bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of reading and face circuits during the first three years of reading acquisition
Authors: Feng Xiaoxia , Monzalvo Karla , Dehaene Stanislas , Dehaene-Lambertz Ghislaine
Published: May 2022

Although words and faces activate neighboring regions in the fusiform gyrus, we lack an understanding of how such category selectivity emerges during development. To investigate the organization of reading and face circuits at the earliest stage of reading acquisition, we measured the fMRI responses to words, faces, houses, and checkerboards in three groups of 60 French children: 6-year-old pre-readers, 6-year-old beginning readers and 9-year-old advanced readers. The results showed that specific responses to written words were absent prior to reading, but emerged in beginning readers, irrespective of age. Likewise, specific responses to faces were barely visible in pre-readers and continued to evolve in the 9-year-olds, yet primarily driven by age rather than by schooling. Crucially, the sectors of ventral visual cortex that become specialized for words and faces harbored their own functional connectivity prior to reading acquisition: the VWFA with left-hemispheric spoken language areas, and the FFA with the contralateral region and the amygdalae. The results support the view that reading acquisition occurs through the recycling of a pre-existing but plastic circuit which, in pre-readers, already connects the VWFA site to other distant language areas. We argue that reading acquisition does not compete with the face system directly, through a pruning of preexisting face responses, but indirectly, by hindering the slow growth of face responses in the left hemisphere, thus increasing a pre-existing right hemispheric bias.

Highlights

Written words and faces activate neighboring areas of the fusiform gyri, but their developmental trajectory is different.

The growth of word-induced activation in VWFA is primarily due to schooling.

The growth of face responses is primarily affected by age rather than by schooling.

Word and face-related areas exhibit distinct functional connectivity even prior to reading acquisition

VWFA is initially functionally connected with left-hemisphere spoken language areas, and FFA with amygdala and contralateral FFA.
Adding a new dimension: Multi-level structure and organization of mixed-species Pseudomonas aeruginosa and Staphylococcus aureus biofilms in a 4-D wound microenvironment
Authors: Dhekane Radhika , Mhade Shreeya , Kaushik Karishma S
Published: May 2022

Biofilms in wounds typically consist of aggregates of bacteria, most often Pseudomonas aeruginosa and Staphylococcus aureus, in close association with each other and the host microenvironment. Given this, the interplay across host and microbial elements, including the biochemical and nutrient profile of the microenvironment, likely influences the structure and organization of wound biofilms. While clinical studies, in vivo and ex vivo model systems have provided insights into the distribution of P. aeruginosa and S. aureus in wounds, they are limited in their ability to provide a detailed characterization of biofilm structure and organization across the host-microbial interface. On the other hand, biomimetic in vitro systems, such as host cell surfaces and simulant media conditions, albeit reductionist, have been shown to support the co-existence of P. aeruginosa and S. aureus biofilms, with species-dependent localization patterns and interspecies interactions. Therefore, composite in vitro models that bring together key features of the wound microenvironment could provide unprecedented insights into the structure and organization of mixed-species biofilms. We have built a four-dimensional (4-D) wound microenvironment consisting of a 3-D host cell scaffold of co-cultured human epidermal keratinocytes and dermal fibroblasts, and an in vitro wound milieu (IVWM); the IVWM provides the fourth dimension that represents the biochemical and nutrient profile of the wound infection state. We leveraged this composite 4-D wound microenvironment to probe the structure of mixed-species P. aeruginosa and S. aureus biofilms across multiple levels of organization such as aggregate dimensions and biomass thickness, species co-localization and organization within the biomass, overall biomass composition and interspecies interactions. In doing so, the composite 4-D wound microenvironment platform provides multi-level insights into the structure of mixed-species biofilms, which we incorporate into the current understanding of P. aeruginosa and S. aureus organization in the wound bed.
tRNA Methylation Resolves Codon Usage Bias at the Limit of Cell Viability
Authors: Masuda Isao , Yamaki Yuka , Detroja Rajesh , Tagore Somnath , Moore Henry , Maharjan Sunita , Nakano Yuko , Christian Thomas , Matsubara Ryuma , Lowe Todd , Frenkel-Morgenstern Milana , Hou Ya-Ming
Published: May 2022

The codon usage of each genome is closely correlated with the abundance of tRNA isoacceptors. How codon-usage bias is resolved by tRNA post-transcriptional modifications is largely unknown. Here we demonstrate that the N1-methylation of guanosine at position 37 (m1G37) on the 3’-side of the anticodon, while not directly responsible for reading of codons, is a neutralizer that resolves differential decoding of proline codons. A genome-wide suppressor screen of a non-viable E. coli strain, m1G37-lacking, identifies proS suppressor mutations, indicating a coupling of methylation with tRNA prolyl-aminoacylation that sets the limit of cell viability. Using these suppressors, where prolyl-aminoacylation is decoupled from tRNA methylation, we show that m1G37 neutralizes differential translation of proline codons by the major isoacceptor. Lacking of m1G37 inactivates this neutralization and exposes the need for a minor isoacceptor for cell viability. This work has medical implications for bacterial genomes that exclusively use the major isoacceptor for survival.
Parvimonas micra, an oral pathobiont associated with colorectal cancer, epigenetically reprograms human primary intestinal epithelial cells
Authors: Bergsten Emma , Mestivier Denis , Donnadieu Francoise , Pedron Thierry , Barau Caroline , Meda Landry Tsoumtsa , Mettouchi Amel , Lemichez Emmanuel , Gorgette Olivier , Chamaillard Mathias , Vaysse Amaury , Volant Stevenn , Doukani Abiba , Sansonetti Philippe J. , Sobhani Iradj , Nigro Giulia
Published: May 2022

Recently, an intestinal dysbiotic microbiota with enrichment in oral cavity bacteria has been described in colorectal cancer (CRC) patients. Here we characterized and investigated one of these oral pathobionts, the Gram-positive anaerobic coccusParvimonas micra.We identified two phylotypes (A and B) exhibiting different phenotypes and adhesion capabilities. We observed a strong association of phylotype A with CRC, with its higher abundance in feces and in tumoral tissue compared with the normal homologous colonic mucosa, which was associated with a distinct methylation status of patients. By developing anin vitrohypoxic co-culture system of human primary colonic cells with anaerobic bacteria, we showed thatP. micraphylotype A alters the DNA methylation profile promoters of key tumor-suppressor genes, oncogenes, and genes involved in epithelial-mesenchymal transition. In colonic mucosa of CRC patients carryingP. micraphylotype A, we found similar DNA methylations alterations, together with significant enrichment of differentially expressed genes in pathways involved in inflammation, cell adhesion, and regulation of actin cytoskeleton, providing evidence ofP. micrapossible role in the carcinogenic process.
Endoplasmic Reticulum membranes are continuously required to maintain mitotic spindle size and forces
Authors: Araújo Margarida , Tavares Alexandra , Vieira Diana V. , Telley Ivo A. , Oliveira Raquel A.
Published: May 2022

Membrane organelle function, localization, and proper partitioning upon cell division depend on interactions with the cytoskeleton. Whether, reciprocally, membrane organelles also impact on the function of cytoskeletal elements remains less clear. Here, we show that acute disruption of the Endoplasmic Reticulum (ER) around spindle poles affects mitotic spindle size and function inDrosophilasyncytial embryos. Acute ER disruption was achieved through the inhibition of ER membrane fusion by the dominant-negative cytoplasmic domain of Atlastin. We reveal that when the ER is disrupted specifically at metaphase, mitotic spindles become smaller, despite no significant changes in microtubule dynamics. These smaller spindles are still able to mediate sister chromatid separation, yet with decreased velocity. Furthermore, by inducing mitotic exit, we found that nuclear separation and distribution are affected upon ER disruption. Our results suggest that ER integrity around spindle poles is crucial for the maintenance of mitotic spindle shape and pulling forces. Additionally, ER integrity also ensures nuclear spacing during syncytial divisions.
The proto-oncogene DEK regulates neuronal excitability and tau accumulation in Alzheimer’s disease vulnerable neurons
Authors: Rodriguez-Rodriguez Patricia , Arroyo-Garcia Luis Enrique , Li Lechuan , Tsagkogianni Christina , Wang Wei , Salas-Allende Isabella , Plautz Zakary , Cedazo-Minguez Angel , Sinha Subhash , Troyanskaya Olga , Flajolet Marc , Yao Vicky , Roussarie Jean-Pierre
Published: May 2022

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer’s disease. Here, we use a data-driven functional genomics approach to model ECII neuronsin silicoand identify the proto-oncogene DEK as a potential driver of tau pathology. By modulating DEK levels in EC neuronsin vitroandin vivo, we first validate the accuracy and cell-type specificity of our network predictions. We then show thatDeksilencing changes the inducibility of immediate early genes and alters neuron excitability, leading to dysregulation of neuronal plasticity genes. We further find that loss of function of DEK leads to tau accumulation in the soma of ECII neurons, reactivity of surrounding microglia, and eventually microglia-mediated neuron loss. This study validates a pathological gene discovery tool that opens new therapeutic avenues and sheds light on a novel pathway driving tau pathology in vulnerable neurons.
Melanogenic Activity Facilitates Dendritic Cell Maturation via FMOD
Authors: Halasi Marianna , Adini Irit
Published: May 2022

According to epidemiological research, autoimmune diseases are more prevalent among African Americans, therefore we hypothesized that pigment production in the microenvironment contribute to local immune regulation. Here, in anin vitrosetting we examined the role for pigment production by murine epidermal melanocytes in immune and inflammatory responses via DC activation. Our results revealed that dark pigmented melanocytes increase the production of IL-3 and the pro-inflammatory cytokines IL-6 and TNF-a, and consequently they induce pDC maturation. Further, we found that low pigment associated FMOD interferes with cytokine secretion and subsequent pDC maturation. To the best of our knowledge, this is the first study to assess the effect of baseline pigmentation on epidermal melanocyte cytokine profile, and its impact on DCs.
Illustration of a Novel Gut-Brain Axis of Alcohol Withdrawal, Withdrawal-Associated Depression, Craving and Alcohol-Severity Index in Alcohol Use Disorder Patients
Authors: Vatsalya Vatsalya , Parthasarathy Ranganathan , Verster Joris , Royer Amor C. , Sagaram Manasa , Zamani Zarlakhta , Hu Huirong , Schwandt Melanie L. , Lorenzo Leggio , Kong Maiying , Ramchandani Vijay A , Feng Wenke , Zhang Xiang , McClain Craig J.
Published: May 2022

Pathways underlying the gut-brain axis and pro-inflammatory cytokine production influence brain functions and behavior. Alcohol use disorder (AUD) patients exhibit domains such as alcohol withdrawal, depression, and craving; and the gut-immune response may play a significant role in these domains of AUD. This study examined the role of intestinal permeability, pro-inflammatory cytokines, and hormones levels on the domains of AUD.

Forty-eight AUD patients [male (n=34) and female (n=14)] aged 23-63 yrs. were grouped categorically using the Clinical Institute Withdrawal Assessment of alcohol scale (CIWA) as either clinically significant CIWA group (CS-CIWA [score>10] Gr.1 [n=22]), and clinically not-significant group (NCS-CIWA [score≤10] Gr.2 [n=26]). A sub-set of 13 AUD patient were also tested for reward response for drug-seeking using Penn-Alcohol Craving Score (PACS). Clinical data and blood samples were collected upon enrollment. Blood samples were analyzed for pro-inflammatory cytokines, and hormones, and markers of intestinal permeability. CIWA, 90-day timeline followback (TLFB90), and lifetime drinking history (LTDH) were also collected for comparison.

As expected, recent and chronic heavy drinking were significantly higher in Gr.1: HDD90 (heavy drinking days), NDD90 (number of drinking days), as was LTDH, especially in Gr.1 females. Further, in Gr.1, adiponectin (associated with withdrawal) was significantly higher; and numerically higher levels of lipopolysaccharide (LPS) and LPS-binding protein (LBP) were also reported. Gr.1 patients exhibited higher effects of association on the withdrawal-associated depression domain for the parameters of LPS, sCD14, IL-6 and IL-8. Leptin also showed a significantly high effect of association with HDD90 in those AUD patients with craving. The craving domain (assessed by PACS, Penn-Alcohol Craving Scale) could be described as a gut-immune-brain model by the gut-dysregulation (LBP and Leptin) markers, and specific pro-inflammatory activity (IL-1β and TNF-α). Such pathway model describes the heavy drinking phenotype, HDD90 with even higher effects (R2=0.955, p=0.006) in the AUD patients who had higher ratings for craving (PACS>5).

Interaction of gut-dysfunction, cytokines involved in both inflammation and in mediating-chemotactic activity constitute a novel pathophysiological gut-brain axis for withdrawal, and alcohol-associated depression and craving domains of AUD. AUD patient with higher craving show higher reinforcing effects of the gut-brain axis response for heavy drinking.
Population genomics of a threespine stickleback tapeworm in Vancouver Island
Authors: Shim Kum C. , Weber Jesse N. , Hernandez Catherine A. , Bolnick Daniel I.
Published: May 2022

We surveyed the genetic structuring of 12 Schistocephalus solidus tapeworm populations from Vancouver Island (BC, Canada) using ddRAD sequencing and compared it to that of their threespine stickleback fish hosts. There were small but mostly significant genetic differences among the tapeworm populations. PCA results separated the populations by watershed (from the lakes where the tapeworms were collected), but we could not determine if the genetic structures seen were due to discrete models (i.e. watershed) or to a continuous model (i.e. isolation by distance). However, the tapeworm genetic differences were significantly smaller (P < 0.001) than those of the fish, which indicates that the parasite disperses more readily than their fish hosts.
On the bacterial ancestry of mitochondria: new insights with triangulated approaches
Authors: Esposti Michelle Degli , Geiger Otto , Sanchez-Flores Alejandro , Esposti Mauro Degli
Published: May 2022

We breathe at the molecular level when mitochondria in our cells consume oxygen to extract energy from nutrients. Mitochondria are characteristic cellular organelles that derive from aerobic bacteria similar to some of those thriving in the oceans nowadays. These organelles carry out most metabolic pathways in eukaryotic cells. The precise bacterial origin of mitochondria and, consequently, the metabolic ancestry of our cells remains controversial - despite the vast genomic information that is now available. Here we triangulate across multiple phylogenomic and molecular approaches to pinpoint the most likely living relatives of the ancestral bacteria from which mitochondria originated.
Senolytic Treatment Reduces Cell Senescence and Necroptosis in Sod1 Knockout Mice that is Associated with Reduced Inflammation and Hepatocellular Carcinoma
Authors: Thadathil Nidheesh , Selvarani Ramasamy , Mohammed Sabira , Nicklas Evan H. , Tran Albert L. , Kamal Maria , Luo Wenyi , Brown Jacob L. , Lawrence Marcus M. , Borowik Agnieszka K. , Miller Benjamin F. , Van Remmen Holly , Richardson Arlan , Deepa Sathyaseelan S.
Published: May 2022

The goal of this study was to test the role cellular senescence plays in the increase in inflammation, chronic liver disease, and hepatocellular carcinoma, which are seen in mice null for Cu/Zn-Superoxide dismutase (Sod1KO). To inhibit senescence, six-month-old wildtype (WT) and Sod1KO mice were given the senolytics, dasatinib and quercetin (D+Q) for seven months. D+Q treatment reduced the expression of p16 in the livers of Sod1KO mice to WT levels as well as the expression of several SASP (senescence associated secretory phenotype) factors (IL-6, IL-1β, CXCL-1, and GDF-15). D+Q treatment also reduced markers of inflammation in livers of the Sod1KO mice, e.g., cytokines, chemokines, macropthage levels, and Kupffer cell clusters. D+Q treatment had no effect on various markers of liver fibrosis in the Sod1KO mice but reduced the expression of genes involved in liver cancer (Myc, Tgfbr2, Socs3, and Cdkn2a) as well as dramatically reducing the incidence of hepatocellular carcinoma. Surprisingly, D+Q also reduced markers of necroptosis (phosphorylated and oligomerized MLKL) in the Sod1KO mice to WT levels. We also found that inhibiting necroptosis in the Sod1KO mice with necrostatin-1s reduced the markers of cellular senescence (p16, p21, and p53). The data from our study suggest that an interaction occurs between cellular senescence and necroptosis in the liver of Sod1KO mice. We propose that these two cell fates interact through a positive feedback loop resulting in a cycle amplifying both cellular senescence and necroptosis leading to inflammaging and age-associated pathology in the Sod1KO mice.
Hecatomb: An End-to-End Research Platform for Viral Metagenomics
Authors: Roach Michael J. , Beecroft Sarah J. , Mihindukulasuriya Kathie A. , Wang Leran , Paredes Anne , Henry-Cocks Kara , Oliveira Lima Lais Farias , Dinsdale Elizabeth A. , Edwards Robert A. , Handley Scott A.
Published: May 2022

Background

Analysis of viral diversity using modern sequencing technologies offers extraordinary opportunities for discovery. However, these analyses present a number of bioinformatic challenges due to viral genetic diversity and virome complexity. Due to the lack of conserved marker sequences, metagenomic detection of viral sequences requires a non-targeted, random (shotgun) approach. Annotation and enumeration of viral sequences relies on rigorous quality control and effective search strategies against appropriate reference databases. Virome analysis also benefits from the analysis of both individual metagenomic sequences as well as assembled contigs. Combined, virome analysis results in large amounts of data requiring sophisticated visualization and statistical tools.

Results

Here we introduce Hecatomb, a bioinformatics platform enabling both read and contig based analysis. Hecatomb integrates query information from both amino acid and nucleotide reference sequence databases. Hecatomb integrates data collected throughout the workflow enabling analyst driven virome analysis and discovery. Hecatomb is available on GitHub at https://github.com/shandley/hecatomb.

Conclusions

Hecatomb provides a single, modular software solution to the complex tasks required of many virome analysis. We demonstrate the value of the approach by applying Hecatomb to both a host-associated (enteric) and an environmental (marine) virome data set. Hecatomb provided data to determine true- or false-positive viral sequences in both data sets and revealed complex virome structure at distinct marine reef sites.
MultiCens: Multilayer network centrality measures to uncover molecular mediators of tissue-tissue communication
Authors: Kumar Tarun , Sethuraman Ramanathan , Mitra Sanga , Ravindran Balaraman , Narayanan Manikandan
Published: May 2022

With the evolution of multicellularity, communication among cells in different organs/tissues became pivotal to life. Molecular basis of such communication has long been studied, but genome-wide screens for biomolecules/genes mediating tissue-tissue signaling are lacking. To systematically identify inter-tissue mediators, we present a novel computational approach MultiCens (Multilayer/Multi-tissue network Centrality measures). Unlike single-layer network methods, MultiCens can distinguish within- vs. across-layer connectivity to quantify the “influence” of any gene in a tissue on a query set of genes of interest in another tissue. MultiCens enjoys theoretical guarantees on convergence and decomposability, and excels on synthetic benchmarks. On human multi-tissue datasets, MultiCens predicts known and novel genes linked to hormones. MultiCens further reveals shifts in gene network architecture among four brain regions in Alzheimer’s disease. MultiCens-prioritized hypotheses from these two diverse applications, and potential future ones like “Multi-tissue-expanded Gene Ontology” analysis, can enable whole-body yet molecular-level investigations in humans.
Neuropathic symptoms with SARS-CoV-2 vaccination
Authors: Safavi Farinaz , Gustafson Lindsey , Walitt Brian , Lehky Tanya , Dehbashi Sara , Wiebold Amanda , Mina Yair , Shin Susan , Pan Baohan , Polydefkis Michael , Oaklander Anne Louise , Nath Avindra
Published: May 2022

Background and Objectives

Various peripheral neuropathies, particularly those with sensory and autonomic dysfunction may occur during or shortly after acute COVID-19 illnesses. These appear most likely to reflect immune dysregulation. If similar manifestations can occur with the vaccination remains unknown.

Results

In an observational study, we studied 23 patients (92% female; median age 40years) reporting new neuropathic symptoms beginning within 1 month after SARS-CoV-2 vaccination. 100% reported sensory symptoms comprising severe face and/or limb paresthesias, and 61% had orthostasis, heat intolerance and palpitations. Autonomic testing in 12 identified seven with reduced distal sweat production and six with positional orthostatic tachycardia syndrome. Among 16 with lower-leg skin biopsies, 31% had diagnostic/subthreshold epidermal neurite densities (≤5%), 13% were borderline (5.01-10%) and 19% showed abnormal axonal swelling. Biopsies from randomly selected five patients that were evaluated for immune complexes showed deposition of complement C4d in endothelial cells. Electrodiagnostic test results were normal in 94% (16/17). Together, 52% (12/23) of patients had objective evidence of small-fiber peripheral neuropathy. 58% patients (7/12) treated with oral corticosteroids had complete or near-complete improvement after two weeks as compared to 9% (1/11) of patients who did not receive immunotherapy having full recovery at 12 weeks. At 5-9 months post-symptom onset, 3 non-recovering patients received intravenous immunoglobulin with symptom resolution within two weeks.

Conclusions

This observational study suggests that a variety of neuropathic symptoms may manifest after SARS-CoV-2 vaccinations and in some patients might be an immune-mediated process.
Reductions and pronounced regional differences in morphine distribution in the United States
Authors: Dowd Megan E. , Tang E. Jessica , Yan Kurlya T. , McCall Kenneth L. , Piper Brian J.
Published: May 2022

Background

Morphine is one of the oldest, most commonly prescribed, and widely used opioids in the United States (US). Morphine’s potent analgesic properties have also been associated with the increase in misuse, addiction and opioid-related deaths in the US since the 1990s. Despite federal regulations, population-adjusted prescription opioid distribution varies markedly between states. The objective of this study was to describe the temporal pattern of morphine distribution nationally and between states.

Methods

Drug weight and population data were obtained from Report 5 of the US Drug Enforcement Administration’s Automation of Reports and Consolidated Orders System (ARCOS) to characterize patterns in the distribution of morphine from 2012 to 2020.

Morphine distribution amounts were separated by state and business type and corrected for population. States outside a 95% confidence interval relative to the national average were considered statistically significant.

Results

Pharmacies and hospitals distributed 24,200 kilograms of morphine in 2012. Tennessee (180.2 mg/person) was 4.7-fold higher than Texas (39.4 mg/person).

National distribution decreased 56.4% to 10,723 kilograms in 2020. Tennessee (56.4 mg/person) was 3.8-fold higher than the District of Columbia (15.0 mg/person). The decline in Illinois (−40.9%) was significantly less than the national average (−56.8%) while that of Oregon (−71.1%) and Arizona (−70.4%) were significantly higher. Hospital decrease (−72.7%) from 2012-2020 was larger than that of pharmacies (−56.12%).

Conclusions

The national 56% decline in the distribution of morphine in the last decade may be attributable to prioritization of the opioid crisis as a public concern, including subsequent growth of opioid misuse and treatment programs and decreased production quotas for opioids, including morphine. This decline also coincides with the national shortage of parenteral opioids resulting in greater prescriptions of alternative opioids such as nalbuphine and buprenorphine. Further research is necessary to understand the persistent four-fold regional difference between states.
Development of a Single Molecule Counting Assay to Differentiate Chromophobe Renal Cancer and Oncocytoma in Clinics
Authors: Satter Khaled Bin , Ramsey Zach , Tran Paul M.H. , Hopkins Diane , Bearden Gregory , Richardson Katherine P. , Terris Martha K. , Savage Natasha M. , Kavuri Sravan K. , Purohit Sharad
Published: May 2022

Malignant chromophobe renal cancer (chRCC) and benign oncocytoma (RO) are two renal tumor types difficult to differentiate using histology and immunohistochemistry-based methods because of their similarity in appearance. We previously developed a transcriptomics-based classification pipeline with “Chromophobe-Oncocytoma Gene Signature” (COGS) on a single-molecule counting platform. Renal cancer patients (n=32, chRCC=17, RO=15) were recruited from Augusta University Medical Center (AUMC). Formalin-fixed paraffin-embedded (FFPE) blocks from their excised tumors were collected. We created a custom single-molecule counting code set for COGS to assay RNA from FFPE blocks. Utilizing hematoxylin-eosin stain, pathologists were able to correctly classify these tumor types (91.8%). Our unsupervised learning with UMAP (accuracy = 0.97) and hierarchical clustering (accuracy = 1.0) identified two clusters congruent with their histology. We next developed and compared four supervised models (random forest, support vector machine, generalized linear model with L2 regularization, and supervised UMAP). Supervised UMAP has shown to classify all the cases correctly (sensitivity = 1, specificity = 1, accuracy = 1) followed by random forest models (sensitivity = 0.84, specificity = 1, accuracy = 1). This pipeline can be used as a clinical tool by pathologists to differentiate chRCC from RO.

Simple Summary

We previously reported a gene signature, “Chromophobe-Oncocytoma Gene Signature” (COGS), to differentiate Chromophobe renal cell carcinoma from oncocytoma. Here, we report our results on a single-molecule counting assay with machine learning as a diagnostic pipeline to differentiate chromophobe and oncocytoma tumors utilizing the COGS signature to be used in clinics.
Linking brain maturation and puberty during early adolescence using longitudinal brain age prediction in the ABCD cohort
Authors: Holm Madelene C. , Leonardsen Esten H. , Beck Dani , Dahl Andreas , Kjelkenes Rikka , de Lange Ann-Marie G. , Westlye Lars T.
Published: May 2022

The temporal characteristics of brain maturation could potentially represent a mediating effect between pubertal development and life outcomes. Using a large longitudinal dataset of children aged 9-12 from the Adolescent Brain Cognitive Development (ABCD) study we tested the associations between pubertal status and brain maturation. Brain maturation was assessed using brain age prediction with a deep learning approach based on convolutional neural networks and minimally processed T1-weighted structural MRI data. Brain age prediction provided highly accurate and reliable estimates of individual age, with an overall mean absolute error of 0.7 and 1.4 years at the two timepoints respectively, and an intraclass correlation of 0.65. Linear mixed effects (LME) models accounting for age and sex showed that on average, advancing pubertal development by one pubertal stage was associated with a 2.4 months higher brain age across time points (β= 0.10, p<.001). Further, significant interactions with time demonstrated that higher rates of pubertal development were associated with larger positive changes in brain age over time (p<.001). These results demonstrate a link between sexual development and brain maturation in early adolescence, and provides a basis for further investigations of the complex sociobiological impacts of puberty on the adolescent brain and mind.
Work-Family conflict among hotel housekeepers in the Balearic Islands (Spain)
Authors: Chela-Alvarez Xenia , Garcia-Buades M. Esther , Ferrer-Perez Victoria A. , Bulilete Oana , Llobera Joan
Published: May 2022

The massive incorporation of women to the labour market has increased academic and applied interest on work-life issues throughout the years. This article aims to describe the domestic burden and difficulties in work-life balance (WLB) and at understanding the intersection of work and family spheres among hotel housekeepers (HHs). A cross-sectional study was conducted through Primary Health Care in the Balearic Islands (Spain); 1,043 HHs were enrolled. 56.7% report difficulties in WLB. Risk factors for perceiving difficulties in WLB were: living with one or two co-habitants, low social support, having difficulties making ends meet, being the main responsible person for domestic tasks, having a dependant, presenting higher levels of stress at work and being younger. Protective factors from experiencing work-family conflict (WFC) were job and wage satisfaction. WFC is strongly influenced by individual, economic, labour and domestic factors: these relationships show that labour and domestic spheres are non-separate worlds.
Morphogen gradient orchestrates pattern-preserving tissue morphogenesis via motility-driven (un)jamming
Authors: Pinheiro Diana , Kardos Roland , Hannezo Édouard , Heisenberg Carl-Philipp
Published: May 2022

Embryo development requires both biochemical signalling generating patterns of cell fates and active mechanical forces driving tissue shape changes. Yet, how these fundamental processes are coordinated in space and time, and, especially, how tissue patterning is preserved despite the complex cellular flows occurring during morphogenesis, remains poorly understood. Here, we show that a Nodal/TGF-β morphogen gradient orchestrates pattern-preserving mesendoderm internalization movements during zebrafish gastrulation by triggering a motility-driven (un)jamming transition. We find that graded Nodal signalling, in addition to its highly conserved role in mesendoderm patterning, mechanically subdivides the tissue into a small fraction of highly protrusive leader cells able to locally unjam and thus autonomously internalize, and less protrusive followers, which remain jammed and need to be pulled inwards by the leaders. Using minimal particle-based simulations and experimental perturbations, we further show that this binary mechanical switch, when combined with Nodal-dependent preferential adhesion coupling leaders to followers, is critical for triggering collective and orderly mesendoderm internalization, thus preserving tissue patterning. This provides a simple, yet quantitative, theoretical framework for how a morphogen-encoded (un)jamming transition can bidirectionally couple tissue mechanics with patterning during complex three-dimensional morphogenesis.
Decoding individual differences in mental information from human brain response predicted by convolutional neural networks
Authors: Kawahata Kiichi , Wang Jiaxin , Blanc Antoine , Maeda Naoya , Nishimoto Shinji , Nishida Satoshi
Published: May 2022

Recent advantages in brain decoding with functional magnetic resonance imaging (fMRI) have enabled us to estimate individual differences in mental information from brain responses to natural stimuli. However, the physical constraints and costs of fMRI measurements prevent brain decoding from achieving real-world applications. We address this issue by building a novel framework to decode individual differences in mental information under natural situations from brain responses predicted using convolutional neural networks (CNNs). Once the CNN-based prediction model is trained using measured response, mental information can be decoded from the predicted responses of individual brains with no need for additional fMRI measurements. The model was found to capture individual-difference patterns consistent with conventional decoding using measured responses in 81/87 items to be decoded. Our framework has great potential to decode personal mental information with low dependence on fMRI measurements, which could help substantially expand the applicability of brain decoding in daily life.
Ants act as olfactory bio-detectors of tumour in patient-derived xenograft mice
Authors: Piqueret Baptiste , Montaudon Élodie , Devienne Paul , Leroy Chloé , Marangoni Elisabetta , Sandoz Jean-Christophe , d’Ettorre Patrizia
Published: May 2022

Early detection of cancer is critical in medical sciences, as the sooner a cancer is diagnosed, the higher the chances of recovery. Tumour cells are characterized by specific volatile organic compounds (VOCs) that can be used as cancer biomarkers. Through olfactory associative learning, animals can be trained to detect these VOCs. Insects, such as ants, have a refined sense of smell and can be easily and rapidly trained with olfactory conditioning. Using urine from patient-derived xenograft mice as stimulus, we demonstrate that individual ants can learn to discriminate the odour of healthy mice from that of tumour bearing mice, and do so after only three conditioning trials. Chemical analyses confirmed that the presence of the tumour changed the urine odour, supporting the behavioural results. Our study demonstrates that ants reliably detect tumour cues in mice urine and have the potential to act as efficient and inexpensive cancer bio detectors.
Quantifying rhythmicity in perceptual reports
Authors: Tosato Tommaso , Rohenkohl Gustavo , Dowdall Jarrod Robert , Fries Pascal
Published: May 2022

Several recent studies investigated the rhythmic nature of cognitive processes that lead to perception and behavioral report. These studies used different methods, and there has not yet been an agreement on a general standard. Here, we present a way to test and quantitatively compare these methods. We simulated behavioral data from a typical experiment and analyzed these data with several methods. We applied the main methods found in the literature, namely sine-wave fitting, the Discrete Fourier Transform (DFT) and the Least Square Spectrum (LSS). DFT and LSS can be applied both on the averaged accuracy time course and on single trials. LSS is mathematically equivalent to DFT in the case of regular, but not irregular sampling - which is more common. LSS additionally offers the possibility to take into account a weighting factor which affects the strength of the rhythm, such as arousal. Statistical inferences were done either on the investigated sample (fixed-effect) or on the population (random-effect) of simulated participants. Multiple comparisons across frequencies were corrected using False-Discovery-Rate, Bonferroni, or the Max-Based approach. To perform a quantitative comparison, we calculated Sensitivity, Specificity and D-prime of the investigated analysis methods and statistical approaches. Within the investigated parameter range, single-trial methods had higher sensitivity and D-prime than the methods based on the averaged-accuracy-time-course. This effect was further increased for a simulated rhythm of higher frequency. If an additional (observable) factor influenced detection performance, adding this factor as weight in the LSS further improved Sensitivity and D-prime. For multiple comparison correction, the Max-Based approach provided the highest Specificity and D-prime, closely followed by the Bonferroni approach. Given a fixed total amount of trials, the random-effect approach had higher D-prime when trials were distributed over a larger number of participants, even though this gave less trials per participant. Finally, we present the idea of using a dampened sinusoidal oscillator instead of a simple sinusoidal function, to further improve the fit to behavioral rhythmicity observed after a reset event.
Single molecule analyses of Salmonella translocated effector proteins reveal targeting to and dynamics in host cell endomembranes
Authors: Göser Vera , Schulte Marc , Scharte Felix , Franzkoch Rico , Liss Viktoria , Psathaki Olympia E. , Hensel Michael
Published: May 2022

Bacterial pathogens deliver proteins in temporal and spatial coordinated manner to manipulate mammalian host cells. The facultative intracellular pathogen Salmonella enterica remodels the host endosomal system for survival and proliferation inside host cells. The pathogen resides in a membrane-bound compartment termed Salmonella-containing vacuole (SCV). By Salmonella- induced fusions of host endomembranes, the SCV is connected with extensive tubular structures termed Salmonella-induced filaments (SIF). The intracellular lifestyle of Salmonella critically depends on effector molecules translocated by the SPI2-encoded type III secretion system (SPI2-T3SS) into host cells. A subset of these effectors is associated with, or integral in SCV and SIF membranes. It remained to be determined how SPI2-T3SS effectors reach their subcellular destination, and how these effectors interact with endomembranes remodeled by Salmonella. We deployed self-labeling enzyme (SLE) tags as novel approach to label translocated effector proteins in living host cells, and analyzed their dynamics on single molecule level. We found that SPI2-T3SS effector proteins diffuse in membranes of SIF with mobility comparable to membrane-integral host proteins in endomembranes. Dynamics differed between various effector proteins investigated and was dependent on membrane architecture of SIF. In the early infection, we observed host endosomal vesicles associated with Salmonella effector proteins. Effector-positive vesicles continuously fused with SCV and SIF membranes, providing a route of effector delivery by SPI2-T3SS translocation, interaction with endosomal vesicles, and ultimately fusion with the continuum of SCV/SIF membranes. This novel mechanism controls membrane deformation and vesicular fusion to generate the specific intracellular niche for bacterial survival and proliferation.
Does sexual conflict contribute to the evolution of novel warning patterns?
Authors: Hausmann Alexander E. , Freire Marília , Alfthan Sara A. , Kuo Chi-Yun , Linares Mauricio , McMillan Owen , Pardo-Diaz Carolina , Salazar Camilo , Merrill Richard M.
Published: May 2022

Why warning patterns are so diverse is an enduring evolutionary puzzle. Because predators associate particular patterns with unpleasant experiences, an individual’s predation risk should decrease as the local density of its warning pattern increases, promoting pattern monomorphism. DistastefulHeliconiusbutterflies are known for their diversity of warning patterns. Here, we explore whether interlocus sexual conflict can contribute to their diversification. MaleHeliconiususe warning patterns as mating cues, but mated females may suffer costs if this leads to harassment, favoring novel patterns. Using simulations, we show that drift alone is unlikely to cause pattern diversification, but that sexual conflict can assist such process. We also find that genetic architecture influences the evolution of male preferences, which track changes in warning pattern due to sexual selection. When male attraction imposes costs on females, this affects the speed at which novel pattern alleles increase. In two experiments, females laid fewer eggs with males present. However, although males in one experiment showed less interest in females with manipulated patterns, we found no evidence that female coloration mitigates sex-specific costs. Overall, male attraction to conspecific warning patterns may impose an unrecognized cost onHeliconiusfemales, but further work is required to determine this experimentally.
Knockouts of positive and negative elements of the circadian clock disrupt photoperiodic diapause induction in the silkworm,Bombyx mori
Authors: Tobita Hisashi , Kiuchi Takashi
Published: May 2022

Diapause is one of the most important traits that have sustained insects to thrive. Insects can prospectively arrest their development and increase environmental stress-resistance by entering diapause. The photoperiod is the signal that indicates insects the proper timing to enter diapause. Circadian clock genes are shown to be involved in photoperiodic diapause induction in various insect species. The silkworm,Bombyx mori, enters diapause at the embryonic stage. In bivoltine strains, diapause determination is affected by embryonic temperature and photoperiodic conditions during embryonic and larval stages. Two independent studies showed that knocking out the core clock gene,period, perturb photoperiodic diapause induction. However, whether the circadian clock as whole or individual clock genes are responsible for the photoperiodic diapause induction remains unknown. In this study, using CRISPR/Cas9 we knocked out negative (periodandtimeless) and positive elements (Clockandcycle) in p50T, a bivoltine strain which exhibits photoperiodic diapause induction during both embryonic and larval stages. The temporal expression patterns of clock genes changed in each core clock gene knockout strain, suggesting disruption of normal feedback loops produced by circadian clock genes. Furthermore, photoperiodic diapause induction during both embryonic and larval stages was lost in all knockout strains. Our results indicate the involvement of circadian clock in photoperiodic diapause induction inB. mori.

Highlights

We established knockoutBombyx moristrains of four core clock genes

The temporal expression patterns of clock genes changed in knockout strains

Photoperiodic diapause induction was not observed in any knockout strains

Graphical abstract
Recalibrating the cerebellum DNA methylation clock: implications for ageing rates comparison
Authors: Wang Yucheng , Grant Olivia A. , Zhai Xiaojun , McDonald-Maier Klaus D. , Schalkwyk Leonard C.
Published: May 2022

Background

DNA methylation (DNAm) based age clocks have been studied extensively as a biomarker of human ageing and risk factor for age-related diseases. Despite different tissues having vastly different rates of proliferation, it is still largely unknown whether they age at different rates. It was previously reported that the cerebellum ages slowly, however, this claim was drawn from a single clock using a small sample size and so warrants further investigation.

Results

We collected the largest cerebellum DNAm dataset (N=752). We found the respective epigenetic ages are all severely underestimated by six representative DNAm age clocks, with the underestimation effects more pronounced in the four clocks whose training datasets do not include brain-related tissues. We identified 613 age-associated CpGs in the cerebellum, which accounts for only 14.5% of the number found in the middle temporal gyrus from the same population (N=404), of which only 201 CpGs are both age-associated in the two tissue types. We built a highly accurate age prediction model for the cerebellum named CerebellumClockspecific(Pearson correlation=0.941, MAD=3.18 years). Furthermore, based on the 201 age-associated CpGs, we built two other clocks CerebellumClockcommonand CortexClockcommonfor the cerebellum and non-cerebellar brain cortex tissues separately, they both support that the cerebellum has a relative lower DNAm ageing rate.

Conclusions

The large underestimation for the cerebellum by previous clocks mainly reflects the improper usage of the age clocks. There exist strong and consistent ageing effects on the cerebellar methylome despite the cerebellum having unique age-dependent methylome changes. The DNAm clock based ageing rates comparisons are valid only upon models constructed on a small group of CpGs, therefore, more evidence is required to support the idea that different DNAm ageing rates represent different biological ageing rates.
Evaluating trait-based sets for taxonomic enrichment analysis applied to human microbiome data sets
Authors: Nguyen Quang P. , Hoen Anne G. , Frost H. Robert
Published: May 2022

Background

Set-based pathway analysis is a powerful tool that allows researchers to summarize complex genomic variables in the form of biologically interpretable sets. Since the microbiome is characterized by a high degree of inter-individual variability in taxonomic compositions, applying enrichment methods using functionally driven taxon sets can increase both the reproducibility and interpretability of microbiome association studies. However, there is still an open question of which knowledge base to utilize for set construction. Here, we evaluate microbial trait databases, which aggregate experimentally determined microbial phenotypes, as a potential avenue for meaningful construction of taxon sets.

Method

Using publicly available microbiome sequencing data sets (both 16S rRNA gene metabarcoding and whole-genome metagenomics), we assessed these trait-based sets on two criteria: first, do they cover the diversity of microbes obtained from a typical data set, and second, do they confer additional predictive power on disease prediction tasks when assessed against measured pathway abundances and PICRUSt2 prediction.

Results

Trait annotations are well annotated to a small number but most abundant taxa within the community, concordant with the concept of the core-peripheral microbiome. This pattern is consistent across all categories of traits and body-sites for whole genome sequencing data, but much more heterogenous and inconsistent in 16S rRNA metabarcoding data due to difficulties in assigning species-level traits to genus. However, trait-set features are well predictive of disease outcomes compared against predicted and measured pathway abundances. Most important trait-set features are more interpreable and reveal interesting insights on the relationship between microbiome, its function, and health outcomes.