bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term Continuity of Antipsychotic Treatment for Schizophrenia: A Nationwide Study
Authors: Rubio Jose M , Taipale Heidi , Tanskanen Antti , Correll Christoph U , Kane John M , Tiihonen Jari
Published: April 2021

Schizophrenia often requires long-term treatment with antipsychotic medication. This study aims to measure the continuity of antipsychotic treatment over the course of illness in schizophrenia, as well as factors involved in the interruption of treatment. For this, we followed up a national cohort of first-episode psychosis patients in Finland for up to 18 years. Stratified Cox proportional hazards regressions were conducted for “within-participant” risk of discontinuation of subsequent treatments compared to the first, and by specific antipsychotic compared to oral olanzapine, the most prescribed antipsychotic in this cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated. Among 3343 participants followed up for a mean of 8 years (SD = 4.93), the median number of continuous treatment episodes was 6 (interquartile range [IQR] = 3–11) with a median duration of 11.4 months (IQR = 5.3–25.6). In the first year after diagnosis, the incidence rate of treatment discontinuation was 30.12 (95% CI = 29.89–30.35) events per 100 participant-years, decreasing to 8.90 (95% CI = 8.75–9.05) in the 10th year. The risk of discontinuation progressively decreased over successive treatment episodes (aHR = 0.30; 95% CI = 0.20–0.46 for episodes after the 15th compared to the first). Individuals were 67% less likely to interrupt treatment with long-acting injectable than oral antipsychotics (aHR = 0.33; 95% CI = 0.27–0.41). Treatment for schizophrenia over the long term is often characterized by recurrent cycles of interruptions and reintroductions of antipsychotic medication, which is typically not recommended by management guidelines. Greater utilization of long-acting injectable formulations earlier in the course of illness may facilitate the continuity of antipsychotic treatment in schizophrenia.
Boosting innovation in small- and medium-sized enterprises through tax incentives: lessons from the UK
Authors: Ehsan Firoz
Published: April 2021

Today’s technological frontrunners are tomorrow’s economic champions. In order to triumph in the global innovation race, nations go to great lengths to boost domestic innovation. An increasingly popular instrument of such government support is known as the ‘R&D tax incentive’. Scholars have particularly noted its greater incentive impact on small- and medium-sized enterprises (SMEs). However, correct use of this fiscal tool remains clouded by legal and economic complexities, often leading to misallocation of tax money. This study draws on the rich experience of the UK as a seasoned lawmaker in this field, to derive internationally transferrable policy lessons and principles that may be used in assessing and optimizing the potency of research and development tax incentives for SMEs. Following a theoretical analysis of the historical legal developments, annual government statistics, literature, and policy papers, this study argues that policymakers must take into account appropriateness, cost-efficiency, and accessibility in the design.
Expression of Exhaustion Markers on CD8+ T-Cell Patterns Predict Outcomes in Septic Patients Admitted to the ICU*
Authors: Guinault Damien , Nicolau-Travers Marie-Laure , Silva Stein , Cointault Olivier , Daniau Barnabé , Del Bello Arnaud , Peres Michael , Rousset David , Rieunier Julie , Lavayssiere Laurence , Nogier Marie-Béatrice , Hourcastagnou Edith , Mari Arnaud , Kamar Nassim , Vergez François , Faguer Stanislas
Published: April 2021

RATIONALE:

There is an unmet need to improve the description of the state of T-cell exhaustion in patients with sepsis, its reproducibility and correlation with the outcomes before including immunotherapy (like recombinant interleukin-7 or immune checkpoint inhibitors) in the therapeutic armamentarium against sepsis.

DESIGN:

Observational prospective study.

SETTING:

Two ICUs in a teaching hospital (France).

PATIENTS:

Eighty patients with sepsis admitted to the ICU.

INTERVENTIONS:

Quantification of CD4+ and CD8+ T-cell exhaustion at days 1 and 3. Quantification of the exhaustion markers (programmed death [PD]-1, 2B4, and cluster of differentiation [CD] 160) on T cells, the number of CD4+ regulatory T cells (CD3+ CD4+ CD25hi CD127Lo cells), and the phorbol myristate acetate/ionomycin/ionomycin-induced cytokines production (tumor necrosis factor-α, interleukin-2, and interferon-γ).

MEASUREMENTS AND MAIN RESULTS:

Using unsupervised clustering analysis, patients could be split in three clusters according to their dominant pattern expression of exhaustion markers on CD8+ T cells (i.e., 2B4lowPD-1lowCD160low, 2B4hiPD-1hiCD160low, and 2B4hiPD-1lowCD160hi) regardless of their underlying morbidities. Only 2B4hiPD-1hiCD160low CD8+ T cells had cytokine production defect, whereas 2B4hi PD-1lowCD160hi pattern correlated with cytokine overproduction. Patients with a predominant “highly activated” 2B4hiPD-1lowCD160hi pattern did not develop secondary bacterial infections. By multivariate analysis, Simplified Acute Physiology Score 2 gravity score at day 1 (p = 0.003) and patterns of exhaustion markers on CD8+ T cells (p = 0.03) were associated with the risk of death. Neither the level of CD4+ regulatory T cells nor the CD4+ exhaustion patterns were associated with the outcomes.

CONCLUSIONS:

Easy-to-use multicolor flow cytometry assessing 2B4, PD-1, and CD160 expression on CD8+ T cells at day 1 identifies septic patients with poor outcome and discriminates patient subsets in who immunomodulatory drugs should be tested.
Electrocautery-enhanced Lumen-apposing Metal Stents in the Management of Symptomatic Pancreatic Fluid Collections
Authors: Nieto Jose , Mekaroonkamol Parit , Shah Raj , Khashab Mouen A. , Loren David E. , Waxman Irving , Edmundowicz Steven A. , Willingham Field F.
Published: April 2021

Background and Aims:

Endoscopic decompression is considered a first-line treatment for symptomatic pancreatic fluid collections (PFCs). A lumen-apposing metal stent (LAMS) with an electrocautery-enhanced delivery system [electrocautery-enhanced lumen-apposing metal stent (ELAMS)] may facilitate this procedure. This study evaluated the safety and efficacy of ELAMS in the management of symptomatic PFCs.

Patients and Methods:

A multicenter, nonblinded, prospective, Food and Drug Administration (FDA)-approved, investigational device exemption clinical trial was conducted. Enrollment criteria included symptomatic PFCs ≥6 cm with ≥70% fluid fraction. Subjects were followed prospectively for safety, efficacy, and resolution of the collections. Primary endpoint success was defined as ≥50% reduction in PFC size. Clinical outcomes were compared with our previously published series of LAMS without the cautery-enhanced delivery system.

Results:

The target enrollment of 30 patients was achieved in 7 US tertiary care centers. All patients underwent successful placement of the ELAMS. The mean procedure duration, stent placement time, and fluoroscopy exposures were 28.1±12.5, 5.8±2.6, and 1.8±1.6 minutes, respectively. Eight patients had no fluoroscopy. The primary endpoint was achieved in 83.3% of patients. Two adverse events were attributed to the ELAMS: 1 bleeding upon stent removal and 1 stent migration. Relative to the comparator noncautery LAMS multicenter trial (N=33, 8 tertiary centers), there was a significantly shorter procedure duration [36 min (P<0.001)] with similar technical and clinical outcomes in the ELAMS cohort.

Conclusion:

LAMS placed using an electrocautery delivery system significantly reduce procedure duration and were safe and effective in the management of symptomatic PFCs.
Speech and language therapy assessment of patients on the 2-week wait head and neck cancer referral pathway: evidence and opinion following a pilot study
Authors: Occomore-Kent Louise , Slade Suzanne
Published: April 2021

Purpose of review

Spiralling numbers of patients are being referred on the two-week wait (2WW) head and neck cancer referral pathway. Only a small proportion are found to have cancer. There is a call for change in the management of these referrals, particularly following coronavirus. Allied health professionals (AHPs) are being encouraged by the NHS to extend their clinical practice to address increased demand. Speech and Language Therapists (SLTs) may offer a solution to some of the 2WW pathway's challenges.

Recent findings

Recent evidence highlights problems with the pathway and reasons for change. Hoarse voice is consistently found to be the most common presenting symptom. Emerging evidence suggests SLTs can extend their scope of practice to manage new hoarse voice referrals. A pilot project is described. Outcomes from this and other ongoing studies explore efficacy and investment required to make this proposal an achievable prospect for the future

The management of 2WW referrals on the head and neck cancer pathway needs to change. Preliminary findings suggest SLTs working within the context of the multidisciplinary team can safely extended their role to improve management of these patients. Professional role outline, recognition, guidance, and training framework are needed.
Incidental Serous Cystadenoma Presenting as a Photopenic Pancreatic Defect on 18F-Fluciclovine PET/CT
Authors: Waltz Jeffrey , Mercer Megan K. , Dani Genta , Rieter William J.
Published: April 2021

18F-fluciclovine (Axumin) PET/CT has been widely used for the evaluation of biochemically recurrent prostate cancer following prior treatment. While lymph node and visceral organ metastases typically show increased radiotracer uptake, altered patterns of normal physiologic activity may also provide insight into other disease processes. We present a case of an incidental pancreatic head mass presenting as a photopenic defect on a staging 18F-fluciclovine PET/CT, which was subsequently confirmed to be a benign serous cystadenoma using multisequence MRI.
The Benefits and Harms of Open Notes in Mental Health: A Delphi Survey of International Experts
Authors: Blease Charlotte , Kharko Anna , Hagglund Maria , O’Neill Stephen , Wachenheim Deborah , Salmi Liz , Harcourt Kendall , Locher Cosima , DesRoches Catherine M. , Torous John
Published: April 2021

Importance

As of April 5, 2021, as part of the 21st Century Cures Act, new federal rules in the U.S. mandate that providers offer patients access to their online clinical records.

Objective

To solicit the view of an international panel of experts on the effects on mental health patients, including possible benefits and harms, of accessing their clinical notes.

Design

An online 3-round Delphi poll.

Setting

In round 1 open-ended questions solicited feedback on the benefits and harms to patients of reading their mental health notes. Responses were coded to produce itemized statements. In Round 2 participants were asked to rate their agreement with each item along 7-point Likert scales. Responses were analyzed for consensus, set at a predetermined interquartile range of ≤ 1. In Round 3 items that did not reach consensus were redistributed.

Participants

International experts identified as clinicians, chief medical information officers, patient advocates, and informaticians with extensive experience and/or research knowledge about patient access to mental health notes.

Main Outcomes, and Measures

An expert-generated consensus on the benefits and risks of sharing mental health notes with patients.

Results

A total of 70 of 92 (76%) experts from 6 countries responded to Round 1. A qualitative review of responses yielded 88 distinct items. A total of 56 of 70 (80%) experts responded to Round 2, and 52 of 56 (93%) responded to Round 3. Consensus was reached on 65 of 88 (74%) of survey items.

Conclusions and Relevance

This iterative process of survey responses and ratings yielded consensus that there would be multiple benefits and few harms to patients from accessing their mental health notes. Questions remain about the impact of open notes on professional autonomy, and further empirical work into this practice innovation is warranted.
Evaluation of the sensitivity, accuracy and currency of the Cochrane COVID-19 Study Register for supporting rapid evidence synthesis production
Authors: Metzendorf Maria-Inti , Featherstone Robin M.
Published: April 2021

Introduction

The Cochrane COVID-19 Study Register (CCSR) is a public, continually updated, curated database of COVID-19 study references. The aim of this study-based register is to support rapid and living evidence synthesis, including a project to build an evidence ecosystem of COVID-19 research (CEOsys). In November and December 2020 we conducted an evaluation of the CCSR for CEOsys, measured its performance and identified areas for improvement.

Methods

For the evaluation we generated a purposive sample of 286 studies from 20 reviews to calculate the CCSR’s sensitivity (comprehensiveness), accuracy (correctly classified and linked studies) and currency (time to publish and process references).

Results

The CCSR had an overall sensitivity of 77.2%, with the highest sensitivity for interventional studies (94.4%) and lowest sensitivity for modelling studies (63.6%). The study register had 100% sensitivity for trial registry records, 86.5% for journal articles and 52.4% for preprints. 98.3% of references were correctly classified with regard to study type, and 93.4% with regard to study aim. 89% of studies were correctly linked. 81.4% of references were published to the register in under 30 days, with 0.5 day (median) for trial registry records, 2 days for journal articles and 56 days for preprints.

Conclusion

The CCSR had high sensitivity, accurate study classifications and short publishing times for journal articles and trial registry records. We identified that the CCSR’s coverage and publishing times for preprints needed improvement. Finally, the evaluation illustrated the value of a study-based register for identifying additional study references for analysis in evidence synthesis.
COVID-19 vaccination beliefs, attitudes, and behaviours among health and social care workers in the UK: a mixed-methods study
Authors: Bell Sadie , Clarke Richard M , Ismail Sharif A , Ojo-Aromokudu Oyinkansola , Naqvi Habib , Coghill Yvonne , Donovan Helen , Letley Louise , Paterson Pauline , Mounier-Jack Sandra
Published: April 2021

Background

The UK began delivering its COVID-19 vaccination programme on 8 December 2020, with health and social care workers (H&SCWs) given high priority for vaccination. Despite well- documented occupational exposure risks, however, there is evidence of lower uptake among some H&SCW groups.

Methods

We used a mixed-methods approach - involving an online cross-sectional survey and semi- structured interviews – to gain insight into COVID-19 vaccination beliefs, attitudes, and behaviours amongst H&SCWs in the UK by socio-demographic and employment variables. 1917 people were surveyed – 1658 healthcare workers (HCWs) and 261 social care workers (SCWs). Twenty participants were interviewed.

Findings

Workplace factors contributed to vaccination access and uptake. SCWs were more likely to not be offered COVID-19 vaccination than HCWs (OR:1.453, 95%CI: 1.244 – 1.696). SCWs specifically reported uncertainties around how to access COVID-19 vaccination. Participants who indicated stronger agreement with the statement‘I would recommend my organisation as a place to work’were more likely to have been offered COVID-19 vaccination (OR:1.28, 95%CI: 1.06 – 1.56). Those who agreed more strongly with the statement ‘I feel/felt under pressure from my employer to get a COVID-19 vaccine’ were more likely to have declined vaccination (OR:1.75, 95%CI: 1.27– 2.41). Interviewees that experienced employer pressure to get vaccinated felt this exacerbated their vaccine concerns and increased distrust.

In comparison to White British and White Irish participants, Black African and Mixed Black African participants were more likely to not be offered (OR:2.011, 95%CI: 1.026 – 3.943) and more likely to have declined COVID-19 vaccination (OR:5.55, 95%CI: 2.29 – 13.43). Reasons for declining vaccination among Black African participants included distrust in COVID-19 vaccination, healthcare providers, and policymakers.

Conclusion

H&SCW employers are in a pivotal position to facilitate COVID-19 vaccination access, by ensuring staff are aware of how to get vaccinated and promoting a workplace environment in which vaccination decisions are informed and voluntary.
Long distance runners in the marine realm: New insights into genetic diversity, kin relationships and social fidelity of Indian Ocean male sperm whales
Authors: Girardet Justine , Sarano Francois , Richard Gaëtan , Tixier Paul , Guinet Christophe , Alexander Alana , Sarano Véronique , Vitry Hugues , Preud’homme Axel , Heuzey René , Garcia-Cegarra Ana M. , Adam Olivier , Madon Bénédicte , Jung Jean-Luc
Published: April 2021

Background

Adult male sperm whales (Physeter macrocephalus) are long distance runners of the marine realm, feeding in high latitudes and mating in tropical and subtropical waters where stable social groups of females and immatures live. Several areas of uncertainty still limit our understanding of their social and breeding behaviour, in particular concerning the potential existence of geographical and/or social fidelities.

In this study, using underwater observation and sloughed-skin sampling, we looked for male social fidelity to a specific matrilineal sperm whale group near Mauritius. In addition, we captured a wider picture of kin relationships and genetic diversity of male sperm whales in the Indian Ocean thanks to biopsies of eight unique individuals taken in a feeding ground near the Kerguelen and Crozet Archipelagos (Southern Indian Ocean).

Results

Twenty-six adult male sperm whales, of which 13 were sampled, were identified when socializing with adult females and immatures off Mauritius. Long-term underwater observation recorded several noteworthy social interactions between adult males and adult females and/or immatures. We identified seven possible male recaptures over different years (three by direct observation, and four at the gametic level), which supports a certain level of male social fidelity. Several first- and second-degree kin relationships were highlighted between members of the social unit and adult males, confirming that some of the adult males observed in Mauritian waters are reproductive. Male social philopatry to their natal group can be excluded, as none of the males sampled shared the haplotype characteristic of the matrilineal social group. Mitochondrial DNA control region haplotype and nucleotide diversities calculated over the 21 total male sperm whales sampled were similar to values found by others in the Indian Ocean.

Conclusions

Our study strongly supports the existence of some levels of male sperm whale social fidelity, not directed to their social group of birth, in the Indian Ocean. Males sampled in breeding and feeding grounds are linked by kin relationships. Our results support a model of male mediated gene flow occurring at the level of the whole Indian Ocean, likely interconnected with large-scale geographical fidelity to ocean basin, and a small-scale social fidelity to matrilineal social groups.
PaIRKAT: A pathway integrated regression-based kernel association test with applications to metabolomics and COPD phenotypes
Authors: Carpenter Charlie M. , Zhang Weiming , Gillenwater Lucas , Severn Cameron , Ghosh Tusharkanti , Bowler Russel , Kechris Katerina , Ghosh Debashis
Published: April 2021

High-throughput data such as metabolomics, genomics, transcriptomics, and proteomics have become familiar data types within the “-omics” family. For this work, we focus on subsets that interact with one another and represent these “pathways” as graphs. Observed pathways often have disjoint components, i.e. nodes or sets of nodes (metabolites, etc.) not connected to any other within the pathway which notably lessens testing power. In this paper we propose thePathwayIntegratedRegression-basedKernelAssociationTest (PaIRKAT), a new kernel machine regression method for incorporating known pathway information into the semi-parametric kernel regression framework. This paper also contributes an application of a graph kernel regularization method for overcoming disconnected pathways. By incorporating a regularized or “smoothed” graph into a score test, PaIRKAT is capable of providing more powerful tests for associations between biological pathways and phenotypes of interest and will be helpful in identifying novel pathways for targeted clinical research. We evaluate this method through several simulation studies and an application to real metabolomics data from the COPDGene study. Our simulation studies illustrate the robustness of this method to incorrect and incomplete pathway knowledge, and the real data analysis shows meaningful improvements of testing power in pathways. PaIRKAT was developed for application to metabolomic pathway data, but the techniques are easily generalizable to other data sources with a graph-like structure.

Author Summary

PaIRKAT is a tool for improving testing power on high dimensional data by including graph topography in the kernel machine regression setting. Studies on high dimensional data can struggle to include the complex relationships between variables. The semi-parametric kernel machine regression model is a powerful tool for capturing these types of relationships. They provide a framework for testing for relationships between outcomes of interest and high dimensional data such as metabolomic, genomic, or proteomic pathways. Our paper proposes PaIRKAT, a method for including known biological connections between high dimensional variables by representing them as edges of ‘graphs’ or ‘networks.’ It is common for nodes (e.g. metabolites) to be disconnected from all others within the graph, which leads to meaningful decreases in testing power whether or not the graph information is included. We include a graph regularization or ‘smoothing’ approach for managing this issue. We demonstrate the benefits of this approach through simulation studies and an application to the metabolomic data from the COPDGene study.
The role of microbial diversity in the formation of soil organic matter quality and persistence
Authors: Domeignoz-Horta Luiz A. , Shinfuku Melissa , Junier Pilar , Poirier Simon , Verrecchia Eric , Sebag David , DeAngelis Kristen M
Published: April 2021

The largest terrestrial carbon sink on earth is soil carbon stocks. As the climate changes, the rate at which the Earth’s climate warms depends in part on the persistence of soil organic carbon. Microbial turnover forms the backbone of soil organic matter (SOM) formation and it has been recently proposed that SOM molecular complexity is a key driver of stability. Despite this, the links between microbial diversity, chemical complexity and biogeochemical nature of soil organic matter remain missing. Here we used a model soil system to test the hypothesis that more diverse microbial communities generate more stable soil organic matter. We inoculated microbial communities of varying diversities into an model soil matrix amended with simple carbon, and measured the thermal stability of the resultant soil organic matter. Using a novel data analysis approach with Rock-Eval®ramped thermal analysis, we found that microbial community diversity drives the chemical fingerprint of soil organic matter. Bacteria-only and low diversity communities lead to less chemically-diverse and more thermally-labile soil carbon pools than highly diverse communities. Our results provide direct evidence for a link between microbial diversity, molecular complexity and SOM stability. This evidence demonstrates the benefits of managing soils for maximum biological diversity as a means of building persistent SOM stocks.

Classification

Biological Sciences: Ecology
Reconciling contrast invariance and non-linear computation in cortical circuits
Authors: Timón L. Bernáez , Ekelmans P. , Konrad S. , Nold A. , Tchumatchenko T.
Published: April 2021

Network selectivity for orientation is invariant to changes in the stimulus contrast in the primary visual cortex. Similarly, the selectivity for odor identity is invariant to changes in odorant concentration in the piriform cortex. Interestingly, invariant network selectivity appears robust to local changes in synaptic strength induced by synaptic plasticity, even though: i) synaptic plasticity can potentiate or depress connections between neurons in a feature-dependent manner, and ii) in networks with balanced excitation and inhibition, synaptic plasticity is a determinant for the network non-linearity. In this study, we investigate whether network contrast invariance is consistent with a variety of synaptic states and connectivities in balanced networks. By using mean-field models and spiking network simulations, we show how the synaptic state controls the non-linearity in the network response to contrast and how it can lead to the emergence of contrast-invariant or contrast-dependent selectivity. Different forms of synaptic plasticity sharpen or broaden the network selectivity, while others do not affect it. Our results explain how the physiology of individual synapses is linked to contrast-invariant selectivity at the network level.
Cooperation enhances structural stability in mutualistic systems
Authors: Portillo José R. , Soler-Toscano Fernando , Langa José A.
Published: April 2021

Dynamical systems on graphs allow to describe multiple phenomena from different areas of Science. In particular, many complex systems in Ecology are studied by this approach. In this paper we analize the mathematical framework for the study of the structural stability of each stationary point, feasible or not, introducing a generalization for this concept, defined asGlobal Structural Stability. This approach would fit with the proper mathematical concept of structural stability, in which we find a full description of the complex dynamics on the phase space due to nonlinear dynamics. This fact can be analyzed as an informational field grounded in a global attractor whose structure can be completely characterized. These attractors are stable under perturbation and suppose the minimal structurally stable sets. We also study in detail, mathematically and computationally, the zones characterizing different levels of biodiversity in bipartite graphs describing mutualistic antagonistic systems of population dynamics. In particular, we investigate the dependence of the region of maximal biodiversity of a system on its connectivity matrix. On the other hand, as the network topology does not completely determine the robustness of the dynamics of a complex network, we study the correlation between structural stability and several graph measures. A systematic study on synthetic and biological graphs is presented, including 10 mutualistic networks of plants and seed-dispersal and 1000 random synthetic networks. We compare the role of centrality measures and modularity, concluding the importance of just cooperation strength among nodes when describing areas of maximal biodiversity. Indeed, we show that cooperation parameters are the central role for biodiversity while other measures act as secondary supporting functions.

Author summary

We introduce the concept of Global Structural Stability as a proper mathematical concept to fully understand biodiversity in some ecological systems. Our concept retakes the definitions in the classical works of R. Thom [1] and Andronov-Pontryagin [2]. Moreover, there exists a close relation between the structure of a complex network, described as a graph, and its associated dynamics. Mutualistic networks introduce cooperation links between two groups of species, as plant and pollinators or seed-dispersal. The understanding of organizational aspects leading to maximizing biodiversity is one of the more important research areas in Theoretical and Applied Ecology. In this work we introduce a systematic study on different graph measures in order to identify optimal organization for maximal biodiversity (defined as structural stability). Our results conclude that, for mutualistic systems, the strength in cooperation parameters are the core fact, i.e., cooperation is the real fact optimizing biodiversity among other possible structural configurations.
Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome
Authors: Krane Markus , Dreßen Martina , Santamaria Gianluca , My Ilaria , Schneider Christine M. , Dorn Tatjana , Laue Svenja , Mastantuono Elisa , Berutti Riccardo , Rawat Hilansi , Gilsbach Ralf , Schneider Pedro , Lahm Harald , Schwarz Sascha , Doppler Stefanie A. , Paige Sharon , Puluca Nazan , Doll Sophia , Neb Irina , Brade Thomas , Zhang Zhong , Abou-Ajram Claudia , Northoff Bernd , Holdt Lesca M. , Sudhop Stefanie , Sahara Makoto , Goedel Alexander , Dendorfer Andreas , Tjong Fleur V.Y. , Rijlaarsdam Maria E. , Cleuziou Julie , Lang Nora , Kupatt Christian , Bezzina Connie , Lange Rüdiger , Bowles Neil E. , Mann Matthias , Gelb Bruce , Crotti Lia , Hein Lutz , Meitinger Thomas , Wu Sean , Sinnecker Daniel , Gruber Peter J. , Laugwitz Karl-Ludwig , Moretti Alessandra
Published: April 2021

Background

Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role.

Methods

To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed: i) whole-exome sequencing of 87 HLHS parent-offspring trios, ii) nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, iii) single cell RNA sequencing and iv) 3D modeling in iPSCs from 3 patients with HLHS and 3 controls.

Results

Gene set enrichment and protein network analyses of damagingde-novomutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell-cycle and cardiomyocyte maturation. Single-cell and 3D modeling with iPSCs demonstrated intrinsic defects in the cell-cycle/UPR/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte-subtype differentiation/maturation in HLHS. Additionally, premature cell-cycle exit of ventricular cardiomyocytes from HLHS patients prevented normal tissue responses to developmental signals for growth leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues.

Conclusions

Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.
Exploring functional protein covariation across single cells using nPOP
Authors: Leduc Andrew , Huffman R. Gray , Cantlon Joshua , Khan Saad , Slavov Nikolai
Published: April 2021

Many biological processes, such as the cell division cycle, are reflected in protein covariation across single cells. This covariation can be quantified and interpreted by single-cell mass-spectrometry (MS) with sufficiently high throughput and accuracy. Towards this goal, we developed nPOP, a method that uses piezo acoustic dispensing to isolate individual cells in 300 picoliter volumes and performs all subsequent sample preparation steps in small droplets on a fluorocarbon-coated slide. This design enabled simultaneous sample preparation of thousands of single cells, including lysing, digesting, and labeling individual cells in volumes of 8-20 nl. Protein covariation analysis identified cell-cycle dynamics that were similar across cell types and dynamics that differed between cell types, even within sub-populations of melanoma cells defined by markers for drug-resistance priming. The melanoma cells expressing these markers accumulated in the G1 phase of the cell cycle, displayed distinct protein covariation across the cell cycle, accumulated glycogen, and had lower abundance of glycolytic enzymes. The non-primed melanoma cells exhibited gradients of protein abundance and covariation, suggesting transition states. These results were validated by different MS methods. Together, they demonstrate that protein covariation across single cells may reveal functionally concerted biological differences between closely related cell states.
Persistent Activity during Working Memory from Front to Back
Authors: Curtis Clayton E. , Sprague Thomas C.
Published: April 2021

Working memory (WM) extends the duration over which information is available for processing. Given its importance in supporting a wide-array of high level cognitive abilities, uncovering the neural mechanisms that underlie WM has been a primary goal of neuroscience research over the past century. Here, we critically review what we consider the two major ‘arcs’ of inquiry, with a specific focus on findings that were theoretically transformative. For the first arc, we briefly review classic studies that led to the canonical WM theory that cast the prefrontal cortex (PFC) as a central player utilizing persistent activity of neurons as a mechanism for memory storage. We then consider recent challenges to the theory regarding the role of persistent neural activity. The second arc, which evolved over the last decade, stemmed from sophisticated computational neuroimaging approaches enabling researchers to decode the contents of WM from the patterns of neural activity in many parts of the brain including early visual cortex. We summarize key findings from these studies, their implications for WM theory, and finally the challenges these findings pose. A comprehensive theory of WM will require a unification of these two ‘arcs’ of research.
Spatial analysis of tumor infiltrating lymphocytes based on deep learning using histopathology image to predict progression-free survival in colorectal cancer
Authors: Xu Hongming , Cha Yoon Jin , Clemenceau Jean R. , Choi Jinhwan , Lee Sung Hak , Kang Jeonghyun , Hwang Tae Hyun
Published: April 2021

Purpose

This study aimed to explore the prognostic impact of spatial distribution of tumor infiltrating lymphocytes (TILs) quantified by deep learning (DL) approaches based on digitalized whole slide images stained with hematoxylin and eosin in patients with colorectal cancer (CRC).

Methods

The prognostic impact of spatial distributions of TILs in patients with CRC was explored in the Yonsei cohort (n=180) and validated in the TCGA cohort (n=268). Concurrently, two experienced pathologists manually measured TILs at the most invasive margin as 0-3 by the Klintrup-Mäkinen (KM) grading method and compared to DL approaches. Interobserver agreement for TILs was measured using Cohen’s kappa coefficient.

Results

On multivariate analysis of spatial TILs features derived by DL approaches and clinicopathological variables including tumor stage, Microsatellite instability, and KRAS mutations, TILs densities within 200 μm of the invasive margin (f_im200) was remained as the most significant prognostic factor for progression-free survival (PFS) (HR 0.004 [95% CI, 0.0001-0.1502],p=.002) in the Yonsei cohort. On multivariate analysis using the TCGA dataset, f_im200 retained prognostic significance for PFS (HR 0.031, [95% CI 0.001-0.645],p=.024). Interobserver agreement of manual KM grading based on Cohen’s kappa coefficient was insignificant in the Yonsei (κ=.109) and the TCGA (κ=.121), respectively. The survival analysis based on KM grading showed statistically significant different PFS from the TCGA cohort, but not the Yonsei cohort.

Conclusions

Automatic quantification of TILs at the invasive margin based on DL approaches showed a prognostic utility to predict PFS, and could provide robust and reproducible TILs density measurement in patients with CRC.

Data and Code Availability

Source code and data used for this study is available at the following link:https://github.com/hwanglab/TILs_Analysis
Data-driven precision nutrition improves clinical outcomes and risk scores for IBS, depression, anxiety, and T2D
Authors: Connell Janelle , Toma Ryan , Ho Cleo Han-Chen , Shen Nan , Moura Pedro , Le Tiep , Patridge Eric , Antoine Grant , Keiser Hilary , Julian Cristina , Naidoo Uma , Tanton Damon , Banavar Guruduth , Vuyisich Momchilo
Published: April 2021

Many studies have shown that foods and nutritional ingredients play an important role in healthy human homeostasis, either directly or via the microbiome. We have developed an objective, integrated, and automated approach to personalized food and supplement recommendations that is powered by artificial intelligence and individualized molecular data from the gut microbiome, the human host, and their interactions. The process starts with a clinically validated transcriptomic analysis of a person’s stool (and some cases also blood) sample, from which the following molecular data are computed using clinically validated bioinformatics: 1. Quantitative strain-level taxonomic classification of all microorganisms, 2. Gene expression level for microbial genes, 3. Gene expression level for all human genes. These molecular data are converted into personalized nutritional recommendations (foods and supplements) using algorithms derived from clinical research studies and domain knowledge. We describe an application of our precision nutrition technology platform to human populations with irritable bowel syndrome (IBS), depression, anxiety, and type 2 diabetes (T2D). In these pilot interventional studies, our precision nutrition program achieved significant improvements in clinical outcomes of IBS (39% for severe IBS), depression (31% for severe depression), anxiety (31% for severe anxiety), and the risk score for T2D (>30% reduction relative to the control arm). These data support the integration of data-driven precision nutrition into the standard of care.
Dissecting the co-transcriptome landscape of plants and microbiota members
Authors: Nobori Tatsuya , Cao Yu , Entila Frederickson , Dahms Eik , Tsuda Yayoi , Garrido-Oter Ruben , Tsuda Kenichi
Published: April 2021

Interactions between plants and neighboring microbial species are fundamental elements that collectively determine the structure and function of the plant microbiota. However, the molecular basis of such interactions is poorly characterized. Here, we monocolonized Arabidopsis leaves with nine plant- associated bacteria from all major phyla of the plant microbiota and profiled co- transcriptomes of plants and bacteria. We detected both common and distinct co- transcriptome signatures among plant-commensal pairs. In planta responses of commensals were similar to those of a disarmed pathogen characterized by the suppression of genes involved in general metabolism in contrast to a virulent pathogen. We identified genes that are enriched in the genome of plant-associated bacteria and induced in planta, which may be instrumental for bacterial adaptation to the host environment and niche separation. This study provides insights into how plants discriminate among bacterial strains and lays the foundation for in- depth mechanistic dissection of plant-microbiota interactions.
Scaling between stomatal size and density in forest plants
Authors: Liu Congcong , Muir Christopher D. , Li Ying , Xu Li , Li Mingxu , Zhang Jiahui , de Boer Hugo Jan , Sack Lawren , Han Xingguo , Yu Guirui , He Nianpeng
Published: April 2021

The size and density of stomatal pores limit the maximum rate of leaf carbon gain and water loss (gmax) in land plants. The limits ofgmaxdue to anatomy, and its constraint by the negative correlation of stomatal size and density at broad phylogenetic scales, has been unclear and controversial. The prevailing hypothesis posits that adaptation to highergmaxis typically constrained by geometry and/or an economic need to reduce the allocation of epidermal area to stomata (stomatal-area minimization), and this would require the evolution of greater numbers of smaller stomata. Another view, supported by the data, is that across plant diversity, epidermal area allocated to guard cells versus other cells can be optimized without major trade-offs, and highergmaxwould typically be achieved with a higher allocation of epidermal area to stomata (stomatal-area increase). We tested these hypotheses by comparing their predictions for the structure of the covariance of stomatal size and density across species, applying macroevolutionary models and phylogenetic regression to data for 2408 species of angiosperms, gymnosperms, and ferns from forests worldwide. The observed stomatal size-density scaling and covariance supported the stomatal-area increase hypothesis for highgmax. A highergmaxinvolves construction costs and maintenance costs that should be considered in models assessing optimal stomatal conductance for predictions of water use, photosynthesis, and water-use efficiency as influences on crop productivity or in Earth System models.
Beyond linear dynamic functional connectivity: a vine copula change point model
Authors: Xiong Xin , Cribben Ivor
Published: April 2021

To estimate dynamic functional connectivity for functional magnetic resonance imaging (fMRI) data, two approaches have dominated: sliding window and change point methods. While computationally feasible, the sliding window approach has several limitations. In addition, the existing change point methods assume a Gaussian distribution for and linear dependencies between the fMRI time series. In this work, we introduce a new methodology called Vine Copula Change Point (VCCP) to estimate change points in the functional connectivity network structure between brain regions. It uses vine copulas, various state-of-the-art segmentation methods to identify multiple change points, and a likelihood ratio test or the stationary bootstrap for inference. The vine copulas allow for various forms of dependence between brain regions including tail, symmetric and asymmetric dependence, which has not been explored before in the dynamic analysis of neuroimaging data. We apply VCCP to various simulation data sets and to two fMRI data sets: a reading task and an anxiety inducing experiment. In particular, for the former data set, we illustrate the complexity of textual changes during the reading of Chapter 9 inHarry Potter and the Sorcerer’s Stoneand find that change points across subjects are related to changes in more than one type of textual attributes. Further, the graphs created by the vine copulas indicate the importance of working beyond Gaussianity and linear dependence. Finally, the R packagevccpimplementing the methodology from the paper is available from CRAN.
Host cytoskeletal vimentin serves as a structural organizer and an RNA-binding protein regulator to facilitate Zika viral replication
Authors: Zhang Yue , Zhao Shuangshuang , Li Min , Li Yian , Feng Fengping , Cui Jie , Xue Yanhong , Jin Xia , Jiu Yaming
Published: April 2021

Emerging microbe infections such as Zika virus (ZIKV) pose an increasing threat to human health. Current investigations on ZIKV replication have revealed the construction of replication compartments (RCs) and the utilization of host cellular endomembranes, without careful examination of the cytoskeletal network. Here, we investigated the function of vimentin, one of the intermediate filaments (IFs) that play a central role in basic cellular functions and diseases, in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments have drastic reorganization upon viral protein synthesis, to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetically removal of vimentin markedly reduced viral genome replication, viral protein production and infectious virions release, without interrupting viral binding and entry. Furthermore, proteomics and transcriptome screens by mass spectrometry and RNA sequencing identified intense interaction and regulation between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1 (RRBP1), an ER transmembrane protein directly binds viral RNA, can interact with vimentin, resulting in modulation of ZIKV replication. Together, our work discovered a dual role for vimentin as being not only a structural element for RCs but also an RNA-binding-regulating hub in the ZIKV infection model, unveiling another layer of the complexity between host and virus interaction.
LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
Authors: Emmenegger Marc , De Cecco Elena , Hruska-Plochan Marian , Eninger Timo , Schneider Matthias M. , Barth Melanie , Tantardini Elena , de Rossi Pierre , Bacioglu Mehtap , Langston Rebekah G. , Kaganovich Alice , Bengoa-Vergniory Nora , Gonzalez-Guerra Andrès , Avar Merve , Heinzer Daniel , Reimann Regina , Häsler Lisa M. , Herling Therese W. , Matharu Naunehal S. , Landeck Natalie , Luk Kelvin , Melki Ronald , Kahle Philipp J. , Hornemann Simone , Knowles Tuomas P. J. , Cookson Mark R. , Polymenidou Magdalini , Jucker Mathias , Aguzzi Adriano
Published: April 2021

While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analyzed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.