bluuebunny/crossref_metadata_2025 huggingface dataset:
Reanalysis of Exome Sequencing Data in the Indian Undiagnosed Diseases Program: Improving Diagnostic Yield and Ending Diagnostic Odyssey
Authors: Garg Neha , Lakshmi Pragna , Singh Suzena M. , Kulshreshta Samarth , Ranganath Prajnya , Moirangthem Amita , Dalal Ashwin , Gahlot Aakanksha , Puri Ratna Dua
Published: January 2025

In 2021, the Indian Undiagnosed Diseases Program was initiated for patients without a definite diagnosis despite extensive evaluation in four participating sites. Between February 2021 and March 2023, a total of 88 patients were recruited and underwent deep phenotyping. A uniform methodology for data re‐analysis was implemented as the first step prior to conducting additional genomic testing. The largest cohort was of 38 patients with neurodevelopmental disorders (NDD). A genetic diagnosis was achieved in 24 of the 88 patients (27.2%), including 7 cases within the NDD cohort. Factors contributing to the increased diagnostic yield included: (a) identification of a novel disease association in DAAM2 gene, and (b) limitations of the standard analysis pipeline, particularly for synonymous variants in SELENOI and KIAA0753 genes, non‐frameshift variant in GLRX5 gene, low‐coverage variant in GJC2 gene, large deletions in PCNT and PHKG2 genes, and intronic variants in VPS33B and FBN1. Improved phenotyping led to a diagnosis in three cases, while genomic variants missed in the previous bioinformatics analysis were identified in 12 cases. The study also contributed to the development of enhanced bioinformatics scripts for variant prioritization and more refined literature search for novel disease associations. It highlights the importance of incorporating data reanalysis into clinical workflows before pursuing advanced diagnostic tests, particularly in resource‐limited settings where healthcare expenses are often borne out of pocket.
Comparison of Different Machine Learning Methodologies for Predicting the Non‐Specific Treatment Response in Placebo Controlled Major Depressive Disorder Clinical Trials
Authors: Gomeni Roberto , Bressolle‐Gomeni Françoise
Published: January 2025

Placebo effect represents a serious confounder for the assessment of treatment effect to the extent that it has become increasingly difficult to develop antidepressant medications appropriate for outperforming placebo. Treatment effect in randomized, placebo‐controlled trials, is usually estimated by the mean baseline adjusted difference of treatment response in active and placebo arms and is function of treatment‐specific and non‐specific effects. The non‐specific treatment effect varies subject by subject conditional to the individual propensity to respond to placebo. This effect is not estimable at an individual level using the conventional parallel‐group study design, since each subject enrolled in the trial is assigned to receive either active treatment or placebo, but not both. The objective of this study was to conduct a comparative analysis of the machine learning methodologies to estimate the individual probability of a non‐specific treatment effect. The estimated probability is expected to support novel methodological approaches for better controlling effect of excessively high placebo response. At this purpose, six machine learning methodologies (gradient boosting machine, lasso regression, logistic regression, support vector machines, k‐nearest neighbors, and random forests) were compared to the multilayer perceptrons artificial neural network (ANN) methodology for predicting the probability of individual non‐specific treatment response. ANN achieved the highest overall accuracy among all methods tested. A fivefold cross‐validation was used to assess performances and risks of overfitting of the ANN model. The analysis conducted without subjects with non‐specific effect indicated a significant increase of signal detection with significant increase in effect size.
From Lab to Clinic: Effect of Academia–Industry Collaboration Characteristics on Oncology Phase 1 Trial Entry
Authors: Yang Wonseok , Lee Sang‐Won
Published: January 2025

This study investigated the success rate of Phase 1 clinical trial entry and the factors influencing it in oncology projects involving academia–industry collaboration during the discovery and preclinical stages. A total of 344 oncology projects in the discovery stage and 360 in the preclinical stage, initiated through collaborations with universities or hospitals between 2015 and 2019, were analyzed. The Phase 1 clinical trial entry success rates for oncology collaborative projects were 9.9% from the discovery stage and 24.2% from the preclinical stage. For discovery stage contracts, strong statistical significance was observed for contract type (co‐development OR 16.45, p = 0.008; licensing OR 42.43, p = 0.000) and technology (cell or gene therapy OR 3.82, p = 0.008). In contrast, for preclinical stage contracts, significant changes were noted for cancer type (blood cancer OR 2.24, p = 0.004), while the year of contract signing showed a relatively weak statistical significance (OR 1.24, p = 0.021). No significant changes were observed concerning partner firm size and the partnership territory. This study sheds light on how the characteristics of partnerships influence the success rates of early‐phase research, providing valuable insights for future strategic planning in oncology drug development.
Risk of insulin initiation with sodium‐glucose cotransporter‐2 inhibitors versus dipeptidyl peptidase‐4 inhibitors in patients with type 2 diabetes mellitus: A real‐world claims database study in Japan
Authors: Suzuki Ryo , Shoji Shingo , Yoshinaga Yoko , Kosakai Yoshinori , Shintani‐Tachi Mami
Published: January 2025

Aims

Insulin therapy is a cornerstone in type 2 diabetes mellitus (T2DM) management, but its use is associated with several barriers, including hypoglycaemia, fear of injections and high costs. We compared the risk of insulin initiation and other treatment intensification between patients with T2DM newly treated with a sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) versus those newly treated with a dipeptidyl peptidase‐4 inhibitor (DPP4i).

Materials and Methods

This Japanese retrospective cohort study was conducted between 1 January 2015 and 31 March 2023 using the JMDC Claims Database. Patients with T2DM newly treated with an SGLT2i or a DPP4i were matched 1:1 using propensity score (n = 18 488 each). Incidence rates (IR) of insulin initiation, other antidiabetic drugs (OAD) and antihypertensive drugs added onto baseline treatment were calculated for each treatment group. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a Cox proportional hazards model.

Results

The IR of insulin initiation was 0.95 and 2.12 per 1000 person‐years in the SGLT2i and DPP4i groups, respectively, with significantly lower risk in the SGLT2i group than in the DPP4i group (HR 0.46, 95% CI: 0.28–0.74, p = 0.001). The risks of OAD (HR 0.66, 95% CI: 0.64–0.69, p < 0.001) and antihypertensive drugs (HR 0.90, 95% CI: 0.85–0.95, p < 0.001) added onto baseline treatment were lower in the SGLT2i group than in the DPP4i group.

Conclusions

The risk of insulin initiation was lower in patients with T2DM newly treated with an SGLT2i than in those newly treated with a DPP4i. SGLT2i may reduce or delay the need for insulin therapy.
Effects of antidiabetic agents on lipid metabolism of skeletal muscle: A narrative review
Authors: Xu Ming , Lv Dongqing , Wei Hongxia , Li Zhe , Jin Shuqing , Liu Qinhao , Zhang Yi , Liu Yunfeng
Published: January 2025

Metabolic syndrome‐related diseases frequently involve disturbances in skeletal muscle lipid metabolism. The accumulation of lipid metabolites, lipid‐induced mitochondrial stress in skeletal muscle cells, as well as the inflammation of adjacent adipose tissue, are associated with the development of insulin resistance and metabolic dysfunction. Consequently, when antidiabetic medications are used to treat various chronic conditions related to hyperglycaemia, the impact on skeletal muscle lipid metabolism should not be overlooked. However, current research has predominantly focused on muscle mass rather than skeletal muscle lipid metabolism and its interplay with glucose metabolism. In this review, we summarised the latest research on the effects of antidiabetic drugs and certain natural compounds with antidiabetic activity on skeletal muscle lipid metabolism, focusing on data from preclinical to clinical studies. Given the widespread use of antidiabetic drugs, a better understanding of their effects on skeletal muscle lipid metabolism merits further attention in future research.
Unexpected cardiovascular risks of glucagon‐like peptide‐1 receptor agonist and aspirin co‐administration in individuals with obesity, with and without type 2 diabetes: A propensity score matched cohort study
Authors: Lin Chia‐Ming , Chen Jo‐Ching , Meyerowitz‐Katz Gideon , Huang Yu‐Nan , Su Pen‐Hua
Published: January 2025

Aims

To examine the cardiovascular safety of combining glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) with aspirin in individuals with obesity, both with and without type 2 diabetes (T2D).

Materials and Methods

This propensity score matched cohort study analysed data from 2 946 579 individuals with obesity, with and without T2D, using the TriNetX US and Global dataset. Participants were categorized into four matched groups: those receiving GLP‐1 RA plus aspirin versus those receiving GLP‐1 RA alone, for both diabetic and non‐diabetic individuals. Cardiovascular outcomes and adverse events were evaluated over 5 years using Cox proportional hazards models.

Results

Individuals with obesity treated with GLP‐1 RAs plus aspirin showed significantly higher risks of various cardiovascular events compared to those on GLP‐1 RAs alone. In non‐diabetic obese individuals, the combination therapy increased risks of hypertensive heart diseases (HR 1.40, 95% CI 1.15–1.60), ischaemic heart disease (HR 2.39, 95% CI 1.92–2.97) and heart failure (HR 1.97, 95% CI 1.54–2.53). Similar patterns were observed in individuals with T2D. Atrial fibrillation and cardiac arrhythmias showed increasing hazard ratios over time. The combination therapy also led to more frequent adverse events, including gastrointestinal bleeding.

Conclusions

The combination of GLP‐1 RAs with aspirin in individuals with obesity, both with and without T2D, was associated with increased cardiovascular risks compared to GLP‐1 RA monotherapy. These findings suggest that there may be risks associated with the combined use of these treatments and highlight the need for further research into this possible complication with regard to treatment.
Predicting Reliable Improvements in Primary Care Youth Mental Health
Authors: Moore Jeff , Doyle Elizabeth , Carey Eleanor , Blix Anna , Booth Ailbhe , Rossouw Joe , O'Reilly Aileen , O'Brien Siobhan , Duffy Joseph
Published: January 2025

Background

Amid a youth mental health crisis, community‐based early intervention services have shown promising outcomes. Understanding the specific factors that predict clinical outcomes is crucial for enhancing intervention efficacy, yet these factors remain insufficiently understood.

Aim

This study examined the individual and service‐related factors associated with reliable improvement for young people (n = 4565) aged 12–25 years attending a brief primary care youth talk therapy mental health service across 14 sites.

Methods

Reliable improvement was measured using the clinical outcomes in routine evaluation (YP‐CORE and CORE‐10) measure at baseline and follow up. Poisson regression was used to identify individual and service‐related factors associated with reliable improvement.

Results

Higher initial distress levels predicted increased levels of reliable improvement (adjusted risk ratios ranged from 235.7 to 415.1, p < 0.001), indicating that this intervention is particularly effective for individuals with higher initial distress levels. Conversely, extended wait times negatively affected therapeutic outcomes for young people aged 12–16, with waiting times exceeding 60 days associated with lower likelihoods of improvement (adjusted risk ratio = 89.2 for > 60 days, p < 0.01). Waiting times did not significantly impact individuals aged 17–25. Attending nine or more sessions was associated with a lower likelihood of reliable improvement.

Conclusion

This study underscores the critical importance of minimising wait times for young people and the importance of tailored approaches to early intervention services. Addressing these factors can enhance the efficacy of early intervention services and better support the mental well‐being of young people.
Lyme neuroborreliosis in Japan: Borrelia burgdorferi sensu lato as a cause of meningitis of previously undetermined etiology in hospitalized patients outside of the island of Hokkaido, 2010–2021
Authors: Ohira Masayuki , Takano Ai , Yoshi Kentaro , Arai Akira , Aso Yashuhiro , Furutani Rikiya , Hamano Tadanori , Takahashi‐Iwata Ikuko , Kaneko Chikako , Matsuura Tohru , Maeda Norihisa , Nakajima Hideto , Shindo Katsuro , Suenaga Toshihiko , Sugie Kazuma , Suzuki Yasuhiro , Yamashita Toru , Angulo Frederick J. , Edwards Juanita , Bender Cody Matthew , Harper Lisa R. , Nakayama Yoshikazu , Ito Shuhei , Pilz Andreas , Stark James H. , Moïsi Jennifer C. , Mizusawa Hidehiro , Takao Masaki
Published: January 2025

Background and Purpose

Clinical manifestations of Lyme borreliosis (LB), caused by Borrelia burgdorferi sensu lato (Bbsl), include erythema migrans, Lyme neuroborreliosis (LNB), carditis, and arthritis. LB is a notifiable disease in Japan with <30 surveillance‐reported LB cases annually, predominately from Hokkaido Prefecture. However, LB, including LNB, may be under‐diagnosed in Japan since diagnostic tests are not readily available. We sought to determine if LNB could be a cause of previously undiagnosed encephalitis or meningitis in Japan.

Methods

Investigators at 15 hospitals in 10 prefectures throughout Japan retrieved serum and/or cerebrospinal fluid (CSF) samples collected in 2010–2021 from 517 patients hospitalized with encephalitis or meningitis which had an etiology that had not been determined. Samples were tested for Bbsl‐specific antibodies using ELISA and Western blot tests. In alignment with the European Union LNB case definition, a confirmed LNB case had CSF pleocytosis and intrathecal production of Bbsl‐specific antibodies and a probable LNB case had a CSF sample with pleocytosis and Bbsl‐specific antibodies.

Results

LNB was identified in three hospitalized patients with meningitis of previously undetermined etiology: a male resident of Aomori Prefecture was a confirmed LNB case, and two female residents of Oita Prefecture were probable LNB cases. None of the patients with confirmed or probable LNB had traveled in the month prior to symptom onset and none had samples previously tested for LB.

Conclusion

The identification of previously undiagnosed LNB cases indicates a need for enhanced disease awareness in Japan, particularly beyond Hokkaido Island, and more readily available LB diagnostic testing.
HIF1α Plays a Crucial Role in the Development of TFE3–Rearranged Renal Cell Carcinoma by Orchestrating a Metabolic Shift Toward Fatty Acid Synthesis
Authors: Nishizawa Hidekazu , Funasaki Shintaro , Ma Wenjuan , Kubota Yoshiaki , Watanabe Kazuhide , Arima Yuichiro , Kuroda Shoichiro , Ito Takaaki , Furuya Mitsuko , Motoshima Takanobu , Nishiyama Akira , Mehanna Sally , Satou Yorifumi , Hasumi Hisashi , Jikuya Ryosuke , Makiyama Kazuhide , Tamura Tomohiko , Oike Yuichi , Tanaka Yasuhito , Suda Toshio , Schmidt Laura S. , Linehan W. Marston , Baba Masaya , Kamba Tomomi
Published: January 2025

Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3–rearranged renal cell carcinoma (TFE3‐RCC) remain poorly understood. TFE3‐RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC‐TFE3 induced a hypoxia‐related signature by transcriptionally upregulating HIF1α and HIF2α. The upregulation of HIF1α by PRCC‐TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3‐RCC mouse models with Hif1α and/or Hif2α knockout mice and found that Hif1α, rather than Hif2α, is essential for tumor development in vivo. RNA‐seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1α/SREBP1‐dependent mechanism in TFE3‐RCC. Our data suggest that the coordinated metabolic shift via the PRCC‐TFE3/HIF1α/SREBP1 axis is a key mechanism by which PRCC‐TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3‐RCC.
Effects of Feed Supplementation With Fulvic Acid on the Systemic and Mucosal Protective Mechanisms of Juvenile Rainbow Trout (Oncorhynchus mykiss)
Authors: Zavvar Fatemeh , Mazandarani Mohammad , Hoseinifar Seyed Hossein , Jafari Valiollah , Lieke Thora
Published: January 2025

Rainbow trout (Oncorhynchus mykiss) is an important fish species raised in aquaculture, but it is susceptible to stress, infections diseases. The present study aimed to determine the effects of fulvic acid feed addition on the systemic and mucosal protective mechanisms of juvenile rainbow trout and to elucidate the underlying molecular mechanisms of changes in the gut. Rainbow trout (4.30 ± 0.6 g) diet was supplemented with different levels of fulvic acid: 0% (Control), 0.5%, 1% and 2%. At the end of 8‐week feeding trial, growth parameters such as final weight gained weight (%), SGR (F1%) increased, and FCR (all levels) decreased significantly compared to the control group. We found that the activity of lysozyme, glutathione peroxidase, and catalase in the serum were significantly improved, especially after the addition of 0.5% and 1% of fulvic acid. At the same time, the immunoglobulin concentration in the skin mucus was increased with 0.5% supplementation. However, the expression of tnf‐α, il‐6 and gpx in the intestine was strongly upregulated after supplementation with 2%, indicating oxidative stress and inflammation with this level of fulvic acid inclusion. Furthermore, the mucus lysozyme activity was reduced at this concentration, which can increase the susceptibility to pathogen invasion. The results suggest that adding 0.5%−1% of fulvic acid to the feed of juvenile rainbow trout can help to improve their immune and antioxidative defenses and thereby support the wellbeing of fish.
Automatic determination of 3D particle morphology from multiview images using uncertainty‐evaluated deep learning
Authors: Liu Hongchen , Su Huaizhi , Sheil Brian
Published: January 2025

Particle morphology is a crucial factor influencing the mechanical properties of granular materials particularly in infrastructure construction processes where accurate shape descriptors are essential. Accurately measuring three‐dimensional (3D) morphology has significant theoretical and practical value for exploring the multiscale mechanical properties of civil engineering materials. This study proposes a novel approach using multiview (two‐dimensional [2D]) particle images to efficiently predict 3D morphology, making real‐time aggregate quality analysis feasible. A 3D convolutional neural network (CNN) model is developed, which combines Monte Carlo dropout and attention mechanisms to achieve uncertainty‐evaluated predictions of 3D morphology. The model incorporates a convolutional block attention module, involving a two‐stage attention mechanism with channel attention and spatial attention, to further optimize feature representation and enhance the effectiveness of the attention mechanism. A new dataset comprising 18,000 images of 300 natural gravel and 300 blasted rock fragment particles is used for model training. The prediction accuracy and uncertainty of the proposed model are benchmarked against a range of alternative models including 2D CNN, 3D CNN, and 2D CNN with attention, in particular, to the influence of the number of input multiview particle images on the performance of the models for predicting various morphological parameters is explored. The results indicate that the proposed 3D CNN model with the attention mechanism achieves high prediction accuracy with an error of less than 10%. Whilst it exhibits initially greater uncertainty compared to other models due to its increased complexity, the model shows significant improvement in both accuracy and uncertainty as the number of training images is increased. Finally, residual challenges associated with the prediction of more complex particle angles and irregular shapes are also discussed.
The aerial epidermis is a major site of quinolizidine alkaloid biosynthesis in narrow‐leafed lupin
Authors: Frick Karen Michiko , Lorensen Marcus Daniel Brandbjerg Bohn , Micic Nikola , Esteban Eddi , Pasha Asher , Schulz Alexander , Provart Nicholas James , Nour‐Eldin Hussam Hassan , Bjarnholt Nanna , Janfelt Christian , Geu‐Flores Fernando
Published: January 2025

Lupins are promising protein crops that accumulate toxic quinolizidine alkaloids (QAs) in the seeds, complicating their end‐use. QAs are synthesized in green organs (leaves, stems, and pods) and a subset of them is transported to the seeds during fruit development. The exact sites of biosynthesis and accumulation remain unknown; however, mesophyll cells have been proposed as sources, and epidermal cells as sinks.

We investigated the exact sites of QA biosynthesis and accumulation in biosynthetic organs of narrow‐leafed lupin (Lupinus angustifolius) using mass spectrometry‐based imaging (MSI), laser‐capture microdissection coupled to RNA‐Seq, and precursor feeding studies coupled to LC‐MS and MSI.

We found that the QAs that accumulate in seeds (‘core’ QAs) were evenly distributed across tissues; however, their esterified versions accumulated primarily in the epidermis. Surprisingly, RNA‐Seq revealed strong biosynthetic gene expression in the epidermis, which was confirmed in leaves by quantitative real‐time polymerase chain reaction. Finally, feeding studies using a stably labeled precursor showed that the lower leaf epidermis is highly biosynthetic.

Our results indicate that the epidermis is a major site of QA biosynthesis in narrow‐leafed lupin, challenging the current assumptions. Our work has direct implications for the elucidation of the QA biosynthesis pathway and the long‐distance transport network from source to seed.
Effects of behavioural types on the problem‐solving performance of wild house mice under controlled and semi‐natural conditions
Authors: Vezyrakis Alexandros , Guenther Anja , Mazza Valeria
Published: January 2025

Animals often face challenges that require them to come up with solutions to novel problems or to find new solutions to existing ones; i.e. they need to innovate. However, not all individuals in a population are equally likely to solve novel problems, and it is unclear which individual characteristics make a successful innovator. Theoretical frameworks suggest the importance of intrinsic (e.g. individual characteristics) and extrinsic (e.g. study condition) factors on problem‐solving performance. Such frameworks have been empirically tested in model, highly neophobic species, leaving the generality of these processes unclear. We examined whether behavioural traits such as exploration and risk‐taking are linked to problem‐solving behaviour, using two replicated populations (n = 121) of wild house mice Mus musculus domesticus living under semi‐natural conditions. There, we presented a battery of four problem‐solving setups that individuals could access voluntarily, and we tested the mice for risk‐taking and exploration. Furthermore, after acclimatising to cages, we tested a subset (n = 50) of the same individuals in controlled conditions, to validate the cross‐context stability of cognitive performance and potential influences of behaviours. We placed single individuals overnight in arenas containing another four novel problem‐solving setups. Contrasting most existing literature, we found no direct effects of behavioural type on the likelihood to problem‐solve in either condition. However, there was an indirect effect, with shyer individuals visiting the problems more, which improved their likelihood of solving them. Additionally, mice were more likely to solve alone, and individuals were not consistent across conditions. Our findings suggest that exploration and risk‐taking do not affect the ability to problem‐solve across different conditions, but impact the non‐cognitive steps that lead to the final performance. Also, individuals did not perform consistently across conditions, questioning the ecological validity of measures taken under controlled, artificial conditions when they do not reflect the animals' natural experience.
The effect of size on mate selection, fecundity and survival in Culex pipiens mosquitoes
Authors: Villarreal Susan , Senior Amelia , Price Matthew
Published: January 2025

Culex pipiens L. is a medically important mosquito due to its abundance and ability to transmit West Nile virus. Despite being the focus of many mosquito control strategies, very little is known about its mating behaviour. Several control strategies rely on knowing female mate preferences to ensure their efficacy. Therefore, the purpose of this study was to characterize mate selection based on mate quality. Because larger individuals should have more resources available to be used towards mating behaviour, it was hypothesized that larger mates (males or females) would be of higher value and preferentially mated with compared to smaller ones. By manipulating food availability, males and females were reared to be either large or small adults and were mated with either a large or small mate. Through a series of experiments, the effect of size on mate success and post‐mating responses was assessed via insemination rates, blood feeding, egg laying, fertility and survival. Despite larger females living longer and being more fecund, males did not preferentially mate with larger females, nor did male size influence female survival or fecundity. Because larval rearing environment had an influence on adult morphology and fitness, it should be taken into consideration in mosquito control programmes.
The implications and challenges of the IMO 2020 regulation: Exploring options for compliance
Authors: Pereira Eduardo G.
Published: January 2025

The International Maritime Organisation (IMO), as a part of its continuing efforts to regulate sulphur oxide emissions, adopted the IMO 2020 Regulation. The regulation established a new worldwide cap on the sulphur content of shipping fuel. This article critically analyses the key provisions of the IMO's latest regulation by examining the economic consequences of the regulation and its impact on the shipping industry, petroleum markets and refineries. This article highlights the challenges that State parties face in enforcing the regulation and the repercussions for non‐compliance. The key findings of this article reveal that since the enforcement of the IMO 2020 Regulation, sulphur emissions have decreased by approximately 8.5 to 8.9 million metric tons. By 2025, this reduction is expected to reach around 77% of pre‐regulation levels. Coastal settlements, particularly highly populated areas, are expected to benefit from the reduction in sulphur concentration levels.
Exploring the Relationship Between Humoral and Cellular T Cell Responses Against SARS‐CoV‐2 in Exposed Individuals From Emilia Romagna Region and COVID‐19 Severity
Authors: Mazzotti Lucia , Borges de Souza Patricia , Azzali Irene , Angeli Davide , Nanni Oriana , Sambri Vittorio , Semprini Simona , Bravaccini Sara , Cerchione Claudio , Gaimari Anna , Nicolini Fabio , Ancarani Valentina , Martinelli Giovanni , Pasetto Anna , Calderon Hugo , Juan Manel , Mazza Massimiliano
Published: January 2025

COVID‐19 remains a significant global health problem with uncertain long‐term consequences for convalescents. We investigated the relationships between anti‐N protein antibody levels, severe acute respiratory syndrome (SARS)‐CoV‐2‐associated TCR repertoire parameters, HLA type and epidemiological information from three cohorts of 524 SARS‐CoV‐2‐infected subjects subgrouped in acute phase, seronegative and seropositive convalescents from the Emilia Romagna region. Epidemiological information and anti‐N antibody index were associated with TCR repertoire data. HLA type was inferred from TCR repertoire using the HLA3 tool and its association with clonal breadth (CB) and clonal depth (CD) was assessed. Age above 58 years, male and COVID‐19 hospitalisation were significantly and independently associated with seropositivity (p = 0.004; p = 0.004; p = 0.04), suggesting an association between high antibody titres and symptoms' severity. As for the TCR repertoire analysis, we found no difference in CB among the cohorts, while CD was higher in seronegative than acute (p = 0.04). However, clustering analysis supported that seronegative patients are endowed with broader CB and deeper CD indicating a compensatory mechanism without effective seroconversion. The CD calculated on the TCRs associated with the single SARS‐CoV‐2 ORFs in convalescents is higher when compared to the acute. Lastly, we identified and reported on novel HLAs significantly associated with increased risk of hospitalisation such as HLA‐C*07:02 carriers (OR = 3.9, CI = 1.1–13.4, p = 0.03) and on HLAs that associate significantly with lower or higher TCR repertoire parameters in a population exposed for the first time to SARS‐CoV‐2.
The Novel HLA‐DPB1*1498:01 Allele, Identified by Sanger Dideoxy Nucleotide Sequencing in a Chinese Individual
Authors: Lou Can , Xie Zhi‐cong , Ma Li , Hu Xiao‐zhuang , Lei Hang
Published: January 2025

The HLA‐DPB1*1498:01 allele differs from HLA‐DPB1*02:02:01:01 by a single non‐synonymous nucleotide change in exon 4.
Independently engaging protein tethers of different length enhance synaptic vesicle trafficking to the plasma membrane
Authors: Berns Manon M. M. , Yildiz Mirza , Winkelmann Stefanie , Walter Alexander M.
Published: January 2025

Synaptic vesicle (SV) trafficking toward the plasma membrane (PM) and subsequent SV maturation are essential for neurotransmitter release. These processes, including SV docking and priming, are co‐ordinated by various proteins, such as SNAREs, Munc13 and synaptotagmin (Syt), which connect (tether) the SV to the PM. Here, we investigated how tethers of varying lengths mediate SV docking using a simplified mathematical model. The heights of the three tether types, as estimated from the structures of the SNARE complex, Munc13 and Syt, defined the SV–PM distance ranges for tether formation. Geometric considerations linked SV–PM distances to the probability and rate of tether formation. We assumed that SV tethering constrains SV motility and that multiple tethers are associated by independent interactions. The model predicted that forming multiple tethers favours shorter SV–PM distances. Although tethers acted independently in the model, their geometrical properties often caused their sequential assembly, from longer ones (Munc13/Syt), which accelerated SV movement towards the PM, to shorter ones (SNAREs), which stabilized PM‐proximal SVs. Modifying tether lengths or numbers affected SV trafficking. The independent implementation of tethering proteins enabled their selective removal to mimic gene knockout (KO) situations. This showed that simulated SV–PM distance distributions qualitatively aligned with published electron microscopy studies upon removal of SNARE and Syt tethers, whereas Munc13 KO data were best approximated when assuming additional disruption of SNARE tethers. Thus, although salient features of SV docking can be accounted for by independent tethering alone, our results suggest that functional tether interactions not yet featured in our model are crucial for biological function.

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Key points

A mathematical model describing the role of synaptic protein tethers to localize transmitter‐containing vesicles is developed based on geometrical considerations and structural information of synaptotagmin, Munc13 and SNARE proteins.

Vesicle movement, along with tether association and dissociation, are modelled as stochastic processes, with tethers functioning independently of each other.

Multiple tethers cooperate to recruit vesicles to the plasma membrane and keep them there: Munc13 and Syt as the longer tethers accelerate the movement towards the membrane, whereas short SNARE tethers stabilize them there.

Model predictions for situations in which individual tethers are removed agree with the results from experimental studies upon gene knockout.

Changing tether length or copy numbers affects vesicle trafficking and steady‐state distributions.
Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition
Authors: Tommasin Ludovica , Carrer Andrea , Nata Federica Boscolo , Frigo Elena , Fogolari Federico , Lippe Giovanna , Carraro Michela , Bernardi Paolo
Published: January 2025

The permeability transition (PT) is a permeability increase of the mitochondrial inner membrane causing mitochondrial swelling in response to matrix Ca2+. The PT is mediated by regulated channel(s), the PT pore(s) (PTP), which can be generated by at least two components, adenine nucleotide translocator (ANT) and ATP synthase. Whether these provide independent permeation pathways remains to be established. Here, we assessed the contribution of ANT to the PT based on the effects of the selective ANT inhibitors atractylate (ATR) and bongkrekate (BKA), which trigger and inhibit channel formation by ANT, respectively. BKA partially inhibited Ca2+‐dependent PT and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT to the PT emerged at pH 6.5 (a condition that inhibits ATP synthase channel opening) in the presence of ATR, which triggered mitochondrial swelling and elicited currents in patch‐clamped mitoplasts. Unexpectedly, ANT‐dependent PT at pH 6.5 could also be stimulated by benzodiazepine‐423 [a selective ligand of the oligomycin sensitivity conferral protein (OSCP) subunit of ATP synthase], suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. In keeping with docking simulations, ANT could be co‐immunoprecipitated with ATP synthase subunits c and g, and oligomycin (which binds adjacent c subunits) decreased the association of ANT with subunit c. These results reveal a close cooperation between ANT and ATP synthase in the PT and open new perspectives in the study of this process.

image

Key points

We have assessed the relative role of adenine nucleotide translocator (ANT) and ATP synthase in generating the mitochondrial permeability transition (PT).

At pH 7.4, bongkrekate had little effect on Ca2+‐dependent PT, and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms.

The contribution of ANT emerged at pH 6.5 (which inhibits ATP synthase channel opening) in the presence of atractylate, which triggered mitochondrial swelling and elicited currents in patch‐clamped mitoplasts.

Benzodiazepine‐423, a selective ligand of the oligomycin sensitivity conferral protein subunit of ATP synthase, stimulated ANT‐dependent PT at pH 6.5, suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase.

ANT could be co‐immunoprecipitated with ATP synthase subunits c and g; oligomycin, which binds adjacent c subunits, decreased the association with subunit c, in keeping with docking simulations.
Spanning the career stages—A conversation about work in bioacoustics
Authors: Garcia Marissa
Published: January 2025

This session will gather participants spanning students to late career professionals to have a conversation about work in bioacoustics. Each participant will give a brief introduction on their background and career path with ample time allotted for Q&A. Topics will include professional development, the importance of mentors, work/life balance, integrating family into careers, and more!
Neural network for geoacoustic inversion of sub-bottom profiler data
Authors: Diamond Justin , Dall'Osto David , Mower John
Published: January 2025

Sub-bottom profilers are utilized to extract features pertaining to the sub-seafloor environment sediment stratification. Acquisition and analysis of sub-bottom profiles can provide insight into the sediment composition and acoustical properties. Typical analysis of profiles involves computationally expensive inversions, such as model-based or Bayesian techniques, which require large computational costs. Here, a neural network is developed to perform a geoacoustic inversion on simulated sub-bottom profiler data. The network is used to derive attenuation and acoustical impedance measurements corresponding to the layered media. Geoacoustic properties of the layered sediments are compared to values determined through a direct inversion of reflection coefficient, testing how well these techniques recover the ground truth values. The network, trained on simulated data, is tested on real sub bottom profiler data acquired over a well-studied area called the New England Mud Patch, roughly 80 km south of Nantucket. The simulated data-trained network is compared to a network trained on experimental data acquired by the R/V Tioga over the same test region.
Five years’ journey in turning sonobiopsy from concept to commercialization
Authors: Chen Hong
Published: January 2025

The standard method for diagnosing brain tumors has traditionally relied on magnetic resonance imaging (MRI). While MRI is informative, it lacks the ability to provide precise genetic information about tumors. Conversely, surgical biopsies can offer genetic insights but come with significant risks of morbidity and are not always feasible. Our team introduced sonobiopsy, a novel technique that uses ultrasound to safely and noninvasively release tumor-derived biomarkers from targeted brain locations into the bloodstream. This method allows for the molecular characterization of brain tumors through simple blood tests. In 2018, we published our proof-of-concept study in mice, followed by the first large animal study in healthy pigs in 2020. In 2022, we conducted our first study in a pig model of brain tumors. Concurrently, we developed neuronavigation-guided focused ultrasound devices for patient use. These milestones culminated in the IRB approval of our sonobiopsy clinical trial. We began recruiting our first patient for sonobiopsy in April 2022 and by September 2023, we published findings from our first-in-human prospective sonobiopsy trial in high-grade glioma patients. In the same year, we licensed our patents to Cordance Medical, which received FDA breakthrough device designation for the sonobiopsy devices. This talk will share the lessons learned throughout our journey from concept to commercialization.
High throughput system for preparing samples for multi-omic assays
Authors: Matula Thomas , Bomsztyk Karol
Published: January 2025

Multi-omics considers the analysis of complex biological “omes” (genome, epigenome, proteome, metabolome, and others). Research in this systems biology approach to analyze associations between biological entities and to find biomarkers of disease, is growing exponentially. The basic workflow is divided into an upstream sample preparation step and a corresponding downstream assay. To prepare samples for these assays, cells must be disrupted, and/or DNA or chromatin sheared into fragments. Most often the sample preparation is done using cavitation. Current tools, such as ultrasonic horns, and even many commercial sample preparation instruments, can be highly inconsistent, leading to unreliable assays. A prototype device was built at the Univ. of Washington. Matchstick Technologies was formed to commercialize the prototype. It uses standard off-the-shelf microplates and treats 1–96 samples simultaneously using an array of transducers mounted below the microplate that focuses acoustic energy into each well of the microplate. Intense cavitation generated in each well\ results in consistent fragmentation that leads to consistent repeatable assays. [Work funded by NIH R33CA191135, R21GM111439, and R01DK103849.]
Decomposing audio recordings with artificial intelligence
Authors: Cosme-Clifford Nicole
Published: January 2025

In the music world, artificial intelligence (AI) can now generate new sound clips, recommend music to listeners, and aid academic analysis of music recordings. Central to this advancement is a novel use of one-dimensional (1D) filter convolution, a decades-old technique broadly used in fields like sound engineering and telecommunications. Traditionally, 1D convolutional filters—small patches of signal that slide over larger signals to extract features—were manually predefined for specific purposes, such as muting frequencies above a threshold. But in audio-based AI systems, they are learned by the AI, making them both more opaque and versatile than their handcrafted counterparts. As AI music systems become more popular, the use of 1D filter convolution has expanded. Yet, the technique remains understudied in music scholarship. This talk shows how musical AI systems leverage 1D convolutional filters to decompose audio into short-term spectral features, suggesting potential new tools for sound analysis. While I will use musical examples, the implications extend beyond music. For example, AI-learned filters could enhance our ability to understand and manipulate environmental sound or improve sound processing in devices like hearing aids and smartphones. Ultimately, this talk aims to challenge existing methodologies and encourage innovative research in acoustics and related fields.
Listeners consider AI-made music less expressive than near-identical human-made content
Authors: White Christopher W.
Published: January 2025

This presentation considers why and how listeners view musical content differently when they believe it be generated by an AI. Empirical studies (e.g., Shank et al. 2023) and historical commentary (e.g., Benjamin 1968) suggest that consumers find AI-made content less useful and expressive than human-made content. However, much of this research assumes noticeable differences between AI-made and human-made content, a less tenable assumption in the last few years. I describe two experiments that test listeners’ reactions to technically comparable music made by humans and AI. In Experiment 1, half of participants were told a piece was composed by a human and half were told the same piece was by an AI. Participants found the piece less expressive when attributed to AI. In Experiment 2, 650 participants were given two excerpts and were asked which was created by a human versus by AI, justifying their choices using technical or expressive qualities. Half of participants was shown actual AI/human pairs, while the other half was presented with two excerpts both by AI or by a human. Analysis shows that even when there were no observable technical differences, listeners believed that the (supposedly) AI-generated content was less expressive. I argue that these sorts of distinctions will be increasingly important as AI-generated content becomes more sophisticated and that experiments like these can be used to advocate for good governance of AI companies.
Centre for immersive wave experimentation
Authors: Thomsen Henrik R. , Müller Jonas , Aichele Johannes , Bärlocher Christoph , van Manen Dirk-Jan , Robertsson Johan
Published: January 2025

The “Centre for Immersive Wave Experimentation” (CIWE), located at “Innovation Park Zürich,” spans 200 m² and was designed to conduct ground-breaking research in the fields of acoustic and elastic wave propagation. In CIWE, we pioneer a novel approach to wave experimentation using immersive boundary conditions, seamlessly integrating the physical laboratory and a desired numerical domain. A cornerstone of CIWE is an advanced system of Field Programmable Gate Arrays (FPGAs), allowing the simultaneous acquisition and driving of 800 input and 800 output channels. This enables real-time interaction between a physical domain (e.g., the 40 m3 water pool or the 2.25 m2 2-D waveguide in CIWE) and arbitrary virtual domains. Recent pioneering experiments in CIWE have demonstrated cloning and cloaking of acoustic scattering objects. Elastic wave experiments benefit from a robotized 3-D laser Doppler vibrometer providing high-resolution velocity vector measurements. The ability to conduct non-contact measurements facilitates research in the areas of metamaterials and small-scale modelling in real-world proxies like sand and clay. Here, such measurements provide ground truth, verifying and complimenting numerical simulations. Furthermore, CIWE also facilitates innovation in the area of non-destructive testing, developing ultrasound full-waveform inversion techniques for precise structural health monitoring of laminated composites.
Design and printing micro-acousto-mechanical metamaterials
Authors: Zheng Xiaoyu
Published: January 2025

Additive manufacturing has shown the promise of freedom of designs, enabling parts customization and tailorable properties where superior structural performances can be achieved by a fraction of weight density compared to bulk material. However, it is presently difficult to combine multiple classes of materials (structural, dielectric, conducting, and ferroelectrics) and create features with hierarchical length-scales. Unlike biological systems where functions, including sensing, actuation, and control, are closely integrated, few materials have comparable system complexity. In this talk, I will present the design and printing of energy transduction devices comprised of heterogenous 3-D microarchitectures. The printed materials consist of a network of micro-unit cells enabling programmed sensitivity and directivity of external stimuli coming from different directions. I will lay out design and printing principles that enable a new class of materials capable of acoustics, tactile, and haptics generation. I will present the manufacturing and synthesis of these materials, as well as their mechanics and design methods underpinning their novel behaviors.
Coding in Acoustics Lessons
Authors: Wright Matthew
Published: January 2025

A picture is said to be worth a thousand words, and in acoustics, moving pictures can be even more valuable in helping students understand complicated and complex phenomena and relationships. My experience has been that the process of creating acoustic animations to use in my teaching has helped me to solidify my understanding, and this has led me to include coding activities in my acoustics lessons, in the hope that my students could get the same benefit. In this webinar, I will demonstrate the use of Jupyter notebooks to combine text, mathematics and coding and explore some of the possibilities, and possible pitfalls, of this approach. My examples will use the Python and Julia languages to explore how choice and use of a particular language can affect the learning process.