bluuebunny/crossref_metadata_2025 huggingface dataset:
The management of locally advanced, ulcerated breast cancer in a menopausal woman: a case report
Authors: Izzo Paolo , Izzo Luciano , Polistena Andrea , Sibio Simone , Codacci-Pisanelli Massimo , Crocetti Daniele , Gabriele Raimondo , De Intinis Claudia , Izzo Sara
Published: August 2023

Introduction and importance:

This case report presents the clinical details of a 46-year-old postmenopausal woman who was diagnosed with a locally advanced, ulcerated, hormone receptor-positive, HER2-negative stage 2B lobular carcinoma of the breast. The complexity of the case necessitated a multidisciplinary, personalized approach.

Case presentation:

The patient, a postmenopausal woman, presented with locally advanced lobular carcinoma of the breast. The tumor was of significant size and exhibited ulceration. Given the hormone receptor-positive status of the tumor, a comprehensive treatment plan was formulated, taking into account the patient’s overall health and potential tolerance to treatment. Surgical removal of the tumor was performed, followed by adjuvant therapy with aromatase inhibitors.

Clinical discussion:

The complexity of this case highlights the importance of a personalized and patient-centered strategy in managing breast cancer. The patient’s menopausal status, tumor characteristics, and potential tolerance to treatment were crucial factors that influenced the treatment plan. The successful outcome of the treatment and the patient’s ability to tolerate the therapy underscores the significance of individualized treatment planning.

Conclusion:

This case report emphasizes the necessity for a comprehensive and patient-centered approach to managing complex cases of breast cancer. The findings support the development of personalized therapeutic strategies aimed at improving patient outcomes and quality of life. The successful treatment of the locally advanced, ulcerated lobular carcinoma of the breast in this postmenopausal patient further highlights the importance of considering individual factors and tailoring treatment plans accordingly.
Preparation of antiviral multispray with cationic antimicrobial dialkyldimethyl ammonium salt and sulfobetaine against new coronaviruses (SARS-CoV-2)
Authors: Morioka Masahiko , Shimaoka Daisuke , Ohnishi Mamoru
Published: August 2023

The novel sudden acute respiratory syndrome coronavirus 2 is an enveloped virus currently causing severe illness and death worldwide. Common antiseptics such as alcohol have some efficacy in disinfecting everyday surroundings, but development of more effective disinfectants is imperative. A series of studies focusing on cationic antimicrobials resulted in the development of a safe and effective novel coronavirus disinfectant, DEA-171, which provides ≥99.98% inhibition of all novel coronavirus variants within 1 min.
Chitinophaga pendula, sp. nov., from an air conditioner condensate drain line
Authors: Onouye T. Chiyoko , Busse Hans-Jürgen , Prescott Rebecca D. , Darris Maxwell K. , Donachie Stuart P.
Published: August 2023

A Gram-negative, rod-shaped and filamentous bacterium designated MD30BT was isolated from a biofilm hanging in water flowing from an air conditioner condensate drain line in Honolulu, Hawai‘i. Based on 1517 nucleotides of the strain’s 16S rRNA gene, its nearest neighbours are

Chitinophaga rhizosphaerae

T16R-86T (96.7 %),

Chitinophaga caseinilytica

S-52T (96.6 %),

Chitinophaga lutea

ZY74T (96.6 %),

Chitinophaga niabensis

JS13-10T (96.6 %) and

Chitinophaga ginsengisoli

Gsoil 052T (96.5 %). MD30BT cells are non-motile, strictly aerobic, and catalase and oxidase positive. Growth occurs between 10 and 45 °C. Major fatty acids in whole cells of MD30BT are 13-methyl tetradecanoic acid (34.1 %), cis-11-hexadecenoic acid (30.3 %), and 3-hydroxy, 15-methyl hexadecanoic acid (13.3 %). The quinone system contains predominantly menaquinone MK-7. The polar lipid profile contains the major lipids phosphatidylethanolamine, one unidentified lipid lacking a functional group, and two unidentified aminolipids. sym-Homospermidine is the major polyamine. The G+C content of the genome is 47.58 mol%. Based on phenotypic and genotypic differences between MD30BT and extant species in the

Chitinophaga

, we propose that MD30BT represents a new

Chitinophaga

species, for which the name Chitinophaga pendula sp. nov. is proposed to accommodate strain MD30BT as the type strain (DSM 112477T=NCTC 14606T).
cazy_webscraper: local compilation and interrogation of comprehensive CAZyme datasets
Authors: Hobbs Emma E. M. , Gloster Tracey M. , Pritchard Leighton
Published: August 2023

Carbohydrate active enzymes (CAZymes) are pivotal in biological processes including energy metabolism, cell structure maintenance, signalling, and pathogen recognition. Bioinformatic prediction and mining of CAZymes improves our understanding of these activities and enables discovery of candidates of interest for industrial biotechnology, particularly the processing of organic waste for biofuel production. CAZy (www.cazy.org) is a high-quality, manually curated, and authoritative database of CAZymes that is often the starting point for these analyses. Automated querying and integration of CAZy data with other public datasets would constitute a powerful resource for mining and exploring CAZyme diversity. However, CAZy does not itself provide methods to automate queries, or integrate annotation data from other sources (except by following hyperlinks) to support further analysis. To overcome these limitations we developed cazy_webscraper, a command-line tool that retrieves data from CAZy and other online resources to build a local, shareable and reproducible database that augments and extends the authoritative CAZy database. cazy_webscraper’s integration of curated CAZyme annotations with their corresponding protein sequences, up-to-date taxonomy assignments, and protein structure data facilitates automated large-scale and targeted bioinformatic CAZyme family analysis and candidate screening. This tool has found widespread uptake in the community, with over 35 000 downloads (from April 2021 to June 2023). We demonstrate the use and application of cazy_webscraper to: (i) augment, update and correct CAZy database accessions; (ii) explore the taxonomic distribution of CAZymes recorded in CAZy, identifying under-represented taxa and unusual CAZy class distributions; and (iii) investigate three CAZymes having potential biotechnological application for degradation of biomass, but lacking a representative structure in the PDB database. We describe in general how cazy_webscraper facilitates functional, structural and evolutionary studies to aid identification of candidate enzymes for further characterization, and specifically note that CAZy provides supporting evidence for recent expansion of the Auxiliary Activities (AA) CAZy family in eukaryotes, consistent with functions potentially specific to eukaryotic lifestyles.
High-Dose Naloxone Formulations Are Not as Essential as We Thought
Authors: Lemen Paige M. , Garrett Daniel P. , Thompson Erin , Aho Megan , Vasquez Christina , Park Ju Nyeong
Published: August 2023

Naloxone is a U.S. Food and Drug Administration (FDA) approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public, and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review aimed to improve understanding regarding the adequacy of the regularly distributed two doses of low-dose IM or IN naloxone in effectively reversing fentanyl overdoses and whether high-dose naloxone formulations (HDNF) formulations are an optimal solution to this problem. Moreover, our initiative incorporated the perspectives and experiences of people who use drugs (PWUD), enabling a more practical and contextually-grounded analysis. We began by discussing the knowledge and perspectives of Tennessee Harm Reduction, a small peer-led harm reduction organization. A comprehensive literature review was then conducted to gather relevant scholarly works on the subject matter. The evidence indicates that, although higher doses of naloxone have been administered in both clinical and community settings, the vast majority of fentanyl overdoses can be successfully reversed using standard IM dosages with the exception of carfentanil overdoses and other more potent fentanyl analogs, which necessitate three or more doses for effective reversal. Multiple studies documented the risk of precipitated withdrawal using high doses of naloxone. Notably, the possibility of recurring overdose symptoms after resuscitation exists, contingent upon the half-life of the specific opioid. Considering these findings and the current community practice of distributing multiple doses, we recommend providing at least four standard doses of IN or IM naloxone to each potential bystander, and training them to continue administration until the recipient achieves stability, ensuring appropriate intervals between each dose. Based on the evidence, we do not recommend HDNF in the place of providing four doses of standard naloxone due to the higher cost, risk of precipitated withdrawal and limited evidence compared to standard IN and IM. All results must be taken into consideration with the inclusion of the lived experiences, individual requirements, and consent of PWUD as crucial factors. It is imperative to refrain from formulating decisions concerning PWUD in their absence, as their participation and voices should be integral to the decision-making process.
TLR8escapes X chromosome inactivation in human monocytes and CD4+T cells
Authors: Youness Ali , Cenac Claire , Faz-López Berenice , Grunenwald Solange , Barrat Franck J. , Chaumeil Julie , Mejía José Enrique , Guéry Jean-Charles
Published: August 2023

Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are encoded by the adjacent X-linked genes,TLR7andTLR8. We previously established thatTLR7evades X chromosome inactivation in female immune cells, and that mononuclear blood cells express more TLR7 protein in women than in men. Using RNA fluorescencein situhybridization, we now show thatTLR8likewise evades X chromosome inactivation in CD14+monocytes and CD4+T lymphocytes, and that cells harboringTLR7orTLR8transcript foci are more frequent in women than in men. In parallel, we foundTLR7andTLR8simultaneous transcription to be disproportionally frequent in female monocytes and T cells, and disproportionally scarce in the male cells, resulting in a 7-fold difference in frequency. These transcriptional biases were again observable when comparing the single X of XY males with the active X of female cells. Among (47,XXY) Klinefelter syndrome males, bothTLR7andTLR8escape X chromosome inactivation, and co-transcription frequencies on the active X of monocytes were intermediate overall between those for XY males and XX females, and encompassed both male- and female-like individual patterns. These findings indicate that theTLR7andTLR8genes form a co-regulated gene cluster, which we have called the X-linked Toll-like receptor locus, with different sex- and sexual karyotype-dependent modes of transcription. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in the male cells. Thus, co-dependent transcription from the active X chromosome and escape from inactivation could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.

Highlights

TLR8, likeTLR7, escapes X chromosome inactivation in immune cells from women and 47,XXY Klinefelter syndrome (KS) men.

The frequency of cells double-positive forTLR7andTLR8primary transcripts is 7-fold higher in women than in men.

TLR7andTLR8form a co-regulated gene cluster on the human X chromosome, with sex-specific, divergent transcriptional patterns observable in monocytes and CD4+T lymphocytes.

Co-dependent transcription of theTLR7andTLR8genes on the active X was observed in women and KS men, contrasting with mutually exclusive transcription in euploid men.

Blood mononuclear cells, including monocyte subsets, expressed higher levels of TLR8 protein in females than in males.
Markerless motion capture to assess upper extremity movements in individuals with dyskinetic cerebral palsy: an accuracy and validity study
Authors: Vanmechelen Inti , Van Wonterghem Ellen , Aerts Jean-Marie , Hallez Hans , Desloovere Kaat , Van de Walle Patricia , Buizer Annemieke I. , Monbaliu Elegast , Haberfehlner Helga
Published: August 2023

Aim

To evaluate clinical utility of markerless motion capture (MMC) during an reaching-sideways-task in individuals with dyskinetic cerebral palsy (DCP) by determining (1) accuracy of key points tracking in individuals with DCP and typically developing (TD) peers, (2) concurrent validity by correlating MMC towards 3D-motion analysis (3DMA) and (3) construct validity by assessing differences in MMC features between a DCP and TD group.

Method

MMC key points were tracked from frontal videos and accuracy was assessed towards human labelling. Shoulder, elbow and wrist angles were calculated from MMC and 3DMA (as gold standard) and correlated. Additionally, execution time and variability features were calculated from key points. MMC features were compared between groups.

Results

Fifty-one individuals (30 DCP;21 TD; age:5-24 years) participated. An accuracy of approximately 1.5 cm was reached for key point tracking. While significant correlations were found for wrist (ρ=0.810;p<0.001) and elbow angles (ρ=0.483;p<0.001), MMC shoulder angles were not correlated (ρ=0.247;p=0.102) to 3DMA. Wrist and elbow angles, execution time and variability features all differed between groups (Effect sizes 0.35-0.81;p<0.05).

Interpretation

Videos of a reaching-sideways-task processed by MMC to assess upper extremity movements in DCP showed promising accuracy and validity. The method is especially valuable to assess movement variability within DCP without expensive equipment.
Transfusion-transmitted infections among blood donors in South-East Italy: Contribution of blood transfusion centres for territory-based surveillance
Authors: Antonucci Francescopaolo , Faleo Antonietta , De Feo Lucia , Lombardi Luciano , Granato Tommaso
Published: August 2023

Background and Objectives

Screening for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV) infections and Syphilis in blood donors is important to evaluate both risk of transfusion-transmitted infections (TTIs) and their current prevalence in apparently healthy individuals. Apulia (South-East Italy) resulted to be one of the two Italian regions with the highest TTI cases.

Screening tests results of blood donors were analysed, with the purpose to provide updated information on the epidemiology of TTIs.

Materials and Methods

117,454 donors referring to blood transfusion centres of the North Apulia between 2019-2022 were analysed; serum samples underwent analysis for TTIs by chemiluminescent-immunoassay and nucleic-acid-amplification tests.

Results

Confirmed reactivities were: 47 HBV (0.04%), 19 HCV (0.02%), 1 HIV (0.001%), and 42 Syphilis (0.04%), respectively. Of 47 HBV-infected donors, 28 were Hepatitis B surface Antigen (HBsAg) positive, including 8 with HBV-DNA positive, and 19 HBsAg negative but with detectable viraemia, identifying the presence of occult B infection (OBI). A higher number of positive cases resulted in the age group 51-65 (34 HBV, 12 HCV, 1 HIV and 25 Syphilis) and over 65 (4 HBV, 5 HCV, 0 HIV and 2 Syphilis) (p-value<0.05). Occasional donors showed higher frequency of TTIs compared to regular donors.

Conclusion

The study shows consistent number of undiagnosed TTIs among blood donors, and the importance of transfusion centres for territory-based surveillance that can contribute to the detection of novel TTI cases among asymptomatic people, helping the diagnosis of submerged infectious diseases that are still a global threat.

HIGHLIGHTS

Apulia is the second Italian region with the highest number of Transfusion-Transmitted Infections (TTI) among blood donors;

In the period 2019-2022, HBV resulted to be the main TTI detected among blood donors, followed by Syphilis, HCV and HIV in North Apulia; the overall TTIs distribution resulted significantly higher among occasional donors than regular donors;

Blood transfusion centres may represent important surveillance points for HBV, HCV, HIV and Syphilis and can contribute to the detection of novel TTI cases in apparently healthy individuals.
Sputum microbiome α-diversity is a key feature of the COPD frequent exacerbator phenotype
Authors: Pragman Alexa A. , Hodgson Shane W. , Wu Tianhua , Zank Allison , Reilly Cavan S. , Wendt Chris H.
Published: August 2023

Background

The lung microbiome is an inflammatory stimulus whose role in chronic obstructive pulmonary disease (COPD) pathogenesis is incompletely understood. We hypothesized that the frequent exacerbator phenotype is associated with decreased α-diversity and increased lung inflammation. Our objective was to assess correlations between the frequent exacerbator phenotype, the microbiome, and inflammation longitudinally during exacerbation-free periods.

Methods

We conducted a case-control longitudinal observational study of the frequent exacerbator phenotype and characteristics of the airway microbiome. Eighty-one subjects (41 frequent and 40 infrequent exacerbators) provided nasal, oral, and sputum microbiome samples at two visits over 2-4 months. Exacerbation phenotype, relevant clinical factors, and sputum cytokine values were associated with microbiome findings.

Results

The frequent exacerbator phenotype was associated with lower sputum microbiome α-diversity (p=0.0031). This decrease in α-diversity among frequent exacerbators was enhanced when the sputum bacterial culture was positive (p<0.001). Older age was associated with decreased sputum microbiome α-diversity (p=0.0030). Between-visit β-diversity was increased among frequent exacerbators and those who experienced a COPD exacerbation between visits (p=0.025, p=0.014). Sputum cytokine values did not differ based on exacerbation phenotype or other clinical characteristics. IL-17A was negatively associated with α-diversity, while IL-6 and IL-8 were positively associated with α-diversity (p=0.012, p=0.012, p=0.0496). IL-22, IL-17A, and IL-5 levels were positively associated withMoraxellaabundance (p=0.027, p=0.0014, p=0.0020).

Conclusions

Even during exacerbation-free intervals, the COPD frequent exacerbator phenotype is associated with decreased sputum microbiome α-diversity and increased β-diversity. Decreased sputum microbiome α-diversity andMoraxellaabundance are associated with lung inflammation.
Association between physical multimorbidity and common mental health disorders in rural and urban Malawian settings: preliminary findings from Healthy Lives Malawi long-term conditions survey
Authors: Nkoka Owen , Munthali-Mkandawire Shekinah , Mwandira Kondwani , Nindi Providence , Dube Albert , Nyanjagha Innocent , Mainjeni Angella , Malava Jullita , Amoah Abena S , McLean Estelle , Stewart Robert , Crampin Amelia C , Price Alison J
Published: August 2023

In low-income Africa, the epidemiology of physical multimorbidity and associated mental health conditions is not well described. We investigated the multimorbidity burden, disease combinations, and relationship between physical multimorbidity and common mental health disorders in rural and urban Malawi using early data from 9,849 adults recruited to an on-going large cross-sectional study on long-term conditions, initiated in 2021. Multimorbidity was defined as having two or more measured (diabetes, hypertension) or self-reported (diabetes, hypertension, disability, chronic pain, HIV, asthma, stroke, heart disease, and epilepsy). Depression and anxiety symptoms were scored using the 9-item Patient Health Questionnaire and 7-item General Anxiety Disorder scale and defined by the total score (range 0–27 and 0–21, respectively). We determined age-standardized multimorbidity prevalence and condition combinations. Additionally, we used multiple linear regression models to examine the association between physical multimorbidity and depression and anxiety symptom scores. Of participants, 81% were rural dwelling, 56% were female, and the median age was 30 years (IQR 21–43). The age-standardized urban and rural prevalence of multimorbidity was 14.1% (95% CI, 12.5–15.8%) and 12.2% (95% CI, 11.6–12.9%), respectively. In adults with two conditions, hypertension, and disability (18%) co-occurred most frequently, and in those with three conditions, hypertension, disability, and chronic pain (23%) were the most common combination. Compared to adults without physical conditions, having one (B-Coefficient (B) 0.78; 95% C1 0.63–0.95%), two-(B1.36; 95% CI 1.14–1.58%), and three- or more-physical conditions (B2.23; 95% CI 1.87–2.59%) were associated with increasing depression score,p-trend <0.001. A comparable ‘dose-response’ relationship was observed between physical multimorbidity and anxiety symptom scores. While the direction of observed associations cannot be determined with these cross-sectional data, our findings highlight the burden of multimorbidity and need for integrating mental and physical health service delivery in Malawi.
ChatGPT-CARE: a Superior Decision Support Tool Enhancing ChatGPT with Clinical Practice Guidelines
Authors: Wang Yanshan , Visweswaran Shyam , Kapoor Sumit , Kooragayalu Shravan , Wu Xizhi
Published: August 2023

ChatGPT has gained remarkable traction since its inception in November 2022. However, it faces limitations in generating inaccurate responses, ignoring existing guidelines, and lacking reasoning when applied in clinical settings. This study introduces ChatGPT-CARE, a tool that integrates clinical practice guidelines with ChatGPT, focusing on COVID-19 outpatient treatment decisions. By employing in-context learning and chain-of-thought prompting techniques, ChatGPT-CARE enhances original ChatGPT’s clinical decision support and reasoning capabilities. We created three categories of various descriptions of patients seeking COVID-19 treatment to evaluate the proposed tool, and asked two physicians specialized in pulmonary disease and critical care to assess the responses for accuracy, hallucination, and clarity. The results indicate that ChatGPT-CARE offers increased accuracy and clarity, with moderate hallucination, compared to the original ChatGPT. The proposal ChatGPT-CARE could be a viable AI-driven clinical decision support tool superior to ChatGPT, with potential applications beyond COVID-19 treatment decision support.
The Influence of Multivalent Charge and PEGylation on Shape Transitions in Fluid Lipid Assemblies: From Vesicles to Discs, Rods, and Spheres
Authors: Steffes Victoria M. , Zhang Zhening , Ewert Kai K. , Safinya Cyrus R.
Published: August 2023

Lipids, and cationic lipids in particular, are of interest as delivery vectors for hydrophobic drugs such as the cancer therapeutic paclitaxel, and the structures of lipid assemblies affect their efficacy. We investigated the effect of incorporating the multivalent cationic lipid MVL5 (+5e) and poly(ethylene glycol)-lipids (PEG-lipids), alone and in combination, on the structure of fluid-phase lipid assemblies of the charge-neutral lipid 1,2-dioleoyl-sn-glycero-phosphocholine (DOPC). This allowed us to elucidate lipid–liposome structure correlations in sonicated formulations with high charge density, which are not accessible with univalent lipids such as the well-studied DOTAP (+1e). Cryogenic TEM allowed us to determine the structure of the lipid assemblies, revealing diverse combinations of vesicles and disc-shaped, worm-like, and spherical micelles. Remarkably, MVL5 forms an essentially pure phase of disc micelles at 50 mol% MVL5. At higher (75 mol%) content of MVL5, short and intermediate-length worm-like micellar rods were observed and, in ternary mixtures with PEG-lipid, longer and highly flexible worm-like micelles formed. Independent of their length, the worm-like micelles coexisted with spherical micelles. In stark contrast, DOTAP forms mixtures of vesicles, disc micelles and spherical micelles at all studied compositions, even when combined with PEG-lipids. The observed similarities and differences in the effects of charge (multivalent versus univalent) and high curvature (multivalent charge versus PEG-lipid) on assembly structure provide insights into parameters that control the size of fluid lipid nanodiscs, relevant for future applications.
Reward actively engages both implicit and explicit components in dual force field adaptation
Authors: Forano Marion , Franklin David W.
Published: August 2023

Motor learning occurs through multiple mechanisms, including unsupervised, supervised (error-based) and reinforcement (reward-based) learning. Although studies have shown that reward leads to an overall better motor adaptation, the specific processes by which reward influences adaptation are still unclear. Here, we examine how the presence of reward affects dual-adaptation to novel dynamics, and distinguish its influence on implicit and explicit learning. Participants adapted to two opposing force fields in an adaptation/de-adaptation/error-clamp paradigm, where five levels of reward (a score and a digital face) were provided as participants reduced their lateral error. Both reward and control (no reward provided) groups simultaneously adapted to both opposing force fields, exhibiting a similar final level of adaptation, which was primarily implicit. Triple-rate models fit to the adaptation process found higher learning rates in the fast and slow processes, and a slightly increased fast retention rate for the reward group. While differences in the slow learning rate were only driven by implicit learning, the large difference in the fast learning rate was mainly explicit. Overall, we confirm previous work showing that reward increases learning rates, extending this to dual-adaptation experiments, and demonstrating that reward influences both implicit and explicit adaptation. Specifically, we show that reward acts primarily explicitly on the fast learning rate and implicitly on the slow learning rates.

New and Noteworthy

Here we show that rewarding participants’ performance during dual force field adaptation primarily affects the initial rate of learning and the early timescales of adaptation, with little effect on the final adaptation level. However, reward affects both explicit and implicit components of adaptation. While the learning rate of the slow process is increased implicitly, the fast learning and retention rates are increased through both implicit components and the use of explicit strategies.
Spatial coding of conspecifics in subpopulations of hindbrain pyramidal cells of the gymnotiform electrosensory system
Authors: Milam Oak E , Marsat Gary
Published: August 2023

Localizing the source of a signal requires sophisticated neural mechanisms and we are still uncovering the coding principles that support accurate spatial processing. Weakly electric fish can detect and localize distant conspecifics, but the way this spatial information is encoded is unclear. Here, we investigate the spatial representation of conspecific signals in the hindbrain to determine how the properties of the heterogenous population of pyramidal cells affect the spatial coding accuracy of conspecific signals. We hypothesize that specific subsets of cells provide more accurate spatial information about conspecific location. We stimulated the fish with an artificial signal that replicates both the spatial and temporal structure of conspecific signals. We recorded from cells with various receptive field positions covering the entire body surface and analyzed the spike train with spike-train distance metrics to determine how accurately the location of the stimulus is encoded. We found that some pyramidal cells (such as ON-type, and those within the deep layer) encode the spatial information more accurately while other subgroups (OFF-type, and superficial layer) provide less accurate information. Our results help us understand how the heterogeneity of a population of cells allow the efficient processing of signals and suggest that a segregation of the spatial information stream starts earlier in the sensory pathway.
High-frequency cortical neural inputs to muscles during movement cancellation
Authors: Zicher B , Avrillon S , Ibáñez J , Farina D
Published: August 2023

Cortical beta (13-30 Hz) and gamma (30-60 Hz) oscillations have been investigated during motor processing. Although they are at frequencies greater than the dynamic bandwidth of muscle contraction, these oscillations are partly transmitted from the cortex to motoneurons and muscles. Little is known about when and why this transmission occurs. We developed an experimental approach to examine these high frequency inputs to motoneurons under different motor states while maintaining a stable force, thus constraining behaviour. We acquired brain and muscle activity during a ‘GO’/’NO-GO’ task. In this experiment, the effector muscle for the task (tibialis anterior) was kept tonically active during the trials, while participants (N=9) reacted to sequences of auditory stimuli by either keeping the contraction unaltered (‘NO-GO’ trials), or by quickly performing a ballistic contraction (‘GO’ trials). Motor unit (MU) firing activity was extracted from high-density surface and intramuscular electromyographic signals, and the changes in its spectral contents in the ‘NO-GO’ trials were analysed. We observed an increase in beta and low-gamma (30-45 Hz) activity post ‘NO-GO’ cue at the brain and muscle levels. There was also an increase in the activity within 8-12 Hz, which was only observed at the muscle level. Overall, our results suggest that the cortical processing of movement cancellation occurs at least in part via increased power of high-frequency oscillations transmitted downstream to the muscles. These changes occur without alterations in behaviour, suggesting that the downstream transmission of these high-frequency oscillations does not have a direct functional impact.
Blood-based Nano-QuIC: Inhibitor-resistant Detection of Seeding Activity in Patients Diagnosed with Parkinson Disease
Authors: Christenson Peter R , Jeong Hyeonjeong , Li Manci , Ahn Hyerim , Schmeichel Ann M , Misra Pinaki , Li Danni , Savica Rodolfo , Low Phillip A , Singer Wolfgang , Larsen Peter A , Park Hye Yoon , Oh Sang-Hyun
Published: August 2023

A hallmark of α-synucleinopathies (e.g. Parkinson disease) is the misfolding and aggregation of α-synuclein in tissues and biological fluids. Protein amplification assays like real-time quaking-induced conversion (RT-QuIC) are sensitive yet currently limited to semi-invasive sample types such as cerebrospinal fluid because more accessible samples, such as blood, contain inhibitors. Here, we show that Nanoparticle-enhanced Quaking-induced Conversion (Nano-QuIC) can double the speed of reactions spiked with misfolded α-synuclein while increasing sensitivity 100-fold in human plasma. Nano-QuIC detected spike concentrations down to 90 pg/ml in lysed whole blood, while reactions without nanoparticles (RT-QuIC) failed to have any detection due to the presence of strong inhibitors. Moreover, Nano-QuIC showed increased seeding activity in plasma samples from Parkinson disease patients (n=4) versus healthy controls (n=4). This sets the groundwork for the noninvasive diagnostic use of Nano-QuIC, potentially enabling early disease detection and management through blood-based testing.
Unveiling the benefits and gaps of wild pollinators on nutrition and income
Authors: Duarte Gabriela T. , Schuster Richard , Mitchell Matthew G.E.
Published: August 2023

Insect pollinators play a crucial role in global crop production, enhancing fruit and seed yield, improving fruit quality, and increasing crop nutritional value. However, wild pollinator populations worldwide have been experiencing alarming declines. This study investigates the contribution of wild pollinators to nutrition and farmers’ income in Canada, while examining the spatial distribution of these services. Using publicly available data on crop types, yields, nutrient content, and farm gate values, alongside information on natural habitats, we estimated the benefits of wild pollinators across national agricultural landscapes. Our findings reveal that these pollinators sustain approximately 24.4 million equivalent people each year in terms of nutrition and generate an annual income of nearly CAD$2.8 billion for farmers. However, significant benefit gaps exist due to the lack of nearby pollinator habitats and insufficient pollination of dependent crops on a national scale. Addressing these gaps could provide an additional nutrition supply for nearly 30 million equivalent people and increase farmer income by CAD$3 billion. We discuss how and where efforts focused on preserving and enhancing wild pollinator habitats, promoting sustainable farming practices, and raising awareness among stakeholders are crucial for the long-term viability of wild pollinator populations and the sustainability of agricultural systems. This research underscores the urgent need for a national strategy aimed at safeguarding wild pollinators. Implementing such a strategy would not only contribute to strengthening local economies in the regions highlighted in our work but also ensure the production of nutritionally essential food.
A Fit for Purpose Approach to Evaluate Detection of Amino Acid Substitutions in Shotgun Proteomics
Authors: Lundgren Taylor J. , Clark Patricia L. , Champion Matthew M.
Published: August 2023

Amino acid substitutions (AAS) change a protein from its genome-expected sequence. Accumulation of substitutions in proteins underlie numerous diseases and antibiotic mechanisms. Accurate global detection of substitutions and their frequencies would help characterize these mechanisms. Measurement of AAS using shotgun proteomics is attractive due to its high sensitivity and untargeted acquisition. However, identifying substituted peptide-spectra requires search strategies that extrapolate beyond the genome, which can introduce bias. To characterize this bias, we constructed a “ground-truth” approach using the similarities between theEscherichia coliandSalmonella typhimuriumproteomes to effectively model the complexity of distinguishing substitutions from genomic peptides. Shotgun proteomics on combined whole cell lysates from both organisms generated a library representing nearly 100,000 peptide-spectra and 4,161 distinct peptide sequences corresponding to genome-level single AAS with defined stoichiometry. We tested the ability to identifyS. typhimuriumpeptide-spectra using only theE. coligenome in substitution-tolerant database searching. Overall, 64.1% of library peptides were correctly identified. We observed a wide range of identification efficiencies based on the specific AAS, but no inherent bias from stoichiometry of the substitution. Short peptides and substitutions near peptide termini, which require specific diagnostic ions for unambiguous identification, are matched with below-average frequency. We also identified “scissor substitutions” that gain or lose protease cleavage sites. Although scissor substitutions are chemically distinct from the genomic peptide, they had poor identification efficiency. This ground-truth AAS library identifies multiple sources of bias in AAS peptide-spectra identification and sets expectations for the application of shotgun proteomics to testing AAS hypotheses.

Significance statement

High-fidelity decoding of the genome is essential for life. Mistranslation leads to amino acid substitutions, which can disrupt protein folding and function, and impact cell fitness. Detection of mistranslated protein products necessitates robust and non-biased approaches. Proteomics is a promising solution, but identifying non-genomic peptide-spectra is a severe bioinformatics challenge. We created a ground-truth library of substituted amino acid peptides by mixing two closely related bacteria in a single sample. We quantitatively defined the degree to which informatics could correctly distinguish substituted peptides when single-organism databases are present. This approach defines intrinsic and informatics limits in substitution detection in shotgun proteomics and identifies previously overlooked challenges with identifying “scissor substitutions”.
MELISSA: Semi-Supervised Embedding for Protein Function Prediction Across Multiple Networks
Authors: Wu Kaiyi , Zhou Di , Slonim Donna , Hu Xiaozhe , Cowen Lenore
Published: August 2023

Motivation

Several popular methods exist to predict function from multiple protein-protein association networks. For example, both the Mashup algorithm, introduced by Cho, Peng and Berger, and deepNF, introduced by Gligorijević, Barotand, and Bonneau, analyze the diffusion in each network first, to characterize the topological context of each node. In Mashup, the high-dimensional topological patterns in individual networks are canonically represented using low-dimensional vectors, one per gene or protein, to yield the multi-network embedding. In deepNF, a multimodal autoencoder is trained to extract common network features across networks that yield a low-dimensional embedding. Neither embedding takes into account known functional labels; rather, these are then used by the machine learning methods applied after embedding.

Results

We introduce MELISSA (MultiNetwork Embedding with Label Integrated Semi-Supervised Augmentation) which incorporates functional labels in the embedding stage. The function labels induce sets of “must link” and “cannot link” constraints which guide a further semi-supervised dimension reduction to yield an embedding that captures both the network topology and the information contained in the annotations. We find that the MELISSA embedding improves on both the Mashup and deepNF embeddings in creating more functionally enriched neighborhoods for predicting GO labels for multiplex association networks in both yeast and humans.

Availability

MELISSA is available athttps://github.com/XiaozheHu/melissa
Role of Adenosine Deaminase in Prostate Cancer Progression
Authors: Charles Christy , Lloyd Stacy M. , Piyarathna Danthasinghe Waduge Badrajee , Gohlke Jie , Rasaily Uttam , Putluri Vasanta , Simons Brian W. , Zaslavsky Alexander , Nallandhighal Srinivas , Palanisamy Nallasivam , Navone Nora , Jones Jeffrey A. , Ittmann Michael M. , Putluri Nagireddy , Rowley David R. , Salami Simpa S. , Palapattu Ganesh S. , Sreekumar Arun
Published: August 2023

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African American (AA) men when compared to European-American (EA) men. PCa tends to be a highly heterogeneous malignancy with a complex biology that is not fully understood. We use metabolomics as a tool to understand the mechanisms behind PCa progression and disparities in its clinical outcome. A key enzyme in the purine metabolic pathway, Adenosine deaminase (ADA) was found upregulated in PCa. ADA was also associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio which is a surrogate for ADA activity was high in the urine of PCa patients and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in the expression of ADA during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis reveals that this tumor growth could be driven by the activation of mTOR signaling. Chronic ADA overexpression shows alterations in the cells’ adhesion machinery and a decrease in the adhesion potential of the cells to the extracellular matrix in vitro. Loss of cell-matrix interaction is critical for metastatic dissemination, suggestive of ADA’s role in promoting metastasis. This is consistent with the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.
Environment predicts the maintenance of reproductive isolation in a mosaic hybrid zone of rubber rabbitbrush
Authors: Faske Trevor M. , Agneray Alison C. , Jahner Joshua P. , Osuna-Mascaró Carolina , Sheta Lana M. , Richardson Bryce A. , Leger Elizabeth A. , Parchman Thomas L.
Published: August 2023

Widely distributed plants of western North America experience divergent selection across environmental gradients, have complex histories shaped by biogeographic barriers and distributional shifts, and often illustrate continuums of reproductive isolation. Rubber rabbitbrush (Ericameria nauseosa) is a foundational shrub species that occurs across diverse environments of western North America. Its remarkable phenotypic diversity is currently ascribed to two subspecies –E. n. nauseosaandE. n. consimilis –and 22 named varieties. We analyzed how genetic variation is partitioned across subspecies, varieties, and environment using high throughput sequencing of reduced representation libraries. We found clear evidence for divergence between the two subspecies, despite largely sympatric distributions. Numerous locations exhibiting admixed ancestry were not geographically localized but were widely distributed across a mosaic hybrid zone. The occurrence of hybrid and subspecific ancestries was strongly predicted by environmental variables as well as the proximity to major ecotones between ecoregions. Although this repeatability illustrates the importance of environmental factors in shaping reproductive isolation, variability in the outcomes of hybridization also indicated these factors likely differ across ecological contexts. There was mixed evidence for the evolutionary cohesiveness of varieties, but several genetically distinct and narrow endemic varieties exhibited admixed subspecific ancestries, hinting at the possibility for transgressive hybridization to contribute to phenotypic novelty and the colonization of new environments inE. nauseosa.
The resolution of face perception varies systematically across the visual field
Authors: Morsi Annie Y. , Goffaux Valérie , Greenwood John A.
Published: August 2023

Visual abilities tend to vary predictably across the visual field – for simple low-level stimuli, visibility is better along the horizontal vs. vertical meridian and in the lower vs. upper visual field. In contrast, face perception abilities have been reported to show either distinct or entirely idiosyncratic patterns of variation in peripheral vision, suggesting a dissociation between the spatial properties of low- and higher-level vision. To assess this link more clearly, we extended methods used in low-level vision to develop an acuity test for face perception, measuring the smallest size at which facial gender can be reliably judged in peripheral vision. In 3 experiments, we show the characteristic inversion effect, with better acuity for upright faces than inverted, demonstrating the engagement of high-level face-selective processes in peripheral vision. We also observe a clear advantage for gender acuity on the horizontal vs. vertical meridian and a smaller-but-consistent lower- vs. upper-field advantage. These visual field variations match those of low-level vision, indicating that higher-level face processing abilities either inherit or actively maintain the characteristic patterns of spatial selectivity found in early vision. The commonality of these spatial variations throughout the visual hierarchy means that the location of faces in our visual field systematically influences our perception of them.
Changes in searching behaviour of CSL transcription complexes in Notch active conditions
Authors: Baloul Sarah , Roussos Charalambos , Gomez-Lamarca Maria , Muresan Leila , Bray Sarah
Published: August 2023

During development cells receive a variety of signals, which are of crucial importance to their fate determination. One such source of signal is the Notch signalling pathway, where Notch activity regulates expression of target genes through the core transcription factor CSL. To understand changes in transcription factor behaviour that lead to transcriptional changes in Notch active cells, we have probed CSL behaviours in real time, usingin vivoSingle Molecule Localisation Microscopy. Trajectory analysis reveals that Notch-On conditions increase the fraction of bound CSL molecules, but also the proportion of molecules with exploratory behaviours. These properties are shared by the co-activator Mastermind. Furthermore, both CSL and Mastermind, exhibit characteristics of local exploration near a Notch target locus. A similar behaviour is observed for CSL molecules diffusing in the vicinity of other bound CSL clusters. We suggest therefore that CSL acquires an exploratory behaviour when part of the activation complex, favouring local searching and retention close to its target enhancers. This change explains how CSL can efficiently increases its occupancy at target sites in Notch-ON conditions.
Elucidating the complex membrane binding of a protein with multiple anchoring domains
Authors: Madsen Jesper J. , Ohkubo Y. Zenmei
Published: August 2023

Membrane binding is a crucial mechanism for many proteins, but understanding the specific interactions between proteins and membranes remains a challenging endeavor. Coagulation factor Va (FVa) is a large protein whose membrane interactions is complicated due to the presence of multiple anchoring domains that individually can bind to lipid membranes. Using molecular dynamics simulations, we investigate the membrane binding of FVa and identify the key mechanisms that govern its interaction with membranes. Our results reveal that can FVa either adopt an upright or a tilted molecular orientation upon membrane binding. We further find that the domain organization of FVa deviates (sometimes significantly) from its crystallographic reference structure, and that the molecular orientation of the protein matches with domain reorganization to align the C2 domain toward its favored membrane-normal orientation. We identify specific amino acid residues that exhibit contact preference with phosphatidylserine lipids over phosphatidylcholine lipids, and we observe that mostly electrostatic effects contribute to this preference. The observed lipid-binding process and characteristics, specific to FVa or common among other membrane proteins, in concert with domain reorganization and molecular tilt, elucidate the complex membrane binding dynamics of FVa and provide important insights into the molecular mechanisms of protein-membrane interactions.