bluuebunny/crossref_metadata_2025 huggingface dataset:
CTPC, a combined transcriptome dataset of prostate cancer cell lines
Authors: Cheng Siyuan , Yu Xiuping
Published: July 2022

Cell lines are the most used model system in cancer research. The transcriptomic data of established prostate cancer (PCa) cell lines help researchers to explore the differential gene expression across the different PCa cell lines and develop hypothesis. Through large scale datamining, we established a curated Combined Transcriptome dataset of PCa Cell lines (CTPC) which contains the transcriptomic data of 1840 samples of seven commonly used PCa cell lines including LNCaP, C4-2, VCaP, 22Rv1, PC3, DU145, and NCI-H660. The CTPC dataset provides an opportunity for researchers to not only compare gene expression across different PCa cell lines but also retrieve the experiment information and associate the differential gene expression with meta data such as gene manipulation and drug treatment information. Additionally, based on the CTPC dataset, we built a platform for users to visualize the data (https://pcatools.shinyapps.io/CTPC_V2/). It is our hope that the combined CTPC dataset and the user-friendly platform are of great service to the PCa research community.
Exploring Ophthalmology Content on TikTok
Authors: Huang Austin , Zhu Dagny
Published: July 2022

TikTok has recently emerged as a rapidly growing global phenomenon that is becoming popular among medical professionals and patients alike. The use of other social media platforms such as Instagram and Twitter by ophthalmologists is well-documented, but the prevalence of ophthalmologists on TikTok is not well understood. We sought to analyze the scope of popular ophthalmology content on TikTok.
Hammersmith Neonatal Neurological Examination of healthy term infants at ages 6 and 10 weeks in Tshwane District, South Africa
Authors: Nel Marna , Feucht Ute , Mulol Helen , Eksteen Carina
Published: July 2022

Background

The neurodevelopmental progress of infants below 3 months is globally not well described. A lack of published data on normative values of child development in this age group has been identified. In South Africa (SA), neurodevelopmental characteristics of infants at well-baby 6- and 10-week visits are omitted from the ‘Road to Health Booklet’, a nationally used patient-held clinical record. The neurodevelopmental status of infants in these age groups is not routinely monitored and data not documented. Important changes occur in the maturation of the central nervous system of infants at 6 weeks that mark this age as an important milestone for monitoring neurodevelopmental progress.

Methodology and findings

A prospective longitudinal study was performed on a sample of 35 healthy term-born, infants from low-risk pregnancies at 6- and 10-weeks postnatal age in the Tshwane District, SA. The status of infants’ posture, tone, reflexes, movements, orientation and behaviour were recorded on the Hammersmith Neonatal Neurological Examination (HNNE). Cut-off points on the 5th and 10th centiles, according to the HNNE ‘optimality scoring system’, were applied to the raw scores of the 34 items in the proforma evaluation form. This study quantitatively supports patterns of characteristic change occurring in muscle tone, posture, and visual behaviour of infants between 6 and 10 weeks.

Conclusion and significance

This study recorded data on the neurodevelopmental assessment of infants from low-risk pregnancies at 6- and 10 weeks post-term age in Tshwane District, SA. The optimality scores obtained in this initial study in a low-middle-income country can guide health professionals using this method of examination during early neurodevelopmental screening at well-baby clinics. Further research is necessary to develop a SA norm for identifying the motor and neuro-behavioural characteristics of 6- and 10-week-old infants.
A national audit of pancreatic enzyme prescribing in pancreatic cancer from 2015 to 2023 in England using OpenSAFELY-TPP
Authors: Lemanska Agnieszka , Andrews Colm , Fisher Louis , Butler-Cole Ben , Mehrkar Amir , Roberts Keith J , Goldacre Ben , Walker Alex J ,   The OpenSAFELY Collaborative, MacKenna Brian
Published: July 2022

Objectives

Cancer treatments were variably disrupted during the COVID-19 pandemic. UK guidelines recommend pancreatic enzyme replacement therapy (PERT) to all people with unresectable pancreatic cancer. The aim was to investigate the impact of COVID-19 on PERT prescribing to people with unresectable pancreatic cancer and to investigate the national and regional rates from January 2015 to January 2023.

Data sources

With the approval of NHS England, we conducted this study using 24 million electronic healthcare records of people within the OpenSAFELY-TPP research platform. There were 22,860 people diagnosed with pancreatic cancer in the study cohort. We visualised the trends over time and modelled the effect of COVID-19 with the interrupted time series analysis.

Conclusions

In contrast to many other treatments, prescribing of PERT was not affected during the pandemic. Overall, since 2015, the rates increased steadily over time by 1% every year. The national rates ranged from 41% in 2015 to 48% in early 2023. There was substantial regional variation with the highest rates of 50% to 60% in West Midlands.

Implications for Nursing Practice

In pancreatic cancer, if PERT is prescribed, it is usually initiated in hospitals by clinical nurse specialists and continued after discharge by primary care. At just under 50% in early 2023, the rates were still below the recommended 100% standard. More research is needed to understand barriers to prescribing of PERT and geographic variation to improve quality of care. Prior work relied on manual audits. With OpenSAFELY, we developed an automated audit allowing for regular updates.
Postoperative radiotherapy timing, molecular subgroups and treatment outcomes of Thai pediatric patients with medulloblastoma
Authors: Jaruthien Thitiporn , Nantavithya Chonnipa , Santisukwongchote Sakun , Shuangshoti Shanop , Techavichit Piti , Sosothikul Darintr , Amornfa Jiraporn , Shotelersuk Kanjana
Published: July 2022

Introduction

Medulloblastoma (MB) is the most common childhood malignant brain tumor worldwide. Recently, molecular classification was established and started to play a role in the management of MB; however, studies involving molecular defined MB in Southeast Asia have been limited. We aimed to describe, and correlate clinical characteristics and molecular subgroups with therapeutic outcomes of Thai pediatric patients with MB.

Materials and Methods

Pediatric MB patients treated at King Chulalongkorn Memorial Hospital in Thailand from 2008 to 2018 were recruited. Patients were classified by clinical characteristics into standard- and high-risk groups, which determined treatment regimen. Retrospectively, available tumor tissues were classified into 3 molecular subgroups using immunohistochemistry: 1) WNT, 2) SHH, and 3) non-WNT/non-SHH. The primary outcome was 5-year overall survival (OS). Risk factors associated with OS were analyzed using cox regression analysis.

Results

Fifty-three Thai pediatric patients with MB were enrolled. The median follow-up time was 60 months. The 5-year OS for all patients, and patients with standard-risk and high-risk were 74.2%, 76.3% and 71.4%, respectively. Tumor tissues of 24 patients were available, of which 23 could be molecularly classified. Two, one and 20 were in the WNT, SHH and non-WNT/non-SHH subtypes with 5-year OS of 100%, 100% and 78.9%, respectively. Using multivariate analysis, the interval of more than 8 weeks between surgery and radiotherapy was significantly correlated with a decrease in the 5-year OS.

Conclusion

Interval between surgery and radiotherapy within 8 weeks was associated with good therapeutic outcomes among Thai pediatric patients with MB. Simplified molecular subtyping combined with clinical characteristics is practical in risk classification of patients with MB in institutes with limited resources.
Possible association of nucleobindin-1 protein with depressive disorder in patients with HIV infection
Authors: Yang Yun , Zhang Qian , Yang Jing , Wang Yun , Zhuang Ke , Zhao Changcheng
Published: July 2022

Objective

To investigate the prevalence for depressive disorder among HIV-infected population and preliminarily explore the underlying mechanisms.

Methods

Individuals who were newly HIV diagnosed were assessed on the Hospital Anxiety and Depression scale (HAD-A and HAD-D). Then SHIV-infected rhesus monkey model was used to investigate the possible involvement of NUCB1 and CB1 protein in depression-like behavior.

Results

The prevalence rate of depression disorder among newly confirmed HIV cases was 27.33% (41/150). The mechanism research results showed elevated NUCB1 levels in cerebrospinal fluid (CSF) from HIV-infected patients suffering from depression were confirmed by western blotting compared to those of HIV-infected patients. Also, immunohistochemical analysis indicated expression of NUCB1 in the cerebral cortex neurons of SHIV-infected monkey was higher than that of healthy control. Conversely, CB1 expression were down-regulated at protein level.

Conclusions

Depression are common in HIV infection and associate with NUCB1 expression increase, and NUCB1 may be a potential target for depression among HIV-infected subjects.
The choline-binding proteins PspA, PspC and LytA of Streptococcus pneumoniae and their role on host cellular adhesion and damage
Authors: Vilhena Cláudia , Du Shanshan , Battista Miriana , Westermann Martin , Kohler Thomas , Hammerschmidt Sven , Zipfel Peter F.
Published: July 2022

Streptococcus pneumoniae is a Gram-positive opportunistic pathogen that can colonize the upper respiratory tract. It is a leading cause of a wide range of infectious diseases, including community-acquired pneumonia, meningitis, otitis media and bacteraemia. Pneumococcal infections cause 1–2 million deaths per year, most of which occur in developing countries, where this bacterial species is probably the most important pathogen during early infancy. Here, we focused on choline-binding proteins (CBPs), i.e., PspC, PspA and LytA, and their integration into and interaction with the cell wall of S. pneumoniae. The three pneumococcal proteins have different surface-exposed regions but share related choline-binding anchors. These surface-exposed pneumococcal proteins are in direct contact with host cells and have diverse functions. PspC and PspA bind several host plasma proteins, whereas LytA plays a role in cell division and the lytic phase. We explored the role of the three CBPs on adhesion and pathogenicity in a human host by performing relevant imaging and functional analyses, such as electron microscopy, confocal laser scanning microscopy and functional quantitative assays targeting biofilm formation and the haemolytic capacity of S. pneumoniae. In vitro biofilm formation assays and electron microscopy experiments were used to examine the ability of knockout mutant strains lacking the lytA, pspC or pspA genes to adhere to surfaces. The mutant strains were compared with the S. pneumoniae D39 reference strain. We found that LytA plays an important role in robust synthesis of the biofilm matrix. PspA and PspC appeared crucial for the haemolytic effects of S. pneumoniae on human red blood cells. Furthermore, all knockout mutants caused less damage to endothelial cells than wild-type bacteria, highlighting the significance of CPBs for the overall pathogenicity of S. pneumoniae. Hence, in addition to their structural function within the cell wall of S. pneumoniae, each of these three surface-exposed CBPs controls or mediates multiple steps during bacterial pathogenesis.
An efficient UV-C disinfection approach and biological assessment strategy for microphones
Authors: Vignali Valentina , Hoff Tobi , de Vries-Idema Jacqueline , Huckriede Anke , van Dijl Jan Maarten , van Rijn Patrick
Published: July 2022

Hygiene is a basic necessity to prevent infections and though it is regarded as vital in general, its importance has been stressed again during the pandemic. Microbes may spread through touch and aerosols and thereby find their way from host to host. Cleaning and disinfection of possibly contaminated surfaces prevents microbial spread thus reducing potential illnesses. One item that is used by several people in a way that promotes close contact by touch and aerosol formation is the microphone. A microphone is a complex piece of equipment with respect to shape and various materials used to fabricate it and, hence, its disinfection is challenging. A new device has been developed to efficiently sterilize microphones using UV-C and the biological assessment has been done to identify its efficacy and translatability. For this investigation, a contamination procedure was developed using M13 bacteriophage as a model to illustrate the effectiveness of the disinfection. The susceptibility to UV-C irradiation of M13 in solution was compared to that of PR8 H1N1 influenza virus, which has a similar UV-C susceptibility as SARS-CoV-2. It was found that 10 min of UV-C treatment reduced the percentage of infectious M13 by 99.3% based on whole microphone inoculation and disinfection. UV-C susceptibility of M13 and influenza in suspension were found to be very similar, indicating that the microphone sterilization method and device function are highly useful and broadly applicable.
Examining the Impact of Increasing Vaccine Coverage and Nonpharmaceutical Interventions against Coronavirus Disease 2019 In Ghana using Mathematical Modeling
Authors: Ofori Sylvia K. , Schwind Jessica S. , Sullivan Kelly L. , Chowell Gerardo , Cowling Benjamin J. , Fung Isaac Chun-Hai
Published: July 2022

Seroprevalence studies assessing community exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Ghana concluded that population-level immunity remained low as of February 2021. Thus, it is important to demonstrate how increasing vaccine coverage reduces the economic and public health impacts associated with transmission of the novel coronavirus. To that end, this study used a Susceptible-Exposed-Presymptomatic-Symptomatic-Asymptomatic-Recovered-Dead-Vaccinated compartmental model to simulate coronavirus disease 2019 (COVID-19) transmission and the role of public health interventions in Ghana. The impact of increasing vaccination rate and decline in transmission rates due to nonpharmaceutical interventions (NPIs) on cumulative infections and deaths averted was explored under different scenarios. Latin hypercube sampling-partial rank correlation coefficient (LHS-PRCC) was used to investigate uncertainty and sensitivity of the outcomes to the parameters. Simulation results suggest that increasing the vaccination rate to achieve 50% coverage was associated with almost 30,000 deaths and 25 million infections averted. In comparison, a 50% decrease in the transmission coefficient was associated with about 50 million infections and 120,000 deaths averted. The LHS-PRCC results also found that cumulative infections and deaths averted were most sensitive to three model parameters: Transmission rate, vaccination rate, and waning immunity rate from infection. There is a need to increase vaccination coverage by ensuring an increased supply. Adherence to NPIs and increased vaccine uptake would successfully mitigate the impact of COVID-19 in Ghana.
Clinical trials are moving to countries with fewer data protections
Authors: Yom-Tov Elad , Ofran Yishai
Published: July 2022

Background

The European Union implemented data privacy laws in mid-2018 and the state of California enacted a similar law several weeks later. These regulations affect medical data collection and analysis.

Methods

Here we investigate the effect of these laws on clinical trials through analysis of clinical trials recorded on ClinicalTrials.gov, the World Health Organization’s International Clinical Trials Registry Platform and scientific papers describing clinical trials.

Results

The number of phase 1 and 2 trials in countries not adhering to data privacy laws rose significantly after implementation of these laws. The largest rise occurred in countries which are less free, as indicated by the negative correlation (−0.48, p=0.008) between the civil liberties freedom score of countries and the increase in the number of trials. This trend was not observed in countries adhering to data privacy laws nor in the paper publication record.

Conclusions

The implementation of data privacy laws is associated with a move of clinical trials to countries where people have fewer protections for their data.
Examining population structure across multiple collections of Cannabis
Authors: Halpin-McCormick Anna , Heyduk Karolina , Kantar Michael B. , Batora Nicholas L. , Masalia Rishi R. , Law Kerin , Kuntz Eleanor J.
Published: July 2022

Population structure ofCannabis sativaL. was explored across nine independent collections that each contained a unique sampling of varieties. Hierarchical Clustering of Principal Components (HCPC) identified a range of three to seven genetic clusters across datasets with inconsistent structure based on use type indicating the importance of sampling particularly when there is limited passport data. There was broader genetic diversity in modern cultivars relative to landraces. Further, in a subset of geo-referenced landrace accessions, population structure was observed based on geography. The inconsistent structure across different collections shows the complexity withinCannabis, and the importance of understanding any particular collection which could then be leveraged in breeding programs for future crop improvement.
Small Molecule Antiviral Compound Collection (SMACC): a database to support the discovery of broad-spectrum antiviral drug molecules
Authors: Martin Holli-Joi , Melo-Filho Cleber C. , Korn Daniel , Eastman Richard T. , Rai Ganesha , Simeonov Anton , Zakharov Alexey V. , Muratov Eugene , Tropsha Alexander
Published: July 2022

Diseases caused by new viruses costs thousands if not millions of human lives and trillions of dollars in damage to the global economy. Despite the rapid development of vaccines for SARS-CoV-2, the lack of small molecule antiviral drugs that work against multiple viral families (broad-spectrum antivirals; BSAs) has left the entire world’s human population vulnerable to the infection between the beginning of the outbreak and the widespread availability of vaccines. Developing BSAs is an attractive, yet challenging, approach that could prevent the next, inevitable, viral outbreak from becoming a global catastrophe. To explore whether historical medicinal chemistry efforts suggest the possibility of discovering novel BSAs, we (i) identified, collected, curated, and integrated all chemical bioactivity data available in ChEMBL for molecules tested in respective assays for 13 emerging viruses that, based on published literature, hold the greatest potential threat to global human health; (ii) identified and solved the challenges related to data annotation accuracy including assay description ambiguity, missing cell or target information, and incorrect BioAssay Ontology (BAO) annotations; (iii) developed a highly curated and thoroughly annotated database of compounds tested in both phenotypic (21,392 entries) and target-based (11,123 entries) assays for these viruses; and (iv) identified a subset of compounds showing BSA activity. For the latter task, we eliminated inconclusive and annotated duplicative entries by checking the concordance between multiple assay results and identified eight compounds active against 3-4 viruses from the phenotypic data, 16 compounds active against two viruses from the target-based data, and 35 compounds active in at least one phenotypic and one target-based assay. The pilot version of our SMACC (Small Molecule Antiviral Compound Collection) database contains over 32,500 entries for 13 viruses. Our analysis indicates that previous research yielded very small number of BSA compounds. We posit that focused and coordinated efforts strategically targeting the discovery of such agents must be established and maintained going forward. The SMACC database publicly available at https://smacc.mml.unc.edu may serve as a reference for virologists and medicinal chemists working on the development of novel BSA agents in preparation for future viral outbreaks.
Inferring cellular and molecular processes in single-cell data with non-negative matrix factorization using Python, R, and GenePattern Notebook implementations of CoGAPS
Authors: Johnson Jeanette , Tsang Ashley , Mitchell Jacob T. , Davis-Marcisak Emily , Sherman Thomas , Liefeld Ted , Loth Melanie , Goff Loyal A , Zimmerman Jacquelyn , Kinny-Köster Ben , Jaffee Elizabeth , Tamayo Pablo , Mesirov Jill P. , Reich Michael , Fertig Elana J. , Stein-O’Brien Genevieve L.
Published: July 2022

Non-negative matrix factorization (NMF) is an unsupervised learning method well suited to high-throughput biology. Still, inferring biological processes requires additional post hoc statistics and annotation for interpretation of features learned from software packages developed for NMF implementation. Here, we aim to introduce a suite of computational tools that implement NMF and provide methods for accurate, clear biological interpretation and analysis. A generalized discussion of NMF covering its benefits, limitations, and open questions in the field is followed by three vignettes for the Bayesian NMF algorithm CoGAPS (Coordinated Gene Activity across Pattern Subsets). Each vignette will demonstrate NMF analysis to quantify cell state transitions in public domain single-cell RNA-sequencing (scRNA-seq) data of malignant epithelial cells in 25 pancreatic ductal adenocarcinoma (PDAC) tumors and 11 control samples. The first uses PyCoGAPS, our new Python interface for CoGAPS that we developed to enhance runtime of Bayesian NMF for large datasets. The second vignette steps through the same analysis using our R CoGAPS interface, and the third introduces two new cloud-based, plug-and-play options for running CoGAPS using GenePattern Notebook and Docker. By providing Python support, cloud-based computing options, and relevant example workflows, we facilitate user-friendly interpretation and implementation of NMF for single-cell analyses.
On Non-Kolmogorov turbulence in blood flow and its possible role in mechanobiological stimulation
Authors: Saqr Khalid M. , Zidane Iham F.
Published: July 2022

The study of turbulence in physiologic blood flow is important due to its strong relevance to endothelial mechanobiology and vascular disease. Recently, Saqr et al (Sci Rep 10, 15492, 2020) discovered non-Kolmogorov turbulence in physiologic blood flow in vivo, traced its origins to the Navier-Stokes equation and demonstrated some of its properties using chaos and hydrodynamic-stability theories. The present work extends these findings and investigates some inherent characteristics of non-Kolmogorov turbulence in monoharmonic and multiharmonic pulsatile flow under ideal physiologic conditions. The purpose of this work is to propose a conjecture for the origins for picoNewton forces that are known to regulate endothelial cells’ functions. The new conjecture relates these forces to physiologic momentum-viscous interactions in the near-wall region of the flow. Here, we used high-resolution large eddy simulation (HRLES) to study pulsatile incompressible flow in a straight pipe of L/D = 20. The simulations presented Newtonian and Carreau-Yasuda fluid flows, at Reynolds number of 256 and 228, respectively, each represented by one, two and three boundary harmonics. Comparison was established based on maintaining constant time-averaged mass flow rate in all simulations. First, we report the effect of primary harmonics on the global power budget using primitive variables in phase space. Second, we describe the non-Kolmogorov turbulence in frequency domain. Third, we investigate the near-wall coherent structures in time, space and frequency domains. Finally, we propose a new conjecture for the role of turbulence in endothelial cells’ mechanobiology. The proposed conjecture correlates near-wall turbulence to a force field of picoNewton scale, suggesting possible relevance to endothelial cells mechanobiology.
Identification and targeting of a unique NaV1.7 domain driving chronic pain
Authors: Gomez Kimberly , Stratton Harrison J. , Duran Paz , Loya Santiago , Tang Cheng , Calderon-Rivera Aida , François-Moutal Liberty , Khanna May , Madura Cynthia L. , Luo Shizhen , Ran Dongzhi , Boinon Lisa , Perez-Miller Samantha , Moutal Aubin , Khanna Rajesh
Published: July 2022

Despite identification of several small molecules directly targeting the voltage-gated sodium channel NaV1.7, none has been clinically successful. We reported that preventing addition of a small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and was antinociceptive in rodents. Here, we discovered a 15 amino acid CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight voltage-gated sodium channel isoforms decreased tetrodotoxin-sensitive NaV1.7 currents in rodent sensory neurons. A cell-penetrant version of NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 localization, reduced spinal neurotransmitter release, and reversed mechanical allodynia in a rat spared nerve injury model of neuropathic pain. Interfering with NaV1.7-CRMP2 coupling did not produce motor impairment and spared thermal, inflammatory, and post-surgical nociception. As proof-of-concept for NaV1.7-targeted gene therapy, we found that NaV1.7-CRS packaged into an adeno-associated virus recapitulated the effects on NaV1.7 function in both rodent and rhesus macaque sensory neurons and both reversed and prevented the development of mechanical allodynia in a neuropathic pain model in male and female rodents.

One Sentence Summary

A novel regulatory domain on the voltage gated sodium channel NaV1.7 that can be targeted to produce analgesia.
The crosstalk between microbial sensors ELMO1 and NOD2 shape intestinal immune responses
Authors: Sharma Aditi , Achi Sajan Chandrangadhan , Ibeawuchi Stella-Rita , Anandachar Mahitha Shree , Gementera Hobie , Chaudhury Uddeep , Usmani Fatima , Vega Kevin , Sayed Ibrahim M , Das Soumita
Published: July 2022

Microbial sensors play an essential role in maintaining cellular homeostasis. Our knowledge is limited on how microbial sensing helps in differential immune response and its link to inflammatory diseases. Recently, we have shown that cytosolic sensor ELMO1 (Engulfment and Cell Motility Protein-1) binds to effectors from pathogenic bacteria and controls intestinal inflammation. Here, we show that ELMO1 interacts with another sensor, NOD2 (Nucleotide-binding oligomerization domain-containing protein 2), that recognizes bacterial cell wall component muramyl dipeptide (MDP). The polymorphism of NOD2 is linked to Crohn’s disease (CD) pathogenesis. Interestingly, we found that overexpression of ELMO1 and mutant NOD2 (L1007fs) were not able to clear the CD-associated adherent invasive E. coli (AIEC-LF82). To understand the interplay of microbial sensing of ELMO1-NOD2 in epithelial cells and macrophages, we used enteroid-derived monolayers (EDMs) from ELMO1 and NOD2 KO mice and ELMO1 and NOD2-depleted murine macrophage cell lines. The infection of murine EDMs with AIEC-LF82 showed higher bacterial load in ELMO1-KO, NOD2 KO EDMs, and ELMO1 KO EDMs treated with NOD2 inhibitors. The murine macrophage cells showed that the downregulation of ELMO1 and NOD2 is associated with impaired bacterial clearance that is linked to reduced pro-inflammatory cytokines and reactive oxygen species. Our results indicated that the crosstalk between microbial sensors in enteric infection and inflammatory diseases impacts the fate of the bacterial load and disease pathogenesis.
Structure-Preserving Visualization for Single-cell RNA-Seq Profiles Using Deep Manifold Transformation with Batch-Correction
Authors: Xu Yongjie , Zang Zelin , Xia Jun , Tan Cheng , Geng Yulan , Li Stan Z.
Published: July 2022

Dimensionality reduction and visualization play an important role in biological data analysis, such as data interpretation of single-cell RNA sequence (scRNA-seq). It is desired to have a visualization method that can not only be applicable to various application scenarios, including cell clustering and trajectory inference, but also satisfy a variety of technical requirements, especially the ability to preserve inherent structure of data and handle with batch effects. However, no existing methods can accommodate these requirements in a unified framework. In this paper, we propose a general visualization method, deep visualization (DV), that possesses the ability to preserve inherent structure of data and handle batch effects and is applicable to a variety of datasets from different application domains and dataset scales. The method embeds a given dataset into a 2- or 3-dimensional visualization space, with either a Euclidean or hyperbolic metric depending on a specified task type with typestatic(at a time point) ordynamic(at a sequence of time points) scRNA-seq data, respectively. Specifically, DV learns a structure graph to describe the relationships between data samples, transforms the data into visualization space while preserving the geometric structure of the data and correcting batch effects in an end-to-end manner. The experimental results on nine datasets in complex tissue from human patients or animal development demonstrate the competitiveness of DV in discovering complex cellular relations, uncovering temporal trajectories, and addressing complex batch factors. We also provide a preliminary attempt to pre-train a DV model for visualization of new incoming data.
End-to-End deep structure generative model for protein design
Authors: Lai Boqiao , McPartlon Matt , Xu Jinbo
Published: July 2022

Abstract

Designing protein with desirable structure and functional properties is the pinnacle of computational protein design with unlimited potentials in the scientific community from therapeutic development to combating the global climate crisis. However, designing protein macromolecules at scale remains challenging due to hard-to-realize structures and low sequence design success rate. Recently, many generative models are proposed for protein design but they come with many limitations. Here, we present a VAE-based universal protein structure generative model that can model proteins in a large fold space and generate high-quality realistic 3-dimensional protein structures. We illustrate how our model can enable robust and efficient protein design pipelines with generated conformational decoys that bridge the gap in designing structure conforming sequences. Specifically, sequences generated from our design pipeline outperform native fixed backbone design in 856 out of the 1,016 tested targets(84.3%) through AF2 validation. We also demonstrate our model’s design capability and structural pre-training potential by structurally inpainting the complementarity-determining regions(CDRs) in a set of monoclonal antibodies and achieving superior performance compared to existing methods.
Parent co-Designed Drug Information for parents and Guardians Taking Neonates home (PADDINGToN) a mixed method approach to defining and evaluating information resources
Authors: Gill Andrea , Bracken Louise , Barker Catrin , Caldwell Neil , Cleary Brian , McCallion Naomi , Morris Stephen , Neary Elaine , Turner Mark , Peak Matthew , O’Brien Fiona
Published: July 2022

Background

A study of premature babies, less than 32 weeks gestation, found that the median number of medicines per patient at discharge was 2.5 (range 2 to 7), with 28% of babies discharged on more than 3 medicines (1). Medication administration to infants can cause anxiety and concern for parents/carers who worry about making mistakes. A systematic review of carers for all ages has estimated the administration error rate at home to be between 2 and 33% (2) while a rate of 66.3% was recorded in medication administered to premature infants where parents were responsible for administration (3). It has also been reported that up to 90% of carers will administer a medicine incorrectly at some point (2).

The aim of this study is to work with healthcare professionals (HCPs) and parents/carers to co-design resources aimed at improving medication safety and reducing parental anxiety for those giving medications to neonates at home.

Methods

Work Package 1: Project management and co-ordination phase: preparation of protocols and survey material and ethics approval applications.

Work Package 2: Stakeholder engagement phase, e-surveys and focus groups: An electronic-survey (e-survey) will be developed by a multi-disciplinary study management group (SMG).

This will be circulated to HCPs involved in the care of neonates and parents/carers whose babies had recently been discharged from hospital. A small number of parents/carers will be invited to take part in focus groups.

Work Package 3: Co-design of resources and quantitative evaluation: Parents/carers willing to co-design educational and information resources to support safe administration of medicines to neonates following discharge will be recruited. A quantitative evaluation of the effect of the resource will be conducted with a new group of caregivers to measure specific outcome(s).

Discussion

This study aims to co-develop, with healthcare professionals (HCPs) and parents/carers, resources aimed at improving medication safety and reducing parental anxiety for those giving medications to neonates at home. Co-development of resources with HCPs and parents, ensures that the project outcomes are relevant and useful, leading to a reduction in parental anxiety.

Trial registration

ISRCTN registry Ref 17332620
baseLess: lightweight detection of sequences in raw MinION data
Authors: Noordijk Ben , Nijland Reindert , Carrion Victor J. , Raaijmakers Jos M. , de Ridder Dick , de Lannoy Carlos
Published: July 2022

Abstract

With its candybar form factor and low initial investment cost, the MinION brought affordable portable nucleic acid analysis within reach. However, translating the electrical signal it outputs into a sequence of bases still requires high-end computer hardware, which remains a caveat when aiming for deployment of many devices at once or usage in remote areas. For applications focusing on detection of a target sequence, such as infectious disease or GMO monitoring, the computational cost of analysis may be reduced by directly detecting the target sequence in the electrical signal instead. Here we present baseLess, a computational tool that enables such target-detection-only analysis. BaseLess makes use of an array of small neural networks, each of which efficiently detects a fixed-size subsequence of the target sequence directly from the electrical signal. We show that baseLess can accurately determine the identity of reads between three closely related fish species and can classify sequences in mixtures of twenty bacterial species, on an inexpensive single-board computer.

Availability

baseLess and all code used in data preparation and validation is available on Github at https://github.com/cvdelannoy/baseLess, under an MIT license. Used validation data and scripts can be found at https://doi.org/10.4121/20261392, under an MIT license.
Mitochondrial Derived Vesicles retain membrane potential and contain a functional ATP synthase
Authors: Hazan (Ben-Menachem) Reut , Lintzer Dvora , Ziv Tamar , Das Koyeli , Rosenhek-Goldian Irit , Porat Ziv , Ben Ami Pilo Hila , Karniely Sharon , Saada Ann , Regev-Rudzki Neta , Pines Ophry
Published: July 2022

Vesicular transport is a means of communication. While cells can communicate between each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, in particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here we show that functional mitochondria, isolated fromSaccharomyces cerevisiaerelease vesicles, independent of the fission machinery. We were then able for the first time to isolate these Mitochondrial Derived Vesicles (MDVs) and found that they are relatively uniform in size, of about 100nm and carry selective protein cargo including enrichment of ATP synthase subunits. Remarkably, we further found that these MDVs harbor a functional ATP synthase complex. Moreover, we demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP producing vesicles, which can potentially regenerate ATP deficient mitochondria and may participate in organelle to organelle communication.
Condensate functionalization with motors directs their nucleation in space and allows manipulating RNA localization
Authors: Cochard Audrey , Safieddine Adham , Combe Pauline , Benassy Marie-Noëlle , Weil Dominique , Gueroui Zoher
Published: July 2022

The localization of RNAs in cells is critical for many cellular processes. Whereas motor-driven transport of RNP condensates plays a prominent role in RNA localization in cells, their studies remain limited by the scarcity of available tools allowing to manipulate condensates in a spatial manner. To fill this gap, we reconstitute in cellula a minimal RNP transport system based on bioengineered condensates which were functionalized with kinesins and dynein-like motors, allowing for their positioning at either the cell periphery or centrosomes. This targeting mostly occurs through the active transport of the condensate scaffolds, which leads to localized nucleation of phase-separated condensates. Then, programming the condensates to recruit specific mRNAs is able to shift the localization of these mRNAs towards the cell periphery or the centrosomes. Our method opens novel perspectives to examine the role of RNA localization as a driver of cellular functions.
Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats
Authors: Herbst Allen , Choi Solbie , Hoang Austin N. , Kim Chiye , Moreno Diana Martinez , McKenzie Debbie , Aiken Judd M. , Wanagat Jonathan
Published: July 2022

Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir’s effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. For the 33-month-old control rats, the average mtDNA copy number per nucleus was 2567, 1100, and 1869 for heart, kidney, and quadriceps, respectively. MtDNA deletion mutation frequency was 2.6×10−4, 1.6×10−4 and 4.7×10−3for heart, kidney, and quadriceps, respectively. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.
Breast Cancer Reaction-Diffusion from Spectral-Spatial Analysis in Immunohistochemistry
Authors: Pasetto Stefano , Zahid Mohammad U. , Diaz Roberto , Montejo Michael , Rosa Marilin , Gatenby Robert , Enderling Heiko
Published: July 2022

Cancer is a prevalent disease, and while many significant advances have been made, the ability to accurately predict how an individual tumor will grow – and ultimately respond to therapy – remains limited. We use spatial-spectral analysis of 20 patients accrued to a phase II study of preoperative SABR with 9.5 x 3 Gy for early-stage breast cancer whose tissues were stained with multiplex immunofluorescence. We employ the reaction-diffusion framework to compare the data-deduced two-point correlation function and the corresponding spatial power spectral distribution with the theoretically predicted ones. A single histopathological slice suffices to characterize the reaction-diffusion equation dynamics through its power spectral density giving us an interpretative key in terms of infiltration and diffusion of cancer on a per-patient basis. This novel approach tackles model-parameter-inference problems for tumor infiltration and can immediately inform clinical treatments.
Carriage of three plasmids in a single human clinical isolate of Clostridioides difficile
Authors: Roseboom Anna M. , Ducarmon Quinten R. , Hornung B.V.H. , Harmanus C. , Crobach M.J.T. , Kuijper Ed J. , Vossen Rolf H.A.M. , Kloet Susan L. , Smits Wiep Klaas
Published: July 2022

A subset of clinical isolates of Clostridioides difficile contains one or more plasmids and these plasmids can harbor virulence and antimicrobial resistance determinants. Despite their potential importance, C. difficile plasmids remain poorly characterized. Here, we describe a human clinical isolate that carries three plasmids from three different plasmid families that are therefore compatible. For two of these, we identify a region capable of sustaining plasmid replication in C. difficile. Together, our data advance our understanding of C. difficile plasmid biology.

Highlights

The complete circular genome sequence is provided for a C. difficile isolate harboring three plasmids

These three plasmids (pJMR5-1, pJMR5-4 and pJRM5-W) are therefore compatible in a single strain

Sequence analysis suggest a modular nature of plasmid families to which the pJMR-plasmids belong

A functional replicon was cloned from pJMR5-1 (pCD-ECE1 family) and pJMR5-W (pCD-WTSI1 family) and plasmids carrying this replicon are compatible with plasmid pCD630
Highly accurate long reads are crucial for realizing the potential of biodiversity genomics
Authors: Hotaling Scott , Wilcox Edward R. , Heckenhauer Jacqueline , Stewart Russell J. , Frandsen Paul B.
Published: July 2022

Background

Generating the most contiguous, accurate genome assemblies given available sequencing technologies is a long-standing challenge in genome science. With the rise of long-read sequencing, assembly challenges have shifted from merely increasing contiguity to correctly assembling complex, repetitive regions of interest, ideally in a phased manner. At present, researchers largely choose between two types of long read data: longer, but less accurate sequences, or highly accurate, but shorter reads (i.e., >Q20 or 99% accurate). To better understand how these types of long-read data as well as scale of data (i.e., mean length and sequencing depth) influence genome assembly outcomes, we compared genome assemblies for a caddisfly,Hesperophylax magnus, generated with longer, but less accurate, Oxford Nanopore (ONT) R9.4.1 and highly accurate PacBio HiFi (HiFi) data. Next, we expanded this comparison to consider the influence of highly accurate long-read sequence data on genome assemblies across 6,750 plant and animal genomes. For this broader comparison, we used HiFi data as a surrogate for highly accurate long-reads broadly as we could identify when they were used from GenBank metadata.

Results

HiFi reads outperformed ONT reads in all assembly metrics tested for the caddisfly data set and allowed for accurate assembly of the repetitive ∼20 KbH-fibroingene. Across plants and animals, genome assemblies that incorporated HiFi reads were also more contiguous. For plants, the average HiFi assembly was 501% more contiguous (mean contig N50 = 20.5 Mb) than those generated with any other long-read data (mean contig N50 = 4.1 Mb). For animals, HiFi assemblies were 226% more contiguous (mean contig N50 = 20.9 Mb) versus other long-read assemblies (mean contig N50 = 9.3 Mb). In plants, we also found limited evidence that HiFi may offer a unique solution for overcoming genomic complexity that scales with assembly size.

Conclusions

Highly accurate long-reads generated with HiFi or analogous technologies represent a key tool for maximizing genome assembly quality for a wide swath of plants and animals. This finding is particularly important when resources only allow for one type of sequencing data to be generated. Ultimately, to realize the promise of biodiversity genomics, we call for greater uptake of highly accurate long-reads in future studies.
The selective autophagy receptor p62 and the heat shock protein HSP27 facilitate lysophagy via the formation of phase-separated condensates
Authors: Gallagher Elizabeth R. , Holzbaur Erika L.F.
Published: July 2022

Lysosomes are membrane-bound organelles that regulate cellular proteostasis. Loss of lysosomal integrity initiates cell death pathways. Thus, cells must rely on quality control mechanisms for protection, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy receptor SQSTM1/p62 is an essential lysophagy receptor recruited to damaged lysosomes in both HeLa cells and neurons. p62 oligomers form liquid-like condensates that are critical in lysophagy. These condensates are regulated by the small heat shock protein HSP27, which binds p62 to prevent p62 aggregation and facilitate autophagosome formation. Mutations in p62 are implicated in Amyotrophic Lateral Sclerosis (ALS), and expression of ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to the cellular pathogenesis of ALS. Thus, p62 oligomers cooperate with HSP27 to promote lysophagy by forming a platform for autophagosome biogenesis at damaged lysosomes.
Temporal single cell atlas of non-neuronal retinal cells reveals dynamic, coordinated multicellular responses to central nervous system injury
Authors: Benhar Inbal , Ding Jiarui , Yan Wenjun , Whitney Irene E. , Jacobi Anne , Sud Malika , Burgin Grace , Shekhar Karthik , Tran Nicholas M. , Wang Chen , He Zhigang , Sanes Joshua R. , Regev Aviv
Published: July 2022

Non-neuronal cells play key roles in the complex cellular interplay that follows central nervous system (CNS) insult. To understand this interplay at a tissue level, we generated a single-cell atlas of immune, glial and retinal pigment epithelial cells from adult mouse retina before and at multiple time points after axonal transection (optic nerve crush; ONC), identifying rare and undescribed subsets, and delineating changes in cell composition, expression programs, and interactions. Computational analysis charted an inflammatory cascade after injury with three phases. The early phase consisted of reactivation of retinal macroglia and microglia, providing chemotactic signals for immune infiltration, concurrent with infiltration of CCR2+monocytes from the circulation. In the second phase, these differentiated to macrophage subsets resembling resident border-associated macrophages. In parallel, a multicellular interferon program, likely driven by microglia-derived type-I interferon, was synchronously activated across resident glia, expanding beyond rare interferon-responding subsets of glia unexpectedly present in the naïve retina. Our findings provide insights regarding post-injury CNS tissue dynamics and a framework to decipher cellular circuitry, spatial relationships and molecular interactions following tissue injury.