bluuebunny/crossref_metadata_2025 huggingface dataset:
Sporadic and Familial Adenomatous Polyposis-associated Foveolar-type Adenoma of the Stomach
Authors: Naka Tomoaki , Hashimoto Taiki , Cho Hourin , Tanabe Noriko , Yoshida Teruhiko , Yatabe Yasushi , Yoshikawa Takaki , Abe Seiichiro , Sekine Shigeki
Published: August 2022

Gastric foveolar-type adenoma (FA) is a rare benign neoplasm occurring either sporadically or in patients with familial adenomatous polyposis (FAP). However, the molecular features of FA and the relationship between sporadic and syndromic lesions remain unclear. In this study, we performed clinicopathological, immunohistochemical, and genetic analyses of 18 sporadic and 30 FAP-associated FAs. Most sporadic and FAP-associated FAs were located in the upper or middle third of the stomach, on a background of fundic gland mucosa. Most lesions were low-grade, but 3 lesions had a high-grade component. Sporadic FAs included 2 morphologically distinct subtypes, that is, flat and raspberry-like FAs, which we distinguished based on the endoscopic features. Seven lesions were regarded as flat FAs, appearing as large, slightly elevated lesions and measuring 11 to 87 mm in size. Conversely, 10 raspberry-like FAs were small bright-red polyps, measuring 2 to 8 mm in size. FAP-associated FAs, particularly larger lesions, exhibited morphologic features resembling flat FAs but varied significantly in size (2 to 103 mm). Mutation analysis identified APC and KRAS mutations in all flat FAs but never in raspberry-like FAs. Remarkably, somatic APC and KRAS mutations were also detected in 19 (63%) and 27 (90%) of FAP-associated FAs, respectively. This indicates that they are genetically equivalent to sporadic, flat FAs. This study showed that sporadic FA includes at least 2 morphologically and genetically distinct subtypes: flat and raspberry-like FA. Furthermore, flat FA represents a sporadic counterpart of FAP-associated FA.
Non-AIDS Events in Individuals With Spontaneous Control of HIV-1: A Systematic Review
Authors: Groenendijk Albert L. , Vos Wilhelm A. J. W. , dos Santos Jéssica C. , Rokx Casper , van der Ven Andre J. A.M. , Verbon Annelies
Published: August 2022

Background:

Despite antiretroviral therapy (ART), people living with HIV (PLHIV) are at increased risk for non–AIDS-defining events (nADEs), including cardiovascular events, non-AIDS malignances, hepatic disease, and bacterial pneumonia.

Setting:

This systematic review seeks to answer the question: are PLHIV who spontaneously control HIV-1 subject to an increased risk of various nADEs relative to noncontrolling PLHIV on ART and people without HIV?

Methods:

Databases were searched on June 9, 2021 with a search syntax focused on the elements “HIV,” “spontaneous control,” and “clinical outcomes”: Embase.com (includes Embase and Medline), Medline Ovid (includes PubMed), Cochrane library, Web of Science, and Google Scholar. Included were studies reporting non-AIDS events in spontaneous controllers. Excluded were case reports, conference papers, editorials, and reviews.

Results:

Of 1134 identified records, 34 were assessed for full-text and 12 studies were included in the qualitative synthesis: 5 cohorts, 2 cross-sectional prevalence studies, 4 cross-sectional imaging studies, and one case series. Four of 5 cohort studies showed that spontaneous controllers have a similar risk to develop nADEs compared with PLHIV on suppressive ART, specifically cardiovascular events, non-AIDS malignancies, hepatic disease, and bacterial pneumonia. Cross-sectional imaging studies showed a higher presence of subclinical cardiovascular disease in spontaneous controllers, than in people without HIV.

Conclusion:

Individuals with spontaneous control of HIV-1 do not seem to be at a greater risk to develop different nADEs compared with PLHIV on suppressive ART. More data are needed, because the present conclusions are based on a limited number of studies that show large heterogeneity among them.
Point Mutation in Prkra Alters miRNA Expression During Embryonic External Ear Development
Authors: Liu Wei , Lin Lin , Yang Qinghua , Jin Shengyang , Jiang Haiyue
Published: August 2022

Microtia is a congenital malformation of the external ear that can lead to conductive hearing impairment. In this study, we investigated the role of the Prkra gene in external ear development. We used advanced sequencing techniques to evaluate the differential expression of microRNAs (miRNAs) involved in external ear development in mouse embryos after point mutation in the Prkra gene. The Prkra Little ear mouse model was used to obtain mouse embryos at the E15.5 and E17.5 developmental stages, and changes in miRNA expression profiles were detected. Gene ontology and Kyoto Encyclopedia of Genes and Genomes functional annotations were performed on differentially expressed miRNAs, and existing and new miRNAs were studied. miRNAs were observed to be involved in multiple signaling pathways during the E15.5 and E17.5 developmental stages. The results show a correlation between miRNA regulation and external ear development in Prkra Little ear mice, and differences were detected in key regulatory miRNAs owing to point mutations in the Prkra gene. This study provides new insights into the biological mechanisms through which miRNAs regulate external ear development in mouse embryos. Changes in the mouse miRNA expression profiles can also provide insights into the pathogenesis of human congenital microtia at the level of miRNA regulation.
Orbital Soft Tissue Displacement After Blow-Out Fracture Repair Using Poly (L-Lactide-Co-Glycolide) Polymer Plates Based on Image Fusion Technique
Authors: Wei Yining , Wang Hui , Song Xuefei , Bi Xiaoping , Li Yinwei , Zhou Huifang , Shi Wodong
Published: August 2022

Purpose:

To analyze the displacement of orbital soft tissue after blow-out fracture (BOF) repair with poly (L-lactide-co-glycolide) plates.

Materials and Methods:

In this retrospective study, all patients who had undergone repair operations for orbital BOF from 2017 to 2021 were evaluated. Poly (L-lactide-co-glycolide) plates were used as repair materials. Preoperative and postoperative computed tomography images were integrated into the same coordinate system applying image fusion technique and were compared to determine the maximum displacement of orbital tissue after surgical repair.

Results:

A total of 15 patients were included. Five were male, and 10 were female. Mean age was 33±16 years. Median waiting period was 18 (12–23) days. Six cases were medial wall fractures, 5 were floor fractures, and 4 were combined fractures. Maxillo-ethmoidal strut was involved in 4. Mean defect area was 176.52±108.48 mm2. Median interval between postoperative imaging examinations was 292 (223–600) days. Mean orbital tissue displacement was 2.6±1.8 mm. Using simple and multivariable linear regression analysis, the fracture defect area (P=0.001) and maxillo-ethmoidal strut involvement (P=0.013) were found to be significantly associated with orbital tissue displacement. Median orbital volume change was 0.804 (0.647–1.010) cm3. Average proptosis variation was 1.2±0.8 mm.

Conclusions:

Poly (L-lactide-co-glycolide) plates were more suitable for orbital BOF with small defect size. Those with large defect or maxillo-ethmoidal strut involved might have greater tissue displacements due to decline of supporting strength of poly (L-lactide-co-glycolide) plates.
Optimizing Perioperative Care in Transsphenoidal Pituitary Surgery: Considerations for Enhanced Recovery After Surgery
Authors: Barrette Louis-Xavier , Douglas Jennifer , Chorath Kevin T. , Shah Mitali , Lu Joseph , Newman Jason G. , Adappa Nithin , Kohanski Michael , Palmer James , Yoshor Daniel , Lee John , White Caitlin A. , Kharlip Julia , Rajasekaran Karthik
Published: August 2022

Objective:

To identify key recommendations for maximizing the efficiency and efficacy of perioperative care in transsphenoidal pituitary surgery.

Methods:

The authors performed a comprehensive literature search of Enhanced Recovery After Surgery protocols implemented for patients undergoing transsphenoidal adenomectomy (TSA); individual recommendations were abstracted, and the evidence base thoroughly reviewed.

Results:

The authors identified 19 individual recommendations pertinent to the care of patients undergoing TSA, which were subdivided into preoperative (n=6), intraoperative (n=6), and postoperative (n=7) interventions. Key factors recommended for minimizing length of stay, preventing readmission, and improving patient outcomes included comprehensive patient education, multidisciplinary evaluation, avoidance of routine lumbar drain placement and nasal packing, and rigorous postoperative monitoring of pituitary function and salt-water imbalances. The overall level of evidence for 7/19 (37%) implemented recommendations was found to be low, suggesting a need for continued research in this patient population.

Conclusion:

Several key interventions should be considered in the development of Enhanced Recovery After Surgery protocols for TSA, which may aid in further decreasing length of stay and promoting positive patient outcomes.
The Utility of Hyaluronidase for the Free and Pedicle Flap Salvage
Authors: Park Tae Hwan
Published: August 2022

Hyaluronidase is commonly used to treat swelling and hematoma for aesthetic and reconstructive purposes. It has also been reported as a stimulator of angiogenesis. The purpose of this study was to introduce the utility of hyaluronidase in patients with flap compromise after free and pedicle flap reconstructions. This study was a retrospective study of 1 case of radial forearm free flap salvage, 2 cases of keystone perforator flap salvage, and 1 case of pectoralis major myocutaneous flap salvage. A radial forearm free flap reconstruction of unilateral mouth floor and tongue defect was complicated with hematoma formation on a postoperative day 1 after taking clopidogrel due to acute-onset non–ST-elevation myocardial infarction but dramatically resolved with hyaluronidase injection into the flap and contralateral unaffected tongue. After this intervention, the flap color dramatically returned to normal and became soft without further treatments. Two keystone design perforator flaps were performed to reconstruct the sacral defect after the debridement of pressure ulcers. Two cases were related to the patients’ medical conditions, such as low platelet count caused by liver cirrhosis. We also salvaged pectoralis major myocutaneous flap in a 91-year-old female patient with large breasts. This study introduced our experience of salvaging the free and pedicled flaps using hyaluronidase. Hyaluronidase is an excellent option when arterial or venous insufficiency occurs after free and perforator flap surgeries.
Anti-interleukin-6 Antibody Clazakizumab in Antibody-mediated Renal Allograft Rejection: Accumulation of Antibody-neutralized Interleukin-6 Without Signs of Proinflammatory Rebound Phenomena
Authors: Borski Anita , Eskandary Farsad , Haindl Susanne , Doberer Konstantin , Mühlbacher Jakob , Mayer Katharina A. , Budde Klemens , Halloran Philip F. , Chong Edward , Jilma Bernd , Böhmig Georg A. , Wahrmann Markus
Published: August 2022

Background.

Blockade of interleukin-6 (IL-6) has emerged as a promising therapeutic option for antibody-mediated rejection. Subtherapeutic anti-IL-6 antibody level or treatment cessation following prolonged cytokine neutralization may result in proinflammatory rebound phenomena via accumulation of IL-6 and/or modulated gene expression of major components of the IL-6/IL-6 receptor (IL-6R) axis.

Methods.

We evaluated biologic material obtained from a randomized controlled, double-blind phase 2 trial designed to evaluate the safety and efficacy of the anti-IL-6 monoclonal antibody clazakizumab in late antibody-mediated rejection. Twenty kidney transplant recipients, allocated to clazakizumab or placebo, received 4-weekly doses over 12 wks, followed by a 40-wk extension where all recipients received clazakizumab. Serum proteins were detected using bead-based immunoassays and RNA transcripts using quantitative real-time polymerase chain reaction (peripheral blood) or microarray analysis (serial allograft biopsies).

Results.

Clazakizumab treatment resulted in a substantial increase in median total (bound and unbound to drug) serum IL-6 level (1.4, 8015, and 13 600 pg/mL at 0, 12, and 52 wks), but median level of free (unbound to drug) IL-6 did not increase (3.0, 2.3, and 2.3 pg/mL, respectively). Neutralization of IL-6 did not boost soluble IL-6R or leukocyte or allograft expression of IL-6, IL-6R, and glycoprotein 130 mRNA. Cessation of treatment at the end of the trial did not result in a meaningful increase in C-reactive protein or accelerated progression of graft dysfunction during 12 mo of follow-up.

Conclusion.

Our results argue against clinically relevant rebound phenomena and modulation of major components of the IL-6/IL-6R axis following prolonged IL-6 neutralization with clazakizumab.
Seeing the Woods for the Trees? Applying Diagnostic Criteria for Dementia with Lewy Bodies to Patients Presenting with Posterior Cortical Atrophy
Authors: Kelly Mark J. , Fearon Conor , O’Dowd Seán
Published: August 2022

Posterior cortical atrophy (PCA) is a clinico-radiological syndrome characterised by progressive decline in visual processing and other posterior cognitive functions, relatively preserved memory and language in the early stages, and atrophy of posterior brain regions. Often considered a “visual variant” of Alzheimer’s disease, a number of other pathological substrates are recognised. Dementia with Lewy Bodies is the second most common neurodegenerative dementia and there is increasing recognition of presentations with little or no parkinsonism, highlighting significant under-recognition of this condition. To complicate matters, some patients with PCA exhibit additional features consistent with other neurodegenerative conditions. We present a series of three such patients presenting with features satisfying the recent consensus criteria for “PCA-Plus (DLB)”. We review the current classification of PCA and highlight the importance of deep clinico-radiological phenotyping in neurodegenerative disease to guide targeted interventions and establish future trial-ready cohorts.
Circulation of respiratory viruses during the COVID-19 pandemic in The Gambia
Authors: Jarju S. , Senghore E. , Brotherton H. , Saidykhan A. , Jallow S. , Krubally E. , Sinjanka E. , Ndene M.N. , Bajo F. , Sanyang M. , Saidy B. , Bah A , Forrest K. , Clarke E. , D’Alessandro U. , Usuf E. , Cerami C. , Roca A. , Kampmann B. , de Silva T. I.
Published: August 2022

In many countries, non-pharmaceutical interventions to limit SARS-CoV-2 transmission resulted in significant reductions in other respiratory viruses. However, similar data from Africa are limited. We explored the extent to which viruses such as influenza and rhinovirus co-circulated with SARS-CoV-2 in The Gambia during the COVID-19 pandemic. Between April 2020 and March 2022, respiratory viruses were detected using RT-PCR in nasopharyngeal swabs from 1397 participants with influenza-like illness. Overall virus positivity was 44.2%, with prevalence higher in children <5 years (80%) compared to children aged 5-17 years (53.1%), adults aged 18-50 (39.5%) and >50 years (39.9%), p<0.0001. After SARS-CoV-2 (18.3%), rhinoviruses (10.5%) and influenza viruses (5.5%) were the most prevalent. SARS-CoV-2 positivity was lower in children <5 (4.3%) and 5-17 years (12.7%) than in adults aged 18-50 (19.3%) and >50 years (24.3%), p<0.0001. In contrast, rhinoviruses were most prevalent in children <5 years (28.7%), followed by children aged 5-17 (15.8%), adults aged 18-50 (8.3%) and >50 years (6.3%), p<0.0001. Four SARS-CoV-2 waves occurred, with 36.1%-52.4% SARS-CoV-2 positivity during peak months. Influenza infections were observed in both 2020 and 2021 during the rainy season as expected (peak positivity 16.4%-23.5%). Peaks of rhinovirus were asynchronous to the months when SARS-CoV-2 and influenza peaked.
Individuals with recent prior SARS-CoV-2 infection are at reduced risk of Omicron infection and associated hospitalization
Authors: Nadig Mihika , Niesen Michiel JM , Lenehan Patrick , Agarwal Vineet , Ross Jason , Ardhanari Sankar , Venkatakrishnan AJ , Soundararajan Venky
Published: August 2022

Omicron sub-lineages such as BA2.12.1 and BA5 have breached prior infection-induced immunity and vaccine-induced immunity. This capacity of Omicron to reinfect patients calls for a characterization of vaccination, infection, and reinfection patterns. We analyzed de-identified longitudinal electronic health records for 389,746 individuals (88,679 fully-vaccinated, 184,205 boosted, 73,184 with prior infection) across multiple US states. Compared to individuals with only full vaccination, the rates of SARS-CoV-2 infections in the Omicron era were reduced for individuals with additional prior infection (1.4 to 1.8-fold reduced, depending on vaccine status) or booster vaccination (1.3 to 2.0-fold reduced). Although prior infection was associated with lower incidence of SARS-CoV-2 infection, we found that the relative risk (RR) of infections for individuals with prior infection has increased during Omicron. During October, 2021, RR was 0.11 [0.10-0.13, 95% CI] while during May, 2022, it increased to 0.57 [0.46-0.68, 95% CI], suggesting an increase in reinfections with Omicron. Furthermore, we found that time since prior infection is associated with risk of reinfection, providing evidence of waning immunity. Prior infections before June, 2021, were associated with marginal reduction in risk of infection (eg., RR = 0.80 [0.68-0.90] for prior infection during January, 2021), while recent prior infections were associated with significant reduction in risk (eg., RR = 0.24 [0.20-0.29, 95% CI] for prior infection during November, 2021). Despite an observed increase in reinfections and vaccine breakthrough infections, our findings emphasize the protective effect of natural and vaccine immunity, with prior infection providing ∼6 months of protection from reinfection.
Transformer Enables Reference Free And Unsupervised Analysis of Spatial Transcriptomics
Authors: Zhao Chongyue , Xu Zhongli , Wang Xinjun , Chen Kong , Huang Heng , Chen Wei
Published: August 2022

The development of spatial transcriptomics technologies makes it possible to study tissue heterogeneity at the scale of spatial expressed microenvironment. However, most of the previous methods collapse the spatial patterns in the low spatial resolution. Existing reference based deconvolution methods integrate single-cell reference and spatial transcriptomics data to predict the proportion of cell-types, but the availability of suitable single-cell reference is often limited. In this paper, we propose a novel Transformer based model (TransfromerST) to integrate the spatial gene expression measurements and their spatial patterns in the histology image (if available) without single cell reference. TransfromerST enables the learning of the locally realistic and globally consistent constituents at nearly single cell resolution. TransfromerST firstly uses a transformer based variational autoencoder to explore the latent representation of gene expression, which is further embedded with the spatial relationship learned from adaptive graph Transformer model. The super-resolved cross-scale graph network improves the model-fit to enhanced structure-functional interactions. The public and in-house experimental results with multimodal spatial transcriptomics data demonstrate TransfromerST could highlight the tissue structures at nearly single cell resolution and detect the spatial variable genes and meta gene for each spatial domain. In summary, TransfromerST provides an effective and efficient alternative for spatial transcriptomics tissue clustering, super-resolution and gene expression prediction from histology image.
Extracellular matrix educates a tumor macrophage phenotype found in ovarian cancer metastasis
Authors: Puttock E. H. , Tyler E. J. , Manni M. , Maniati E. , Butterworth C. , Peerani E. , Hirani P. , Gauthier V. , Liu Y. , Maniscalco G. , Rajeeve V. , Cutillas P. , Trevisan C. , Pozzobon M. , Lockley M. , Rastrick J. , Läubli H. , White A. , Pearce O. M. T.
Published: August 2022

Recent studies have shown the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and immunotherapy response. A question that remains is whether the ECM is directly educating the immune phenotypes seen in cancer. We identified a tumor-associated macrophage (TAM) population correlated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether ECM was capable of generating the TAM phenotype seen, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissues. ECM educated macrophages have a tissue remodeling and immunoregulatory phenotype, inducing altered T cell function. We conclude that the tumor ECM is directly educating this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.
Modular response analysis reformulated as a multilinear regression problem
Authors: Borg Jean-Pierre , Colinge Jacques , Ravel Patrice
Published: August 2022

Motivation

Modular response analysis (MRA) is a well-established method to infer biological networks from perturbation data. Classically, MRA requires the solution of a linear system and results are sensitive to noise in the data and perturbation intensities. Applications to networks of 10 nodes or more are difficult due to noise propagation.

Results

We propose a new formulation of MRA as a multilinear regression problem. This enables to integrate all the replicates and potential, additional perturbations in a larger, over determined and more stable system of equations. More relevant confidence intervals on network parameters can be obtained and we show competitive performance for networks of size up to 100. Prior knowledge integration in the form of known null edges further improves these results.

Availability and implementation

The R code used to obtain the presented results is available from GitHub: https://github.com/J-P-Borg/BioInformatics

Contact

Patrice.ravel@umontpellier.fr
Tensor Image Registration Library: Automated Deformable Registration of Stand-Alone Histology Images to Whole-Brain Post-Mortem MRI Data
Authors: Huszar Istvan N. , Pallebage-Gamarallage Menuka , Bangerter-Christensen Sarah , Brooks Hannah , Fitzgibbon Sean , Foxley Sean , Hiemstra Marlies , Howard Amy F.D. , Jbabdi Saad , Kor Daniel Z. L. , Leonte Anna , Mollink Jeroen , Smart Adele , Tendler Benjamin C. , Turner Martin R. , Ansorge Olaf , Miller Karla L. , Jenkinson Mark
Published: August 2022

Background

Accurate registration between microscopy and MRI data is necessary for validating imaging biomarkers against neuropathology, and to disentangle complex signal dependencies in microstructural MRI. Existing registration methods often rely on serial histological sampling or significant manual input, providing limited scope to work with a large number of stand-alone histology sections. Here we present a customisable pipeline to automate the registration of stand-alone histology sections to whole-brain MRI data.

Methods

Our pipeline registers stained histology sections to whole-brain post-mortem MRI in 4 stages, with the help of two photographic intermediaries: a block face image (to undistort histology sections) and coronal brain slice photographs (to insert them into MRI space). Each registration stage is implemented as a configurable stand-alone Python script using our novel platform, Tensor Image Registration Library (TIRL), which provides flexibility for wider adaptation. We report our experience of registering 87 PLP-stained histology sections from 14 subjects and perform various experiments to assess the accuracy and robustness of each stage of the pipeline.

Results

All 87 histology sections were successfully registered to MRI. Histology-to-block registration (Stage 1) achieved 0.2-0.4 mm accuracy, better than commonly used existing methods. Block-to-slice matching (Stage 2) showed great robustness in automatically identifying and inserting small tissue blocks into whole brain slices with 0.2 mm accuracy. Simulations demonstrated sub-voxel level accuracy (0.13 mm) of the slice-to-volume registration (Stage 3) algorithm, which was observed in over 200 actual brain slice registrations, compensating 3D slice deformations up to 6.5 mm. Stage 4 combined the previous stages and generated refined pixelwise aligned multi-modal histology-MRI stacks.

Conclusions

Our open-source pipeline provides robust automation tools for registering stand-alone histology sections to MRI data with sub-voxel level precision, and the underlying framework makes it readily adaptable to a diverse range of microscopy-MRI studies.

Highlights

New software framework for prototyping bespoke image registration pipelines

Automated pipeline to register stand-alone histology sections to whole-brain MRI

Novel deformable slice-to-volume registration algorithm

No strict necessity for serial histological sectioning for MRI-histology registration
Effects of Connectivity on Narrative Temporal Processing in Structured Reservoir Computing
Authors: Dominey Peter Ford , Ellmore Timothy M. , Ventre-Dominey Jocelyne
Published: August 2022

Computational models of language are having an increasing impact in understanding the neural bases of language processing in humans. A recent model of cortical dynamics based on reservoir computing was able to account for temporal aspects of human narrative processing as revealed by fMRI. In this context the current research introduces a form of structured reservoir computing, where network dynamics are further constrained by the connectivity architecture in order to begin to explain large scale hierarchical network properties of human cortical activity during narrative comprehension. Cortical processing takes place at different time scales depending on the position in a “hierarchy” from posterior sensory input areas to higher level associative frontal cortical areas. This phenomena is likely related to the cortical connectivity architecture. Recent studies have identified heterogeneity in this posterior-anterior hierarchy, with certain frontal associative areas displaying a faster narrative integration response than much more posterior areas. We hypothesize that these discontinuities can be due to white matter connectivity that would create shortcuts from fast sensory areas to distant frontal areas. To test this hypothesis, we analysed the white matter connectivity of these areas and discovered clear connectivity patterns in accord with our hypotheses. Based on these observations we performed simulations using reservoir networks with connectivity patterns structured with an exponential distance rule, yielding the sensory-associative hierarchy. We then introduce connectivity short-cuts corresponding to those observed in human anatomy, resulting in frontal areas with unusually fast narrative processing. Using structured reservoir computing we confirmed the hypothesis that topographic position in a cortical hierarchy can be dominated by long distance connections that can bring frontal areas closer to the sensory periphery.
Merging Bioactivity Predictions from Cell Morphology and Chemical Fingerprint Models Using Similarity to Training Data
Authors: Seal Srijit , Yang Hongbin , Trapotsi Maria-Anna , Singh Satvik , Carreras-Puigvert Jordi , Spjuth Ola , Bender Andreas
Published: August 2022

The applicability domain of machine learning models trained on structural fingerprints for the prediction of biological endpoints is often limited by the lack of diversity of chemical space of the training data. In this work, we developed similarity-based merger models which combined the outputs of individual models trained on cell morphology (based on Cell Painting) and chemical structure (based on chemical fingerprints) and the structural and morphological similarities of the compounds in the test dataset to compounds in the training dataset. We applied these similarity-based merger models using logistic regression models on the predictions and similarities as features and predicted assay hit calls of 177 assays from ChEMBL, PubChem and the Broad Institute (where the required Cell Painting annotations were available). We found that the similarity-based merger models outperformed other models with an additional 20% assays (79 out of 177 assays) with an AUC>0.70 compared with 65 out of 177 assays using structural models and 50 out of 177 assays using Cell Painting models. Our results demonstrated that similarity-based merger models combining structure and cell morphology models can more accurately predict a wide range of biological assay outcomes and further expanded the applicability domain by better extrapolating to new structural and morphology spaces.

Abstract Figure

Figure:

For TOC Only
Human Satellite 1 (HSAT1) analysis provides novel evidence of pericentromeric transcription
Authors: Lopes Mariana , Louzada Sandra , Ferreira Daniela , Veríssimo Gabriela , Eleutério Daniel , Gama-Carvalho Margarida , Chaves Raquel
Published: August 2022

Pericentromeric regions of human chromosomes are composed of tandem-repeated and highly organized sequences named satellite DNAs. Although being known for a long time as the most AT-rich fraction of the human genome, classical satellite HSAT1 has been disregarded in genomic and transcriptional studies, falling behind other human satellites in terms of knowledge. The path followed herein trails with HSAT1 isolation and cloning, followed byin silicoanalysis. Monomer copy number and expression data was obtained in a wide variety of human cell lines, with greatly varying profiles in tumoral/non-tumoral samples. HSAT1 was mapped in human chromosomes and applied inin situtranscriptional assays. Additionally, it was possible to observe the nuclear organization of HSAT1 transcripts and further characterize them by 3’ RACE-Seq. Size-varying polyadenylated HSAT1 transcripts were detected, which possibly accounts for the intricate regulation of alternative polyadenylation. As far as we know, this work pioneers HSAT1 transcription studies. With the emergence of new human genome assemblies, acrocentric pericentromeres are becoming relevant characters in disease and other biological contexts. HSAT1 sequences and associated noncoding RNAs will most certainly prove significant in the future of HSAT research.
Sex-specificity of the C. elegans metabolome
Authors: Burkhardt Russell N. , Artyukhin Alexander B. , Aprison Erin Z. , Curtis Brian J. , Fox Bennett W. , Ludewig Andreas H. , Chaturbedi Amaresh , Panda Oishika , Wrobel Chester J. J. , Lee Siu S. , Ruvinsky Ilya , Schroeder Frank C.
Published: August 2022

Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and a series of germline mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provides a blueprint for the discovery of sex-dependent metabolites in other animals.
Heat stress induces unreduced male gamete formation by targeting the meiotic cyclin TAM/CYCA1;2
Authors: Schindfessel Cédric , Jin Chunlian , Geelen Danny
Published: August 2022

Heat stress promotes the formation of unreduced (2n) male gametes, a driving force of evolutionary polyploidization in the plant kingdom. Here we report that the molecular mechanism underlying heat tolerance of the reproductive system in Arabidopsis thaliana relies on sustained synthesis of the cell cycle protein TAM/CYCA1;2. Under heat stress TAM protein accumulates in stress granules when expressed from a gene that is derived from a heat tolerant Arabidopsis accession such as Col-0. Heat sensitive TAM alleles do not support TAM protein synthesis at elevated temperatures resulting in over 80% of the pollen being diploid. However, sustained expression of TAM is not sufficient as heat stress also promotes formation of unreduced male gametes in Col-0 mutants of the meiosis exit regulators THREE DIVISION MUTANT1 (TDM1) and SUPPRESSOR WITH MORPHOGENETIC EFFECTS ON GENITALIA7 (SMG7). These findings reveal a TDM1 and SMG7 dependent licencing mechanism securing protein synthesis and male meiosis progression under heat stress conditions. Arabidopsis accessions that do not possess this heat tolerant translation mechanism are poised to produce high frequencies of unreduced male gametes and generate polyploid offspring at elevated temperature.
Antagonistic, synergistic, and social pleiotropy in microbial cheaters
Authors: Manhes Pauline , Schaal Kaitlin A. , Velicer Gregory J.
Published: August 2022

Cooperation is widespread among microbes. One mechanism proposed to constrain cheating is antagonistic pleiotropy, wherein mutations that cause defection from cooperation, while potentially under positive selection for this effect, reduce fitness at other traits. The bacterium Myxococcus xanthus engages in pleiotropically connected complex multicellular behaviors, including motility, predation, and starvation-induced fruiting-body development. Sporulation during development is susceptible to cheating. Here we investigate pleiotropic impacts on how cheater spores respond to stressful environmental changes after development, relative to cooperator spores. A cheater with a mutation in the developmental-signaling gene asgB shows antagonistic pleiotropy under both heat and basic-pH stress, while a cheater mutated at csgA shows synergistic pleiotropy under basic-pH stress. Further, in a social form of pleiotropy, cooperator spores formed in mixture with the asgB cheater are less resilient under basic pH than those from pure groups; interaction of cooperators with cheaters reduces the cooperators’ physical robustness. Our results indicate that, depending on the mutation, pleiotropy can promote as well as limit cheating alleles. They additionally demonstrate that alleles can pleiotropically alter traits in organisms not carrying those alleles. Synergistic and social pleiotropy may contribute to shaping the evolutionary dynamics of cooperation and cheating in many social systems.
Unraveling the Myotis Morass: Ultraconserved-Element Analysis Reveals Introgression, Cryptic Diversity, and Taxonomic Trouble in the Most Species-rich Bat Genus
Authors: Korstian Jennifer M. , Stevens Richard D. , Lee Thomas E. , Baker Robert J. , Ray David A.
Published: August 2022

Using sequences from 2615 UCE loci and multiple methodologies we inferred phylogenies for the largest genetic dataset of New World Myotis to date. The resulting phylogenetic trees were populated with short branch lengths and widespread conflict, hallmarks consistent with rapid adaptive radiations. The degree of conflict observed in Myotis has likely contributed to difficulties disentangling deeper evolutionary relationships. Unlike earlier phylogenies based on 1-2 gene sequences, this UCE dataset places M. brandtii outside the New World clades. Introgression testing of a small subset of our samples revealed evidence of historical but not contemporary gene flow, suggesting that hybridization occurs less frequently in the Neotropics than the Nearctic. We identified several instances of cryptic lineages within described species as well as several instances of potential taxonomic over-splitting. Evidence from Central and South American localities suggests that diversity in those regions is not fully characterized. In light of the accumulated evidence of the evolutionary complexity in Myotis and our survey of the taxonomic implications from our phylogenies it is apparent that the definition of species and regime of species delimitation need to be re-evaluated for Myotis. This will require substantial collaboration and sample sharing between geneticists and taxonomists to build a system that is both robust and applicable in a genus as diverse as Myotis.
Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme
Authors: Alber Andrea B. , Marquez Hector A. , Ma Liang , Kwong George , Thapa Bibek R. , Villacorta-Martin Carlos , Lindstrom-Vautrin Jonathan , Bawa Pushpinder , Luo Yongfeng , Ikonomou Laertis , Shi Wei , Kotton Darrell N.
Published: August 2022

The successful generation of endodermal, ectodermal, and most mesodermal lineages from pluripotent stem cells has resulted in basic discoveries and regenerative medicine clinical trials of cell-based therapies. In contrast, the derivation of tissue-specific mesenchyme via directed differentiation in vitro has markedly lagged, due in part to a limited understanding of the signaling pathways regulating in vivo mesenchymal development and a lack of specific markers or reporters able to purify such lineages. The derivation of lung-specific mesenchyme is a particularly important goal since this tissue plays important roles in lung development and respiratory disease pathogenesis. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer facilitating the tracking and purification of engineered lung-specific mesenchyme. We identify the key signaling pathways (RA and Shh) necessary to specify lung mesenchyme from lateral plate mesodermal precursors and find that mouse iPSC-derived lung mesenchyme (iLM) expresses the molecular and functional phenotypes of primary developing lung mesenchyme. Purified iLM can be recombined with separately engineered lung epithelial progenitors, self-organizing into 3-dimensional organoids featuring significantly augmented structural complexity and lineage purity, including interacting juxtaposed layers of epithelium and mesenchyme. Co-culture with iLM increases the yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional epithelial-mesenchymal crosstalk. Our iPSC-derived population thus expresses key features of developing lung mesenchyme, providing an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.
Time-of-day defines the efficacy of NAD+to treat diet-induced metabolic disease by adjusting oscillations of the hepatic circadian clock
Authors: Escalante-Covarrubias Q , Mendoza-Viveros L , González-Suárez M , Becerril-Pérez F , Pacheco-Bernal I , Carreño-Vázquez E , Mass-Sánchez P , Bustamante-Zepeda M , Orozco-Solís R , Aguilar-Arnal L
Published: August 2022

The circadian clock is a time-tracking endogenous system which anticipates and coordinates adaptation to daily environmental fluctuations. Circadian misalignment leads to obesity, which is accompanied by reduced levels of the clock-controlled metabolite NAD+. Concomitantly, increasing NAD+levels is emerging as a therapy for diet-induced obesity and type 2 diabetes; however, the impact of daily fluctuations of NAD+on these therapies remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+as a therapy for diet-induced metabolic disease in mice. Restoring regular NAD+oscillations at the onset of the active phase ameliorates metabolic markers of disease such as body weight and glucose and insulin tolerance, and restores hepatic gene expression related to inflammatory response and lipid metabolism. However, the same treatment designed to increase NAD+at the onset of the rest phase severely compromises these beneficial responses. Notably, hepatic nutrient-sensing mTOR, AMPK or AKT signaling, became rhythmic specifically in obese mice treated just before the active phase. Remarkably, NAD+at the onset of the rest phase was accompanied by uncoupled oscillations between the SCN and the hepatic clock, which were phase inverted in the liver, while keeping behavioral rhythms largely intact. These findings demonstrate that the time of day determines the beneficial effects of NAD+-based therapies and pave the way for the basic strategy of a chronobiology-based therapeutic approach.
The spatiotemporal neural dynamics of object recognition for natural images and line drawings
Authors: Singer Johannes J.D. , Cichy Radoslaw M. , Hebart Martin N.
Published: August 2022

1.

Drawings offer a simple and efficient way to communicate meaning. While line drawings capture only coarsely how objects look in reality, we still perceive them as resembling real-world objects. Previous work has shown that this perceived similarity is mirrored by shared neural representations for drawings and natural images, which suggests that similar mechanisms underlie the recognition of both. However, other work has proposed that representations of drawings and natural images become similar only after substantial processing has taken place, suggesting distinct mechanisms. To arbitrate between those alternatives, we measured brain responses resolved in space and time using fMRI and MEG, respectively, while human participants (female and male) viewed images of objects depicted as photographs, line drawings, or sketch-like drawings. Using multivariate decoding, we demonstrate that object category information emerged similarly fast and across overlapping regions in occipital, ventral-temporal and posterior parietal cortex for all types of depiction, yet with smaller effects at higher levels of visual abstraction. In addition, cross-decoding between depiction types revealed strong generalization of object category information from early processing stages on. Finally, by combining fMRI and MEG data using representational similarity analysis, we found that visual information traversed similar processing stages for all types of depiction, yet with an overall stronger representation for photographs. Together our results demonstrate broad commonalities in the neural dynamics of object recognition across types of depiction, thus providing clear evidence for shared neural mechanisms underlying recognition of natural object images and abstract drawings.

2.

Significance Statement

When we see a line drawing, we effortlessly recognize it as an object in the world despite its simple and abstract style. Here we asked to what extent this correspondence in perception is reflected in the brain. To answer this question, we measured how neural processing of objects depicted as photographs and line drawings with varying levels of detail (from natural images to abstract line drawings) evolves over space and time. We find broad commonalities in the spatiotemporal dynamics and the neural representations underlying the perception of photographs and even abstract drawings. These results indicate a shared basic mechanism supporting recognition of drawings and natural images.
SIC50: Determination of IC50 by an optimized Sobel operator and a vision transformer
Authors: Wang Yongheng , Zhang Weidi , Yip Hoyin , Qu Chuyuan , Hu Hongru , Chen Xiaotie , Lee Teresa , Yang Xi , Yang Bingjun , Kumar Priyadarsini , Lee Su Yeon , Casimiro Javier J. , Zhang Jiawei , Lam Kit S. , Wang Aijun
Published: August 2022

As a measure of cytotoxic potency, half-maximal inhibitory concentration (IC50) is the concentration at which a drug exerts half of its maximal inhibitory effect against target cells. It can be determined by various methods that require applying additional reagents or lysing the cells. Here, we describe a label-free Sobel-edge-based method, which we name SIC50, for the evaluation of IC50. SIC50 classifies pre-processed phase-contrast images with a state-of-art vision transformer and allows for the continuous assessment of IC50 in a faster and more cost-efficient manner. We have validated this method using four drugs and 1536-well plates, as well as built a first-of-its-kind web application. We anticipate this method will assist in the high-throughput screening of chemical libraries (e.g., small molecule drugs, siRNA, and microRNA and drug discovery.
Deep generative modeling of transcriptional dynamics for RNA velocity analysis in single cells
Authors: Gayoso Adam , Weiler Philipp , Lotfollahi Mohammad , Klein Dominik , Hong Justin , Streets Aaron , Theis Fabian J. , Yosef Nir
Published: August 2022

RNA velocity has been rapidly adopted to guide the interpretation of transcriptional dynamics in snapshot single-cell transcriptomics data. Current approaches for estimating and analyzing RNA velocity can empirically reveal complex dynamics but lack effective strategies for quantifying the uncertainty of the estimate and its overall applicability to the system of interest. Here, we present veloVI (velocity variational inference), a deep generative modeling framework for estimating RNA velocity. veloVI learns a gene-specific dynamical model of RNA metabolism and provides a transcriptome-wide quantification of velocity uncertainty. We show in a series of examples that veloVI compares favorably to previous approaches for inferring RNA velocity with improvements in fit to the data, consistency across transcriptionally similar cells, and stability across preprocessing pipelines for quantifying RNA abundance. Further, we demonstrate that properties unique to veloVI, such as posterior velocity uncertainty, can be used to assess the appropriateness of analysis with velocity to the data at hand. Finally, we highlight veloVI as a flexible framework for modeling transcriptional dynamics by adapting the underlying dynamical model to use time-dependent transcription rates.
Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia
Authors: Toyoda Kosuke , Yasunaga Jun-ichirou , Arima Yuichiro , Tsujita Kenichi , Tanaka Azusa , Hussein Osama , Sonoda Miyu , Watanabe Miho , Shichijo Takafumi , Kurita Daisuke , Nakashima Kazutaka , Yamada Kyohei , Miyoshi Hiroaki , Ohshima Koichi , Matsuoka Masao
Published: August 2022

Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is properly secreted from cancer cells, since its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminished development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreased the growth of ATL cells in vitro and in vivo. MCT1/4 expression was positively correlated with TAp73 in many cancers, and their upregulations were associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to oncogenesis.