bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic characterisation of Sarculator nomogram-defined risk groups in soft tissue sarcomas of the extremities and trunk wall
Authors: Chadha Madhumeeta , Iadecola Sara , Jenks Andrew , Burns Jessica , Arthur Amani , Pankova Valeriya , Wilding Christopher P , Callegaro Dario , Strauss Dirk C , Thway Khin , Gronchi Alessandro , Jones Robin L , Miceli Rosalba , Pasquali Sandro , Huang Paul H
Published: November 2023

Background

High-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outcomes remain unknown.

Methods

We analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define 4 risk groups. A DNA replication protein signature - Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification.

Results

DNA replication and cell cycle proteins were upregulated in high risk versus very low risk patients. Evaluation of the functional effects of CRISPR-Cas9 gene knockdown of proteins enriched in high risk patients identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e-06), histology (p = 1.4e-05) and risk groups (p = 2.6e-06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy =0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6).

Conclusions

Risk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next-generation nomograms.
Ocean acidification alters the transcriptomic response in the nervous system ofAplysia californicaduring reflex behaviour
Authors: Sourisse Jade M. , Schunter Celia
Published: November 2023

Ocean acidification (OA) has numerous impacts on marine organisms including behaviour. While behaviours are controlled in the neuro system, its complexity makes linking behavioural impairments to environmental change difficult. Here we use a neurological modelAplysia californicawith well-studied simple neuro system and behaviours. By exposingAplysiato current day (∼500 µatm) or near-future CO2conditions (∼1100 µatm), we test the effect of OA on their tail withdrawal reflex (TWR) and the underlying neuromolecular response of the pleural-pedal ganglia, responsible for the behaviour. Under OA,Aplysiarelax tails faster due to increased sensorin-A expression, an inhibitor of mechanosensory neurons. We further investigate how OA affects habituation, which produced a “sensitization-like” behaviour and affected vesicle transport and stress response, revealing an influence of OA on neuronal and behavioural outputs associated with learning. Finally, we test whether GABA-mediated neurotransmission is involved in impaired TWR, but exposure to gabazine did not restore normal behaviour and provoked little molecular response, rejecting the involvement in TWR impairment. Instead, vesicular transport and cellular signalling link other neurotransmitter processes directly with TWR impairment. Our study shows effects of OA on neurological tissue parts that control for behaviour revealing the neurological mechanisms when faced with OA.
Deceased donor kidney function is determined by branch chained amino acid metabolism during ex vivo normothermic perfusion
Authors: Ahmadi Armin , Yu Jacquelyn , Loza Jennifer E. , Howard Brian C. , Palma Ivonne , Than Peter A. , Goussous Naeem Makarm G , Sageshima Junichiro , Roshanravan Baback , Perez Richard V.
Published: November 2023

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion (EVNP) may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. We assessed the association of tissue metabolic changes with changes in kidney injury biomarkers and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12- hour ex vivo normothermic perfusion (EVNP). The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean age of the deceased kidney donors was 43±16 years with an average cold ischemia time of 37±12 hours. Urine output and creatinine clearance progressively increased and peaked at 6 hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% CI 1.5, 140) urinary neutrophil gelatinase-associated lipocalin (NGAL) at 6 hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branch- chained amino acid (BCAA) metabolism. Tissue BCAA levels negatively correlated with urine output among all kidneys at 6 hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Overall, we showed that 6 hours is needed for kidney functional recovery during ENVP and that BCAA metabolism may be a major determinant of organ function and resilience.
‘Look up from the waiting list and see the bigger picture’: A qualitative analysis of clinical specialist physiotherapist perspectives on low back pain care in Ireland
Authors: Murphy Cathriona , French Helen , McCarthy Geraldine , Cunningham Caitriona
Published: November 2023

Introduction

Healthcare systems are struggling to deliver high-quality low back pain (LBP) care. In 2012 specialist physiotherapist-led musculoskeletal (MSK) triage services were introduced in Irish hospitals to expedite patient care and alleviate pressure on elective orthopaedic/ rheumatology consultant clinics. Specialist physiotherapists have expertise to inform health service improvement and reform, but their perspectives of LBP healthcare delivery have received scant attention.

Objectives

To explore specialist physiotherapists’ perspectives on LBP care in Ireland, the barriers and facilitators to quality LBP care and the development of MSK interface services in primary care settings.

Design

Cross-sectional observational study using an anonymous electronic survey with thematic framework analysis of response data from open-ended questions.

Participants

Thirty-four clinical specialist physiotherapists in Irish MSK triage services.

Results

Thematic analysis resulted in six overarching themes, grouped into two categories. One category pertained to LBP healthcare in Ireland with the following three themes: 1) Inadequate health services for patients with LBP; 2) Need for defined LBP clinical pathways; 3) Need for a multisectoral approach to spine health. Themes in the second category, pertaining to the development of community-based MSK interface services, were: 4) Concern regarding isolation from secondary care services; 5) Unrealistic expectations of MSK triage; 6) Improved communication and collaboration with primary care services.

Conclusion

Specialist physiotherapists have concerns regarding LBP health services and persistence of a biomedical, secondary care-led approach. They advocate for investment in primary care multi-disciplinary teams, enhanced integration across primary and secondary care, development of a national clinical pathway and a multisectoral approach.
The impact of pre-existing eye donation awareness of the next of kin on donation rate after grief counseling - A cross-sectional study
Authors: Puri Oshin , Gupta Neeti , Mittal Sanjeev
Published: November 2023

This cross-sectional study was conducted to assess the impact of pre-existing eye donation awareness of the next of kin on the donation rate after grief counseling with due ethical approval. The N=164 most stable next-of-kin, mostly the Brother (20.7%) or Father (20.1%) of the deceased, were approached by the Eye Donation Counselor (EDC). After assessing their awareness about eye donation through the “Awareness and Perception on Eye Donation” questionnaire (Ronanki, V.R, et. al), the EDC grief counseled the next of kin. 84.8% of all participants were aware of eye donation. The mean awareness, knowledge, and perception scores of the study population were 2.46 +/- 1.34 out of 4, 2.73 +/- 2.37 out of 6, and 1.79 +/- 1.72 out of 4 respectively. Eye care professionals (N=105 (64%)) and mass media (N=61 (37.2%)) were identified as the most common sources of information. While 52.4% expressed willingness to donate, only 7.3% donated and there was 1 voluntary donation. Counseling and the belief of eye donation being a noble deed were identified as the major motivators, and objections by other family members, and religious beliefs were the major barriers. There is no significant association between eye donation and the pre-existing awareness of the next of kin regarding eye donation. Although awareness is associated with the increased willingness to donate eyes.
CD206 upregulation in monocytes within whole blood cultures correlates with lung function in Cystic Fibrosis: a pilot study
Authors: Singh Sonali , Longmate Jessica , Onion David , Williams Paul , Camara Miguel , Smyth Alan , Barr Helen , Martinez-Pomares Luisa
Published: November 2023

Chronic inflammation dominates disease pathogenesis in Cystic Fibrosis (CF) and there is a need to characterise CF immunity. Whole blood cultures offer a cost-effective and non-invasive approach to investigate immune responses within the host environment. Here we used whole blood cultures to investigate the differentiation potential of monocytes (CD45+CD14+ cells) in CF (N=10) and controls (N=8) in the presence and absence of exogenous macrophage-colony stimulatory factor (M-CSF) or granulocyte-macrophage (GM)-CSF with and without interleukin (IL)-4. In CF and control cultures, CD45+CD14+ cells upregulated HLA-DR expression in all instances, and increased CD206 in the presence of GM-CSF with and without IL-4, and CD209 in the presence of GM-CSF and IL-4. In CF, we consistently observed reduced upregulation of CD206 in response to GM-CSF and a positive correlation between CD206 expression and lung function (FEV1). This was unique to cultured monocytes, and not seen with any other marker. These results highlight the potential of whole blood cultures to reveal cellular characteristics in differentiating monocytes related to clinical parameters that could guide the identification of novel biomarkers in CF.
Assessing GPT-4 Multimodal Performance in Radiological Image Analysis
Authors: Brin Dana , Sorin Vera , Barash Yiftach , Konen Eli , Nadkarni Girish , Glicksberg Benjamin S , Klang Eyal
Published: November 2023

Objectives

This study aims to assess the performance of OpenAI’s multimodal GPT-4, which can analyze both images and textual data (GPT-4V), in interpreting radiological images. It focuses on a range of modalities, anatomical regions, and pathologies to explore the potential of zero-shot generative-AI in enhancing diagnostic processes in radiology.

Methods

We analyzed 230 anonymized emergency room diagnostic images, consecutively collected over one week, using GPT-4V. Modalities included ultrasound (US), computerized tomography (CT) and X-ray images. The interpretations provided by GPT-4V were then compared with those of senior radiologists. This comparison aimed to evaluate the accuracy of GPT-4V in recognizing the imaging modality, anatomical region, and pathology present in the images.

Results

GPT-4V identified the imaging modality correctly in 100% of cases (221/221), the anatomical region in 87.1% (189/217), and the pathology in 35.2% (76/216).

However, the model’s performance varied significantly across different modalities, with anatomical region identification accuracy ranging from 60.9% (39/64) in US images to 97% (98/101) and 100% (52/52) in CT and X-ray images (p<0.001).

Similarly, Pathology identification ranged from 9.1% (6/66) in US images to 36.4% (36/99) in CT and 66.7% (34/51) for X-ray images (p <0.001).

These variations indicate inconsistencies in GPT-4V’s ability to interpret radiological images accurately.

Conclusion

While the integration of AI in radiology, exemplified by multimodal GPT-4, offers promising avenues for diagnostic enhancement, the current capabilities of GPT-4V are not yet reliable for interpreting radiological images. This study underscores the necessity for ongoing development to achieve dependable performance in radiology diagnostics.
Virtual and remote opioid poisoning education and naloxone distribution programs: a scoping review
Authors: dos Santos Bruna , Nipun Rifat Farzan , Subic Anna Maria , Kubica Alexandra , Rondinelli Nick , Marentette Don , Muise Joanna , Paes Kevin , Riley Meghan , Bhuiya Samiya , Crosby Jeannene , McBride Keely , Salter Joe , Orkin Aaron M.
Published: November 2023

The opioid poisoning crisis is a complex and multi-faceted global epidemic with far-reaching public health effects. Opioid Poisoning Education and Naloxone Distribution (OPEND) programs destigmatize and legitimize harm reduction measures while increasing participants’ ability to administer naloxone and other life-saving interventions in opioid poisoning emergencies. While virtual OPEND programs existed prior to the COVID-19 pandemic and were shown to be effective in improving knowledge of opioid poisoning response, they were not widely implemented and evaluated. The COVID-19 pandemic brought both urgent and sustained interest in virtual health services, including harm reduction interventions and OPEND programs.

We aimed to assess the scope of literature related to fully virtual OPEND programming, with or without naloxone distribution, worldwide. A search of the literature was conducted and yielded 7,722 articles, of which 31 studies fit the inclusion criteria. Type and content of the educational component, duration of training, scales used, and key findings were extracted and synthesized. Our search shows that virtual and remote OPEND programs appear effective in increasing knowledge, confidence, and preparedness to respond to opioid poisoning events while improving stigma regarding people who use substances. This effect is shown to be true in a wide variety of populations but is significantly relevant when focused on laypersons. Interventions ranged from the use of videos, websites, telephone calls, and virtual reality simulations. A lack of consensus was found regarding the duration of the activity and the scales used to measure its effectiveness. Despite increasing efforts, access remains an issue, with most interventions addressing White people in urban areas. These findings provide insights for planning, implementation, and evaluation of future virtual and remote OPEND programs.

Author Summary

Facing a global health challenge, the opioid poisoning crisis affects individuals across all communities, ages, and socioeconomic groups, leading to high fatality rates. Educational programs addressing opioid poisoning have emerged as life-saving and cost-effective interventions. This review focuses on these programs conducted in a virtual setting, eliminating the need for in-person contact between staff and participants. We have identified and summarized evidence about the outcomes of these programs, which may include naloxone distribution. Our findings offer valuable insights for planning, implementing, and evaluating such programs. Furthermore, we highlight gaps in current knowledge, paving the way for future research.
The development and validation of a survey to measure fecal-oral child exposure to zoonotic enteropathogens: The FECEZ Enteropathogens Index
Authors: Ballard April M. , Haardörfer Regine , Angulo Betty Corozo , Freeman Matthew C. , Eisenberg Joseph N.S. , Lee Gwenyth O. , Levy Karen , Caruso Bethany A.
Published: November 2023

Child exposure to animal feces and associated enteropathogens contribute to a significant burden of disease in low- and middle-income countries. However, there are no standardized, validated survey-based approaches to enable accurate assessment of child exposure to zoonotic enteropathogens. We developed and validated a survey-based measure of fecal-oral child exposure to zoonotic enteropathogens, the FECEZ Enteropathogens Index. First, we identified critical attributes of child exposure through in-depth interviews (IDIs) in Ecuador among individuals who care for animals (n=29) and mothers of children under two years old (n=58), and through a systematic review of existing exposure measures. Second, based on these findings, we developed a 105-question survey and administered it to 297 mothers with children under age five. Third, we refined the survey, using principal component analysis to determine the optimal number of components. The final index consisted of 34 items across two sub-domains: the childEnvironmentand childBehavior. Lastly, we compared index scores to two commonly used, unvalidated measures of child exposure – maternal reported household animal ownership and presence of animal feces. Using the FECEZ Enteropathogens Index revealed varying degrees of exposure in our study population, with only two children having no exposure. In contrast, if we had used animal ownership or the presence of animal feces as a measure of exposure, 44% and 33% of children would have been classified as having no exposure, respectively. These common binary exposure measures may be inadequate because they do not provide sufficient information to identify the relative risk of zoonotic pathogen exposure. The FECEZ Enteropathogens Index overcomes this limitation, advancing our ability to assess exposure by quantifying the multiple components of child exposure to zoonotic enteropathogens with higher resolution. Additional testing and evaluation of the index is needed to ensure its reliability, validity, and cross-cultural equivalence in other contexts.
Prognostic value of the mitral E/e’ ratio during exercise in asymptomatic patients with low-gradient severe aortic stenosis and preserved ejection fraction
Authors: Miyahara Daisuke , Izumo Masaki , Sato Yukio , Shoji Tatsuro , Murata Risako , Oda Ryutaro , Okuno Taishi , Kuwata Shingo , Akashi Yoshihiro J
Published: November 2023

Background

Current evidence on the prognostic value of exercise stress echocardiography (ESE) in asymptomatic patients with low-gradient severe AS is limited. Therefore, this study aimed to elucidate its prognostic implications for patients with low-gradient severe AS and determine the added value of ESE in risk stratification for this population.

Methods

This retrospective observational study included 122 consecutive asymptomatic patients with either moderate (mean pressure gradient [MPG] <40 mmHg and aortic valve area [AVA] 1.0–1.5 cm2) or low-gradient severe (MPG <40 mmHg and AVA <1.0 cm2) AS and preserved left ventricular ejection fraction (≥50%) who underwent ESE. All patients were followed up for AS-related events.

Results

Of 143 patients, 21 who met any exclusion criteria, including early interventions, were excluded, and 122 conservatively managed patients (76.5 [71.0–80.3] years; 48.3% male) were included in this study. During a median follow-up period of 989 (578–1571) days, 64 patients experienced AS-related events. Patients with low-gradient severe AS had significantly lower event-free survival rates than those with moderate AS (log-rank test, p<0.001). Multivariable Cox regression analysis showed that the mitral E/e’ ratio during exercise was independently associated with AS-related events (hazard ratio=1.075, p<0.001) in patients with low-gradient severe AS.

Conclusions

This study suggests that asymptomatic patients with low-gradient severe AS have worse prognoses than those with moderate AS. Additionally, the mitral E/e’ ratio during exercise is a useful parameter for risk stratification in patients with low-gradient severe AS.

Clinical Perspective

Aortic stenosis (AS) is increasingly prevalent in aging society, and risk stratification of patients with low-gradient severe AS and preserved ejection fraction remains controversial. Exercise testing has been useful for identifying symptoms or abnormal hemodynamic responses during exercise in patients with asymptomatic AS. Limited evidence supports exercise stress echocardiography (ESE) as a valuable tool for evaluating asymptomatic AS. This study investigated the prognoses of patients with low-gradient severe AS and the utilization of ESE for risk stratification of these patients. Patients with low-gradient severe AS had worse prognoses than those with moderate AS. The mitral E/e’ ratio during exercise can be utilized as a parameter for risk stratification of patients with low-gradient severe AS.
Feature analysis of joint motion while reaching the occiput in patients with mild hemiplegia: a cross-sectional study
Authors: Sakamoto Daigo , Hamaguchi Toyohiro , Kanemura Naohiko , Yasojima Takashi , Kubota Keisuke , Suwabe Ryota , Nakayama Yasuhide , Abo Masahiro
Published: November 2023

This cross-sectional study aimed to clarify the kinematic characteristics of reaching the occiput in patients with mild hemiplegia. Ten patients with post-stroke hemiplegia who attended the Department of Rehabilitation Medicine of the Jikei University Hospital and met the eligibility criteria were included. Reaching motion to the back of the head by the participants’ paralyzed and non-paralyzed upper limbs was measured using three-dimensional motion analysis, and the motor time, joint angles, and angular velocity were calculated. Multivariate analysis of covariance was performed on these data. After confirming the fit to the binomial logistic regression model, the cutoff values were calculated using the receiver operating characteristic curve. The cutoff values for the movement until the hand reached the back of the head were 1.6 s for the motor time, 55° for the maximum shoulder joint flexion angle, and 145° for the maximum elbow joint flexion angle. The cutoff values for the movement from the back of the head to the hand being returned to its original position were 1.6 s for the motor time, 145° for the maximum elbow joint flexion angle, 53°/s for the maximum angular velocity of shoulder joint abduction, and 62°/s for the maximum angular velocity of elbow joint flexion. The numbers of clusters were three, four, and four for the outward non-paralyzed side, outward and return paralyzed side, and return non-paralyzed side, respectively. The findings obtained by this study can be used for practice planning in patients with mild hemiplegia who aim to improve the reaching motion to the occiput.
The unusual structural properties and potential biological relevance of switchback DNA
Authors: Madhanagopal Bharath Raj , Talbot Hannah , Rodriguez Arlin , Louis Jiss Maria , Zeghal Hana , Vangaveti Sweta , Reddy Kaalak , Chandrasekaran Arun Richard
Published: November 2023

Synthetic DNA motifs form the basis of nucleic acid nanotechnology, and their biochemical and biophysical properties determine their applications. Here, we present a detailed characterization of switchback DNA, a globally left-handed structure composed of two parallel DNA strands. Compared to a conventional duplex, switchback DNA shows lower thermodynamic stability and requires higher magnesium concentration for assembly but exhibits enhanced biostability against some nucleases. Strand competition and strand displacement experiments show that component sequences have an absolute preference for duplex complements instead of their switchback partners. Further, we hypothesize a potential role for switchback DNA as an alternate structure in sequences containing short tandem repeats. Together with small molecule binding experiments and cell studies, our results open new avenues for switchback DNA in biology and nanotechnology.
Visual interpretability of image-based classification models by generative latent space disentanglement applied to in vitro fertilization
Authors: Rotem Oded , Schwartz Tamar , Maor Ron , Tauber Yishay , Tsarfati Shapiro Maya , Meseguer Marcos , Gilboa Daniella , Seidman Daniel S. , Zaritsky Assaf
Published: November 2023

The success of deep learning in identifying complex patterns exceeding human intuition comes at the cost of interpretability. Non-linear entanglement of image features makes deep learning a “black box” lacking human meaningful explanations for the models’ decision. We present DISCOVER, a generative model designed to discover the underlying visual properties driving image-based classification models. DISCOVER learns disentangled latent representations, where each latent feature encodes a unique classification-driving visual property. This design enables “human-in-the-loop” interpretation by generating disentangled exaggerated counterfactual explanations. We apply DISCOVER to interpret classification of in-vitro fertilization embryo morphology quality. We quantitatively and systematically confirm the interpretation of known embryo properties, discover properties without previous explicit measurements, and quantitatively determine and empirically verify the classification decision of specific embryo instances. We show that DISCOVER provides human-interpretable understanding of “black-box” classification models, proposes hypotheses to decipher underlying biomedical mechanisms, and provides transparency for the classification of individual predictions.
Evidence that recent climatic changes have expanded the potential geographical range of the Mediterranean fruit fly
Authors: Szyniszewska Anna M. , Bieszczak Hanna , Kozyra Karol , Papadopoulos Nikos T. , Meyer Marc De , Nowosad Jakub , Ota Noboru , Kriticos Darren J.
Published: November 2023

The species distributions migration poleward and into higher altitudes in a warming climate is especially concerning for economically important insect pest species, as their introduction can potentially occur in places previously considered unsuitable for year-round survival. We explore the expansion of the climatically suitable areas for a horticultural pest, the Mediterranean fruit fly (medfly)Ceratitis capitata(Diptera, Tephritidae), with an emphasis on Europe and California. We reviewed and refined a published CLIMEX model forC. capitata, taking into consideration new records in marginal locations, with a particular focus on Europe. To assess the model fit and to aid in interpreting the meaning of the new European distribution records, we used a time series climate dataset to explore the temporal patterns of climate suitability forC. capitatafrom 1970 to 2019. At selected bellwether sites in Europe, we found statistically significant trends in increasing climate suitability, as well as a substantial northward expansion in the modelled potential range. In California, we also found a significant trend of northward and altitudinal expansion of areas suitable forC. capitataestablishment. These results provide further evidence of climate change impacts on species distributions and the need for innovative responses to increased invasion threats.
A chemical structure and machine learning approach to assess the potential bioactivity of endogenous metabolites and their association with early-childhood hs-CRP levels
Authors: Lovric Mario , Wang Tingting , Staffe Mads Ronnow , Sunic Iva , Casni Kristina , Lasky-Su Jessica , Chawes Bo , Rasmussen Morten Arendt
Published: November 2023

Metabolomics has gained much attraction due to its potential to reveal molecular disease mechanisms and present viable biomarkers. In this work we used a panel of untargeted serum metabolomes in 602 childhood patients of the COPSAC2010 mother-child cohort. The annotated part of the metabolome consists of 493 chemical compounds curated using automated procedures. Using predicted quantitative-structure-bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines, we created a filtering method for the vast number of quantified metabolites. The metabolites measured in childrens serums used here have predicted potential against the chosen target modelled targets. The targets from Tox21 have been used with quantitative structure-activity relationships (QSARs) and were trained for ~7000 structures, saved as models, and then applied to 493 metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation. The significant metabolites were reported.
Learning to segment self-generated from externally caused optic flow through sensorimotor mismatch circuits
Authors: Brucklacher Matthias , Pezzulo Giovanni , Mannella Francesco , Galati Gaspare , Pennartz Cyriel M. A.
Published: November 2023

Efficient sensory detection requires the capacity to ignore task-irrelevant information, for example when optic flow patterns created by egomotion need to be disentangled from object perception. To investigate how this is achieved in the visual system, predictive coding with sensorimotor mismatch detection is an attractive starting point. Indeed, experimental evidence for sensorimotor mismatch signals in early visual areas exists, but it is not understood how they are integrated into cortical networks that perform input segmentation and categorization. Our model advances a biologically plausible solution by extending predictive coding models with the ability to distinguish self-generated from externally caused optic flow. We first show that a simple three neuron circuit produces experience-dependent sensorimotor mismatch responses, in agreement with calcium imaging data from mice. This microcircuit is then integrated into a neural network with two generative streams. The motor-to-visual stream consists of parallel microcircuits between motor and visual areas and learns to spatially predict optic flow resulting from self-motion. The second stream bidirectionally connects a motion-selective higher visual area (mHVA) to V1, assigning a crucial role to the abundant feedback connections: the maintenance of a generative model of externally caused optic flow. In the model, area mHVA learns to segment moving objects from the background, and facilitates object categorization. Based on shared neurocomputational principles across species, the model also maps onto primate vision. Our work extends the Hebbian predictive coding to sensorimotor settings, in which the agent actively moves - and learns to predict the consequences of its own movements.

Significance statement

This research addresses a fundamental challenge in sensory perception: how the brain distinguishes between self-generated and externally caused visual motion. Using a computational model inspired by predictive coding and sensorimotor mismatch detection, the study proposes a biologically plausible solution. The model incorporates a neural microcircuit that generates sensorimotor mismatch responses, aligning with experimental data from mice. This microcircuit is integrated into a neural network with two streams: one predicting self-motion-induced optic flow and another maintaining a generative model for externally caused optic flow. The research advances our understanding of how the brain segments visual input into object and background, shedding light on the neural mechanisms underlying perception and categorization not only in rodents, but also in primates.
The speed of sight: individual variation in critical flicker fusion thresholds
Authors: Haarlem Clinton S. , O’Connell Redmond G. , Mitchell Kevin J. , Jackson Andrew L.
Published: November 2023

The critical flicker fusion threshold is a psychophysical measure commonly used to quantify visual temporal resolution; the fastest rate at which a visual system can discriminate visual signals. Critical flicker fusion thresholds vary substantially among species, reflecting different ecological niches and demands. However, it is unclear how much variation exists in flicker fusion thresholds between healthy individuals of the same species, or how stable this attribute is over time within individuals. In this study, we assessed both inter- and intra-individual variation in critical flicker fusion thresholds in a cohort of healthy human participants within a specific age range, using two common psychophysical methods and three different measurements during each session. The resulting thresholds for each method were highly correlated. We found a between-participant maximum difference of roughly 30 Hz in flicker fusion thresholds and we estimated a 95% prediction interval of 21 Hz. We used random-effects models to compare between- and within-participant variance and found that approximately 80% of variance was due to between-individual differences, and about 10% of the variance originated from within-individual differences over three sessions. Within-individual thresholds did not differ significantly between the three sessions in males, but did in females (P<0.001 for two methods and P<0.05 for one method), indicating that critical flicker fusion thresholds may be more variable in females than in males.
hURAT1Transgenic Mouse Model for Evaluating Targeted Urate-Lowering Agents
Authors: De Gejing , Cai Weiyan , Yang Miyi , Zhao Qinghe , Yi Guohua , Lin Peihui , Chen Apeng
Published: November 2023

Objective

Urate transporter 1 (URAT1), a well-established urate-lowering therapeutic target for hyperuricemia and gout treatment, expresses in the kidney proximal tubule and is responsible for uric acid (UA) reabsorption. However, non-primate animal models currently used in pharmacological studies failed to evaluate URAT1 inhibitor’s effectiveness because their URAT1 has a very low UA affinity compared to human URAT1, resulting in a lag in targeting drug screening and novel therapy development for gout treatment. We established a human URAT1 (hURAT1) transgenic knock-in (KI) mouse model to assess uricosuric agents’ effectiveness and characterize URAT1-caused pathogenesis.

Methods

We generatedhURAT1transgenic mice using CRISPR/Cas9 knock-in technique.mUrat1knockout was achieved by replacing exon 1 coding sequence with a humanSLC22A12CDS-pA cassette. Based on the above transgenic mice, a hyperuricemia model was further established by hypoxanthine administration.

Results

ThehURAT1-KI mice successfully expressed hURAT1 protein to the apical side of the kidney proximal tubule epithelium, where a native human URAT1 kidney localization in human body. Upon hypoxanthine challenge, the blood UA level was elevated inhURAT1-KI mice, exhibiting an approximately 37% increase compared towild-type (WT)mice. The elevated blood UA level could be alleviated by hURAT1 inhibitor benzbromarone treatment in thehURAT1-KI mice whereas no response was observed inWTlittermates. Therefore,hURAT1transgenic mice responded well to inhibitors and can be used to evaluate the therapeutic effects.

Conclusion

ThehURAT1-KI hyperuricaemia mouse model would be valuable for preclinical evaluation of urate-lowering agents toward gout treatment and studying UA metabolic complexities in humans.
Invasive traits of freshwater fish database (ITOFF)
Authors: Jessop Aaron , Michalopoulou Anna , Coonan Carolyn , Mazzei Lewis , Sutherland O'Brien Eilidh , Brady Grace , Davison Carly , Gourlay Wayne , Henderson Ethan , Lornie Anna , McCloskey Emily , Ramsay Hannah , Wilson Sophie , Shimadzu Hideyasu , Barbosa Miguel
Published: November 2023

AIM

Species invasions are a major driver of global biodiversity loss, but only a minority of invasions are successful. Evidence suggests that invasive success is linked to life-history traits. Yet, data on invasive success and species’ traits remain fragmented across multiple sources. Here we present the Invasive Traits of Freshwater Fish (ITOFF) database, an interdisciplinary framework that integrates multiple datasets to elucidate the role of life-history traits in shaping invasive success. ITOFF allows seamless access to invasive species data and fosters collaborative actions through knowledge sharing. ITOFF is supported by an innovative web-application that makes complex relationships between invasive and native species accessible to a broad audience. The scientific contribution of ITOFF is illustrated by examining the role of life-history traits and phylogeny in invasion success.

LOCATION

Global.

METHODS

Generalized linear models were used to test the contribution of generation time, trophic level, longevity, and temperature range to invasive success. Through divisive cluster analysis we investigate the role of multiple traits in determining invasive success. Finally, we construct phylogenetic trees to investigate the role of evolutionary history in the invasion process.

RESULTS

ITOFF unifies data for 1917 freshwater fish species representative of invasive species, those species they endanger, and species impacted by invasives but not considered endangered. Invasive species are generally characterized by greater temperature ranges, but are indistinguishable from impacted, endangered, and critically endangered species for the remaining life-history traits. Further, we show that invasive species are generally not distinct from impacted or endangered species when considering multiple traits or phylogeny.

MAIN CONCLUSIONS

ITOFF provides an accessible platform for the improved forecasting of species invasions. ITOFF data shows that classical predictions of life-history traits determining invasive success do not hold amongst freshwater fish species. Forecasting of invasive species must therefore shift towards a wholistic approach encompassing the species and the environment.
Theoretical Analysis of Divalent Cation Effects on Aptamer Recognition of Neurotransmitter Targets
Authors: Douaki Ali , Stuber Annina , Hengsteler Julian , Momotenko Dmitry , Rogers David M. , Rocchia Walter , Hirst Jonathan D. , Nakatsuka Nako , Garoli Denis
Published: November 2023

Aptamer-based sensing of small molecules such as dopamine and serotonin in the brain, requires characterization of the specific aptamer sequences in solutions mimicking thein vivoenvironment with physiological ionic concentrations. In particular, divalent cations (Mg2+and Ca2+) present in brain fluid, have been shown to affect the conformational dynamics of aptamers upon target recognition. Thus, for biosensors that transduce aptamer structure switching as the signal response, it is critical to interrogate the influence of divalent cations on each unique aptamer sequence. Herein, we demonstrate the potential of molecular dynamics (MD) simulations to predict the behaviour of dopamine and serotonin aptamers on sensor surfaces. The simulations enable molecular-level visualization of aptamer conformational changes that, in some cases, are significantly influenced by divalent cations. The correlations of theoretical simulations with experimental findings validate the potential for MD simulations to predict aptamer-specific behaviors on biosensors.
MYC–NFATC2 axismaintains cell cycle and mitochondrial function in AML cells
Authors: Patterson S.D. , Massett M.E. , Huang X. , Jørgensen H.G. , Michie A.M.
Published: November 2023

Acute myeloid leukaemia (AML) is a clonal haematological malignancy affecting the myeloid lineage with generally poor patient outcomes, owing to the lack of targeted therapies. The histone lysine demethylase 4A (KDM4A) has been established as a novel therapeutic target in AML, due to its selective oncogenic role within leukaemic cells.

We identify that the transcription factorNFATC2is a novel binding and transcriptional target of KDM4A in the human AML THP-1 cell line. Further, cytogenetically diverse AML cell lines, including THP-1, were dependent onNFATC2for colony formationin vitro, highlighting a putative novel mechanism of AML oncogenesis.

Our study demonstrates thatNFATC2maintenance of cell cycle progression in human AML cells was driven primarily byCCND1. Through RNA-seq and ChIP-seq,NFATC2was shown to bind to the promoter region of genes involved in oxidative phosphorylation and subsequently regulate their gene expression in THP-1 cells. Furthermore, our data show thatNFATC2shares transcriptional targets with the transcription factor c-MYC, withMYCknockdown phenocopyingNFATC2knockdown. These data suggest a novel co-ordinated role forNFATC2andMYCin the maintenance of THP-1 cell function, indicative of a potential means of therapeutic targeting in human AML.

Graphical Abstract

Acute myeloid leukaemia (AML) cells of diverse cytogenetic backgrounds are dependent onNFATC2for survival; in THP-1 cells,NFATC2is downstream of the epigenetic regulatorKDM4A.NFATC2promotes G1/S phase transition in the cell cycle and oxidative phosphorylation. In addition,NFATC2functions downstream of transcription factorMYC, and maintainsCCND1expression.
Investigating the Association Between Nitrate Dosing and Nitrite Generation by the Human Oral Microbiota in Continuous Culture
Authors: Willmott Thomas , Serrage Hannah J. , Cottrell Elizabeth C. , Humphreys Gavin J. , Myers Jenny , Campbell Paul M. , McBain Andrew J.
Published: November 2023

The generation of nitrite by the oral microbiota is believed to contribute to healthy cardiovascular function, with oral nitrate reduction to nitrite associated with systemic blood pressure regulation. There is the potential to manipulate the composition or activities of the oral microbiota to a higher nitrate-reducing state through nitrate supplementation. The current study examined microbial community composition and enzymatic responses to nitrate supplementation in in sessile oral microbiota grown in continuous culture. Nitrate reductase activity and nitrite concentrations were not significantly different to tongue-derived inocula in model biofilms. These were generally dominated byStreptococcusspp., initially, and a single nitrate supplementation resulted in the increased relative abundance of the nitrate-reducing generaVeillonella, NeisseriaandProteusspp. Nitrite concentrations increased concomitantly and continued to increase throughout oral microbiota development. Continuous nitrate supplementation, over a 7-day period, was similarly associated with an elevated abundance of nitrate-reducing taxa and increased nitrite concentration in the perfusate. In experiments in which the models were established in continuous low or high nitrate environments, there was an initial elevation in nitrate reductase, and nitrite concentrations reached a relatively constant concentration over time similar to the acute nitrate challenge with a similar expansion ofVeillonellaandNeisseria. In summary, we have investigated nitrate metabolism in continuous culture oral biofilms, showing that nitrate addition increases nitrate reductase activity and nitrite concentrations in oral microbiota with the expansion of putatively NaR-producing taxa.

Importance

Clinical evidence suggests that blood pressure regulation can be promoted by nitrite generated through the reduction of supplemental dietary nitrate by the oral microbiota. We have utilised oral microbiota models to investigate the mechanisms responsible, demonstrating that nitrate addition increases nitrate reductase activity and nitrite concentrations in oral microbiota with the expansion of nitrate-reducing taxa.
An electromyography-based multi-muscle fatigue model to investigate operational task performance
Authors: Wei Leonardo H. , Chowdhury Suman K.
Published: November 2023

We developed a multi-muscle fatigue model (MMFM) by incorporating electromyography (EMG)-based amplitude and frequency parameters, the fast-to-slow twitch muscle fiber ratio, a time multiplier to linearize the cumulative effect of time, and a muscle multiplier to standardize the combined effect of the number of muscles being considered. We validated the model by investigating fatigue development patterns of ten male subjects performing one sustained-till-exhaustion static and two repetitive dynamic tasks (low and high task difficulty levels) using 0.91 Kg and 2.72 Kg dumbbells. The results indicated that the MMFM was sensitive to fatigue-related neuromuscular changes and predicted shoulder joint fatigue accurately.
Ice formation and its elimination in cryopreservation of bovine oocytes
Authors: Abdelhady Abdallah W. , Mittan-Moreau David W. , Crane Patrick L. , McLeod Matthew J. , Cheong Soon Hon , Thorne Robert E.
Published: November 2023

Damage from ice and potential toxicity of ice-inhibiting cryoprotective agents (CPAs) are key issues in assisted reproduction using cryopreserved oocytes and embryos. We use synchrotron-based time-resolved x-ray diffraction and tools from protein cryocrystallography to characterize ice formation within bovine oocytes after cooling at rates between ∼1000 °C/min and ∼600,000°C /min and during warming at rates between 20,000 and 150,000 °C /min. Maximum crystalline ice diffraction intensity, maximum ice volume, and maximum ice grain size are always observed during warming. All decrease with increasing CPA concentration, consistent with the decreasing free water fraction. With the cooling rates, warming rates and CPA concentrations of current practice, oocytes may show no ice after cooling but always develop substantial ice fractions on warming, and modestly reducing CPA concentrations causes substantial ice to form during cooling. With much larger cooling and warming rates achieved using cryocrystallography tools, oocytes soaked as in current practice remain essentially ice free during both cooling and warming, and when soaked in half-strength CPA solution oocytes remain ice free after cooling and develop small grain ice during warming. These results clarify the roles of cooling, warming, and CPA concentration in generating ice in oocytes, establish the character of ice formed, and suggest that substantial further improvements in warming rates are feasible. Ice formation can be eliminated as a factor affecting post-thaw oocyte viability and development, allowing other deleterious effects of the cryopreservation cycle to be studied, and osmotic stress and CPA toxicity reduced.

Significance Statement

Cryopreservation of oocytes and embryos is critical in assisted reproduction of humans and domestic animals and in preservation of endangered species. Success rates are limited by damage from crystalline ice, toxicity of cryoprotective agents (CPAs), and damage from osmotic stress. Time-resolved x-ray diffraction of bovine oocytes shows that ice forms much more readily during warming than during cooling, that maximum ice fractions always occur during warming, and that the tools and large CPA concentrations of current protocols can at best only prevent ice formation during cooling. Using tools from cryocrystallography that give dramatically larger cooling and warming rates, ice formation can be completely eliminated and required CPA concentrations substantially reduced, expanding the scope for species-specific optimization of post-thaw reproductive outcomes.