bluuebunny/crossref_metadata_2025 huggingface dataset:
In Search of the Most Attractive Lip Proportions and Lip Volume: An Eye Tracking– and Survey-Based Investigation
Authors: Frank Konstantin , Moellhoff Nicholas , Swift Arthur , Green Jeremy B. , Schuster Luca , Gotkin Robert H. , Hernandez Claudia A. , Voropai Daria , Haas Elisabeth M. , Cotofana Sebastian
Published: June 2022

Background:

Despite various aesthetic trends, the ideal lip proportion and lip volume remains elusive. Thus, the aim of this study was to investigate the aesthetic perception of various lip shapes to identify the most attractive lips.

Methods:

Fifty-nine White study participants with a mean age of 32.73 ± 9.4 years were asked to assess lips of various proportions and of various volumes. Gaze assessment and aesthetic rating of the same set of modified lip images were performed.

Results:

The results revealed that the lip proportion that was rated to be most attractive was the 1:1.6 ratio (upper-to-lower lip, 4.21 of a possible 5). This lip proportion, however, was not the first one to be viewed on initial image display (1.20 sec) and had the shortest duration of a stable eye fixation within the 6-second image display interval (2.18 of 6 seconds). The lip volume that received the highest aesthetic rating was the 100 percent volume (original lip size), with 4.56 of a possible 5. This lip volume, however, had the third longest interval between initial image exposure and the first stable eye fixation (0.81 second) and had the shortest duration of stable eye fixations during the 6 seconds of image display (2.22 of 6 seconds).

Conclusion:

The results presented could be potentially reflective of the internal cognitive processes during the involuntary and voluntary assessment of lip attractiveness.
Mass Switch From Intravenous to Subcutaneous Tocilizumab in Rheumatic Diseases During the SARS-COV-2 Pandemic
Authors: Cáceres Vicente Aldasoro , Piñeiro María Laíño , Ibáñez-Beróiz Berta , Enguita-Germán Mónica
Published: June 2022

Background

With the arrival of the SARS-CoV-2 pandemic in 2020, it was proposed to make the change from intravenous (IV) tocilizumab (TCZ) to its subcutaneous formulation, in order to avoid rheumatological patients having to go to the day hospital and guarantee enough IV TCZ for those critical patients with COVID who needed it. The aim of this study was to describe the rate and reasons for switching back to IV TCZ from subcutaneous TCZ.

Methods

We included patients from the rheumatology service that were on treatment with IV TCZ in February 2020 and were followed up until March 2021. Patients that remained on subcutaneous TCZ were compared with those who switched back to IV TCZ (switch-back group). A subgroup analysis according to rheumatic disease was performed.

Results

Fifty-five patients switched to subcutaneous TCZ: 28 rheumatoid arthritis, 19 giant cell arteritis, 4 polymyalgia rheumatica, 2 juvenile idiopathic arthritis, and 2 systemic sclerosis. Seventeen patients switched back to IV TCZ due to ineffectiveness (n = 8), patient preference (n = 4), adverse events (n = 4), and difficulty with the SC administration route (n = 1). In the analysis by disease, 4 of 23 patients switched back to IV TCZ in giant cell arteritis/polymyalgia rheumatica group due to ineffectiveness (n = 2), injection site reaction (n = 1), or patient preference (n = 1). In rheumatoid arthritis group, 11 of 28 patients switched back to IV TCZ: ineffectiveness (n = 5), patient preference (n = 3), headache (n = 1), injection site reaction (n = 1), and due to difficulty with the SC administration route (n = 1).

Conclusions

Mass switch from IV to subcutaneous TCZ during the SARS-CoV-2 pandemic has been safe, effective, and well tolerated after 1 year of follow-up.
Effects of Theophylline on ADCY5 Activation - From Cellular Studies to Improved Therapeutic Options for ADCY5-Related Dyskinesia Patients
Authors: Tänzler Dirk , Kipping Marc , Lederer Marcell , Günther Wiebke F. , Arlt Christian , Hüttelmaier Stefan , Merkenschlager Andreas , Sinz Andrea
Published: June 2022

We show the effects of the three purine derivatives, caffeine, theophylline, and istradefylline, on the cAMP production of adenylyl cyclase 5 (ADCY5)-overexpressing cell lines. A comparison of cAMP levels was performed for ADCY5 wild-type and R418W mutant cells. ADCY5-catalyzed cAMP production was reduced with all three purines, while the most pronounced effects on cAMP reduction were observed for ADCY5 R418W mutant cells. The gain-of-function ADCY5 R418W mutant is characterized by an increased catalytic activity resulting in elevated cAMP levels, resulting in kinetic disorders or dyskinesia in patients. Based on our findings in ADCY5 cells, a slow-release formulation of theophylline was administered to a preschool aged patient with ADCY5-related dyskinesia. A striking improvement of symptoms was observed, outperforming the effects of caffeine that had previously been administered to the same patient.
A kinetic modeling platform for predicting the efficacy of siRNA formulations in vitro and in vivo
Authors: Roh Esther H. , Sullivan Millicent O. , Epps Thomas H.
Published: June 2022

We present a computational modeling protocol that can accurately predict changes in both in vitro and in vivo gene expression levels in response to the application of various siRNA formulations. Users can obtain crucial information (i.e., maximum silencing level; duration of silencing) towards the design of therapeutically relevant dosing regimens with experimental measurements from a single time point as an input. This ability to simulate numerous experimental gene silencing scenarios has not been demonstrated previously with other RNA interference models.

Graphical abstract
Temporal and spatial segregations between phenotypes of the Diablotin Black-capped PetrelPterodroma hasitataduring the breeding and non-breeding periods
Authors: Satgé Yvan G. , Keitt Bradford S. , Gaskin Chris P. , Patteson J. Brian , Jodice Patrick G.R.
Published: June 2022

Aim

Despite growing support for ecosystem-based approaches, conservation is mostly implemented at the species level. However, genetic differentiation exists within this taxonomic level, putting genetically distinct populations at risk of local extinction. In seabirds, reproductive isolation is one of the principal drivers of genetic structure. In the Diablotin Black-capped PetrelPterodroma hasitata, an endangered gadfly petrel endemic to the Caribbean, two phenotypes have been described: a smaller dark form and a heavier light form, which are genetically distinct. We hypothesized that color forms have a similar non-breeding distribution at sea but distinct nesting distributions.

Location

Western North Atlantic and northern Caribbean islands.

Methods

In May 2019, we captured 5 adult Black-capped Petrels of each phenotype at sea and equipped them with satellite transmitters. We used generalized linear mixed models to test the importance of phenotype on geographic distribution. Using kernel density estimations, we located use areas, quantified spatial overlap between forms, and assessed form-specific exposure to marine threats. Finally, we used tracking data to estimate the distribution and timing of nesting.

Results

Petrels were tracked for 11 – 255 d (mean = 102.1 d±74.2). During the non-breeding period, all individuals ranged from 28.4 – 43.0 degrees latitude. Phenotypes had significantly distinct non-breeding distributions. In the western North Atlantic, the dark form was exposed to more marine threats than the light form. We recorded two trips (1 individual of each form) to known breeding areas, with the light form initiating breeding 1.5 months before the dark form.

Main conclusions

Phenotypic differences in the Black-capped Petrel were linked to differences in nesting phenology, non-breeding marine distribution, and at-sea threat exposure. To sustain the species’ representation, redundancy, and resiliency in the light of environmental changes, it is likely that the evolutionary processes that resulted in genetic differentiation will also need to be conserved.
Protection promotes energetically efficient structures in marine communities
Authors: Tabi Andrea , Gilarranz Luis J. , Wood Spencer A. , Dunne Jennifer A. , Saavedra Serguei
Published: June 2022

The sustainability of marine communities is critical for supporting many biophysical processes that provide ecosystem services that promote human well-being. It is expected that anthropogenic disturbances such as climate change and human activities will tend to create less energetically-efficient ecosystems that support less biomass per unit energy flow. It is debated, however, whether this expected development should translate into bottom-heavy (with small basal species being the most abundant) or top-heavy communities (where more biomass is supported at higher trophic levels with species having larger body sizes). Here, we combine ecological theory and empirical data to demonstrate that full marine protection promotes shifts towards top-heavy energetically-efficient structures in marine communities. First, we use metabolic scaling theory to show that protected communities are expected to display stronger top-heavy structures than disturbed communities. Similarly, we show theoretically that communities with high energy transfer efficiency display stronger top-heavy structures than communities with low transfer efficiency. Next, we use empirical structures observed within fully protected marine areas compared to disturbed areas that vary in stress from thermal events and adjacent human activity. Using a nonparametric causal-inference analysis, we find a strong, positive, causal effect between full marine protection and stronger top-heavy structures. Our work corroborates ecological theory on community development and provides a quantitative framework to study the potential restorative effects of different candidate strategies on protected areas.

Preprint

The manuscript [1] is deposited on bioRxiv (https://doi.org/10.1101/2022.06.02.494503).
Distinct Single-cell Immune Ecosystems Distinguish True and De Novo HBV-related Hepatocellular Carcinoma Recurrences
Authors: Chen Shuling , Huang Cheng , Liao Guanrui , Sun Huichuan , Xie Yubin , Wang Jianping , He Minghui , Hu Huanjing , Dai Zihao , Ren Xiaoxue , Zeng Xuezhen , Zeng Qianwen , Zhang Guopei , Liao Changyi , Xie Wenxuan , Shen Shunli , Li Shaoqiang , Peng Sui , Kuang Dongming , Zhao Qiang , Duda Dan G. , Kuang Ming
Published: June 2022

Revealing differential tumor immune microenvironment (TIME) characteristics between true versus de novo hepatocellular carcinoma (HCC) recurrence could help optimal development and use of immunotherapies. Here, we studied the TIME of recurrent HBV-related HCCs by 5’and VDJ single-cell and bulk RNA-sequencing, flow cytometry, and multiplexed immunofluorescence. Analyses of mutational profiles, evolutionary trajectories, and clonal architecture using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The TIME of truly recurrent HCCs was characterized by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed an upregulated GDF15 expression level on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited anti-tumor immunity in the TIME of truly recurrent lesions. In contrast, we found that myeloid cells’ crosstalk with T cells mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCC. In conclusion, our results support genomic diagnosis and immune profiling for guiding immunotherapy implementation based on the type of HCC recurrence and TIME.

Highlights

Truly recurrent lesions are seeded before primary tumor diagnosis, and that de novo cancer can occur earlier than the clinically used 2-year limit.

ScRNA-seq unravels distinct immune ecosystems in true versus de novo HCC recurrences, highlighting the need for different immunotherapy strategies for two types of HCC recurrence.

CD8+ T cells in de novo recurrence displayed cytotoxic and exhausted phenotypes while those in truly recurrent lesions showed a memory phenotype with weak cytotoxicity.

HCC cells expressing the inhibitory molecule GDF15 were in the proximity of DCs only in truly recurrent lesions.

High GDF15 expression level was associated with truly recurrent HCC and worse prognosis.

Graphical abstract
Controllable membrane damage by tunable peptide aggregation with albumin
Authors: Hamsici Seren , Gunay Gokhan , Acar Handan
Published: June 2022

Aggregation of otherwise soluble proteins into amyloid structures is a hallmark of many disorders, such as Alzheimer’s and Parkinson’s diseases. There is increasing evidence and acceptance that instead of ordered amyloid assemblies, the misfolded oligomer aggregations are the main toxic structures. However, there is no system to study the mechanism and kinetics of aggregation, distinguish between ordered structures and misfolded oligomers, and correlate the structures to their toxicity. The exact role of oligomer aggregation in the pathological process remains to be elucidated. Here, we use an engineered co-assembling oppositely charged amyloid-like peptide pair ([II]) to relate its aggregation to toxicity. The toxicity mechanism of [II] is through cell membrane damage and stress, as shown with YAP and eIF2α biomarkers, as in the amyloid protein-initiated diseases. Albumin is used to control the aggregation of [II], and so its toxicity. This study represents a molecular engineering strategy to study the aggregation process of amyloid-like structures in diseases. Understanding the nature of protein aggregation through engineered peptides paves the way for future designs and drug development applications.
Heat stress does not induce wasting symptoms in the giant California sea cucumber (Apostichopus californicus)
Authors: Taylor Declan , Farr Jonathan James , Lim Em G , Fleet Jenna Laurel , Smith Wuitchik Sara Jayne , Wuitchik Daniel Michael
Published: June 2022

Oceanic heat waves have significant impacts on disease dynamics in marine ecosystems. A severe sea cucumber wasting event occurred in Nanoose Bay, British Columbia, Canada, following an extreme heat wave, resulting in mass mortality of Apostichopus californicus. Here, we sought to determine if heat stress in isolation could trigger wasting symptoms in A. californicus. We exposed sea cucumbers to i) a simulated marine heat wave (22ºC), ii) an elevated temperature treatment (17ºC), or iii) control conditions (12ºC). We measured the presence of skin ulcers, mortality, posture maintenance, antipredator defences, spawning, and organ evisceration during the 79-hour thermal exposure, as well as 7-days post-exposure. Both the 22°C and 17°C treatments elicited stress responses where individuals exhibited a reduced ability to maintain posture and an increase in stress spawning. The 22ºC heat wave was particularly stressful, as it was the only treatment where mortality was observed. However, none of the treatments induced wasting symptoms as observed in the Nanoose Bay event. This study provides evidence that sea cucumber wasting is not triggered by heat stress in isolation, leaving the cause of the mass mortality event observed in Nanoose unknown.
Preferential catabolism of L- vs D-serine by Proteus mirabilis contributes to pathogenesis and catheter-associated urinary tract infection
Authors: Brauer Aimee L. , Learman Brian S. , Taddei Steven M. , Deka Namrata , Hunt Benjamin C. , Armbruster Chelsie E.
Published: June 2022

Proteus mirabilis is a common cause of urinary tract infection, especially in catheterized individuals. Amino acids are the predominant nutrient for bacteria during growth in urine, and our prior studies identified several amino acid import and catabolism genes as fitness factors for P. mirabilis catheter-associated urinary tract infection (CAUTI), particularly D- and L-serine. In this study, we sought to determine the hierarchy of amino acid utilization by P. mirabilis and to examine the relative importance of D- vs L-serine catabolism for critical steps in CAUTI development and progression. Herein, we show that P. mirabilis preferentially catabolizes L-serine during growth in human urine, followed by D-serine, threonine, tyrosine, glutamine, tryptophan, and phenylalanine. Independently disrupting catabolism of either D- or L-serine has minimal impact on in vitro phenotypes while completely disrupting both pathways decreases motility, biofilm formation, and fitness due to perturbation of membrane potential and cell wall biosynthesis. In a mouse model of CAUTI, loss of either serine catabolism system decreased fitness, but disrupting L-serine catabolism caused a greater fitness defect than disrupting D-serine catabolism. We therefore conclude that hierarchical utilization of amino acids may be a critical component of P. mirabilis colonization and pathogenesis within the urinary tract.

Abbreviated Summary

Amino acids are a predominant nutrient in urine, and their import and catabolism has been hypothesized to contribute to the ability of bacteria to cause urinary tract infection. We demonstrate that a common uropathogen, Proteus mirabilis, preferentially catabolizes L-serine followed by D-serine, threonine, tyrosine, and glutamine during growth in human urine. We further demonstrate that L-serine catabolism provides a greater fitness advantage than D-serine catabolism, yet both pathways contribute to pathogenesis in the urinary tract.

Graphical Abstract

(Created using BioRender.com)
Subtherapeutic doses of vancomycin synergize with bacteriophages for treatment of experimental methicillin-resistant Staphylococcus aureus infective endocarditis
Authors: Save Jonathan , Que Yok-Ai , M. Entenza José , Resch Grégory
Published: June 2022

Background

Recurrent therapeutic failures reported for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) with vancomycin may be due to poor bactericidal activity. Alternative antibacterial approaches using bacteriophages may overcome this limitation.

Objective

An experimental rat model of MRSA IE (EE) was used to examine the efficacy of vancomycin combined with a 1:1 bacteriophage cocktail composed of Herelleviridae vB_SauH_2002 and Podoviridae 66.

Methods

Six hours after inoculation with ca. 5 log10 CFU of MRSA strain AW7, animals were treated with either: (i) saline, (ii) an equimolar two-phage cocktail (bolus of 1 mL followed by a 0.3 mL/h continuous infusion of 10 log10PFU/mL phage suspension), (iii) vancomycin (at a dose mimicking the kinetics in humans of 0.5 g b.i.d.), or (iv) a combination of both. Bacterial loads in vegetations, and phage loads in vegetations, liver, kidney, spleen, and blood, were measured outcomes.

Results

Phage cocktail alone was unable to control growth of strain AW7 in cardiac vegetations. However, when combined with subtherapeutic doses of vancomycin, a statistically significant decrease of Δ4.05 ± 0.94 log10 CFU/g at 24 h compared to placebo was detected (p < 0.001). Administration of vancomycin was found to significantly impact local concentrations of phages in the vegetations and in the organs examined.

Conclusions

Lytic bacteriophages as an adjunct treatment to standard of care antibiotics could potentially improve management of MRSA IE. Further studies are needed to investigate the impact of antibiotics on phage replication in vivo.
COVID-19 Endemic Plan: Impact of Vaccination and Non-pharmaceutical Interventions with Viral Variants and Waning Immunity Using an Agent-Based Simulation
Authors: Lee Serin , Zabinsky Zelda B. , Wasserheit Judith N. , Ross Jennifer M. , Chen Shi , Liu Shan
Published: June 2022

Backgrounds

Despite the widespread distribution of SARS-CoV-2 vaccines, the COVID-19 pandemic continues with highly contagious variants and waning immunity. Low disease severity of the Omicron variant gives society hope that the COVID-19 pandemic could end.

Methods

We develop an agent-based simulation to explore the impact of COVID-19 vaccine willingness, booster vaccination schedule, vaccine effectiveness, and non-pharmaceutical interventions (NPIs) on reducing COVID-19 deaths while considering immunity duration and disease severity against the Omicron variant. The model is calibrated to the greater Seattle in year 2020 by observing local epidemic data. The simulation is run to the end of year 2024 to observe long-term effects.

Results

Results show that an NPI policy that maintains low levels of NPIs can reduce mortality by 35.1% compared to fully opening the society. A threshold NPI policy is especially helpful when the disease severity of the Omicron variant is high, or booster vaccines are not scheduled. A periodic booster schedule is needed to achieve the goal of lowering the number of deaths from COVID-19 to the level of influenza and pneumonia. Except for one scenario, 80% or more vaccine willingness is also needed to achieve this goal.

Conclusions

We find that a periodic booster vaccination schedule and mild disease severity of the Omicron variant play a crucial role in reducing deaths by the end of year 2024. If a booster schedule is not planned and the Omicron variant is not mild, NPI policies that limit society from fully opening are required to control the outbreak.
Human hematopoietic stem cell vulnerability to ferroptosis
Authors: Zhao Jiawei , Jia Yuemeng , Mahmut Dilnar , Deik Amy A. , Jeanfavre Sarah , Clish Clary B. , Sankaran Vijay G.
Published: June 2022

Hematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency, but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illuminating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.
Portrait of a genus: genome sequencing reveals evidence of adaptive variation inZea
Authors: Chen Lu , Luo Jingyun , Jin Minliang , Yang Ning , Liu Xiangguo , Peng Yong , Li Wenqiang , Philips Alyssa , Cameron Brenda , Bernal Julio , Rellán-Álvarez Rubén , Sawers Ruairidh JH , Qing Liu , Yin Yuejia , Ye Xinnan , Yan Jiali , Zhang Qinghua , Zhang Xiaoting , Wu Shenshen , Gui Songtao , Wei Wenjie , Wang Yuebin , Luo Yun , Jiang Chengling , Deng Min , Jin Min , Jian Liumei , Yu Yanhui , Zhang Maolin , Yang Xiaohong , Hufford Matthew B. , Fernie Alisdair R. , Warburton Marilyn L. , Ross-Ibarra Jeffrey , Yan Jianbing
Published: June 2022

Maize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in the wild relatives of maize. Here, we characterize a high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genusZea, identifying over 70 million single nucleotide polymorphisms (SNPs) and nearly 9 million Insertion/Deletion (InDel) polymorphisms. The variation map reveals evidence of selection within taxa displaying novel adaptations to traits such as waterlogging, perenniality and regrowth. We focus in detail on adaptive alleles in highland teosinte and temperate maize and highlight the key role of flowering time related pathways in highland and high latitude adaptation. To show how this data can identify useful genetic variants, we generated and characterized novel mutant alleles for two flowering time candidate genes. This work provides the most extensive sampling to date of the genetic diversity of the genusZea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.
The neuroeconomics of individual differences in saccadic decisions
Authors: Thomas Tobias , Hoppe David , Rothkopf Constantin A.
Published: June 2022

Active exploration of the visual environment requires choosing the next gaze target, which has been characterized as depending on attentional biases and on oculomotor biases. However, disentangling these two factors has provided contradictory results. Here, we conceptualize active gaze selection as a decision-making process in the context of neuroeconomics, allowing us to employ a new saccadic preference elicitation experiment and to quantify behavioral biases with a random utility model. Subjects showed similar preferences for shorter amplitude saccades in line with previous research and shared a preference for saccades back towards the previous gaze location, contrary to numerous reports on spatial “inhibition of return”. Surprisingly, the experiment revealed marked individual differences in the preferences for global gaze directions, which were stable across most participants after one week. Thus, this study provides the first measurement of intrinsic saccadic utilities independently of spatial image properties and quantitatively dissociates stable individual differences in global gaze selection.
FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner
Authors: Pifer Phillip M. , Yang Liangpeng , Kumar Manish , Xie Tongxin , Frederick Mitchell , Hefner Andrew , Beadle Beth , Molkentine David , Molkentine Jessica , Dhawan Annika , Abdelhakiem Mohamed , Osman Abdullah A. , Myers Jeffrey N. , Pickering Curtis R. , Sandulache Vlad C. , Heymach John , Skinner Heath D.
Published: June 2022

Radiation and platinum-based chemotherapy form the backbone of therapy in HPV-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcome in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remain unclear. We performed an in vivo shRNA screen using targetable libraries to address these questions and identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage and repressed homologous recombination and non-homologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. Mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared to wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized a HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors. Thus, FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.
Single-cell RNA-sequencing data analysis reveals a highly correlated triphasic transcriptional response to SARS-CoV-2 infection
Authors: Gutiérrez Pablo A. , Elena Santiago F.
Published: June 2022

Single-cells RNA sequencing (scRNA-seq) is currently one of the most powerful techniques available to study the transcriptional response of cells to external perturbations. However, the use of conventional bulked RNA-seq analysis methods can miss important patterns underlying in the scRNA-seq data. Here, we present a reanalysis of scRNA-seq data from human bronchial epithelial cells and colon and ileum organoids using pseudo-time profiles based on the degree of virus accumulation which reflect the progress of infection. Our analysis revealed a transcriptional response to infection characterized by three distinct up- and down-regulatory phases, that cannot be detected using classical two-group comparisons. Interrogation of results, focused on genes involved in interferon-response, transcription factors and RNA-binding proteins, suggests a highly correlated transcriptional response for most genes. In addition, correlation network analysis revealed a distinct response of genes involved in translation and mitochondrially-encoded genes. Based on our data, we propose a model where modulation of nucleocytoplasmic traffic by the viral protein nsp1 explains the triphasic transcriptional response to SARS-CoV-2 infection.
Bumetanide increases microglia-interneuron contact following traumatic brain injury
Authors: Tessier Marine , Garcia Marta Saez , Goubert Emmanuelle , Tian Li , Molinari Florence , Blasco Edith , Laurin Jerome , Guillemot François , Hübner Christian , Pellegrino Christophe , Rivera Claudio
Published: June 2022

Objective

The Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects on the pathophysiology of many neurological disorders. Here we studied whether bumetanide could influence post-traumatic cognitive decline and inflammatory processes by regulating astrocyte and microglia activation.

Method

Controlled cortical impacted (CCI) animals were treated with bumetanide during the first post-CCI week. Immunochemistry, flow cytometry, immunoassay, and in vivo imaging were used to study astrocytic and microglial morphology and phenotype as well as adult neurogenesis. Telemetric electroencephalograms and cognitive behavioral test were performed at one-month post CCI.

Results

Bumetanide prevented CCI-induced decrease in hippocampal neurogenesis and parvalbumin positive interneuron loss. Deletion of NKCC1 in astrocytes neither rescued interneurons nor promote neurogenesis. Interestingly, bumetanide had a strong effect on microglial activation by inducing polarization towards the M1-like phenotype 3 days post-CCI and the M2-like phenotype 7 days post-CCI. Bumetanide increased microglial Brain-derived neurotrophic factor (BDNF) expression and interaction with parvalbumin interneurons. The early treatment with bumetanide resulted in improvements in working and episodic memory, one-month post-CCI, as well as the normalization of theta band oscillations.

Interpretation

Here, we disclose a novel mechanism for the neuroprotective action of bumetanide mediated by an acceleration of microglial activation dynamics that leads to an increase of parvalbumin interneuron survival following CCI, possibly resulting from increased microglial BDNF expression and contact with interneurons. Salvage of interneurons may normalize ambient gamma-aminobutyric acid (GABA) resulting in the preservation of adult neurogenesis processes as well as contributing to bumetanide-mediated improvement of cognitive performance.
Comparative analysis of the caecal tonsil transcriptome in two hen lines experimentally infected withSalmonellaEnteritidis
Authors: Cazals Anaïs , Rau Andrea , Estellé Jordi , Bruneau Nicolas , Coville Jean-Luc , Menanteau Pierrette , Rossignol Marie-Noëlle , Jardet Deborah , Bevilacqua Claudia , Bed’hom Bertrand , Velge Philippe , Calenge Fanny
Published: June 2022

ManagingSalmonella entericaEnteritidis (SE) carriage in chicken is necessary to ensure human food safety and enhance chicken breeding viability.Salmonellacan contaminate poultry products, causing human foodborne disease and economic losses for farmers. Both genetic selection for a decreased carriage and gut microbiota modulation strategies could reduceSalmonellapropagation in farms.

Two-hundred and twenty animals from the White Leghorn inbred lines N and 61were raised together on floor, infected by SE at 7 days of age, transferred into isolators to prevent oro-fecal recontamination and euthanized at 19 days. Caecal content DNA was used to measure individualSalmonellacounts (ISC) by droplet digital PCR. A RNA sequencing approach was used to measure gene expression levels in caecal tonsils after infection of 48 chicks with low or high ISC.

The analysis between lines identified 7516 differentially expressed genes (DEGs) corresponding to 62 enriched Gene Ontology (GO) Biological Processes (BP) terms. A comparison between low and high carriers allowed us to identify 97 DEGs and 23 enriched GO BP terms within line 61, and 1034 DEGs and 288 enriched GO BP terms within line N. Among these genes, we identified several candidate genes based on their putative functions, includingFUT2orMUC4, which could be involved in the control of SE infection, maybe through interactions with commensal bacteria. Altogether, we were able to identify several genes and pathways associated with differences in SE carriage level. These results are discussed in relation to individual caecal microbiota compositions, obtained for the same animals in a previous study, which may interact with host gene expression levels for the control of the caecal SE load.
Mixed origin of juvenile Atlantic cod (Gadus morhua) along the Swedish west coast
Authors: Henriksson Simon , Pereyra Ricardo T. , Sodeland Marte , Ortega-Martinez Olga , Knutsen Halvor , Wennhage Håkan , André Carl
Published: June 2022

Cryptic population structure in exploited fish species poses a major challenge for fisheries management. Atlantic cod (Gadus morhua) is a species in which the presence of sympatric ecotypes has been known for a long time, for instance off the coast of Northern Norway. More recently, two sympatric ecotypes of cod have also been documented in the Skagerrak and Kattegat; one ecotype is of an apparent offshore origin and undertakes spawning migrations to the North Sea, and the other is resident at the coast throughout its life. However, their relative contributions of juveniles to the Swedish west coast remain poorly understood. The lack of adult cod along the Skagerrak and Kattegat coasts in recent years has led to the hypothesis that the offshore ecotype is the main source of juveniles to the area, but recent studies have shown large proportions of coastal cod inside Norwegian Skagerrak fjords. In this study, juvenile cod were collected at a high spatial resolution along the Swedish west coast, and genetically assigned to each of the two ecotypes. The results reveal that there is a considerable proportion of juvenile coastal cod in the southern Kattegat, Öresund, and in inshore Swedish Skagerrak, but that the offshore ecotype dominates in offshore areas. Model selection suggests that differences in bottom depth, rather than distance from the open sea, may explain the heterogenous spatial distribution of the two ecotypes. In addition, the two ecotypes displayed differences at loci known to be associated with environmental adaptation, suggesting that their spatial distribution is maintained by natural selection in response to specific environmental conditions.
Lower air humidity reduced both the plant growth and activities of photosystems I and II under prolonged heat stress
Authors: Lysenko Eugene A. , Kozuleva Marina. A. , Klaus Alexander A. , Pshybytko Natallia L. , Kusnetsov Victor V.
Published: June 2022

The warming is global problem. In natural environments, a heat stress is accompanied with a drought usually. The effect of lower air humidity remains obscure. Maize and barley plants were supplied with an unlimited source of water for the root uptake and undergone to heat stress for 48 h at contrast conditions of air humidity. The lower air humidity decreased photochemical activities of photosystem I and photosystem II. The small effect was revealed in control. The temperature elevation to 37°C and 42°C increased relative activities of the both photosystems; the photosystem II was activated more. The effect of air humidity disappeared at 37°C; at 42°C, the effect was small. At 46°C, lower air humidity magnified substantially the inhibitory effect of heat. Consequently, the maximal and relative activities of the both photosystems were decreased in maize and barley; the plant growth was reduced greatly. The photosystem II was inhibited more. At 46°C, maize plants increased water uptake by roots at lower air humidity and survived; barley plants were unable to increase water uptake and died. Therefore, air humidity is the important component of environmental heat stress influencing activities of photosystem I and photosystem II and thereby plant growth and viability.

Highlight

The effect of severe heat stress was magnified with lower air humidity. At 46°C, their mutual action inhibited photosystem I and II and reduced greatly the plant growth and viability.
Integrative signatures of signaling pathway response increase robustness and accuracy of pathway predictions
Authors: Clark Nicholas A. , Ren Yan , Plas David R. , Sivaganesan Siva , Medvedovic Mario
Published: June 2022

Motivation

Aberrant cell signaling is known to drive progression of cancer and many other diseases. The study of signaling pathways within cells is central to identifying drugs that seek to modulate these pathways. Expression of pathway genes (i.e. genes that code for pathway proteins) correlates poorly with signaling pathway activity, making prediction of signaling pathway activity changes based on transcriptional disease signatures a challenging problem. Pathway architecture and response also varies across cell lines, which reflects how drug response varies across a patient population.

Results

Here, we present a transcriptional footprinting framework for predicting changes in activity of signaling pathway by integrating transcriptional signatures of genetic perturbations of pathway genes over a diverse set of cell lines into a integrative Pathway Activity Signature (iPAS). We use an unsupervised multi-task learning approach to create pathway signatures across 12 cell lines using genetic loss of function data from the LINCS project. We also use supervised learning to construct an optimal predictor based on the ensemble of 12 cell line signatures. Our methods achieve a sizeable increase in performance, as measured by prediction of pathways targeted by LINCS chemical perturbagens.

Availability

Open source R package iPAS is available at https://github.com/uc-bd2k/iPAS.

Contact

medvedm@ucmail.uc.edu

Supplementary information

Supplementary data are available online.
Tubule jamming in the developing mouse kidney creates cyclical mechanical stresses in nephron-forming niches
Authors: Viola John M. , Liu Jiageng , Prahl Louis S. , Huang Aria , Chan Trevor J. , Hayward-Lara Gabriela , Porter Catherine M. , Shi Chenjun , Zhang Jitao , Hughes Alex J.
Published: June 2022

The kidney develops through branching of progressively crowded ureteric bud (UB) tubules at the organ surface. The elongating tubule tips are surrounded by traveling cap mesenchyme niches consisting of nephron progenitors and separated by stromal boundaries. Dynamic interactions between these tissues coordinate a balance between UB tip branching, elongation, and nephron induction that sets nephron numbers for life, impacting the likelihood of adult disease. Such a crowded tissue environment could place geometric limits on the number of niches that can be formed while maintaining mechanical integrity of the tissue. Since space is at a premium, crowding could also force a given niche to prioritize between nephron formation or UB branching differently depending on its spatial context. Here we study the geometric and mechanical consequences of tubule tip crowding at the embryonic kidney surface. Organ curvature reduces and tubule ‘tip domain’ niches pack more closely over developmental time. These together create a semi-crystalline geometry of tips at the kidney surface and a rigidity transition to more solid-like tissue properties at later developmental stages. To infer mechanical dynamics over the branching timescale, we define a new method to infer tip domain ‘ages’ relative to their most recent branch events from fixed kidneys. We find that new tip domains overcome mechanical resistance as they branch and displace close-packed neighbors, transiently increasing mechanical stress in the niche. Ongoing efforts to understand geometric and mechanical effects on niche regulation will clarify variation in kidney tissue composition and advance engineering control strategies for synthetic regenerative tissues.
Towards generalizable prediction of antibody thermostability using machine learning on sequence and structure features
Authors: Harmalkar Ameya , Rao Roshan , Honer Jonas , Deisting Wibke , Anlahr Jonas , Hoenig Anja , Czwikla Julia , Sienz-Widmann Eva , Rau Doris , Rice Austin , Riley Timothy P. , Li Danqing , Catterall Hannah B. , Tinberg Christine E. , Gray Jeffrey J. , Wei Kathy Y.
Published: June 2022

Over the last three decades, the appeal for monoclonal antibodies (mAbs) as therapeutics has been steadily increasing as evident with FDA’s recent landmark approval of the 100th mAb. Unlike mAbs that bind to single targets, multispecific biologics (bsAbs) with their single-chain variable fragment (scFv) modules have garnered particular interest owing to the advantage of engaging distinct targets. Despite their exquisite specificity and affinity, the relatively poor thermostability of these scFv modules often hampers their development as a potential therapeutic drug. In recent years, engineering antibody sequences to enhance their stability by mutations has gained considerable momentum. As experimental methods for antibody engineering are time-intensive, laborious, and expensive, computational methods serve as a fast and inexpensive alternative to conventional routes. In this work, we show two machine learning methods - one with pre-trained language models (PTLM) capturing functional effects of sequence variation, and second, a supervised convolutional neural network (CNN) trained with Rosetta energetic features - to better classify thermostable scFv variants from sequence. Both these models are trained over temperature-specific data (TS50 measurements) derived from multiple libraries of scFv sequences. In this work, we show that a sufficiently simple CNN model trained with energetic features generalizes better than a pre-trained language model on out-of-distribution (blind) sequences (average Spearman correlation coefficient of 0.4 as opposed to 0.15). Further, we demonstrate that for an independent mAb with available thermal melting temperatures for 20 experimentally characterized thermostable mutations, these models trained on TS50 data could identify 18 residue positions and 5 identical amino-acid mutations showing remarkable generalizability. Our results suggest that such models can be broadly applicable for improving the biological characteristics of antibodies. Further, transferring such models for alternative physico-chemical properties of scFvs can have potential applications in optimizing large-scale production and delivery of mAbs or bsAbs.
Processing UMI Datasets at High Accuracy and Efficiency with the Sentieon ctDNA Analysis Pipeline
Authors: Hu Jinnan , Jiang Cai , Huang Yu S. , Chen Haodong , Feng Hanying , Freed Donald , Qu Yan , Fan Rui , Su Zhencheng , Chen Weizhi
Published: June 2022

Liquid biopsy enables identification of low allele frequency (AF) tumor variants and novel clinical applications such as minimum residual disease (MRD) monitoring. However, challenges remain, primarily due to limited sample volume and low read count of low-AF variants. Because of the low AFs, some clinically significant variants are difficult to distinguish from errors introduced by PCR amplification and sequencing. Unique Molecular Identifiers (UMIs) have been developed to further reduce base error rates and improve the variant calling accuracy, which enables better discrimination between background errors and real somatic variants. While multiple UMI-aware ctDNA analysis pipelines have been published and adopted, their accuracy and runtime efficiency could be improved.

In this study, we present the Sentieon ctDNA pipeline, a fast and accurate solution for small somatic variant calling from ctDNA sequencing data. The pipeline consists of four core modules: alignment, consensus generation, variant calling, and variant filtering. We benchmarked the ctDNA pipeline using both simulated and real datasets, and found that the Sentieon ctDNA pipeline is more accurate than alternatives.
Cortical-brainstem interplay during speech perception in older adults with and without hearing loss
Authors: Lai Jesyin , Alain Claude , Bidelman Gavin M.
Published: June 2022

Real-time modulation of brainstem frequency-following responses (FFRs) by online changes in cortical arousal state via the corticofugal (top-down) pathway has been demonstrated previously in young adults and is more prominent in the presence of background noise. FFRs during high cortical arousal states also have a stronger relationship with speech perception. Aging is associated with increased auditory brain responses, which might reflect degraded inhibitory processing within the peripheral and ascending pathways, or changes in attentional control regulation via descending auditory pathways. Here, we tested the hypothesis that online corticofugal interplay is impacted by age-related hearing loss. We measured EEG in older adults with normal-hearing (NH) and mild to moderate hearing-loss (HL) while they performed speech identification tasks in different noise backgrounds. We measured α power to index online cortical arousal states during task engagement. Subsequently, we split brainstem speech-FFRs, on a trial-by-trial basis, according to fluctuations in concomitant cortical α power into low or high α FFRs to index cortical-brainstem modulation. We found cortical α power was smaller in the HL than NH group. In NH listeners, α-FFRs modulation for clear speech (i.e., without noise) also resembled that previously observed in younger adults for speech in noise. Cortical-brainstem modulation was further diminished in HL older adults in the clear condition and by noise in NH older adults. Machine learning classification showed low α FFR frequency spectra yielded higher accuracy for classifying listeners’ perceptual performance in both NH and HL participants. Moreover, low α FFRs decreased with increased hearing thresholds at 0.5-2 kHz for clear speech but noise generally reduced low α FFRs in the HL group. Collectively, our study reveals cortical arousal state actively shapes brainstem speech representations and provides a potential new mechanism for older listeners’ difficulties perceiving speech in cocktail party-like listening situations in the form of a miss-coordination between cortical and subcortical levels of auditory processing.