bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of fluorescence lifetime of organic fluorophores for molecular imaging in the SWIR window
Authors: Chavez Luis , Gao Shan , Intes Xavier
Published: December 2022

Significance

Fluorescence lifetime imaging in the short-wave infrared (SWIR) is expected to enable high resolution multiplexed molecular imaging in highly scattering tissue.

Aim

To characterize the brightness and fluorescence lifetime of commercially available organic SWIR fluorophores and benchmark them against the tail emission of conventional NIR-excited probes.

Approach

Characterization was performed through our established Time-domain Mesoscopic Fluorescence Molecular Tomography (TD-MFMT) system integrated around a TCSPC-SPAD array. Brightness and fluorescence lifetime was measured for NIR and SWIR probes above 1000 nm. Simultaneous probe imaging was then performed to assess their potential for multiplexed studies.

Results

NIR probes outperformed SWIR probes in brightness while the mean fluorescence lifetimes of the SWIR probes were extremely short. The phantom study demonstrated the feasibility of lifetime multiplexing in the SWIR window with both NIR and SWIR probes.

Conclusions

Long tail emission of NIR probes outperformed the SWIR probes in brightness beyond 1000 nm. Fluorescence lifetime was readily detectable in the SWIR window, where the SWIR probes showed shorter lifetimes compared to the NIR probes. We demonstrate the feasibility of lifetime multiplexing in the SWIR window, which paves the way for in vivo multiplexed studies of intact tissues at improved resolution.
Age but not menopausal status is linked to lower resting energy expenditure
Authors: Karppinen Jari E. , Wiklund Petri , Ihalainen Johanna K. , Juppi Hanna-Kaarina , Isola Ville , Hyvärinen Matti , Ahokas Essi K. , Kujala Urho M. , Laukkanen Jari , Hulmi Juha J. , Ahtiainen Juha P. , Cheng Sulin , Laakkonen Eija K.
Published: December 2022

Context

It remains uncertain whether aging before late adulthood and menopause are associated with fat-free mass and fat mass–adjusted resting energy expenditure (REEadj).

Objectives

We investigated whether REEadjdiffers between middle-aged and younger women and between middle-aged women with different menopausal statuses. We repeated the age group comparison between middle-aged mothers and their daughters to partially control for genotype. We also explored whether serum estradiol and follicle-stimulating hormone concentrations explain REEadjin midlife.

Methods

We divided 120 women, including 16 mother–daughter pairs, into age groups; group I (n= 26) consisted of participants aged 17–21, group II (n= 35) of those aged 22–38 and group III (n= 59) of those aged 41–58 years. The women in group III were further categorized as pre- or perimenopausal (n= 19), postmenopausal (n= 30) or postmenopausal hormone therapy users (n= 10). REE was assessed using indirect calorimetry, body composition using dual-energy X-ray absorptiometry and hormones using immunoassays.

Results

The REEadjof group I was 126 kcal/d (95% CI: 93–160) higher than that of group III, and the REEadjof group II was 88 kcal/d (95% CI: 49–127) higher. Furthermore, daughters had a 100 kcal/d (95% CI: 63–138 kcal/d) higher REEadjthan their middle-aged mothers (allP< 0.001). In group III, REEadjwas not lower in postmenopausal women and did not vary by sex hormone concentrations.

Conclusions

We demonstrated that REEadjdeclines with age in women before late adulthood, also when controlling partially for genetic background, and that menopause may not contribute to this decline.
Consistent typing of plasmids with the mge-cluster pipeline
Authors: Arredondo-Alonso Sergio , Gladstone Rebecca A. , Pöntinen Anna K. , Gama João A. , Schürch Anita C. , Lanza Val F. , Johnsen Pål Jarle , Samuelsen Ørjan , Tonkin-Hill Gerry , Corander Jukka
Published: December 2022

Extrachromosomal elements of bacterial cells such as plasmids are notorious for their importance in evolution and adaptation to changing ecology. However, high-resolution population-wide analysis of plasmids has only become accessible recently with the advent of scalable long-read sequencing technology. Current typing methods for the classification of plasmids remain limited in their scope which motivated us to develop a computationally efficient approach to simultaneously recognize novel types and classify plasmids into previously identified groups. Our method can easily handle thousands of input sequences which are compressed using a unitig representation in a de Bruijn graph. We provide an intuitive visualization, classification and clustering scheme that users can explore interactively. This provides a framework that can be easily distributed and replicated, enabling a consistent labelling of plasmids across past, present, and future sequence collections. We illustrate the attractive features of our approach by the analysis of population-wide plasmid data from the opportunistic pathogenEscherichia coliand the distribution of the colistin resistance genemcr-1.1in the plasmid population.
MultiGML: Multimodal Graph Machine Learning for Prediction of Adverse Drug Events
Authors: Krix Sophia , DeLong Lauren Nicole , Madan Sumit , Domingo-Fernández Daniel , Ahmad Ashar , Gul Sheraz , Zaliani Andrea , Fröhlich Holger
Published: December 2022

Adverse drug events constitute a major challenge for the success of clinical trials. Several computational strategies have been suggested to estimate the risk of adverse drug events in preclinical drug development. While these approaches have demonstrated high utility in practice, they are at the same time limited to specific information sources and thus neglect a wealth of information that is uncovered by fusion of different data sources, including biological protein function, gene expression, chemical compound structure, cell-based imaging, etc. In this work we propose an integrative and explainable Graph Machine Learning approach (MultiGML), which fuses knowledge graphs with multiple further data modalities to predict drug related adverse events. MultiGML demonstrates excellent prediction performance compared to alternative algorithms, including various knowledge graph embedding techniques. MultiGML distinguishes itself from alternative techniques by providing in-depth explanations of model predictions, which point towards biological mechanisms associated with predictions of an adverse drug event.

Motivation

Adverse drug events are a major risk for failure of late-stage clinical trials. Attempts to prevent adverse drug events in preclinical drug development include experimental procedures for measuring liver-toxicity, cardio-toxicity, etc. Yet these procedures are costly and cannot fully guarantee success in later clinical studies, specifically in situations without a reliable animal model. Computational approaches developed for adverse event prediction have shown to be valuable, but are mostly limited to single data sources. Our approach successfully integrates various data sources on protein functions, gene expression, chemical compound structures and more, into the prediction of adverse events. A main distinguishing characteristic is the explainability of our model predictions which allow further insight into biological mechanisms.
Decoupled neoantigen cross-presentation in tumors with high intratumor heterogeneity reduces dendritic cell activation to limit anti-tumor immunity
Authors: Nguyen Kim B. , Copeland Christopher J. , Backlund Coralie M. , Klop-Packel Nory G. , Remba Tanaka , Kim Byungji , Singh Nishant K. , Birnbaum Michael E. , Irvine Darrell J. , Spranger Stefani
Published: December 2022

Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable responses. However, the majority of patients currently do not respond to CBT and the molecular determinants of resistance have not been fully elucidated. Mounting clinical evidence suggests that the clonal status of neoantigens (NeoAg) impacts the anti-tumor T cell response. High intratumor heterogeneity (ITH), where the majority of NeoAgs are expressed subclonally, is correlated with poor clinical response to CBT and poor infiltration with tumor-reactive T cells. However, the mechanism by which ITH blunts tumor-reactive T cells is unclear. We developed a transplantable murine lung cancer model to characterize the immune response against a defined set of NeoAgs expressed either clonally or subclonally to model low or high ITH, respectively. Here we show that clonal expression of a weakly immunogenic NeoAg with a relatively strong NeoAg increased the immunogenicity of tumors with low but not high ITH. Mechanistically we determined that clonal NeoAg expression allowed cross-presenting dendritic cells to acquire and present both NeoAgs. Dual NeoAg presentation by dendritic cells was associated with a more mature DC phenotype and a higher stimulatory capacity. These data suggest that clonal NeoAg expression can induce more potent anti-tumor responses due to more stimulatory dendritic cell: T cell interactions. Therapeutic vaccination targeting subclonally expressed NeoAgs could be used to boost anti-tumor T cell responses.
Unraveling MLL1-fusion Leukemia: Epigenetic Revelations from an iPS Cell Point Mutation
Authors: Kobrossy Laila , Xu Weiyi , Zhang Chunling , Feng Wenyi , Turner Christopher E. , Cosgrove Michael S.
Published: December 2022

Our understanding of acute leukemia pathology is heavily dependent on 11q23 chromosomal translocations involving the mixed lineage leukemia-1 (MLL1) gene, a key player in histone H3 lysine 4 (H3K4) methylation. These translocations result in distinct MLL1-fusion (MLL1F) proteins that are thought to drive leukemogenesis. However, the mechanism behind increased H3K4 trimethylation in MLL1F-leukemic stem cells (MLL1F-LSCs), following loss of catalytic SET domain of MLL1 (known for H3K4 mono- and dimethylation), remains unclear. In our investigation, we introduced a homozygous loss-of-function point mutation in MLL1 within human induced pluripotent stem cells. Remarkably, this mutation mimics the histone methylation, gene expression, and EMT phenotypes of MLL1F-LSCs- without the need for a translocation or functional wild-type MLL1. This observation underscores the essential role of MLL1’s enzymatic activity in restraining the cascade of epigenetic changes associated with the gene activating H3K4 trimethylation mark, which we show is catalyzed by mislocalized SETd1a H3K4 trimethyltransferase in the absence of MLL1’s enzymatic activity. Challenging existing models, our findings imply that MLL1F-induced leukemias arise from a dominant-negative impact on MLL1’s histone methyltransferase activity. We advocate for a therapeutic paradigm shift, targeting SETd1a for precision medicine. This work opens new avenues for addressing the complexities of MLL1-associated leukemias and improving targeted therapies.

Epigenomic and gene expression changes in iPS cells with a mutated MLL1 histone methyltransferase suggest an oncogenic mechanism for MLL1-fusion leukemias.
Comprehensive profiling of wastewater viromes by genomic sequencing
Authors: Wyler Emanuel , Lauber Chris , Manukyan Artür , Deter Aylina , Quedenau Claudia , Teixeira Alves Luiz Gustavo , Seitz Stefan , Altmüller Janine , Landthaler Markus
Published: December 2022

Genomic material in wastewater provides a rich source of data for detection and surveillance of microbes. Used for decades to monitor poliovirus and other pathogens, the SARS-CoV-2 pandemic and the falling costs of high-throughput sequencing have substantially boosted the interest in and the usage of wastewater monitoring. We have longitudinally collected over 100 samples from a wastewater treatment plant in Berlin/Germany, from March 2021 to July 2022, in order to investigate three aspects. First, we conducted a full metagenomic analysis and exemplified the depth of the data by temporal tracking strains and to a certain extent also variants of human astroviruses and enteroviruses. Second, targeting respiratory pathogens, a broad enrichment panel enabled us to detect waves of RSV, influenza, or common cold coronaviruses in high agreement with clinical data. Third, by applying a profile Hidden Markov Model-based search for novel viruses, we identified more than 100 thousand novel transcript assemblies likely not belonging to known virus species, thus substantially expanding our knowledge of virus diversity. Taken together, we present a longitudinal and deep investigation of the viral genomic information in wastewater that underlines the value of sewage surveillance for both public health purposes and planetary virome research.
Mediator subunit MDT-15 promotes expression of propionic acid breakdown genes to prevent embryonic lethality inCaenorhabditis elegans
Authors: Goh Grace Ying Shyen , Beigi Arshia , Yan Junran , Doering Kelsie R. S. , Taubert Stefan
Published: December 2022

The micronutrient vitamin B12 is an essential cofactor for two enzymes: methionine synthase, which plays a key role in the one-carbon cycle; and methylmalonyl-CoA mutase, an enzyme in a pathway that breaks down branched-chain amino acids and odd-chain fatty acids. A second, vitamin B12-independent pathway that degrades methylmalonyl-CoA and its upstream metabolite propionic acid was recently described inCaenorhabditis elegans, the propionate shunt pathway. Activation of five shunt pathway genes in response to low vitamin B12 availability or high propionic acid levels is accomplished by a transcriptional regulatory mechanism involving two nuclear hormone receptors, NHR-10 and NHR-68. Here, we report that theC. elegansMediator subunitmdt-15is also essential for the activation of the propionate shunt pathway genes, likely by acting as a transcriptional coregulator for NHR-10.C. elegans mdt-15mutants fed a low vitamin B12 diet have transcriptomes resembling those of wild-type worms fed a high vitamin B12 diet, with low expression of the shunt genes. Phenotypically, the embryonic lethality ofmdt-15mutants is specifically rescued by diets high in vitamin B12, but not by dietary polyunsaturated fatty acids, which rescue many other phenotypes of themdt-15mutants. Finally, NHR-10 binds to MDT-15 in yeast-two-hybrid assays, and the transcriptomes ofnhr-10mutants resemble those ofmdt-15mutants. Our data show that MDT-15 is a key coregulator for an NHR regulating propionic acid detoxification, adding to roles played by NHR:MDT-15 partnerships in metabolic regulation and pinpointing vitamin B12 availability as a requirement formdt-15dependent embryonic development.
Reproducible And Clinically Translatable Deep Neural Networks For Cervical Screening
Authors: Ahmed Syed Rakin , Befano Brian , Lemay Andreanne , Egemen Didem , Rodriguez Ana Cecilia , Angara Sandeep , Desai Kanan , Jeronimo Jose , Antani Sameer , Campos Nicole , Inturrisi Federica , Perkins Rebecca , Kreimer Aimee , Wentzensen Nicolas , Herrero Rolando , Pino Marta del , Quint Wim , de Sanjose Silvia , Schiffman Mark , Kalpathy-Cramer Jayashree
Published: December 2022

Cervical cancer is a leading cause of cancer mortality, with approximately 90% of the 250,000 deaths per year occurring in low- and middle-income countries (LMIC). Secondary prevention with cervical screening involves detecting and treating precursor lesions; however, scaling screening efforts in LMIC has been hampered by infrastructure and cost constraints. Recent work has supported the development of an artificial intelligence (AI) pipeline on digital images of the cervix to achieve an accurate and reliable diagnosis of treatable precancerous lesions. In particular, WHO guidelines emphasize visual triage of women testing positive for human papillomavirus (HPV) as the primary screen, and AI could assist in this triage task. Published AI reports have exhibited overfitting, lack of portability, and unrealistic, near-perfect performance estimates. To surmount recognized issues, we implemented a comprehensive deep-learning model selection and optimization study on a large, collated, multi-institutional dataset of 9,462 women (17,013 images). We evaluated relative portability, repeatability, and classification performance. The top performing model, when combined with HPV type, achieved an area under the Receiver Operating Characteristics (ROC) curve (AUC) of 0.89 within our study population of interest, and a limited total extreme misclassification rate of 3.4%, on held-aside test sets. Our work is among the first efforts at designing a robust, repeatable, accurate and clinically translatable deep-learning model for cervical screening.
De novo protein backbone generation based on diffusion with structured priors and adversarial training
Authors: Liu Yufeng , Chen Linghui , Liu Haiyan
Published: December 2022

In de novo deisgn of protein backbones with deep generative methods, the designability or physical plausibility of the generated backbones needs to be emphasized. Here we report SCUBA-D, a method using denoising diffusion with priors of non-zero means to transform a low quality initial backbone into a high quality backbone. SCUBA-D has been developed by gradually adding new components to a basic denoising diffusion module to improve the physical plausibility of the denoised backbone. It comprises a module that uese one-step denoising to generate prior backbones, followed by a high resolution denoising diffusion module, in which structure diffusion is assisted by the simultaneous diffusion of a language model representation of the amino acid sequence. To ensure high physical plausibility of the denoised output backbone, multiple generative adversarial network (GAN)-style discriminators are used to provide additional losses in training. We have computationally evaluated SCUBA-D by applying structure prediction to amino acid sequences designed on the denoised backbones. The results suggest that SCUBA-D can generate high quality backbones from initial backbones that contain noises of various types or magnitudes, such as initial backbones coarsely sketched to follow certain overall shapes, or initial backbones comprising well-defined functional sites connected by unknown scaffolding regions.
A-ring-fused pyrazoles of dihydrotestosterone targeting prostate cancer cells via the downregulation of the androgen receptor
Authors: Peřina Miroslav , Kiss Márton A. , Mótyán Gergő , Szczyrbová Eva , Eliáš Martin , Študent Vladimír , Kurfurstová Daniela , Kovalová Markéta , Mada Lukáš , Bouchal Jan , Frank Éva , Jorda Radek
Published: December 2022

High expression of the androgen receptor (AR) and the disruption of its regulation are strongly responsible for the development of prostate cancer (PCa). Therapeutically relevant non-steroidal or steroidal antiandrogens are able to block the AR effect by eliminating AR-mediated signalling. Herein we report the synthesis of novel steroidal pyrazoles derived from the natural sex hormone 5α-dihydrotestosterone (DHT). 2-Ethylidene or 2-(hetero)arylidene derivatives of DHT obtained by regioselective Claisen-Schmidt condensation with acetaldehyde or (hetero)aromatic aldehydes in alkaline ethanol were reacted with monosubstituted hydrazines to give A-ring-fused 1,5-disubstituted pyrazoles as main or exclusive products, depending on the reaction conditions applied. Spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the primarily formed pyrazolines resulted in the desired products in moderate to good yields, while 17-oxidation also occurred by using the Jones reagent as a strong oxidant. Transcriptional activity of the AR in a reporter cell line was examined for all novel compounds, and several previously synthesized similar DHT-based pyrazoles with differently substituted heteroring were also included to obtain information about the structure-activity relationship. Two specific regioisomeric groups of derivatives significantly diminished the transcriptional activity of AR in reporter cell line in 10 μM concentration, and displayed reasonable antiproliferative activity in AR-positive PCa cell lines. Lead compound (3d) was found to be a potent AR antagonist (IC50= 1.18 μM), generally suppressed AR signalling in time and dose dependent manner, moreover, it also led to a sharp decrease in wt-AR protein level probably caused by proteasomal degradation. We confirmed the antiproliferative activity selective for AR-positive PCa cell lines (with GI50in low micromolar ranges), cellular, biochemical and in silico binding of3din AR ligand-binding domain. Moreover, compound3dwas shown to be potent evenex vivoin patient-derived tissues, which highlights the therapeutic potential of A-ring-fused pyrazoles.

Table of content graphic

Highlights

A-ring-fused pyrazoles of 5α-dihydrotestosterone were introduced as AR modulators

SAR study of 55 differently substituted derivatives was discussed

Compound3dsuppressed the expression of AR targets in prostate cell lines

Compound3dcaused AR degradation in time-dependent manner

Ex vivo activity of3dwas demonstrated in patient-derived explants
Single-Cell Analysis of 5-ALA Intraoperative Labeling Specificity for Glioblastoma
Authors: Liu Zhouzerui , Mela Angeliki , Furnari Julia , Argenziano Michael G. , Kotidis Corina , Sperring Colin P. , Humala Nelson , Bruce Jeffrey N. , Canoll Peter , Sims Peter A.
Published: December 2022

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor, and surgical resection is a key part of the standard-of-care. In fluorescence-guided surgery (FGS), fluorophores are used to differentiate tumor tissue from surrounding normal brain. The heme synthesis pathway converts 5-aminolevulinic acid (5-ALA), a fluorogenic substrate used for FGS, to fluorescent protoporphyrin IX (PpIX). The resulting fluorescence is thought to be specific to transformed glioma cells, but this specificity has not been examined at single-cell level. We performed paired single-cell imaging and RNA sequencing of individual cells (SCOPE-seq2) on human GBM surgical specimens with visible PpIX fluorescence from patients who received 5-ALA prior to surgery. SCOPE-seq2 allows us to simultaneously image PpIX fluorescence and unambiguously identify transformed glioma cells from single-cell RNA-seq (scRNA-seq). We observed that 5-ALA treatment results in labeling that is not specific to transformed tumor cells. In cell culture, we further demonstrated that untransformed cells can be labeled by 5-ALA directly or by PpIX secreted from surrounding transformed cells. In acute slice cultures from mouse glioma models, we showed that 5-ALA preferentially labels GBM tumor tissue over non-neoplastic brain tissue, and that this contrast is not due to blood-brain-barrier disruption. Taken together, our findings support the use of 5-ALA as an indicator of GBM tissue, but not as a specific marker of transformed glioma cells.
The Megachilidae (Hymenoptera, Apoidea, Apiformes) of the Democratic Republic of Congo curated at the Royal Museum for Central Africa (RMCA, Belgium)
Authors: Nkulu Alain Tshibungu , Pauly Alain , Dorchin Achik , Vereecken Nicolas J.
Published: December 2022

Natural history collections (NHCs) are a cornerstone of entomology, and the conservation of specimens is the essential prerequisite for the development of research into systematics, biogeography, ecology, evolution and other disciplines. Yet, specimens collected during decades of entomological research conducted in less developed countries across Sub-Saharan Africa on pests, beneficial insects and insect biodiversity in general have largely been exported to be permanently preserved in developed countries, primarily in South Africa, Europe and the United States of America.

This is particularly true for the Democratic Republic of the Congo’s (DRC) diverse wild bee fauna, which has been investigated throughout the colonial period by visiting or resident entomologists and missionaries who have then transferred their collected material primarily to Belgium as part of a wider legacy of scientific exploration and colonialism. Digitizing NHC is one way to mitigate this current bias, by making samples accessible to researchers from the target post-colonial countries as well as to the wider international scientific community.

In this study, we compiled and digitized 6,490 specimens records relevant to 195 wild bee species grouped in 18 genera within the biodiverse family Megachilidae, essentially from the colonial era (i.e., mostly between 1905-1960, with additional records up to 1978), and curated at the Royal Museum for Central Africa (RMCA) in Belgium. We provide a detailed catalogue of all records with updated locality and province names, including 26 species only available as type specimens. We also explore the historical patterns of diversity and distribution across DRC, and we provide a list of the research entomologists involved. This study is an important first step that uses digital technologies to democratize and repatriate important aspects of DRC’s natural heritage of insect biodiversity, to stimulate more contemporary field surveys, as well as to identify and characterize research gaps and biodiversity shortfalls in little-explored regions of Sub-Saharan Africa.
Prediction of vasospasms as complication in ischemic stroke patients receiving anterior circulation endovascular stroke treatment
Authors: Jesser Jessica , Awounvo Sinclair , Vey Johannes A. , Vollherbst Dominik , Hilgenfeld Tim , Chen Min , Schönenberger Silvia , Bendszus Martin , Möhlenbruch Markus A. , Weyland Charlotte S.
Published: December 2022

Background and Purpose

Vasospasms are a common and dreaded complication of endovascular stroke treatment (EST). There is a lack of understanding of risk factors for periprocedural vasospasms. Here, we aimed to identify prognostic factors for vasospasms in patients with acute ischemic stroke and EST.

Methods

Retrospective single-center analysis of patients receiving EST for anterior circulation vessel occlusion between January 2015 and December 2021. Exclusion criteria were intracranial stenting and intraarterial (i.a.) thrombolysis. Study groups were defined as patients developing vasospasms during EST (V+) and patients, who did not (V-). The study groups were compared in univariate analysis. Further, multivariable regression models were developed to predict the patients’ risk for developing vasospasms based on pre-identified potential prognostic factors. Secondary endpoint was clinical outcome as modified Rankin Scale (mRS) difference between pre-stroke mRS and discharge mRS (delta mRS).

Results

In total, 132 of 1768 patients (7.5 %) developed vasospasms during EST in this study cohort. Patients with vasospasms were younger and had a lower pre-stroke disability (as per mRS). Vasospasms were more likely to occur in ESTs with multiple thrombectomy attempts in total and after several stent retriever maneuvers. Factors with predictive value for developing vasospasms were younger (OR = 0.967, 95%-CI = 0.96 - 0.98) and had a lower pre-stroke mRS (OR = 0.759, 95%-CI = 0.63 - 0.91). The prediction model incorporating patient age, pre-stroke mRS, stent retriever thrombectomy attempts, and total attempts as prognostic factors was found to predict vasospasms with decent accuracy (AUC = 0.714, 95%-CI = 0.709-0.720). V+ patients showed higher delta mRS (median (Q1 - Q3); V-: 2 (1-3) vs. V+: 2(1-4); p = 0.014).

Conclusion

This study shows that vasospasms are a common complication in EST affecting younger and previously healthier patients and are more likely after multiple stent retriever thrombectomy attempts. As independent predictors patient age, pre-stroke mRS, thrombectomy maneuvers and stent-retriever attempts predict the occurrence of vasospasms during EST with decent accuracy.
COVID-19 and Health System Response for Management of Diabetes in Bangladesh: A national qualitative study of patients with diabetes and key healthcare professionals/policy makers
Authors: Talukder Shamim Hayder , Islam Tasneem , Salahin Kazi Fayzus , Akter Shahin , Farhana Dina , Sultana Ummay Farihin , Shariful Islam Sheikh Mohammed , Shi Zumin , Hussain Akhtar , Godman Brian , Kurdi Amanj
Published: December 2022

Background

Uncontrolled diabetes can lead to exacerbation of symptoms and life-threatening complications. Consequently, there is a need to explore patient experience regarding the prevention and treatment of diabetic patients amidst the restrictions and lockdown measures in response to COVID-19. The objective of this study was to assess the response of the healthcare system for preventive care and treatment of people with diabetes in Bangladesh during COVID-19, and to analyze the health-seeking behavior of diabetes patients amidst social distancing and lockdown measures

Method

A descriptive qualitative design was used to collect data regarding the ability of people living with diabetes to access medication, laboratory services, and preventative care during the pandemic. The data collection process involved 12 focus group discussions (FGDs) with people living with diabetes, and 30 key informants’ interviews (KIIs) with senior diabetologist, health service managers, leaders of different diabetes-related associations, and policymakers from the local to the national level. The discussion issues were structured around the WHO framework that describes health systems in terms of six “building blocks”. In addition, different treatment guidelines, scientific articles, relevant reports, and 20 well-circulated newspapers were analyzed concerning the treatment of diabetic patients.

Results

44% of the respondents were aged 55-60 years, with an informed noticeable disruption of essential diabetes care services, intensified by high COVID-19 infection rates. Besides, 78% of the service receiver participants reported not seeing any government-issued public announcements regarding diabetes management on television or newspapers. There are also concerns with the current heath sector.

Conclusions

The study findings highlighted major concerns surrounding the healthcare response to deliver care for patients with diabetes during the pandemic, driven mainly by restricted access to treatment under lockdown measures coupled with a reluctance from health care providers to see patients due to high COVID-19 infection rates arising from concerns with a lack of personal protective equipment. Necessary measures can gradually bring some change in the healthcare system promote healthy lifestyles and adherence to prescribed medicines together with raising awareness about the potential risk factors of diabetes.
Health care workers’ level of adherence to infection prevention and control and its impact on puerperal and neonatal sepsis among delivering women and neonates in Central Tanzania: A protocol for prospective cohort study
Authors: Marandu Laura Edward , Masika Golden
Published: December 2022

Introduction

Delivering women and neonates are at a great risk of acquiring infections due to lack of adherence to infection prevention and control (IPC) and low level of immunity and extended exposure to care procedures that can lead to infections. This prospective study aims to assess the level of adherence to IPC among health care workers and its impact on puerperal and neonatal sepsis in Dodoma region.

Methods and Analysis

Level of adherence to IPC is examined cross-sectionally among health care workers (HCWs’) in contact with delivering women and their neonates. Prospective cohort approach is used to assess level of exposure of 294 delivering women and their neonates to poor hygienic practices of HCW through observation checklist. Outcomes including incidence of puerperal and neonatal sepsis are evaluated clinically two days later before discharge. Laboratory culture and sensitivity confirmatory tests of blood samples are done on positive cases. Data analysis for level of adherence to IPC practices, incidence of puerperal and neonatal sepsis as well as relative risk among the exposed women and neonates will be performed.

Ethics and Dissemination

The University of Dodoma Research Ethics Committee (UDOM-REC) approved this study (Ref No. MA.84/261/’A’/25). Findings of this study will be published in international peer reviewed journals, disseminated in international conferences, to the participating hospitals, the University of Dodoma and the Tanzanian Ministry of Health for informing practice and policy.

Strengths and limitations of this study

By capturing data from both health care workers and patients using mixed methods approach, the study can examine the impact of health care worker’s infection prevention, and control practice on patient’s outcomes at the same time.

Compared to other studies, this study objectively tracks and quantify the risk of infection from all possible points of contact between a health care worker and a client.

The study can enable early identification of puerperal or neonatal infection and initiate treatment before discharge Exposure to pre-admission infection long incubation period and manifest at the hospital post-delivery may be difficult to capture and may confound the results without culture and sensitivity.

The post-delivery women and their neonates will be followed for two days only to abide to hospital discharge protocol; this will limit the data to early onset of sepsis only.
Targeting MAdCAM-1 can prevent colitic cancer progression by suppressing immune cell infiltration and inflammatory signals
Authors: Ozawa Naoya , Yokobori Takehiko , Osone Katsuya , Bilguun Erkhem-Ochir , Okami Haruka , Shimoda Yuki , Shiraishi Takuya , Okada Takuhisa , Sano Akihiko , Sakai Makoto , Sohda Makoto , Miyazaki Tatsuya , Ide Munenori , Ogawa Hiroomi , Yao Takashi , Oyama Tetunari , Shirabe Ken , Saeki Hiroshi
Published: December 2022

Chronic inflammation by infiltrating immune cells promotes colitis-associated dysplasia/colitic cancer in ulcerative colitis (UC) via activating inflammatory cytokine signalling (IL-6/p-STAT3 and TNFα/NF-κB). Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a cell adhesion molecule expressed on high endothelial venules that promote immune cell migration from the bloodstream to the gut. MAdCAM-1 targeting strategy is attracting attention as a novel therapeutic option for UC. However, the significance of MAdCAM-1-positive vessels in dysplasia/colitic cancers remains unclear. We conducted immunohistochemistry against MAdCAM-1, and immune cell markers in surgically resected samples from 11 UC patients with dysplasia/colitic cancer and 17 patients with sporadic colorectal cancer (SCRC). Moreover, we used a colitic cancer model, azoxymethane (AOM)/dextran sodium sulphate (DSS) mouse, to evaluate whether anti-MAdCAM-1 blocking antibody can suppress colitic cancer progression. MAdCAM-1-positive vessel number and infiltrating CD8-, CD68-, and CD163-positive immune cell numbers were significantly higher in dysplasia/colitic cancer than in normal mucosa, SCRC, and UC mucosa. In the AOM/DSS mouse model, MAdCAM-1 antibody reduced the tumour number, tumour diameter, number of CD8-, CD68-, and CD163-positive immune cells, and IL-6/p-STAT3 and TNFα/NF-κB expression levels. Targeting MAdCAM-1 could be promising for inflammatory carcinogenesis, and tumour progression by regulating inflammation/immune cell infiltration in patients with UC.

Lay summary:

MAdCAM-1 targeting strategy can control ulcerative colitis severity, carcinogenesis, and tumour progression by regulating inflammation/immune cell infiltration in patients with ulcerative colitis.
Moving from Total Concentrations to Measures of Harm in Grain Sold at Selected Markets of Southwest Nigeria
Authors: Oshatunberu Modupe Abeke , Oladimeji Adebayo , Henry Sawyerr Olawale , Olaniyan Opasola Afolabi , Raimi Morufu Olalekan
Published: December 2022

Regardless of where you live or who you are, food safety is crucial for human health. Pesticide residues are commonly exposed to consumers in Nigeria through their food. What consequences, if any, such chemical pollutants cause to consumer health remain unclear given the presence of pesticide residues in food. To this end, the objective is to determine the concentration of the identified pesticide in grains commonly used by farmers, and which are available directly from the open markets in the Nigerian market. Pesticide residues were quantified through a multiresidue method using a varian 3800/4000 gas chromatograph mass spectrometer was used to analyze pesticide residues. The simultaneous determination of four classes of pesticides: carbamates, organochlorines, organophosphates, and pyrethroids by gas chromatography-mass spectrometry (GC/MS) method using sample preparation on QuEChERS-citrate, was developed and validated. The results frequently showed high inter- and intra-specific contamination, which makes sense given the target market and dietary diversity in the area. This study found that grains purchased from particular markets in southwest Nigeria contained numerous pesticide residues. The MRLs set by the EU or FAO/WHO or both were surpassed by 17 out of the total 27 pesticides reported in this work in at least one grain, despite the fact that there were no published codex MRLs for some pesticide residues in some grains.These residues were dispersed among the four classes of pesticides: carbamates, organochlorines, organophosphates, and pyrethroids. In actuality, 90% of the mainly banned organochlorine pesticides exceeded MRLs. Thus, this study revealed concentration levels of organo-chloride pesticides and organo-phosphate pesticides in grain samples drawn from selected markets in southwest Nigeria. Consumers seeking high-quality food in Nigeria should take note of these facts. Notwithstanding, the small percentage of samples with detectable residues suggests that there is a need to increase the monitoring of pesticides in grains, educate farmers, and raise their awareness of the dangers of unauthorized use of pesticides that are restricted for use in agriculture, which can harm the industry’s reputation as a whole.
Hypergraphs and centrality measures identifying key features in gene expression data
Authors: Barton Samuel , Broad Zoe , Ortiz-Barrientos Daniel , Donovan Diane , Lefevre James
Published: December 2022

Multidisciplinary approaches can significantly advance our understanding of complex systems. For instance, gene co-expression networks align prior knowledge of biological systems with studies in graph theory, emphasising pairwise gene to gene interactions. In this paper, we extend these ideas, promoting hypergraphs as an investigative tool for studying multi-way interactions in gene expression data. Additional freedoms are achieved by representing individual genes with hyperedges, and simultaneous testing each gene against many features/vertices. Further gene/hyperedge interactions can be captured and explored using the line graph representations, a techniques that also reduces the complexity of dense hypergraphs. Such an approach provides access to graph centrality measures, which in turn identify salient features within a data set, for instance dominant or hub-like hyperedges leading to key knowledge on gene expression. The validity of this approach is established through the study of gene expression data for the plant speciesSenecio lautusand results will be interpreted within this biological setting.
A sigmoid curve analysis method for pharmacological experimental results
Authors: Niu Qingxia , Zhao Chengyan
Published: December 2022

Sigmoid curve (S-curve) is a basic exhibition form of dose-effect relationship in drug reaction. To analyze S-curve is an important method to well-understand drug reaction performance (DRP). The present study introduced an S-curve analysis method for pharmacological experiment results (PERs), the core of which was to solve the problem of the linear fitting of S-curve equation (S-Eq). The linear fitting Eqs of S-Eq were established with 100% fitness. Meanwhile, mathematical and pharmacological meaning of S-curve constants, ED50and maximum effect (ymax) were clarified. The same group of experimental data was analyzed by the present method and four traditional analysis methods. The result indicates that the experimental parameters and their values displaying DRP got by different methods are different. The S-curve analysis method is closer to real drug reaction law.
Finding the best cell lines across pan-cancer to use in pre-clinical research as a proxy for patient tumor samples considering immune cells, multi-omics, and cancer pathways
Authors: Bose Banabithi , Bozdag Serdar
Published: December 2022

In pre-clinical trials of anti-cancer drugs, cell lines are utilized as a model for patient tumor samples to understand the response of drugs. However,in vitroculture of cell lines, in general, alters the biology of the cell lines and likely gives rise to systematic differences from the tumor samples’ genomic profiles; hence the drug response of cell lines may deviate from actual patients’ drug response. In this study, we computed a similarity score for the selection of cell lines depicting the close and far resemblance to patient tumor samples in twenty-two different cancer types at genetic, genomic, and epigenetic levels integrating multi-omics datasets. We also considered the presence of immune cells in tumor samples and cancer-related biological pathways in this score which aids personalized medicine research in cancer. We showed that based on these similarity scores cell lines were able to recapitulate the drug response of patient tumor samples for several FDA-approved cancer drugs in multiple cancer types. Based on these scores, several of the high-rank cell lines were shown to have a close likeness to the corresponding tumor type in previously reported in vitro experiments.
A Unified Filtering Method for Estimating Asymmetric Orientation Distribution Functions: Where and How Asymmetry Occurs in the Brain
Authors: Poirier Charles , Descoteaux Maxime
Published: December 2022

Numerous filtering methods have been proposed for estimating asymmetric orientation distribution functions (ODFs) for diffusion magnetic resonance imaging (dMRI). It can be hard to make sense of all these different methods, which share similar features and result in similar outputs. The objectives of this work are two-fold: to disentangle the various filtering methods proposed in the past for estimating asymmetric ODFs, and to study the occurrence of asymmetric patterns in dMRI brain acquisitions. Hence, we describe a new filtering equation for estimating asymmetric ODFs resulting from the unification of these previously proposed filtering methods. Our method is distributed as an open-source GPU-accelerated python software to facilitate its integration into any existing dMRI processing pipeline. Following its validation on toy datasets, we apply our method to multi-shell multi-tissue fiber ODF reconstructions for 21 subjects from the Human Connectome Project in test-retest acquisitions. Our results show that our method estimates branching, fanning, bending, ending and other complex asymmetric fiber configurations in less than 2 minutes. Also, our novel number of fiber directions (NuFiD) index reveals that the filtering reduces the number of peak directions in the resulting asymmetric representation. Finally, our MNI-aligned template of asymmetries, describing the degree of asymmetry of each voxel, suggests that at least 60% of brain voxels in a dMRI acquisition contain asymmetric fiber configurations.
Persistent spectral theory-guided protein engineering
Authors: Qiu Yuchi , Wei Guo-Wei
Published: December 2022

While protein engineering, which iteratively optimizes protein fitness by screening the gigantic mutational space, is constrained by experimental capacity, various machine learning models have substantially expedited protein engineering. Three-dimensional protein structures promise further advantages, but their intricate geometric complexity hinders their applications in deep mutational screening. Persistent homology, an established algebraic topology tool for protein structural complexity reduction, fails to capture the homotopic shape evolution during the filtration of a given data. This work introduces aTopology-offeredproteinFitness (TopFit) framework to complement protein sequence and structure embeddings. Equipped with an ensemble regression strategy, TopFit integrates the persistent spectral theory, a new topological Laplacian, and two auxiliary sequence embeddings to capture mutation-induced topological invariant, shape evolution, and sequence disparity in the protein fitness landscape. The performance of TopFit is assessed by 34 benchmark datasets with 128,634 variants, involving a vast variety of protein structure acquisition modalities and training set size variations.
Homeostasis, injury and recovery dynamics at multiple scales in a self-organizing intestinal crypt
Authors: Gall Louis , Duckworth Carrie , Jardi Ferran , Lammens Lieve , Parker Aimée , Bianco Ambra , Kimko Holly , Pritchard D. Mark , Pin Carmen
Published: December 2022

We have built a multi-scale agent-based model (ABM) that reproduces the self-organizing behaviour reported for the intestinal crypt. We demonstrate that a stable spatial organization emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, RNF43/ZNRF3 and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms and modulate the dynamics of the cell cycle protein network.

The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disturbs the cell cycle, cell signalling, proliferation, differentiation and migration and leads to loss of barrier integrity. During recovery, our in-silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops.

Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug discovery.