bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.

Summary
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.
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

AbstractPurposeAn 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.MethodsRetrospective 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.Results1791 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.ConclusionOur 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

AbstractFollowing 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

AbstractPulmonary 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

AbstractReducing 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 briefWe 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.HighlightsA 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

AbstractAcyl 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.SignificanceCross-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

ABSTRACTThe 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

AbstractHow 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

ABSTRACTA 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.