bluuebunny/crossref_metadata_2025 huggingface dataset:
A new, adaptive, self-administered, and generalizable method used to measure visual acuity
Authors: Skerswetat Jan , He Jingyi , Shah Jay Bijesh , Aycardi Nicolas , Freeman Michelle , Bex Peter John
Published: August 2024

SIGNIFICANCE

Angular Indication Measurement (AIM) is an adaptive, self-administered, and generalizable orientation-judgment method designed to interrogate visual functions. We introduce AIM Visual Acuity (VA) and show its features and outcome measures. Angular Indication Measurement VA's ability to detect defocus was comparable with that of an Early Treatment of Diabetic Retinopathy Study (ETDRS) letter chart and showed greater sensitivity to astigmatic blur.

PURPOSE

This proof-of-concept study introduces Angular Indication Measurement and applies it to VA.

METHODS

First, we compared the ability of AIM-VA and ETDRS to detect defocus and astigmatic blur in 22 normally sighted adults. Spherical and cylindrical lenses in the dominant eye induced blur. Second, we compared repeatability over two tests of AIM-VA and ETDRS.

RESULTS

A repeated-measure analysis of variance showed a main effect for defocus blur and test. For the astigmatism experiment, an interaction between blur and orientation was found. Pairwise comparisons showed that AIM was more sensitive to astigmatic-induced VA loss than ETDRS. Bland-Altman plots showed small bias and no systematic learning effect for either test type and improved repeatability with more than two adaptive steps for AIM-VA.

CONCLUSIONS

Angular Indication Measurement VA's ability to detect defocus was comparable with that of an ETDRS letter chart and showed greater sensitivity to induced astigmatic blur, and AIM-VA's repeatability is comparable with ETDRS when using two or more adaptive steps. Angular Indication Measurement's self-administered orientation judgment approach is generalizable to interrogate other visual functions, e.g., contrast, color, motion, and stereovision.
Underrepresented Populations on Public Health Data Dashboards: Design Considerations for Improving Usability and Usefulness
Authors: Ansari Bahareh , Barati Mehdi , Yuan Xiaojun
Published: August 2024

Context

Representation of racial and ethnic minority groups and sexual and gender minority groups is limited on public health data dashboards. The small size of these populations leads to data being aggregated or suppressed to produce stable estimations and preserve individuals’ information privacy. This might, however, limit the usefulness of the represented data for identifying individuals’ risk factors and allocating services.

Objective

To explore public health practitioners’ concerns about underrepresented populations on public health data dashboards that emerged during a usability evaluation study.

Participants

20 public health practitioners from New York State, US.

Setting

Virtual Zoom meetings were conducted to monitor the participants’ use of a public health dashboard and ask about their experience using it. The collected data, in the form of researchers’ notes and audio transcripts, were analyzed using the thematic analysis approach.

Results

Participants were very concerned about the underrepresentation of sexual and gender minority groups and racial and ethnic minority groups on public health data dashboards. Four themes emerged regarding the consequences of the underrepresentation: (1) misinterpretation of risk for underrepresented groups, (2) exacerbating the mistrust between underrepresented populations and the government, (3) a potential disservice to underserved populations if the data is used as the basis for allocating resources, and (4) and unknown impact for the individuals whose demographic information is unknown.

Conclusions

We propose considerations for displaying underrepresented populations on public health data dashboards to improve the utility of the represented data.
The effects of experimental pain on episodic memory and its top-down modulation: a preregistered pooled analysis
Authors: Kaur Jaspreet , Bingel Ulrike , Kincses Balint , Forkmann Katarina , Schmidt Katharina
Published: August 2024

Introduction:

Pain can automatically interfere with ongoing cognitive processes such as attention and memory. The extent of pain's negative effects on cognitive functioning seems to depend on a balance between top-down and bottom-up factors.

Objectives:

In this large, preregistered, pooled reanalysis of 8 studies, we investigated the robustness of the detrimental effect of acute pain on recognition memory and whether top-down mechanisms such as pain-related expectations or cognitions (pain-related fear, pain catastrophizing) modulate this effect.

Methods:

Two hundred forty-seven healthy participants underwent similar experimental paradigms, including a visual categorization task with images randomly paired with (or without) concomitant painful stimulation and a subsequent unannounced recognition task. Recognition memory (ie, d’, recollection, and familiarity) and categorization performance (ie, reaction time, accuracy) served as proxies for the effect of pain on cognitive performance.

Results:

Acute painful stimulation significantly impaired recognition performance (d’, familiarity). However, recognition performance was not significantly modulated by participants' expectations regarding the effect of pain on task performance or pain-related cognitions in this sample of healthy participants.

Conclusion:

Our results corroborate the negative effects of pain on (visual) memory encoding reported in previous studies and reports of “memory problems” from patients with chronic pain. To characterize the role of bottom-up and top-down factors for the detrimental effects of pain, large-scale studies with more nuanced study designs are necessary. Future studies in patient cohorts must unravel the interaction of maladaptive pain-related cognitions and the often-reported impaired cognitive performance in chronic pain patients.
Medical comorbidities and lower myelin content are associated with poor cognition in young adults with perinatally acquired HIV
Authors: Patel Payal B. , Prince David K. , Bolenzius Jacob , Ch’en Peter , Chiarella Jennifer , Kolind Shannon , Vavasour Irene , Pedersen Taylor , Levendovszky Swati Rane , Spudich Serena , Marra Christina , Paul Robert
Published: August 2024

Objective:

Approximately 40% of adults living with HIV experience cognitive deficits. Little is known about the risk factors for cognitive impairment and its association with myelin content in young adults living with perinatally acquired HIV (YApHIV), which is assessed in our cross-sectional study.

Design:

A prospective, observational cohort study.

Methods:

All participants underwent an 11-test cognitive battery and completed medical and social history surveys. Cognitive impairment was defined asZscores falling at least 1.5 SD below the mean in at least two domains. Twelve participants underwent myelin water imaging. Neuroimaging data were compared to age and sex-matched HIV-uninfected controls. Regression analyses were used to evaluate for risk factors of lower cognitive domain scores and association between myelin content and cognition in YApHIV.

Results:

We enrolled 21 virally suppressed YApHIV across two sites in the United States. Ten participants (48%) met criteria for cognitive impairment. Participants with any non-HIV related medical comorbidity scored lower across multiple cognitive domains compared to participants without comorbidities. Myelin content did not differ between YApHIV and controls after adjusting for years of education. Lower cognitive scores were associated with lower myelin content in the cingulum and corticospinal tract in YApHIV participants after correcting for multiple comparisons.

Conclusion:

Poor cognition in YApHIV may be exacerbated by non-HIV related comorbidities as noted in older adults with horizontally acquired HIV. The corticospinal tract and cingulum may be vulnerable to the legacy effect of untreated HIV in infancy. Myelin content may be a marker of cognitive reserve in YApHIV.
Harnessing artificial intelligence microscopy to improve diagnostics for soil-transmitted helminthiasis and schistosomiasis: a review of recent advances and future pathways
Authors: Ward Peter , Levecke Bruno , Ajjampur Sitara
Published: August 2024

Purpose of review

This opinion piece aims to explore the transformative potential of integrating artificial intelligence with digital microscopy to enhance diagnostics for soil-transmitted helminthiasis (STH) and schistosomiasis (SCH), two pervasive neglected tropical diseases (NTDs). By aligning innovative artificial intelligence-driven solutions with WHO's strategic objectives and calls for better, more accessible, and more integrated diagnostics, we highlight the latest advancements that may support improved health outcomes in affected communities.

Recent findings

The review covers recent advancements in artificial intelligence-based diagnostic technologies, emphasizing automated egg detection and quantification. These technologies promise to mitigate challenges such as human error and the need for skilled technicians.

The findings have significant implications for public health, ethical considerations and regulatory pathways, particularly in resource-limited settings. The authors advocate for interdisciplinary collaboration and a strategic focus on meeting WHO target product profiles to ensure uptake, ultimately to support reaching WHO NTD targets.
New diagnostic strategies to distinguish Crohn's disease and gastrointestinal tuberculosis
Authors: Narang Himanshu , Kedia Saurabh , Ahuja Vineet
Published: August 2024

Purpose of review

Despite advances in our radiological, histological and microbiological armamentarium, distinguishing between Crohn's disease (CD) and intestinal tuberculosis (ITB), especially in a TB endemic country, continues to be a challenging exercise in a significant number of patients. This review aims to summarize current available evidence on novel diagnostic techniques which have a potential to fill the gap in our knowledge of differentiating between ITB and CD.

Recent findings

Both ITB and CD are associated with altered host immune responses, and detection of these altered innate and adaptive immune cells has potential to distinguish ITB from CD. ITB and CD have different epigenetic, proteomic and metabolomic signatures, and recent research has focused on detecting these differences. In addition, the gut microbiome, which is involved in mucosal immunity and inflammatory responses, is considerably altered in both ITB and CD, and is another potential frontier, which can be tapped to discriminate between the two diseases. With technological advancements, we have newer radiological modalities including perfusion CT and dual-layer spectral detector CT enterography and evidence is emerging of their role in differentiating ITB from CD. Finally, time will tell whether the advent of artificial intelligence, with rapidly accumulating data in this field, will be the gamechanger in solving this puzzle of diagnostic dilemma between ITB and Crohn's disease.

Recent advances need to be clinically validated before they can be used as novel diagnostic measures to differentiate Intestinal TB from CD.
A Systematic Preoperative Evaluation and Skin Excision Design for Incisional Blepharoplasty
Authors: Gao Fulei , Zhao Qiuyu , Zhang Liucheng , Mao Xiyuan , Sun Xiaoming , Zhang Yuguang
Published: August 2024

Background:

The prevalence of skin redundancy and lack of creases in the Asian upper eyelids makes blepharoplasty popular. Although many incision designs have been developed to improve upper eyelid laxity, there is a lack of a universal method to match various upper eyelid conditions. We present a systematic preoperative evaluation and design approach that incorporates eye esthetics to determine the shape and amount of skin to be removed to create attractive eyes.

Methods:

A retrospective review of 352 patients who underwent incisional blepharoplasty from May 2020 to May 2022 was performed. The excised area was determined preoperatively according to the degree of upper eyelid skin laxity, and the best of the three precise designs is chosen.

Results:

All patients undergoing the procedure achieved a satisfactory eyelid appearance immediately after surgery. Patients were followed up for 3 to 12 months. All patients had significant improvement in upper eyelid skin laxity and a natural shape of the eyelid. No defects that required revision surgery to improve were present, and 91.7% of the patients were satisfied with the long-term outcome.

Conclusions:

This systematic approach to preoperative design is simple, effective, and feasible to avoid scar exposure while addressing the lateral hood and achieve an attractive blepharoplasty appearance.
Clinical Efficacy of Concentrated Growth Factors for the Management of Marginal Tissue Recession: A Systematic Review and Meta-Analysis
Authors: Yerte Shivani B. , Kulloli Anita , Mehta Vini , Mathur Ankita , Cicciù Marco , Fiorillo Luca
Published: August 2024

Introduction:

To systematically review existing scientific literature to determine, compare, and evaluate whether concentrated growth factors (CGF) or connective tissue grafts (CTG) is a better treatment alternative for patients with marginal tissue recession (MTR).

Methods:

Electronic databases like PubMed, Embase, Scopus, and Google Scholar were screened from the last 20 years reporting treatment of MTR using CGF or CTG and other techniques. Periodontal parameters like probing depth, clinical attachment level, recession depth, recession width, keratinized tissue width, root coverage, increase in gingival thickness and plaque index, and gingival index were compared. Standardized mean difference was used as a summary statistic measure with a random effect model and P value <0.05 as statistically significant.

Results:

Six studies fulfilled eligibility criteria and were included in qualitative synthesis, of which only 4 studies were suitable for meta-analysis. The pooled estimate through standardized mean difference signifies that CGF was superior to CTG in the reduction of probing depth, gingival index, and plaque index and gain in clinical attachment level while CTG was superior in reducing the recession depth and recession width. Both the procedures had an overall equal effect on keratinized tissue width and root coverage, but these differences were statistically insignificant (P>0.05). Publication bias through the funnel plot showed symmetric distribution without systematic heterogeneity.

Conclusion:

The present study suggests that treatment of MTR with CTG or CGF resulted in clinically favorable outcomes, but no statistically significant differences was observed between these 2 procedures regarding the outcome.
Unilateral Dacryoadenitis as the First Symptom of Systemic Lupus Erythematous
Authors: Yoon Heejin , Ahn Junghyo
Published: August 2024

This case report focuses on a patient with systemic lupus erythematous whose first symptom was dacryoadenitis. A 42-year-old Asian woman presented with a 3-day history of left periorbital swelling and pain. Gross examination revealed left periorbital swelling with no definite tenderness. Initial computed tomography with contrast showed diffuse enhancement and enlargement of the left lacrimal gland with adjacent fluid collection, indicating periorbital soft tissue swelling. She was diagnosed with left dacryoadenitis and treated with intravenous methylprednisolone (60 mg/day) and oral prednisolone (10 mg/day). Over the next 6 months, she experienced numerous instances of recurrence, which was shortly responsive to oral and intravenous high-dose steroids. Immunosuppressive therapy was selected, and upon conducting laboratory tests, she was diagnosed with systemic lupus erythematous. Since then, the patient has undergone treatment involving hydroxychloroquine (200 mg/day) and azathioprine (50 mg/day) with no recurrence.
Clinical Study of Photobiomodulation Effect at Postoperative Clefted Alveolar Ridge Bone Grafting
Authors: Guerrini Luísa Belluco , de Freitas Nicole Rosa , de Azevedo-Silva Lucas José , dos Santos Caroline Chapernate Vieira , Machado Maria Aparecida de Andrade Moreira , de Oliveira Thais Marchini , Almeida Ana Lúcia Pompéia Fraga de
Published: August 2024

This study aimed to evaluate photobiomodulation (PBM) adjunct effect on pain, swelling, and face temperature in individuals with oral cleft submitted to alveolar ridge bone grafting (ABG). The sample consisted of 46 patients with either incomplete or complete unilateral cleft lip and palate aged from 9 to 18 years, both sexes, who underwent ABG with chin donor area. Subjects were randomly divided into 3 groups: (1) Control (C): ABG (n=17); (2) PBM: ABG with PBM (n=14); (3) Simulated photobiomodulation (SPBM): ABG with SPBM (n=15). Aluminum Gallium Arsenide (GaAlAs) infrared laser was used at 808±10 nm and power of 100 mW±20%. GaAlAs infrared laser was applied on 14 points in the subject’s face at 4J per point, at 2 times: Immediate postoperative period and 24 hours postoperative. The authors evaluated pain, swelling, and face temperature at 24 hours postoperative; at 7-day postoperative, the authors evaluated pain, medication use, and swelling decreasing perception. No statistically significant difference occurred between groups C, PBM, and SPBM. At 24 hours postoperative, pain values showed statistically significant difference (P=0.04) between group C and SPBM. PBM at the tested parameters did not reduce pain and swelling and did not significantly change face temperature of individuals submitted to ARBG.
In-depth Clinical, Hemodynamic, and Volumetric Assessment of the Resection and Partial Liver Transplantation With Delayed Total Hepatectomy-Type Auxiliary Liver Transplantation in Noncirrhotic Setting
Authors: Coubeau Laurent , Fontaine Alix , Ciccarelli Olga , Bonaccorsi Eliano , Derudder Max , Dahqvist Géraldine , Marique Lancelot , Reding Raymond , Leclercq Isabelle A. , Dili Alexandra
Published: August 2024

Background:

The Resection And Partial Liver Transplantation with Delayed total hepatectomy (RAPID) procedure involves left hepatectomy with orthotopic implantation of a left lobe and right portal vein ligation. This technique induces volumetric graft increase, allowing for a right completion hepatectomy within 15 days. Notably, there is a lack of data on the hemodynamics of small-for-size grafts exposed to portal overflow without triggering small-for-size syndrome.

Methods:

A prospective single-center protocol included 8 living donors and 8 RAPID noncirrhotic recipients. Comprehensive clinical and biological data were collected, accompanied by intraoperative arterial and portal flow and pressure measurements. Early kinetic growth rate (eKGR%) and graft function were assessed using computed tomography and 99Tc-mebrofenin scintigraphy on postoperative days 7 and 14. Findings were compared with retrospective data from 13 left living donor liver transplantation (LDLT) recipients.

Results:

The median Graft-body weight ratio was 0.41% (interquartile range: 0.34–0.49), markedly lower than in LDLT. However, there was no significant difference in eKGR between RAPID and LDLT grafts. Sequential analysis revealed variable eKGR per day: 10.6% (7.8–13.2) in the first week and 7.6% (6–9.1) in the second week posttransplantation. Indexed portal flow (indexed portal vein flow) was significantly higher in RAPID compared with left LDLT (P = 0.01). No hemodynamic parameters were found to correlate with regeneration speed. We modulated portal flow in 2 out of 8 cases.

Conclusions:

This study presents the first report of hemodynamic and volumetric data for the RAPID technique. Despite initial graft volumes falling below conventional LDLT recommendations, the study highlights acceptable clinical outcomes.
Barriers to Adherence to Overactive Bladder Treatment for Hispanic Women
Authors: Vurture Gregory , Jenkins Nicole , Jacobson Nina , Smilen Scott W.
Published: August 2024

Importance

Adherence to overactive bladder (OAB) therapy is low among the general population. Prior studies suggest that OAB is more prevalent among Hispanic women compared with other ethnicities.

Objectives

The aims of this study were to analyze nonadherence to OAB therapy among Hispanic compared with non-Hispanic women and identify potential barriers to treatment to reduce disparities in care.

Study Design

All patients who received treatment for OAB between 2018 and 2022 were included in this retrospective study. Race and ethnicity were self-reported. Nonadherence was defined as failure to initiate therapy within 1 year. Non-Hispanic women were selected at random to form a control group. The study was powered to detect a 50% difference in treatment nonadherence. Comparisons were made using the Fisher exact test or χ2 test as appropriate for nominal variables, and the Mann-Whitney test for continuous variables.

Results

The analysis included 126 Hispanic and 126 non-Hispanic women. Both cohorts were similar in demographics. Nonadherence to OAB therapy was more frequent among Hispanic women (44.0 vs 20.9%, P < 0.0001). After adjusting for age, body mass index, primary language, parity, insurance type, and treatment offered, Hispanic women were at a 2.54-fold increased risk of nonadherence (P = 0.007). A subanalysis of only Hispanic women found that younger age (P = 0.033), higher parity (P = 0.035) underinsured status (P = 0.027), and fewer office visits (P = 0.0002) were associated with nonadherence.

Conclusions

Nonadherence to OAB therapy was greater among Hispanic women despite no difference in treatment patterns. Younger age, greater parity, lack of insurance, and fewer office visits may be barriers for Hispanic women.
Unravelling the mechanics of knitted fabrics through hierarchical geometric representation
Authors: Ding Xiaoxiao , Sanchez Vanessa , Bertoldi Katia , Rycroft Chris H.
Published: August 2024

Knitting interloops one-dimensional yarns into three-dimensional fabrics that exhibit behaviour beyond their constitutive materials. How extensibility and anisotropy emerge from the hierarchical organization of yarns into knitted fabrics has long been unresolved. We seek to unravel the mechanical roles of tensile mechanics, assembly and dynamics arising from the yarn level on fabric nonlinearity by developing a yarn-based dynamical model. This physically validated model captures the mechanical response of knitted fabrics, analogous to flexible metamaterials and biological fibre networks due to geometric nonlinearity within such hierarchical systems. Fabric anisotropy originates from observed yarn–yarn rearrangements during alignment dynamics and is topology-dependent. This yarn-based model also provides a design space of knitted fabrics to embed functionalities by varying geometric configuration and material property in instructed procedures compatible to machine manufacturing. Our hierarchical approach to build up a knitted fabric computationally modernizes an ancient craft and represents a first step towards mechanical programmability of knitted fabrics in wide engineering applications.
Quantum-like states on complex synchronized networks
Authors: Scholes Gregory D.
Published: August 2024

Recent work has exposed the idea that interesting quantum-like (QL) probability laws, including interference effects, can be manifest in classical systems. Here, we propose a model for QL states and QL bits. We suggest a way that huge, complex systems can host robust states that can process information in a QL fashion. Axioms that such states should satisfy are proposed. Specifically, it is shown that building blocks suited for QL states are networks, possibly very complex, that we defined based on

k

-regular random graphs. These networks can dynamically encode a lot of information that is distilled into the emergent states we can use for QL processing. Although the emergent states are classical, they have properties analogous to quantum states. Concrete examples of how QL functions are possible are given. The possibility of a ‘QL advantage’ for computing-type operations and the potential relevance for new kinds of function in the brain are discussed and left as open questions.
Multi-decadal warming alters predator’s effect on prey community composition
Authors: Niu Jingyao , Huss Magnus , Garnier Aurélie , Vasemägi Anti , Gårdmark Anna
Published: August 2024

Predator responses to warming can occur via phenotypic plasticity, evolutionary adaptation or a combination of both, changing their top-down effects on prey communities. However, we lack evidence of how warming-induced evolutionary changes in predators may influence natural food webs. Here, we ask whether wild fish subject to warming across multiple generations differ in their impacts on prey communities compared with their nearby conspecifics experiencing a natural thermal regime. We carried out a common garden mesocosm experiment with larval perch (
Perca fluviatilis
), originating from a heated or reference coastal environment, feeding on zooplankton communities under a gradient of experimental temperatures. Overall, in the presence of fish of heated origin, zooplankton abundance was higher and did not change with experimental warming, whereas in the presence of fish of unheated origin, it declined with experimental temperature. Responses in zooplankton taxonomic and size composition suggest that larvae of heated origin consume more large-sized taxa as the temperature increases. Our findings show that differences between fish populations, potentially representing adaptation to their long-term thermal environments, can affect the abundance, biomass, size and species composition of their prey communities. This suggests that rapid microevolution in predators to ongoing climate warming might have indirect cross-generational ecological consequences propagating through food webs.
Olfactory learning in
Pieris brassicae
butterflies is dependent on the intensity of a plant-derived oviposition cue
Authors: Peftuloglu Dimitri , Bonestroo Stefan , Lenders Roos , Smid Hans M. , Dicke Marcel , van Loon Joop J. A. , Haverkamp Alexander
Published: August 2024

Butterflies, like many insects, use gustatory and olfactory cues innately to assess the suitability of an oviposition site and are able to associate colours and leaf shapes with an oviposition reward. Studies on other insects have demonstrated that the quality of the reward is a crucial factor in forming associative memory. We set out to investigate whether the large cabbage white
Pieris brassicae
(Linnaeus) has the ability to associate an oviposition experience with a neutral olfactory cue. In addition, we tested whether the strength of this association is dependent on the gustatory response to the glucosinolate sinigrin, which is a known oviposition stimulus for
P. brassicae
. Female butterflies were able to associate a neutral odour with an oviposition experience after a single oviposition experience, both in a greenhouse and in a semi-natural outdoor setting. Moreover, butterflies performed best when trained with concentrations of sinigrin that showed the strongest response by specific gustatory neurons on the forelegs. Our study provides novel insight into the role of both gustatory and olfactory cues during oviposition learning in lepidopterans and contributes to a better understanding of how these insects might be able to adapt to a rapidly changing environment.
The potential of regulatory variant prediction AI models to improve cattle traits
Authors: Zhao R , Owen R , Marr M , Siddharth J , Chue Hong N , Talenti A , Hassan MA , Prendergast JGD
Published: August 2024

Considerable progress has been made in developing machine learning models for predicting human functional variants, but progress in livestock species has been more limited. This is despite the disproportionate potential benefits such models could have to livestock research, from improving breeding values to prioritising functional variants at trait-associated loci. A key open question is what datasets and modelling approaches are most important to close this performance gap between species. In this work we have developed a new framework for predicting regulatory variants, that includes deriving key conservation metrics in cattle for the first time, variant annotation and model training. When trained on expression quantitative trait loci (eQTL) and massively parallel reporter assay (MPRA) data for human and cattle we show that this framework has a high performance at predicting regulatory variants, with a maximum area under the receiver operating characteristic curve (AUROC) score of 0.92 in human and 0.81 in cattle. We explore various approaches to further close this performance gap, including integrating advanced DNA sequence models and generating extra chromatin data, but illustrate that the best approach would be generating improved gold-standard sets of known cattle regulatory variants. Importantly we demonstrate both the human and cattle models substantially enrich for variants linked to important traits, with up to 25-fold enrichments for functional variants observed. Consequently, with our framework developed to be applicable across species these results not only demonstrate its potential utility for fine-mapping functional variants and improving breeding values in cattle, but also its potential for wider use across animal species.
Attenuation of Atherosclerosis with PAR4 Deficiency: Differential Platelet Outcomes in apoE-/-vs. Ldlr-/-Mice
Authors: Wadding-Lee Caris A. , Jay Megan , Jones Shannon M. , Thompson Joel , Howatt Deborah A. , Daugherty Alan , Mackman Nigel , Owens A. Phillip
Published: August 2024

Objective

Cardiovascular disease (CVD) is a significant burden globally and, despite current therapeutics, remains the leading cause of death. Platelet inhibitors are of interest in CVD treatment to reduce thrombus formation post-plaque rupture as well their contribution to inflammation throughout the progression of atherosclerosis. Protease activated receptor 4 (PAR4) is a receptor highly expressed by platelets, strongly activated by thrombin, and plays a vital role in platelet activation and aggregation. However, the role of PAR4

Approach and Results

Mice on a low-density lipoprotein receptor-deficient (Ldlr-/-) background were bred withPar4deficient (Par4-/-) mice to createLdlr-/-/Par4+/+andLdlr-/-/Par4-/-cousin lines. Mice were fed high fat (42%) and cholesterol (0.2%) ‘Western’ diet for 12 weeks for all studies. Bone marrow transplant (BMT) studies were conducted by irradiatingLdlr-/-/Par4+/+andLdlr-/-/Par4-/-mice with 550 rads (2x, 4 hours apart) and then repopulated withPar4+/+orPar4-/-bone marrow. To determine if the effects of thrombin were mediated solely by PAR4, the thrombin inhibitor dabigatran was added to the ‘Western’ diet.Ldlr-/-/Par4-/-given dabigatran did not further decrease their atherosclerotic burden. Differences between apolipoprotein E deficient (apoE-/-) andLdlr-/-platelets were assessed for changes in reactivity. We observed higher PAR4 abundance in arteries with atherosclerosis in human and mice versus healthy controls. PAR4 deficiency attenuated atherosclerosis in the aortic sinus and root versus proficient controls. BMT studies demonstrated this effect was due to hematopoietic cells, most likely platelets. PAR4 appeared to be acting independent of PAR1, as there werer no changes with addition of dabigatran to PAR4 deficient mice.apoE-/-platelets are hyperreactive compared toLdlr-/-platelets.

Conclusions

Hematopoietic-derived PAR4, most likely platelets, plays a vital role in the development and progression of atherosclerosis. Specific targeting of PAR4 may be a potential therapeutic target for CVD.

Highlights

Deficiency of protease-activated receptor 4 attenuates the development of diet-induced atherosclerosis in aLdlr-/-mouse model.

PAR4 deficiency in hematopoietic cells is atheroprotective.

PAR4 deficiency accounts for the majority of thrombin-induced atherosclerosis in aLdlr-/-mouse model.

The examination of platelet-specific proteins and platelet activation should be carefully considered before using theapoE-/-orLdlr-/-mouse models of atherosclerosis.
PD-1 controls differentiation, survival, and TCR affinity evolution of stem-like CD8+ T cells
Authors: Hor Jyh Liang , Schrom Edward C. , Wong-Rolle Abigail , Vistain Luke , Shang Wanjing , Dong Qiang , Zhao Chen , Jin Chengcheng , Germain Ronald N.
Published: August 2024

Stem-like progenitors are a critical subset of cytotoxic T cells that self-renew and give rise to expanded populations of effector cells critical for successful checkpoint blockade immunotherapy. Emerging evidence suggests that the tumor-draining lymph nodes can support the continuous generation of these stem-like cells that replenish the tumor sites and act as a critical source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Using advanced 3D multiplex immunofluorescence imaging, here we identified antigen-presentation niches in tumor-draining lymph nodes that support the expansion, maintenance, and affinity evolution of a unique population of TCF-1+PD-1+SLAMF6histem-like CD8+ T cells. Our results show that contrary to the prevailing view that persistent TCR signaling drives terminal effector differentiation, prolonged antigen engagement well beyond the initial priming phase sustained the proliferation and self-renewal of these stem-like T cellsin vivo. The inhibitory PD-1 pathway plays a central role in this process by mediating the fine-tuning of TCR and co-stimulatory signal input that enables selective expansion of high affinity TCR stem-like clones, enabling them to act as a renewable source of high affinity effector cells. PD-1 checkpoint blockade disrupts this fine tuning of input signaling, leading to terminal differentiation to the effector state or death of the most avid anti-tumor stem-like cells. Our results thus reveal an unexpected relationship between TCR ligand affinity recognition, a key negative feedback regulatory loop, and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 checkpoint blockade during cancer immunotherapy provides a short-term anti-tumor effect that comes at the cost of diminishing efficacy due to progressive loss of these critical high affinity stem-like precursors.
Pathophysiological response in experimental trauma-related acute kidney injury
Authors: Halbgebauer Rebecca , Schult Lorena , Borgel Onno , Maes Arne , Weißhaupt Florian , Rastner Christina , Ast Alitsia , Lupu Ludmila , Palmer Annette , Wachter Ulrich , Schmidt Stefan A. , Boor Peter , Rösler Reinhild , Wiese Sebastian , Kerckhofs Greet , Huber-Lang Markus S.
Published: August 2024

Background

Trauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes.

Methods

To study the pathophysiology of TRAKI, we developed a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage that induces mild transient TRAKI.

Results

The mice showed early and transient increased plasma creatinine, urea, NGAL, and urine albumin, resolving 5 days after TRAKI induction. Despite normal kidney morphology, significant damage to proximal tubular cells and a loss of the brush border was observed. This included kidney stress responses, e.g., with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes after trauma. 3D x-ray-based whole-organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood flow, especially during the first day post THS, which was partly resolved by day 5.

Conclusions

Our novel model of murine TRAKI has revealed previously unknown aspects of the complex temporal pathophysiological response of the kidney along the nephron after trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches.
Thrombo-inflammation analyzed in a validated seven-layer platelet decision model: cellular decisions are tough problems fast and heuristically solved
Authors: Prada Juan , Balkenhol Johannes , Osmanoglu Özge , Afshar Maral , Kaltdorf Martin , Hofmann Sarah , von Mammen Sebastian , Heinze Katrin G. , Schulze Harald , Dandekar Thomas
Published: August 2024

Decisions in biology happen fast and are driven by evolution to optimize survival chances. In platelets, this is achieved by organizing signaling cascades into rapid decision-funnels with modulatory crosstalk. We show that network decision processes underlying cellular decisions are tough to solve (equivalent to classical satisfiability problems, SAT). Hence, heuristics, modular decision-making, and decision funnels are required for efficient decisions.

We establish this using a seven-layer platelet decision network that agrees well with all available genetic and functional experimental data. Platelet decision cascades are robust to perturbations: For example, receptors such as TRPM7 modulate platelet activity. However, knockouts of the receptors still leave platelets reactive overall. Dynamic control resolves relaying functions from kinases to cytoskeleton alterations. This allows fast execution of platelet shape change or aggregation. Stress conditions can shift platelet decision funnels towards constant activation of aggregation or immune signaling, causing thrombosis or thrombo-inflammation. Based on the network dynamics, we conclude that platelets pragmatically resolve the complex (non-polynomial (NP)) cellular decision problems by using a similar relaxation to those proposed in mathematics – many different configurations end up in similar states. Metamathematical considerations (no mathematical proof) suggest that NP problems are more complex then P problems.

One sentence abstract

We show that cellular decision problems like the platelet signaling cascade may need unexpectedly long to solve but in general, they are efficiently solved using heuristics (“decision funnels”), implying fast decisions but the risk of chronic stress and inflammation.
On the same side: The immune regulatory protein Vista and its ligands interact in cis
Authors: Smorodinsky-Atias Karina , Wiseglass Gil , Salem Mariana , Kashani Maya , Boni Nadir , Artyukhova Alina , Levy Rachel , Rubinstein Rotem
Published: August 2024

VISTA, an essential immune checkpoint regulatory protein, regulates peripheral T-cell quiescence and tolerance. Despite its potential as a target for anti-tumor and autoimmune disease therapies, uncertainty regarding VISTA’s binding mode and membrane orientation has hindered these developments. Contrary to the prevailing paradigm, we found using cell aggregation assays that VISTA cannot interact with its ligands intrans(between cells). Using MST and flow cytometry, we showed that soluble VISTA binds to its ligands, suggesting that VISTA’s membrane orientation restrictstransinteractions. In contrast, split luciferase complementation assays showed that VISTA interacts with its ligands incis. We propose that a disulfide bond bends VISTA’s Ig domain towards the membrane in an orientation that preventstranswhile enablingcisinteractions. Co-expression data analysis from the cancer genome atlas showed a strong correlation between VISTA and its ligand, PSGL-1, consistent with our in-vitrocisinteraction data. Our findings reveal VISTA’s binding mechanism and suggest an intrinsic inhibition signaling pathway independent of additional cells. Importantly, our experimental framework provides a platform for identifying novel VISTA-targeted therapeutics.
Performance and Robustness of Parameter Estimation from Phylogenetic Trees Using Neural Networks
Authors: Qin Tianjian , van Benthem Koen J. , Valente Luis , Etienne Rampal S.
Published: August 2024

Species diversification is characterized by speciation and extinction, the rates of which can, under some assumptions, be estimated from time-calibrated phylogenies. However, maximum likelihood estimation methods (MLE) for inferring rates are limited to simpler models and can show bias, particularly in small phylogenies. Likelihood-free methods to estimate parameters of diversification models using deep learning have started to emerge, but how robust neural network methods are at handling the intricate nature of phylogenetic data remains an open question. Here we present a new ensemble neural network approach to estimate diversification parameters from phylogenetic trees that leverages different classes of neural networks (dense neural network, graph neural network, and long short-term memory recurrent network) and simultaneously learns from graph representations of phylogenies, their branching times and their summary statistics. Our best-performing ensemble neural network (which corrects graph neural network result using a recurrent neural network) can compute estimates faster than MLE and is less affected by tree size. Our analysis suggests that the primary limitation to accurate parameter estimation is the amount of information contained within a phylogeny, as indicated by its size and the strength of effects shaping it. In cases where MLE is unavailable, our neural network method provides a promising alternative for estimating phylogenetic tree parameters. If there are detectable phylogenetic signals present, our approach delivers results that are comparable to MLE but without inherent biases.
Nutrient Challenges in a Changing Atmosphere: Investigating Biomass Growth and Mineral Concentration Changes in Soybean Plants under Elevated CO2
Authors: Kaur Ravneet , Durstock Mary , Prior Stephen A. , Runion G. Brett , Ainsworth Elizabeth A. , Baxter Ivan , Sanz-Sáez Alvaro , Leisner Courtney P.
Published: August 2024

Rising atmospheric CO2levels, projected to reach ∼650 ppm by 2050, threaten the nutritional value of food crops. This rise is expected to increase biomass yield in C3plants through enhanced photosynthesis and water-use efficiency. However, elevated CO2(eCO2) reduces protein, nitrogen, and essential minerals like zinc (Zn) and iron (Fe) in plant leaves and seeds, posing a global nutrition risk. We conducted an experiment using Open Top Chambers to examine the response of three soybean cultivars (Clark, Flyer, and Loda) to ambient (∼410 ppm) and eCO2(∼610 ppm) conditions. These cultivars were selected due to their contrasting responses to eCO2. Measurements of physiological parameters (i.e., biomass, and nutrient concentration) were taken at different growth stages. Our results showed that eCO2increased carbon assimilation, leading to higher aboveground biomass and seed yield (through increased seed number) while root biomass remained unchanged. eCO2also reduced stomatal conductance and transpiration. There was a significant decrease in seed nutrient concentration at maturity, particularly iron (Fe), phosphorous (P), potassium (K), and magnesium (Mg), in plants grown in eCO2. These findings suggest that increased yield, reduced transpiration, and unchanged root biomass are key drivers of nutrient dilution in seeds under eCO2.
CHRONIC LUNG INFLAMMATION LEADS TO MYELOID SKEWING OF HEMATOPOIETIC STEM CELLS IN A CYSTIC FIBROSIS MOUSE MODEL
Authors: Braga Cassia Lisboa , Isler Mancuso Rubia , Thompson Evrett N. , Öz Hasan H. , Gudneppanavar Ravindra , Zhang Ping-Xia , Huang Pamela , Murray Thomas , Egan Marie , Krause Diane S. , Bruscia Emanuela M.
Published: August 2024

Persistent lung inflammation is a hallmark of Cystic fibrosis (CF) lung disease. Inflammation can lead to functional decline in hematopoietic stem cell (HSCs), tipping the balance towards myelopoiesis and contributing to chronic inflammation. However, it’s unknown whether the HSCs are dysfunctional in CF. We tested whether chronic lung inflammation impacts hematopoietic stem and progenitor cells (HSPCs) in a CF mouse model.

Wild-type (WT) andCftr-/- mice were nebulized with lipopolysaccharide (LPS) from Pseudomonas aeruginosa for 5 weeks. The mice were euthanized before the exposure (T0), 24 hours after the last LPS nebulization (T1), or 6 weeks (T2) after the last LPS nebulization. The bone marrow (BM) and lung tissue were collected for flow cytometry analysis of the HSPC population and immune cells in the lungs, respectively. Peripheral blood was collected for complete blood count analysis.

At baseline,Cftr-/- mice show a larger HSPC population with a myeloid bias, indicated by higher frequencies of LSK, LT-HSC, CD41+LT-HSC, GMPs, and MkPs. Following chronic LPS nebulization,Cftr-/- mice exhibit greater HSPC expansion and myeloid differentiation, alongside increased peripheral myeloid cell counts. Post-recovery, while most HSPC populations return to baseline,Cftr-/- mice retain elevated myeloid-biased LT-HSCs, suggesting a persistent myeloid bias. These findings underscore a prominent shift toward myeloid hematopoiesis in CF, which is accentuated by chronic inflammation and remains even after recovery.

Further experiments are underway to assess maladaptive epigenetic changes in HSC as well as if chronic lung inflammation impacts HSC functionality.
Cancer therapy via neoepitope-specific monoclonal antibody cocktails
Authors: Hartman Colin J. , Mohamed Asmaa O. , Shukla Girja S. , Pero Stephanie C. , Sun Yu-Jing , Rodríguez Roberto S. , Genovese Nicholas F. , Kohler Nico M. , Hemphill Thomas R. , Huang Yina H. , Krag David N. , Ackerman Margaret E.
Published: August 2024

Background

Cellular heterogeneity presents a significant challenge to cancer treatment. Antibody therapies targeting individual tumor-associated antigens can be extremely effective but are not suited for all patients and often fail against tumors with heterogeneous expression as tumor cells with low or no antigen expression escape targeting and develop resistance. Simultaneously targeting multiple tumor-specific proteins with multiple antibodies has the potential to overcome this barrier and improve efficacy, but relatively few widely expressed cancer-specific antigens are known. In contrast, neoepitopes, which arise from mutations unique to tumor cells, are considerably more abundant. However, since neoepitopes are not commonly shared between individuals, a patient-customized approach is necessary and motivates efforts to develop an efficient means to identify suitable target mutations and isolate neoepitope-specific monoclonal antibodies.

Methods

Here, focusing on the latter goal, we use directed evolution in yeast and phage display systems to engineer antibodies from non-immune, human antibody fragment libraries that are specific for neoepitopes previously reported in the B16F10 melanoma model.

Results

We demonstrate proof-of-concept for a pipeline that supports rapid isolation and functional enhancement of multiple neoepitope peptide-targeted monoclonal antibodies and demonstrate their robust binding to B16F10 cells and potent effector functionsin vitro. These antibodies were combined and evaluatedin vivofor anti-cancer activity in tumor-bearing mice, where they suppressed B16F10 tumor growth and prolonged survival.

Conclusions

These findings emphasize the potential for clinical application of patient-customized antibody cocktails in the treatment of the many cancers poorly addressed by current therapies.