interestingly, in contrast to spike rate, spike times do depend on dendrite morphology. In summary, a neuron’s excitability in response to synaptic inputs is not affected by total dendrite length. It rather provides a homeostatic input-output relation that specialised synapse distributions, local non-linearities in the dendrites and synaptic plasticity can modulate. Our work reveals a new fundamental principle of dendritic constancy that has consequences for the overall computation in neural circuits.

In brief

We show that realistic neuron models essentially collapse to point neurons when stimulated by randomly distributed inputs instead of by single synapses or current injection in the soma.

Highlights

A simple equation that predicts voltage in response to distributed synaptic inputs.

Responses to distributed and clustered inputs are largely independent of dendritic length.

Spike rates in various Hodgkin Huxley (HH) like or Leaky Integrate-and-Fire (LIF) models are largely independent of morphology.

Precise spike timing (firing pattern) depends on dendritic morphology.

NeuroMorpho.Org database-wide analysis of the relation between dendritic morphology and electrophysiology.

Our equations set precise input-output relations in realistic dendrite models.
Multi-glomerular projection of single olfactory receptor neurons is conserved among amphibians
Authors: Weiss Lukas , Jungblut Lucas D. , Pozzi Andrea G. , Zielinski Barbara S. , O’Connell Lauren A. , Hassenklöver Thomas , Manzini Ivan
Published: October 2019

Individual receptor neurons in the peripheral olfactory organ extend long axons into the olfactory bulb forming synapses with projection neurons in spherical neuropil regions, called glomeruli. Generally, odor map formation and odor processing in all vertebrates is based on the assumption that receptor neuron axons exclusively connect to a single glomerulus without any axonal branching. We comparatively tested this hypothesis in multiple fish and amphibian species by applying sparse cell electroporation to trace single olfactory receptor neuron axons. Sea lamprey (jawless fish) and zebrafish (bony fish) support the unbranched axon concept, with 94% of axons terminating in single glomeruli. Contrastingly, axonal projections of the axolotl (salamander) branch extensively before entering up to six distinct glomeruli. Receptor neuron axons labeled in frog species (Pipidae, Bufonidae, Hylidae and Dendrobatidae) predominantly bifurcate before entering a glomerulus and 59% and 50% connect to multiple glomeruli in larval and post-metamorphotic animals, respectively. Independent of developmental stage, lifestyle and adaptations to specific habitats, it seems to be a common feature of amphibian olfactory receptor neuron axons to frequently bifurcate and connect to multiple glomeruli. Our study challenges the unbranched axon concept as a universal vertebrate feature and it is conceivable that also later diverging vertebrates deviate from it. We propose that this unusual wiring logic evolved around the divergence of the terrestrial tetrapod lineage from its aquatic ancestors and could be the basis of an alternative way of odor processing.

Abstract Figure
Expanding AHL Acylases Horizon - Insights From Structural Analysis of Choloylglycine Hydrolases FromShewanella lohicaPV-4
Authors: Philem Pushparani D , Yadav Yashpal , Sunder Avinash V , Ghosh Deepanjan , Prabhune Asmita , Ramasamy Sureshkumar
Published: October 2019

Acyl homoserine lactone acylases are quorum quenching enzymes that degrade the Gram negative bacterial autoinducerN-acyl homoserine lactone (AHL) and belong to the Ntn-hydrolases superfamily of enzymes. Recent findings reported AHL acylase activity of pencillin V acylases (PVA) which, alongside bile salt hydrolases, are members of the cholyolglycine hydrolase (CGH) family of the Ntn-hydrolases superfamily. The present study reports the unique activity profile of two CGHs from a marine bacteriumShewanella loihica-PV4, designated here asSlCGH1 andSlCGH2, including the structural analysis ofSlCGH1. Both the enzymes exhibit AHL acylase activity while unexpectedly being inactive on standard CGH substrates PenV and bile salts.SlCGH1 differs from known homotetrameric CGHs in being a homodimer displaying a reduced active site volume attributed to loop orientation, which subsequently directs the substrate specificity. Moreover a ligand bound complex structure revealed an unusual bent conformation of the saturated acyl chain bound to the active site and also predicts a single oxyanion hole forming residue during catalysis instead of the usual two residues. Phylogenetic analysis revealsSlCGH1 homologs cluster separate from reported CGHs and AHL acylases. On the whole,SlCGH1 could represent a functionally distinct new sub-class of CGH as an adaptation to the marine environment and its structure could provide the structural framework for understanding such a novel subclass. We also make a modest proposal of a probable evolutionary link between AHL acylases and β lactam acylases based on the overlap in activity and structural features.

Significance

Cross-reactivity between AHL acylases and b lactam acylases has been recently identified giving us a vivid glimpse of a possible evolutionary relationship between the phenomena of quorum sensing and antibiotic resistance. We report here the first AHL acylase of the CGH structural framework.SlCGH1 fromShewanella loihicaPV-4 is also the first report of a marine CGH with a unique activity and a new structural subclass of CGH family with AHL acylase activity. This finding highlights the vast diversity of AHL acylases and by extension quorum quenching enzymes as adaptation to different habitats. The results from this study also bolster the link between signal molecules and antibiotics, extending our understanding of the inadequately understood physiological roles of b-lactam acylases.
Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor
Authors: Saitou M. , Resendez S. , Pradhan A.J. , Wu F. , Lie N.C. , Hall N.J. , Zhu Q. , Reinholdt L. , Satta Y. , Nakagome S. , Hanchard N.A. , Churchill G. , Lee C. , Atilla-Gokcumen G.E. , Mu X. , Gokcumen O.
Published: October 2019

The deletion of the third exon of the growth hormone receptor (GHR) is one of the most common genomic structural variants in the human genome. This deletion (GHRd3)has been linked to response to growth hormone, placenta size, birth weight, growth after birth, time of puberty, adult height, and longevity. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. Here, we analyzed thousands of genomes and provide evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals. However, it underwent a paradoxical adaptive reduction in frequency approximately 30 thousand years ago in East Asia that roughly corresponds with the emergence of archaeological evidence for multiple modern human behaviors, dramatic changes in climate, and a concurrent population expansion. Further, we provide evidence that GHRd3 is associated with protection from edematous severe acute malnutrition primarily in males. Using a mouse line engineered to contain the deletion, we foundGhrd3’s effect on the liver transcriptome of male mice grown without any calorie restriction mimics response to calorie restriction through regulation of circadian pathways. In contrast, under calorie restriction,Ghrd3leads to the female-like gene expression in male livers. As a likely consequence, the dramatic weight difference between male and female mice disappears amongGHRd3mice under calorie restriction. Our data provide evidence for sex- and environment-dependent effects ofGHRd3and are consistent with a model in which the allele frequency ofGHRd3varies throughout human evolution as a response to fluctuations in resource availability.
Condition-dependent trade-offs maintain honest signaling: A laboratory experiment
Authors: Számadó Szabolcs , Samu Flóra , Takács Károly
Published: October 2019

How and why animals and humans signal reliably is a key issue in biology and social sciences. For many years the dominant paradigm in biology was the Handicap Principle. It claims a causal relationship between honesty and signal cost and thus predicts that honest signals have to be costly to produce. However, contrary to the Handicap Principle, game theoretical models predict that honest signaling is maintained by condition dependent signaling trade-offs and honest signals need not be costly at the equilibrium. Due to the difficulties of manipulating signal cost and signal trade-offs there is surprisingly little evidence to test these predictions either from biology or from social sciences. Here we conduct a human laboratory experiment with a two-factorial design to test the role of equilibrium signal cost vs. signalling trade-offs in the maintenance of honest communication. We have found that the trade-off condition has much higher influence on the reliability of communication than the equilibrium cost condition. The highest level of honesty was observed in the condition dependent trade-off condition as predicted by recent models. Negative production cost, i.e. fix benefit-contrary to the prediction of the Handicap Principle-promoted even higher level of honesty than the other type of costs under this condition.
Scarce and directly beneficial reputations support cooperation
Authors: Samu Flóra , Számadó Szabolcs , Takács Károly
Published: October 2019

A human solution to the problem of cooperation is the construction and maintenance of informal reputation hierarchies. Reputational information contributes to cooperation by providing guidelines about previous group-beneficial or free-rider behavior of opponents in social dilemma interactions. How reputation information could be credible, however, when outcomes of interactions are not publicly known, remains a puzzle. In this study, we propose that credibility could be ensured if reputation is a scarce resource and it is not believed to be earned for direct benefits. We tested these propositions in a laboratory experiment in which participants played two-person Prisoner’s Dilemma games without partner selection, could observe some other interactions and could communicate reputational information about possible prospective opponents to each other. We found that scarcity is a necessary condition for reputation scores to be informative. While cooperation has not been sustained at a high level in any of the conditions, reputational information clearly influenced cooperation decisions. The possibility of exchanging third-party information was able to increase the level of cooperation the most if reputation was a scarce resource and contrary to our expectations, when reputational scores have been directly translated into monetary benefits.
Genetic Mapping in Autohexaploid Sweet Potato with Low-coverage NGS-based Genotyping Data
Authors: Yamamoto Eiji , Shirasawa Kenta , Kimura Takumi , Monden Yuki , Tanaka Masaru , Isobe Sachiko
Published: October 2019

Next-generation sequencing (NGS)-based genotyping methods can generate numerous genetic markers in a single experiment and have contributed to plant genetic mapping. However, the benefits of NGS-based methods are limited in autopolyploids as their genetic segregation mode is complex. Moreover, autopolyploids have large genomes and require abundant sequencing data to obtain sufficient genetic markers. There are several methods for genetic mapping in autopolyploids. These approaches may be impractical for plant genetic studies as they require large amounts of data and are not cost-effective. In the present study, we propose a simple strategy for genetic mapping of polyploids in a cost-effective manner. The allele dosage probabilities calculated from NGS read counts were used in association analyses to detect loci associated with specific phenotypes. This approach is superior to conventional methods of determining allele dosage, which usually result in the filtering of many genetic markers with low read depth. The validity of the strategy was demonstrated using real phenotype data from autohexaploid sweet potato populations to detect genetic loci for both qualitative and quantitative traits, the latter of which required the use of allele dosage probabilities for the detection of loci. We demonstrate that this proposed method is useful with reasonable NGS read counts.