bluuebunny/crossref_metadata_2025 huggingface dataset:
A biocodicological analysis of the medieval library and archive from Orval Abbey, Belgium
Authors: Ruffini-Ronzani Nicolas , Nieus Jean-François , Soncin Silvia , Hickinbotham Simon , Dieu Marc , Bouhy Julie , Charles Catherine , Ruzzier Chiara , Falmagne Thomas , Hermand Xavier , Collins Matthew J. , Deparis Olivier
Published: June 2021

Biocodicological analysis of parchments from manuscript books and archives offers unprecedented insight into the materiality of medieval literacy. Using ZooMS for animal species identification, we explored almost the entire library and all the preserved single leaf charters of a single medieval Cistercian monastery (Orval Abbey, Belgium). Systematic non-invasive sampling of parchment collagen was performed on every charter and on the first bifolium from every quire of the 118 codicological units composing the books (1490 samples in total). Within the genuine production of the Orval scriptorium (26 units), a balanced use of calfskin (47.1%) and sheepskin (48.5%) was observed, whereas calfskin was less frequent (24.3%) in externally produced units acquired by the monastery (92 units). Calfskin was preferably used for higher quality manuscripts while sheepskin tends to be the standard choice for ‘ordinary’ manuscript book production. This finding is consistent with thirteenth-century parchment accounts from Beaulieu Abbey (England) where calfskin supply was more limited and its price higher. Our study reveals that the making of archival documents does not follow the same pattern as the production of library books. Although the five earliest preserved charters are made of calfskin, from the 1230s onwards, all charters from Orval are written on sheepskin.
The reflection of a blast wave by a very intense explosion
Authors: Cook Andrew W. , Bauer Joseph D. , Spriggs Gregory D.
Published: June 2021

We demonstrate that the geometric similarity of Taylor’s blast wave persists beyond reflection from an ideal surface. Upon impacting the surface, the spherical symmetry of the blast wave is lost but its cylindrical symmetry endures. As the flow acquires dependence on a second spatial dimension, an analytic solution of the Euler equations becomes elusive. However, the preservation of axisymmetry, geometric similarity and planar symmetry in the presence of a mirror-like surface causes all flow solutions to collapse when scaled by the height of burst (HOB) and the shock arrival time at the surface. The scaled blast volume for any yield, HOB and ambient air density follows a single universal trajectory for all scaled time, both before and after reflection.
Ten-year projection of white-nose syndrome disease dynamics at the southern leading-edge of infection in North America
Authors: Meierhofer Melissa B. , Lilley Thomas M. , Ruokolainen Lasse , Johnson Joseph S. , Parratt Steven R. , Morrison Michael L. , Pierce Brian L. , Evans Jonah W. , Anttila Jani
Published: June 2021

Predicting the emergence and spread of infectious diseases is critical for the effective conservation of biodiversity. White-nose syndrome (WNS), an emerging infectious disease of bats, has resulted in high mortality in eastern North America. Because the fungal causative agentPseudogymnoascus destructansis constrained by temperature and humidity, spread dynamics may vary by geography. Environmental conditions in the southern part of the continent are different than the northeast, where disease dynamics are typically studied, making it difficult to predict how the disease will manifest. Herein, we modelled WNS pathogen spread in Texas based on cave densities and average dispersal distances of hosts, projecting these results out to 10 years. We parameterized a predictive model of WNS epidemiology and its effects on bat populations with observed cave environmental data. Our model suggests that bat populations in northern Texas will be more affected by WNS mortality than southern Texas. As such, we recommend prioritizing the preservation of large overwintering colonies of bats in north Texas through management actions. Our model illustrates that infectious disease spread and infectious disease severity can become uncoupled over a gradient of environmental variation and highlight the importance of understanding host, pathogen and environmental conditions across a breadth of environments.
Multiomics implicate gut microbiota in altered lipid and energy metabolism in Parkinson’s disease
Authors: Pereira Pedro A. B. , Trivedi Drupad K. , Silverman Justin , Duru Ilhan Cem , Paulin Lars , Auvinen Petri , Scheperjans Filip
Published: June 2021

We aimed to investigate the link between serum metabolites, gut bacterial community composition, and clinical variables in Parkinson’s disease (PD) and healthy control subjects (HC). 139 metabolite features were found to be differentially abundant between the PD and Control groups. No associations were found between metabolite features and within-PD clinical variables. The results suggest alterations in serum metabolite profiles in PD, and the results of correlation analysis between metabolite features and microbiota suggest that several bacterial taxa are associated with altered lipid and energy metabolism in PD.
Modern UNOS Data Reveals Septuagenarians have Inferior Heart Transplant Survival
Authors: Suryapalam Manish , Kanaparthi Jay , Kashem Mohammed , Zhao Huaqing , Toyoda Yoshiya
Published: June 2021

Background

While heart transplantation is increasingly performed in the United States for elderly patients, survival outcomes have primarily been analyzed in single-center studies. The few existing long-term studies have indicated no difference in HTx outcomes between patients ≥70 years and 60-69 years age, but these studies only assessed to 5-years post-transplant and included data from the 1980-90s, introducing significant variance due to poorer outcomes in that era. We analyzed the UNOS database from 1987-2020, stratified by timeframe at 2000, to derive a more representative comparison of modern HTx survival outcomes.

Methods

All UNOS HTx recipients over 18 years of age (n=66,186) were divided into 3 cohorts: 18-59, 60-69 and ≥70 years old. Demographic data as well as perioperative factors were evaluated for significance using Chi-Squared and H-Tests as appropriate. Kaplan-Meier Curve and cox regressions with log-rank tests were used to assess 5 through 10 year survival outcomes.

Results

45,748 were 18-59 years old, 19,129 were 60-69 years old and 1,309 were ≥70 year old. The distribution of most demographic and perioperative factors significantly differed between cohorts. Pairwise survival analysis involving the 18-59 cohort always indicated significance. While there was no significance between the two older cohorts in the earlier timeframe, there was significance in the later timeframe from 6-10 years post-HTx (p<0.05). Cox regressions confirmed results.

Conclusions

The results indicate that since 2000, recipients 60-69 years of age have better 6 through 10-year post-transplant survival than older recipients, a relationship previously obscured by worse outcomes in early data.
Reliability of wastewater analysis for monitoring COVID-19 incidence revealed by a long-term follow-up study
Authors: Sanjuán Rafael , Domingo-Calap Pilar
Published: June 2021

Background

Wastewater-based epidemiology has been used for monitoring human activities and waterborne pathogens. Although wastewaters can also be used for tracking SARS-CoV-2 at the population level, the reliability of this approach remains to be established, especially for early warning of outbreaks.

Methods

We collected 377 samples from different treatment plants processing wastewaters of >1 million inhabitants in Valencia, Spain, between April 2020 and March 2021. Samples were cleaned, concentrated, and subjected to RT-qPCR to determine SARS-CoV-2 concentrations. These data were compared with cumulative disease notification rates over 7 and 14 day periods.

Results

We amplified SARS-CoV-2 RNA in 75% of the RT-qPCRs, with an estimated detection limit of 100 viral genome copies per liter (gc/L). SARS-CoV-2 RNA concentration correlated strongly with disease notification rates over 14-day periods (Pearson r = 0.962, P < 0.001). A concentration >1000 gc/L showed >95% sensitivity and specificity as an indicator of more than 25 new cases per 100,000 inhabitants. Albeit with slightly higher uncertainty, these figures were reproduced using a 7-day period. Time series were similar for wastewaters data and declared cases, but wastewater RNA concentrations exhibited transient peaks that were not observed in declared cases and preceded major outbreaks by several weeks.

Interpretation

Wastewater analysis provides a reliable tool for monitoring COVID-19, particularly at low incidence values, and is not biased by asymptomatic cases. Moreover, this approach might reveal previously unrecognized features of COVID-19 transmission.

Funding

Conselleria d’Agricultura, Desenvolupament Rural, Emergencia Climàtica i Transició Ecològica of the Generalitat Valenciana (project OTR2020-20593SUBDI), Instituto de Salud Carlos III (FONDO-COVID19 COV20/00210), CSIC (Salud Global CSIC 202020E292), and Ministerio de Ciencia e Innovación (Ramón y Cajal contract, Call 2019).
Use of respirator vs. surgical masks in healthcare personnel and its impact on SARS-CoV-2 acquisition – a prospective multicentre cohort study
Authors: Haller Sabine , Güsewell Sabine , Egger Thomas , Scanferla Giulia , Thoma Reto , Leal-Neto Onicio B. , Flury Domenica , Brucher Angela , Lemmenmeier Eva , Möller J. Carsten , Rieder Philip , Ruetti Markus , Stocker Reto , Vuichard-Gysin Danielle , Wiggli Benedikt , Besold Ulrike , Kuster Stefan P. , McGeer Allison , Risch Lorenz , Schlegel Matthias , Friedl Andrée , Vernazza Pietro , Kahlert Christian R. , Kohler Philipp
Published: June 2021

Background

There is insufficient evidence regarding the role of respirators in the prevention of SARS-CoV-2 infection. We analysed the impact of filtering facepiece class 2 (FFP2)vs. surgical masks on the risk of SARS-CoV-2 acquisition among Swiss healthcare workers (HCW).

Methods

Our prospective multicentre cohort enrolled patient-facing HCWs from June to August 2020. Participants were asked about COVID-19 risk exposures/behaviours, including preferred mask type when caring for COVID-19 patients outside of aerosol-generating procedures (AGP). For those performing AGPs, we asked whether they used FFP2 irrespective of the patient’s COVID-19 status (i.e. universal use). The impact of FFP2 on i) self-reported SARS-CoV-2-positive nasopharyngeal PCR/rapid antigen tests captured during weekly surveys, and ii) SARS-CoV-2 seroconversion between baseline and January/February 2021 was assessed.

Results

We enrolled 3’259 participants from nine healthcare institutions, whereof 716 (22%) preferentially used FFP2 respirators. Among these, 81/716 (11%) reported a SARS-CoV-2-positive swab, compared to 352/2543 (14%) surgical mask users (median follow-up 242 days); seroconversion was documented in 85/656 (13%) FFP2 and 426/2255 (19%) surgical mask users. Adjusted for baseline characteristics, COVID-19 exposure, and risk behaviour, FFP2 use was non-significantly associated with a decreased risk for SARS-CoV-2-positive swab (adjusted hazard ratio [aHR] 0·8, 95% CI 0·6-1·0, p=0·052) and seroconversion (adjusted odds ratio [aOR] 0·7, 95% CI 0·5-1·0, p=0·053); household exposure was the strongest risk factor (aHR for positive swab 10·1, p<0·001; aOR for seroconversion 5·0, p<0·001). In subgroup analysis, FFP2 use was clearly protective among those with frequent (>20 patients) COVID-19 exposure (aHR 0·7, p<0·001; aOR 0·6, p=0·035). Universal FFP2 use during AGPs showed no protective effect (aHR 1·1, p=0·7; aOR 0·9, p=0·53).

Conclusion

Respirators compared to surgical masks may convey additional protection from SARS-CoV-2 for HCW with frequent exposure to COVID-19 patients.

Funding

Swiss National Sciences Foundation, Federal Office of Public Health, Cantonal Health Department St.Gallen
Acute kidney injury in hospitalized patients due to COVID-19
Authors: Fernández Pehuén , Saad Emanuel José , Douthat Augusto , Marucco Federico Ariel , Heredia María Celeste , Barra Ayelén Tarditi , Bonazzi Silvina Trinidad Rodriguez , Zlotogora Melani , Barovero María Antonella Correa , Villada Sofía , Maldonado Juan Pablo , Caeiro Juan Pablo , Albertini Ricardo Arturo , De La Fuente Jorge , Douthat Walter Guillermo
Published: June 2021

The incidence of acute kidney injury (AKI) in hospitalized patients with coronavirus disease 2019 (COVID-19) is variable, being associated with worse outcomes. The objectives of the study were to evaluate the incidence, risk factors and impact of AKI in subjects hospitalized for COVID-19 in two third- level hospitals in Córdoba, Argentina.

A retrospective cohort study was conducted. 448 adults who were consecutively hospitalized for COVID-19 between March and the end of October 2020 at Hospital Privado Universitario de Córdoba and Hospital Raúl Angel Ferreyra were included. The incidence of AKI was 19% (n = 85). 50.6% presented AKI stage 1 (n=43), 20% stage 2 (n=17) and 29.4% stage 3 (n=25, of which 18 required renal replacement therapy). In the multivariate analysis, the variables that were independently associated with AKI were: age (adjusted Odd ratio -aOR- =1.30, 95%CI=1.04-1.63, p=0.022), history of chronic kidney disease (aOR=9.92, 95%CI=4.52-21.77, p<0.001), blood neutrophil count at admission (aOR=1.09, 95%CI=1.01-1.18, p=0.037) and requirement for mechanical ventilation (MV) (aOR=6.69, 95%CI=2.24-19.9, p=0.001). AKI was associated with longer hospitalization, greater admission and length of stay in the intensive care unit, a positive association with bacterial superinfection, sepsis, respiratory distress syndrome, MV requirement and mortality (mortality with AKI=47.1% vs without AKI=12.4%, p<0.001). AKI was independently associated with higher mortality (aOR=3.32, 95%CI=1.6-6.9, p=0.001).

In conclusion, the incidence of AKI in adults hospitalized for COVID-19 was 19% and had a clear impact on morbidity and mortality. Local predisposing factors for AKI were identified.
Albumin-dependent and independent mechanisms in the syndrome of kwashiorkor
Authors: Gonzales Gerard Bryan , Njunge James M , Gichuki Bonface M , Wen Bijun , Ngari Moses , Potani Isabel , Thitiri Johnstone , Laukens Debby , Vanmassenhove Jill , Voskuijl Wieger , Bandsma Robert , Berkley James A
Published: June 2021

The syndrome of kwashiorkor is a striking phenotype of childhood severe malnutrition (SM) comprising oedema, fatty liver, and skin and hair changes. Despite high fatality, the aetiology and pathophysiology of kwashiorkor remain enigmatic, including the role of serum albumin on oedema development. Here, we demonstrate that serum albumin is associated with the presence and severity of oedema among severely malnourished children. Further, in two independent cohorts of children in Malawi and Kenya, we show albumin-independent mechanisms are associated with oedema in SM, including oxidative stress and extracellular matrix (ECM) remodelling. Plasma concentrations of ECM-related proteins: lumican, podoplanin, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) and matrix metalloproteinase (MMP)2 were associated with kwashiorkor. We therefore conclude that the pathophysiology of kwashiorkor has both albumin-dependent and independent mechanisms. We discuss the ways in which albumin-independent mechanisms may explain the clinical features observed in kwashiorkor.
The COVID-19 pandemic shifted the Veterans Affairs System toward being a payer and virtual care provider: is it sustainable?
Authors: Rose Liam , Tran Linda Diem , Asch Steven M. , Vashi Anita
Published: June 2021

Structured Abstract

Objective

To examine how VA shifted care delivery methods one year into the pandemic.

Study Setting

All encounters paid or provided by VA between January 1, 2019 and February 27, 2021.

Study Design

We aggregated all VA paid or provided encounters and classified them into community (non-VA) acute and non-acute visits, VA acute and non-acute visits, and VA virtual visits. We then compared the number of encounters by week over time to pre-pandemic levels.

Data Extraction Methods

Aggregation of administrative VA claims and health records.

Principal Findings

VA has experienced a dramatic and persistent shift to providing virtual care and purchasing care from non-VA providers. Before the pandemic, a majority (63%) of VA care was provided in-person at a VA facility. One year into the pandemic, in-person care at VA’s constituted just 33% of all visits. Most of the difference made up by large expansions of virtual care; total VA provided visits (in person and virtual) declined (4.9 million to 4.2 million) while total visits of all types declined only 3.5%. Community provided visits exceeded prepandemic levels (2.3 million to 2.9 million, +26%).

Conclusion

Unlike private health care, VA has resumed in-person care slowly at its own facilities, and more rapidly in purchased care with different financial incentives a likely driver. The very large expansion of virtual care nearly made up the difference. With a widespread physical presence across the U.S., this has important implications for access to care and future allocation of medical personnel, facilities, and resources.
Calsyntenin-3, an atypical cadherin, suppresses inhibitory basket- and stellate-cell synapses but boosts excitatory parallel-fiber synapses in cerebellum
Authors: Liu Zhihui , Jiang Man , Liakath-Ali Kif , Ko Jaewon , Zhang Roger Shen , Südhof Thomas C.
Published: June 2021

Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic adaptors for kinesin-mediated vesicular transport. Here, we show that acute CRISPR-mediated deletion of calsyntenin-3 in cerebellar Purkinje cellsin vivocauses a large decrease in inhibitory synapses, but a surprisingly robust increase in excitatory parallel-fiber synapses. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Thus, by promoting formation of an excitatory type of synapses and decreasing formation of an inhibitory type of synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells. No similarly opposing function of a synaptic adhesion molecule was previously observed, suggesting a new paradigm of synaptic regulation.
SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease
Authors: Genin Emmanuelle C. , Bannwarth Sylvie , Ropert Baptiste , Mauri-Crouzet Alessandra , Lespinasse Françoise , Augé Gaelle , Fragaki Konstantina , Cochaud Charlotte , Lacas-Gervais Sandra , Paquis-Flucklinger Véronique
Published: June 2021

CHCHD10 is an ALS/FTD gene, also involved in a large clinical spectrum, that encodes a protein whose precise function within mitochondria is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) to control the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. In affected tissues, SLP2 forms aggregates with prohibitins and the instability of the PHB complex results in activation of OMA1 and accelerated OPA1 proteolysis leading to mitochondrial fragmentation, loss of mitochondrial cristae and apoptosis. Abnormal cristae morphogenesis depends on both the PHB complex destabilization leading to MICOS complex instability, via disruption of OPA1/Mitofilin interaction, and the activation of PINK1-mediated pathways. We also show that the increase of mitophagy found in both heart and hippocampus of Chchd10S59L/+ mito-QC mice is PINK1/Parkin-dependent. Thus, SLP2/PHBs aggregates and destabilization of the PHB complex with PINK1 activation are critical in the sequence of events leading to CHCHD10S59L-related disease.
End-of-life targeted auxin-mediated degradation of DAF-2 Insulin/IGF-1 receptor promotes longevity free from growth-related pathologies
Authors: Venz Richard , Pekec Tina , Katic Iskra , Ciosk Rafal , Ewald Collin Y.
Published: June 2021

Preferably, lifespan-extending therapies should work when applied late in life without causing undesired pathologies. However, identifying lifespan-extending interventions that are effective late in life and which avoid undesired secondary pathologies remains elusive. Reducing Insulin/IGF-1 signaling (IIS) increases lifespan across species, but the effects of reduced IIS interventions in extreme geriatric ages remains unknown. Using the nematode C. elegans, we engineered the conditional depletion of the DAF-2/insulin/IGF-1 transmembrane receptor using an auxin-inducible degradation (AID) system that allows for the temporal and spatial reduction in DAF-2 protein levels at time points after which interventions such as RNAi may lose efficacy. Using this system, we found that AID-mediated depletion of DAF-2 protein efficiently extends animal lifespan. Depletion of DAF-2 during early adulthood resulted in multiple adverse phenotypes, including growth retardation, germline shrinkage, egg-retention, and reducing offspring. By contrast, however, AID-mediated depletion of DAF-2 specifically in the intestine resulted in an extension of lifespan without these deleterious effects. Importantly, AID-mediated depletion of DAF-2 protein in animals past their median lifespan allowed for an extension of lifespan without affecting growth or behavioral capacity. Thus, both late-in-life targeting and tissue-specific targeting of IIS minimize the deleterious effects typically seen with interventions that reduced IIS, suggesting potential therapeutic methods by which longevity and healthspan can be increased in even geriatric populations.
The giant staphylococcal protein Embp facilitates colonization of surfaces through Velcro-like attachment to fibrillated fibronectin
Authors: Khan Nasar , Aslan Hüsnü , Büttner Henning , Rohde Holger , Golbek Thaddeus Wayne , Roeters Steven Joop , Woutersen Sander , Weidner Tobias , Meyer Rikke Louise
Published: June 2021

Staphylococcus epidermidis causes some of the most hard-to-treat clinical infections by forming biofilms: Multicellular communities of bacteria encased in a protective matrix, supporting immune evasion and tolerance against antibiotics. Biofilms occur most commonly on medical implants, and a key event in implant colonization is the robust adherence to the surface, facilitated by interactions between bacterial surface proteins and host matrix components. S. epidermidis is equipped with a giant adhesive protein, Embp, which facilitates bacterial interactions with surface-deposited, but not soluble fibronectin. The structural basis behind this selective binding process has remained obscure. Using a suite of single-cell and single-molecule analysis techniques, we show that S. epidermidis is capable of such distinction because Embp binds specifically to fibrillated fibronectin on surfaces, while ignoring globular fibronectin in solution. S. epidermidis adherence is critically dependent on multi-valent interactions involving 50 fibronectin-binding repeats of Embp. This unusual, Velcro-like interaction proved critical for colonization of surfaces under high flow, making this newly identified attachment mechanism particularly relevant for colonization of intravascular devices, such as prosthetic heart valves or vascular grafts. Other biofilm-forming pathogens, such as Staphylococcus aureus, express homologs of Embp and likely deploy the same mechanism for surface colonization. Our results may open for a novel direction in efforts to combat devastating, biofilm-associated infections, as the development of implant materials that steer the conformation of adsorbed proteins is a much more manageable task than avoiding protein adsorption altogether.

Graphical abstract

Fibronectin exists in two different conformations in the body. It circulates in the bodily fluids in globular conformation, however, it become fibrillated once adsorbed to an implant surface. S. epidermidis possess a giant 1 MDa receptor known as Embp bind specifically to fibrillated Fn but not to the globular Fn.
Local field potentials reflect cortical population dynamics in a region-specific and frequency-dependent manner
Authors: Gallego-Carracedo Cecilia , Perich Matthew G. , Chowdhury Raeed H. , Miller Lee E. , Gallego Juan A.
Published: June 2021

The spiking activity of populations of cortical neurons is well described by a small number of population-wide covariance patterns, the “latent dynamics”. These latent dynamics are largely driven by the same correlated synaptic currents across the circuit that determine the generation of local field potentials (LFP). Yet, the relationship between latent dynamics and LFPs remains largely unexplored. Here, we characterised this relationship for three different regions of primate sensorimotor cortex during reaching. The correlation between latent dynamics and LFPs was frequency-dependent and varied across regions. However, for any given region, this relationship remained stable across behaviour: in each of primary motor and premotor cortices, the LFP-latent dynamics correlation profile was remarkably similar between movement planning and execution. These robust associations between LFPs and neural population latent dynamics help bridge the wealth of studies reporting neural correlates of behaviour using either type of recordings.
One shot generalization in humans revealed through a drawing task
Authors: Tiedemann Henning , Morgenstern Yaniv , Schmidt Filipp , Fleming Roland W
Published: June 2021

Humans have the striking ability to learn and generalize new visual concepts from just a single exemplar. We suggest that when presented with a novel object, observers identify its significant features and infer a generative model of its shape, allowing them to mentally synthesize plausible variants. To test this, we showed participants abstract 2D shapes (‘Exemplars’) and asked them to draw new objects (‘Variations’) belonging to the same class. We show that this procedure created genuine novel categories. In line with our hypothesis, particular features of each Exemplar were preserved in its Variations and there was striking agreement between participants about which shape features were most distinctive. Also, we show that strategies to create Variations were strongly driven by part structure: new objects typically modified individual parts (e.g., limbs) of the Exemplar, often preserving part order, sometimes altering it. Together, our findings suggest that sophisticated internal generative models are key to how humans analyze and generalize from single exemplars.
Self-resetting Molecular Probes for Nucleic Acids Enabled by Fuel Dissipative Systems
Authors: Li Na , Liu Yu , Yin Zhe , Liu Rui , Zhang Linghao , Zhao Yuee , Ma Liang , Dai Xiaochuan , Zhou Dongsheng , Su Xin
Published: June 2021

Withdraw disclaimer statement

The authors have withdrawn this manuscript because lots of additional experiments which are not discussed in this version have been performed to further support the conclusion. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Dissociating the neural correlates of subjective visibility from those of decision confidence
Authors: Mazor Matan , Dijkstra Nadine , Fleming Stephen M.
Published: June 2021

A key goal of consciousness science is identifying neural signatures of being aware vs. unaware of simple stimuli. This is often investigated in the context of near-threshold detection, with reports of stimulus awareness being linked to heightened activation in a frontoparietal network. However, due to reports of stimulus presence typically being associated with higher confidence than reports of stimulus absence, these results could be explained by frontoparietal regions encoding stimulus visibility, decision confidence or both. In an exploratory analysis, we leverage fMRI data from 35 human participants (20 females) to disentangle these possibilities. We first show that, whereas stimulus identity was best decoded from the visual cortex, stimulus visibility (presence vs. absence) was best decoded from prefrontal regions. To control for effects of confidence, we then selectively sampled trials prior to decoding to equalize confidence distributions between absence and presence responses. This analysis revealed striking differences in the neural correlates of subjective visibility in prefrontal cortex regions of interest, depending on whether or not differences in confidence were controlled for. We interpret our findings as highlighting the importance of controlling for metacognitive aspects of the decision process in the search for neural correlates of visual awareness.

Significance statement

While much has been learned over the past two decades about the neural basis of visual awareness, the role of the prefrontal cortex remains a topic of debate. By applying decoding analyses to functional brain imaging data, we show that prefrontal representations of subjective visibility are contaminated by neural correlates of decision confidence. We propose a new analysis method to control for these metacognitive aspects of awareness reports, and use it to reveal confidence-independent correlates of perceptual judgments in a subset of prefrontal areas.
A benchmark study of simulation methods for single-cell RNA sequencing data
Authors: Cao Yue , Yang Pengyi , Yang Jean Yee Hwa
Published: June 2021

Single-cell RNA-seq (scRNA-seq) data simulation is critical for evaluating computational methods for analysing scRNA-seq data especially when ground truth is experimentally unattainable. The reliability of evaluation depends on the ability of simulation methods to capture properties of experimental data. However, while many scRNA-seq data simulation methods have been proposed, a systematic evaluation of these methods is lacking. We developed a comprehensive evaluation framework, SimBench, including a novel kernel density estimation measure to benchmark 12 simulation methods through 35 scRNA-seq experimental datasets. We evaluated the simulation methods on a panel of data properties, ability to maintain biological signals, scalability and applicability. Our benchmark uncovered performance differences among the methods and highlighted the varying difficulties in simulating data characteristics. Furthermore, we identified several limitations including maintaining heterogeneity of distribution. These results, together with the framework and datasets made publicly available as R packages, will guide simulation methods selection and their future development.
Characterizing Human Mesenchymal Stromal Cells Immune Modulatory Potency Using Targeted Lipidomic Profiling of Sphingolipids
Authors: DeVeaux S’Dravious A. , Ogle Molly E. , Vyshnya Sofiya , Chiappa Nathan F. , Leitmann Bobby , Rudy Ryan , Day Abigail , Mortensen Luke J. , Kurtzberg Joanne , Roy Krishnendu , Botchwey Edward A.
Published: June 2021

Cell therapies are expected to increase over the next decade due to increasing demand for clinical applications. Mesenchymal stromal cells (MSCs) have been explored to treat a number of diseases, with some successes in early clinical trials. Despite early successes, poor MSC characterization results in lessened therapeutic capacity oncein vivo. Here, we characterized bone–marrow (BM), adipose derived and umbilical cord tissue MSCs’ sphingolipids (SLs), a class of bioactive lipids, using liquid chromatography – tandem mass spectrometry. We found ceramide levels differed based upon donor’s sex in BM-MSCs. We detected fatty acyl chain variants in MSCs from all 3 sources. Linear discriminant analysis revealed that MSCs separated based on tissue source. Principal component analysis showed IFN-γ primed and unstimulated MSCs separated according to their SL signature. Lastly, we detected higher ceramide levels in low IDO MSCs, indicating sphingomeylinase or ceramidase enzymatic activity may be involved in their immune potency.
Bacterial predation on T4 phages
Authors: Godon Jean-Jacques , Bize Ariane , Ngo Hoang , Cauquil Laurent , Almeida Mathieu , Petit Marie Agnès , Zemb Olivier
Published: June 2021

Background

Bacterial consumption of viruses has never yet been reported, even though bacteria feed on almost anything. Viruses are omnipresent predators for all organisms, but have no acknowledged active biocontrol. The viral biomass undoubtedly reintegrates the trophic cycles, however the mechanisms of this phase still remain unknown.

Methods

Here, we used stable isotope probing with 13C labelled T4 phages to monitor the increase of density of the bacterial DNA concomitant with the decrease of plaque forming units. We used 12C T4 phages as control.

Results

T4 phage disappearance in wastewater sludge was found to occur mainly through predation by Aeromonadacea. Phage consumption also favours significant in situ bacterial growth. Furthermore, an isolated strain of Aeromonas was observed to grow on T4 phages as sole source of carbon, nitrogen and phosphorus.

Conclusions

bacterial species are capable of consuming bacteriophages in situ, which is likely a widespread and underestimated type of biocontrol.This assay is anticipated as a starting point for harnessing the bacterial potential in limiting the diffusion of harmful viruses within environments such as gut or water.
The metabolome and lipidome of colorectal adenomas and cancers
Authors: Laczko Endre , Manser Christine , Marra Giancarlo
Published: June 2021

Introduction

In-depth knowledge of metabolic dysregulations in colorectal cancer (CRC) (and other cancers as well) is essential for developing treatments that specifically kill neoplastic cells. It may also allow us to pinpoint metabolites or lipids with potential for development as tumor biomarkers for use in body-fluid or breath assays. CRC onset is preceded by an interval of ∼10 years characterized by the presence of precancerous lesions, and our previous studies have revealed epigenomic, transcriptomic, and proteomic evidence in these lesions of certain metabolic changes typical of CRC. These findings prompted us to conduct untargeted metabolomic and lipidomic analyses of CRCs and colorectal adenomas (the most common precancerous lesions of the gut).

Methods

We analyzed 29 endoscopically collected tumor tissue samples (29 adenomas [ADNs], 10 CRCs, each with a colon segment-matched sample of normal mucosa [i.e., 29 NM-ADN, 10 NM-CRC]). The freshly collected samples were promptly frozen in liquid nitrogen and later processed to obtain metabolite and lipid extracts. Each of the 78 samples was analyzed with nano-flow LC-MS/MS (liquid chromatography with mass spectrometry) to characterize its metabolome (using HILIC, Hydrophilic Interaction Liquid Chromatography) and lipidome (using RP, Reversed Phase chromatography). The data acquired were processed using Progenesis QI. For statistical and multivariate analysis of the resulting peak tables, we used basic R packages and the R package made4.

Results

Unsupervised between-group analysis based on the full set of detected metabolites (n=1830) and lipids (n=2365) clearly discriminated ADNs and CRCs from their matched samples of normal mucosa at both the metabolome and lipidome levels. Compared with the NM-ADN, the ADNs contained significantly different levels of 14.6% of the metabolites and 10.8% of the lipids. Fewer compounds (9.1% of metabolites, 6.2% of lipids) displayed differential abundance in CRCs (vs. NM-CRC). The metabolome and lipidome of the NM-ADN also differed from those of the NM-CRC, probably reflecting the presence of a field cancerization effect exerted by the invasive tumors. A substantial number of metabolites (n=340) and lipids (n=201) also displayed abundance differentials across the sequential tumorigenic stages represented by the NM-ADN (considered more representative of NM from a lesion-free colon) → ADN → CRC. In most cases, the trend consisted of progressive increases or progressive decreases in abundance as the tumorigenesis advanced.

Conclusions

Our findings provide a preliminary picture of the progressive metabolomic and lipidomic changes occurring during the adenomatous phase of colorectal tumorigenesis. Once definitively annotated, the numerous differentially abundant compounds detected in this study may well shed valuable light on the metabolic dysregulations occurring during this process and provide useful clues for the development of novel tools for the diagnosis and treatment of colorectal tumors.
Tracking-based rolling angles recovery method for holographic tomography of flowing cells
Authors: Pirone Daniele , Memmolo Pasquale , Merola Francesco , Miccio Lisa , Mugnano Martina , Capozzoli Amedeo , Curcio Claudio , Liseno Angelo , Ferraro Pietro
Published: June 2021

Holographic Tomography (HT) is an emerging label-free technique for microscopic bioimaging applications, that allows reconstructing the three-dimensional (3D) refractive index (RI) distribution of biological specimens. Recently, an in-flow HT technique has been proposed in which multiple digital holograms are recorded at different viewing angles around the sample while it flows and rotates within a microfluidic channel. However, unlike conventional HT methods, there is no a priori information about cell 3D orientations, that are instead requested to perform any tomographic algorithm. Here we investigate a tracking-based rolling angles recovery method, showing robustness against the sample’s features. It is based on a phase images similarity metric recently demonstrated, that exploits the local contrast phase measurements to recognize a full cell rotation within the microfluidic channel. Hence, the orientations of the flowing cells are retrieved from their positions, which are in turn computed through the 3D holographic tracking. The performances of the rolling angles recovery method have been assessed both numerically, by simulating a 3D cell phantom, and experimentally, by reconstructing the 3D RI tomograms of two cancer cells. Both the numerical and the experimental analysis have been performed at different spatial resolutions. This rolling angles recovery method, not depending on the cell shapes, the RI contents, and the optical experimental conditions, could pave the way to the study of circulating tumor cells (CTCs) in the challenging tool of liquid biopsy.
Spatial and temporal autocorrelation weave complexity in brain networks
Authors: Shinn Maxwell , Hu Amber , Turner Laurel , Noble Stephanie , Preller Katrin H. , Ji Jie Lisa , Moujaes Flora , Achard Sophie , Scheinost Dustin , Constable R. Todd , Krystal John H. , Vollenweider Franz X. , Lee Daeyeol , Anticevic Alan , Bullmore Edward T. , Murray John D.
Published: June 2021

High-throughput experimental methods in neuroscience have led to an explosion of techniques for measuring complex interactions and multi-dimensional patterns. However, whether sophisticated measures of emergent phenomena can be traced back to simpler low-dimensional statistics is largely unknown. To explore this question, we examine resting state fMRI (rs-fMRI) data using complex topology measures from network neuroscience. We show that spatial and temporal autocorrelation are reliable statistics which explain numerous measures of network topology. Surrogate timeseries with subject-matched spatial and temporal autocorrelation capture nearly all reliable individual and regional variation in these topology measures. Network topology changes during aging are driven by spatial autocorrelation, and multiple serotonergic drugs causally induce the same topographic change in temporal autocorrelation. This reductionistic interpretation of widely-used complexity measures may help link them to neurobiology.
Intermediate structural hierarchy in biological networks modulates the fractal dimension and force distribution of percolating clusters
Authors: Hanson Benjamin S. , Dougan Lorna
Published: June 2021

Globular protein hydrogels are an emerging class of materials with the potential for rational design, and a generalised understanding of how their network properties emerge from the structure and dynamics of the building block is a key challenge. Here we computationally investigate the effect of intermediate (polymeric) nanoscale structure on the formation of protein hydrogels. We show that changes in both the cross-link topology and flexibility of the polymeric building block lead to changes in the force transmission around the system, and provide insight into the dynamic network formation processes.
Prepubertal ovariectomy alters dorsomedial striatum indirect pathway neuron excitability and explore/exploit balance in female mice
Authors: Delevich Kristen , Hall Christopher D. , Wilbrecht Linda
Published: June 2021

Decision-making circuits are modulated across life stages (e.g. juvenile, adolescent, or adult)—as well as on the shorter timescale of reproductive cycles in females—to meet changing environmental and physiological demands. Ovarian hormonal modulation of relevant neural circuits is a potential mechanism by which behavioral flexibility is regulated in females. Here we examined the influence of prepubertal ovariectomy (pOVX) versus sham surgery on performance in an odor-based multiple choice reversal task. We observed that pOVX females made different types of errors during reversal learning compared to sham surgery controls. Using reinforcement learning models fit to trial-by-trial behavior, we found that pOVX females exhibited lower inverse temperature parameter (β) compared to sham females. These findings suggest that OVX females solve the reversal task using a more exploratory choice policy, whereas sham females use a more exploitative policy prioritizing estimated high value options. To seek a neural correlate of this behavioral difference, we performed whole-cell patch clamp recordings within the dorsomedial striatum (DMS), a region implicated in regulating action selection and explore/exploit choice policy. We found that the intrinsic excitability of dopamine receptor type 2 (D2R) expressing indirect pathway spiny projection neurons (iSPNs) was significantly higher in pOVX females compared to both unmanipulated and sham surgery females. Finally, to test whether mimicking this increase in iSPN excitability could recapitulate the pattern of reversal task behavior observed in pOVX females, we chemogenetically activated DMS D2R(+) neurons within intact female mice. We found that chemogenetic activation increased exploratory choice during reversal, similar to the pattern we observed in pOVX females. Together, these data suggest that pubertal status may influence explore/exploit balance in females via the modulation of iSPN intrinsic excitability within the DMS.
3-hydroxyanthranilic acid – a new metabolite for healthy lifespan extension
Authors: Dang Hope , Castro-Portuguez Raul , Espejo Luis , Backer Grant , Freitas Sam , Spence Erica , Meyers Jeremy , Shuck Karissa , Corban Caroline , Liu Teresa , Bean Shannon , Sheehan Susan , Korstanje Ron , Sutphin George L.
Published: June 2021

The metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD+) through the kynurenine pathway is increasingly linked to aging and age-associated disease. Kynurenine pathway enzymes and metabolites influence a range of molecular processes critical to healthy aging, including regulation of inflammatory and immune responses, cellular redox homeostasis, and energy production. Aberrant kynurenine metabolism is observed during normal aging and has been implicated in a range of age-associated pathologies, including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. In previous work, we and others identified three genes—kynu-1, tdo-2, andacsd-1—encoding kynurenine pathway enzymes for which decreasing expression extends lifespan in invertebrate models. Here we report that knockdown ofhaao-1, a fourth kynurenine pathway gene encoding the enzyme 3-hydroxyanthranilic acid dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated decline in health inCaenorhabditis elegans. This lifespan extension is mediated by increased physiological levels of the HAAO substrate 3-hydroxyanthranilic acid (3HAA). 3HAA increases resistance to oxidative stress during aging by directly degrading hydrogen peroxide and activating the Nrf2/SKN-1 oxidative stress response. Aging mice fed a diet supplemented with 3HAA are similarly long-lived. Our results identify HAAO and 3HAA as novel therapeutic targets for age-associated disease. This works provides a foundation for more detailed examination of the molecular mechanisms underlying the benefits of 3HAA, and how these mechanisms interact with other interventions both within and beyond the kynurenine pathway. We anticipate that these findings will bolster growing interest in developing pharmacological strategies to target tryptophan metabolism to improve health aging.
XCVATR: Characterization of Variant Impact on the Embeddings of Single -Cell and Bulk RNA-Sequencing Samples
Authors: Harmanci Arif O , Harmanci Akdes Serin , Klisch Tiemo , Patel Akash J
Published: June 2021

Gene expression profiling via RNA-sequencing has become standard for measuring and analyzing the gene activity in bulk and at single cell level. Increasing sample sizes and cell counts provides substantial information about transcriptional architecture of samples. In addition to quantification of expression at cellular level, RNA-seq can be used for detecting of variants, including single nucleotide variants and small insertions/deletions and also large variants such as copy number variants. The joint analysis of variants with transcriptional state of cells or samples can provide insight about impact of mutations. To provide a comprehensive method to jointly analyze the genetic variants and cellular states, we introduce XCVATR, a method that can identify variants, detect local enrichment of expressed variants, within embedding of samples and cells. The embeddings provide information about cellular states among cells by defining a cell-cell distance metric. Unlike clustering algorithms, which depend on a cell-cell distance and use it to define clusters that explain cell clusters globally, XCVATR detects the local enrichment of expressed variants in the embedding space such that embedding can be computed using any type of measurement or method, for example by PCA or tSNE of the expression levels. XCVATR searches local patterns of association of each variant with the positions of cells in an embedding of the cells. XCVATR also visualizes the local clumps of small and large-scale variant calls in single cell and bulk RNA-sequencing datasets. We perform simulations and demonstrate that XCVATR can identify the enrichments of expressed variants. We also apply XCVATR on single cell and bulk RNA-seq datasets and demonstrate its utility.
Plasma-derived cell-free DNA methylomes might not enable detection and discrimination of intracranial tumors
Authors: Vitting-Seerup Kristoffer
Published: June 2021

Intracranial tumors are both hard to detect and diagnose, resulting in poor patient outcomes. For that reason, non-invasive methods enabling detection and discrimination of intracranial tumors have significant clinical potential. Recently Nassiri et al. propose plasma-derived cell-free DNA methylomes as such a method. Here I show that the results have been misinterpreted, and for many comparisons, no evidence supporting the conclusions are actually presented. While my analysis highlights the potential of plasma-derived cell-free DNA methylomes, the evidence provided by Nassiri et al. is simply currently insufficient.