bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive vs Invasive Respiratory Support for Patients with Acute Hypoxemic Respiratory Failure
Authors: Mosier Jarrod M , Subbian Vignesh , Pungitore Sarah , Prabhudesai Devashri , Essay Patrick , Bedrick Edward J , Stocking Jacqueline C. , Fisher Julia M
Published: December 2023

Rationale

Noninvasive respiratory support modalities are common alternatives to mechanical ventilation for patients with early acute hypoxemic respiratory failure. These modalities include noninvasive positive pressure ventilation, using either continuous or bilevel positive airway pressure, and nasal high flow using a high flow nasal cannula system. However, outcomes data historically compare noninvasive respiratory support to conventional oxygen rather than to mechanical ventilation.

Objectives

The goal of this study was to compare the outcomes of in-hospital death and alive discharge in patients with acute hypoxemic respiratory failure when treated initially with noninvasive respiratory support compared to patients treated initially with invasive mechanical ventilation.

Methods

We used a validated phenotyping algorithm to classify all patients with eligible International Classification of Diseases codes at a large healthcare network between January 1, 2018 and December 31, 2019 into noninvasive respiratory support and invasive mechanical ventilation cohorts. The primary outcome was time-to-in-hospital death analyzed using an inverse probability of treatment weighted Cox model adjusted for potential confounders, with estimated cumulative incidence curves. Secondary outcomes included time-to-hospital discharge alive. A secondary analysis was conducted to examine potential differences between noninvasive positive pressure ventilation and nasal high flow.

Results

During the study period, 3177 patients met inclusion criteria (40% invasive mechanical ventilation, 60% noninvasive respiratory support). Initial noninvasive respiratory support was not associated with a decreased hazard of in-hospital death (HR: 0.65, 95% CI: 0.35 - 1.2), but was associated with an increased hazard of discharge alive (HR: 2.26, 95% CI: 1.92 - 2.67). In-hospital death varied between the nasal high flow (HR 3.27, 95% CI: 1.43 - 7.45) and noninvasive positive pressure ventilation (HR 0.52, 95% CI 0.25 - 1.07), but both were associated with increased likelihood of discharge alive (nasal high flow HR 2.12, 95 CI: 1.25 - 3.57; noninvasive positive pressure ventilation HR 2.29, 95% CI: 1.92 - 2.74),

Conclusion

These observational data from a large healthcare network show that noninvasive respiratory support is not associated with reduced hazards of in-hospital death but is associated with hospital discharge alive. There are also potential differences between the noninvasive respiratory support modalities.
Resonance sonomanometry for noninvasive, continuous monitoring of blood pressure
Authors: Jimenez Raymond , Yurk Dominic , Dell Steven , Rutledge Austin C. , Fu Matt K. , Dempsey William P. , Abu-Mostafa Yaser , Rajagopal Aditya , Rajagopal Alaina Brinley
Published: December 2023

Cardiovascular disease is the leading cause of death worldwide. Existing methods for continuous, noninvasive blood pressure monitoring suffer from poor accuracy, uncomfortable form factors, or a need for frequent calibration, limiting their adoption. We introduce a new framework for continuous BP measurement that is noninvasive and calibration-free. The method uses acoustic stimulation to induce resonance of the artery wall. Ultrasound imaging is used to measure resonance and capture arterial dimensions which are related to blood pressure via a fully-determined physical model. The approach and model are validatedin vitrousing arterial mock-ups and then in multiple arteries in human subjects. Further development could facilitate more robust continuous blood pressure measurement, providing significant benefits for early diagnosis and treatment of cardiovascular disease.
Pharmacokinetics, Tissue Distribution, and Formulation Study of a Small-molecule Inhibitor of MKLP2, LG157
Authors: CHOUDHRY NAMRTA , Li Jinhua , Zhang Ting , Chenyu Jiadai , Zhou Xiaohu , Shi Qiong , Lv Gang , Yang Dun
Published: December 2023

LG157 is a recently identified small-molecule inhibitor of mitotic kinesin-like protein 2 (MKLP2), an overlooked oncology target. This study aims to explore the drug developability of LG157, by assessing its druglike properties, determining plasma drug exposure in various oral formulations, and exploring the self-emulsifying drug delivery system (SEDDS). Solubility of LG157 ranges from 175 to 228 μM across pH 1.0 to 13.0, with a LogD of 2.41 at pH 7.4. It showed a high protein binding rate of 92.58% in mouse plasma and 90.30% in human serum. The bioavailability radar plot aligns with experimental data (69-85%), indicating good bioavailability. In line with the computation prediction, preclinical formulation studies in mice reveal that all five formulations tested offer decent plasma LG157 exposure, with the highest level of LG157 exposure in the PEG300-based formulation. Subsequent tissue distribution studies in rats indicated that the compound is widely distributed with the highest concentration of LG157 in the liver and the lowest level in the brain. The optimal SEDDS formulation, SEDDS-F14, consists of 65% Oleic acid, 26.25% Tween 20, and 8.75% PEG400 as oil, surfactant, and co-surfactant, respectively. SEDDS optimization, based on the central composite design, has achieved the maximum loading of 188.7 mg/mL for LG157. These findings support the developability of LG157 and encourage continued exploration and refinement of formulations for improved therapeutic efficacy.
Age prediction using resting-state functional MRI
Authors: Chang Jose Ramon , Yao Zai-Fu , Hsieh Shulan , Nordling Torbjörn E. M.
Published: December 2023

The increasing lifespan and large individual differences in cognitive capability highlight the importance of comprehending the aging process of the brain. Contrary to visible signs of bodily ageing, like greying of hair and loss of muscle mass, the internal changes that occur within our brains remain less apparent until they impair function. Brain age, distinct from chronological age, reflects our brain’s health status and may deviate from our actual chronological age. Notably, brain age has been associated with mortality and depression. The brain is plastic and can compensate even for severe structural damage by rewiring. Functional characterization offers insights that structural cannot provide. Contrary to the multitude of studies relying on structural magnetic resonance imaging (MRI), we utilize resting-state functional MRI (rsfMRI). We also address the issue of inclusion of subjects with abnormal brain ageing through outlier removal.

In this study, we employ the Least Absolute Shrinkage and Selection Operator (LASSO) to identify the 39 most predictive correlations derived from the rsfMRI data. The data is from a cohort of 116 healthy right-handed volunteers, aged 18-18 years (9 81 male female, mean age 8, SD 11) collected at the Mind Research Imaging Center at the National Cheng Kung University.

We establish a normal reference model by excluding 68 outliers, which achieves a leave-one-out mean absolute error of 2. 8 years. By asking which additional features that are needed to predict the chronological age of the outliers with a smaller error, we identify correlations predictive of abnormal aging. These are associated with the Default Mode Network (DMN).

Our normal reference model has the lowest prediction error among published models evaluated on adult subjects of almost all ages and is thus a candidate for screening for abnormal brain aging that has not yet manifested in cognitive decline. This study advances our ability to predict brain aging and provides insights into potential biomarkers for assessing brain age, suggesting that the role of DMN in brain aging should be studied further.
Impact of Insurance Status on Late-Stage Disease Presentation and Disease-Specific Survival among US Patients With Gastric Cancer
Authors: Akhiwu Ted O. , Freeman Jincong Q. , Scott Adam W. , Umutoni Victoria , Kanemo Philip O.
Published: December 2023

Purpose

The impact of insurance status on cause-specific survival and late-stage disease presentation among US patients with gastric cancer (GC) has been less well-defined.

Materials and Methods

A retrospective study analyzed the 2007-2016 Surveillance Epidemiology and End Results. GC events were defined as GC-specific deaths; patients without the event were censored at the time of death from other causes or last known follow-up. Late-stage disease was stage III-IV. Insurance status was categorized as “uninsured/Medicaid/private.” Five-year survival rates were compared using log-rank tests. Cox regression was used to assess the association between insurance status and GC-specific survival. Logistic regression was used to examine the relationship of insurance status and late-stage disease presentation.

Results

Of 5,529 patients, 78.1% were aged ≥50 years; 54.2% were White, 19.4% Hispanic, and 14.0% Black; 73.4% had private insurance, 19.5% Medicaid, and 7.1% uninsured. The 5-year survival was higher for the privately insured (33.9%) than those on Medicaid (24.8%) or uninsured (19.2%) (p<0.001). Patients with Medicaid (adjusted hazard ratio [aHR] 1.22, 95%CI: 1.11-1.33) or uninsured (aHR 1.43, 95%CI: 1.25-1.63) had worse survival than those privately insured. The odds of late-stage disease presentation were higher in the uninsured (adjusted odds ratio [aOR] 1.61, 95%CI: 1.25-2.08) or Medicaid (aOR 1.32, 95%CI: 1.12-1.55) group than those with private insurance. Hispanic patients had greater odds of late-stage disease presentation (aOR 1.35, 95%CI: 1.09-1.66) than Black patients.

Conclusions

Findings highlight the need for policy interventions addressing insurance coverage among GC patients and inform screening strategies for populations at risk of late-stage disease.
High stakes slow responding, but do not help overcome Pavlovian biases in humans
Authors: Algermissen Johannes , den Ouden Hanneke E. M.
Published: December 2023

“Pavlovian” or “motivational” biases are the phenomenon that the valence of prospective outcomes modulates action invigoration: the prospect of reward invigorates actions, while the prospect of punishment suppresses actions. Effects of the valence of prospective outcomes are well established, but it remains unclear how the magnitude of outcomes (“stake magnitude”) modulates these biases. In this pre-registered study (N= 55), we manipulated stake magnitude (high vs. low) in an orthogonalized Motivational Go/NoGo Task. We tested whether higher stakes (a) strengthen biases or (b) elicit cognitive control recruitment, enhancing the suppression of biases in motivationally incongruent conditions. Confirmatory tests showed that high stakes slowed down responding, especially in motivationally incongruent conditions. However, high stakes did not affect whether a response was made or not, and did not change the magnitude of Pavlovian biases. Reinforcement-learning drift- diffusion models (RL-DDMs) fit to the data suggested that response slowing was best captured by stakes prolonging the non-decision time. There was no effect of the stakes on the response threshold (as in typical speed-accuracy tradeoffs). In sum, these results suggest that high stakes slow down responses without affecting the expression of Pavlovian biases in behavior. We speculate that this slowing under high stakes might reflect heightened cognitive control, which is however ineffectively used, or reflect positive conditioned suppression, i.e., the interference between goal-directed and consummatory behaviors, a phenomenon previously observed in rodents that might also exist in humans. Pavlovian biases and slowing under high stakes may arise in parallel to each other.
Temporal Transcriptome Analysis Uncovers Regulatory Modules Programming Embryo Development from Embryonic Morphogenesis to Post-Germination
Authors: Wang Yen-Ching , Hsieh Wei-Hsun , Huang Chu-Jun , Jhan Ya-Ting , Zhan Junpeng , Chang Ching-Chun , Hsieh Tzung-Fu , Lin Jer-Young
Published: December 2023

We profiled the soybean seed embryo transcriptome across embryonic development to post-germinative development to understand gene activities and regulatory networks promoting these processes. Transcriptomic landscapes feature highly prevalent transcripts which are categorized into early and late groups with major functions of reserve accumulation and energy generation, respectively, and both functions are dominant during late reserve accumulation as the transitioning stage. During the mid-reserve accumulation, regulatory events simultaneously dominate at the transcriptional and chromatin levels, followed by the emergence of distinct mRNA populations during late reserve accumulation throughout germination. We identified diverse functions conducted by sequentially activated genes across developmental stages. Gene coexpression network analysis reveals modules associated with developmental stages, some of which are enriched in genes with functions involved in specific developmental processes. We identified an early-desiccation-associated gene module, containing most transcription factors responsive to abiotic stress, within which one transcription factor is functionally validated to demonstrate increased drought tolerance in Arabidopsis overexpression lines. Finally, we found that a subset of genes is under purifying selection, surpasses the number of their Arabidopsis germination-specific homologs and most are active before germination from embryonic morphogenesis through dormancy, suggesting a potential role in governing physical dormancy in soybean compared to physiological dormancy in Arabidopsis. Our data represent a step toward identifying genes and regulatory networks in the soybean genome facilitating developmental programs across transition phases to bridge embryonic and germinative development.
Plasticity of the MFS1 promotor is not the only driver of Multidrug resistance in Zymoseptoria tritici
Authors: Patry-Leclaire Simon , Neau Elza , Pitarch Anaïs , Walker Anne-Sophie , Fillinger Sabine
Published: December 2023

Background

Multidrug resistance has been identified in the fungal pathogen responsible for Septoria leaf blotch,Zymoseptoria tritici, since 2011. It has been linked to the overexpression of the gene encoding the MFS1 transporter due to inserts in the promoter region ofMFS1(PMFS1), namely types I-III. Recently, two new inserts were discovered in PMFS1that were not linked to MDR, interrogating about whether PMFS1inserts are the only drivers of MDR inZ. tritici.

The goal of our study was to gain a more complete view of MDR inZ. triticiby examining the genotypic diversity associated with the MDR phenotype in a large sample of the modern population.

Results

We isolated 384 potential MDR strains between 2020 and 2021 in northern Europe for PMFS1genotype and MDR assessment. We discovered six new inserts in PMFS1, bringing the total count to 13 including one insertion-deletion in the 5’ UTR region. Of these, 11 display similarities with transposable elements, and 3 are not linked to MDR. Some field strains were significantly more resistant than their respective reference of the same PMFS1genotype and some strains without insert displayed MDR phenotype.

Conclusion

We described the landscape of the MDR in modernZ. triticipopulation and postulate that PMFS1is a hot-spot for insertions involving transposition events. Our study shows that MDR cannot be solely explained by inserts found in PMFS1, and that additional mechanisms might be at work.
Chewing Through Challenges: Exploring the Evolutionary Pathways to Wood-Feeding in Insects
Authors: Beza-Beza Cristian F. , Wiegmann Brian M. , Ware Jessica A. , Petersen Matt , Gunter Nicole , Cole Marissa E. , Schwarz Melbert , Bertone Matthew A. , Young Daniel , Mikaelyan Aram
Published: December 2023

Decaying wood, while an abundant and stable resource, presents considerable nutritional challenges due to its structural rigidity, chemical recalcitrance, and low nitrogen content. Despite these challenges, certain insect lineages have successfully evolved saproxylophagy (consuming and deriving sustenance from decaying wood), impacting nutrient recycling in ecosystems and carbon sequestration dynamics. This study explores the uneven phylogenetic distribution of saproxylophagy across insects and delves into the evolutionary origins of this trait in disparate insect orders. Employing a comprehensive analysis of gut microbiome data, encompassing both previously published datasets and newly generated data, from both saproxylophagous insects and their non-saproxylophagous relatives, thisHypothesispaper discusses the broader phylogenetic context and potential morphological, physiological, and symbiotic adaptations necessary for this dietary specialization. The study proposes the “Detritivore-First Hypothesis,” suggesting an evolutionary pathway to saproxylophagy through detritivory, and highlights the critical role of symbiotic gut microbiomes in the digestion of decaying wood. The article aims to provide a deeper understanding of the macroevolutionary landscape and mechanisms underpinning the multiple origins and distribution of saproxylophagy in insects.
Emerging dynamic regimes and tipping points from finite empirical principles
Authors: Cobo-López Sergio , Witt Matthew , Carbajal Lucas J. , Rohwer Forest L. , Luque Antoni
Published: December 2023

All dynamical systems are transient. The dynamics of our world at biogeochemical, ecological, and astronomical scales exist in a transient state because the Earth, Sun, and universe are evolving toward thermodynamic equilibrium. However, predicting the tipping points associated with major dynamical shifts in these systems remains a significant challenge. Here, we introduce a new theoretical framework to predict tipping points. Our approach builds on two empirical principles: Observations occur over a finite time, and changes are perceptible when system variations are substantial relative to reference values. As a consequence, processes governing the dynamics of a system can become inactive over an observation time, and tipping points are reached when the processes switch off or on. The two principles were encoded mathematically, defining dynamic weights: contributions relative to reference values of the dynamic processes to the rate-of-change of agents in the system for a finite observational time. Operationally, processes were considered active if their weights were above a critical threshold. Tipping points were defined as reaching critical thresholds that activated or inactivated processes. This Finite Observational Dynamics Analysis Method (FODAM) predicted that a system with n underlying dynamic processes could display 2ndifferent dynamic regimes. However, the structure of regimes depend on the observational time. The tipping points predicted the conditions for regime shifts. The application of FODAM was illustrated with a Lotka-Volterra predator-prey model featuring the interaction of bacteria and bacteriophage. The error of the method was analyzed and discussed. Also, Colab notebook was developed and deployed online to facilitate the application of the method to other systems. We conclude the article by discussing how our new approach bridges prior frameworks describing tipping point dynamics and critical transitions. We also outline the application of the method to empirical data to predict tipping points in complex systems.
Contrasting urban adaptations of seed dispersal traits in two closely-related plant species
Authors: Nakano Shuhei H , Ushimaru Atushi
Published: December 2023

Urbanisation has largely altered city landscapes, resulting in habitat loss, fragmentation, and environmental degradation. City plants often have adapting traits and ecologies to such urban habitat environments. The existing literature on urban adaptation has often focused on species that shrink the abundances in urban areas compared to rural areas. Meanwhile, the studies on species that expand their range in cities remain limited, although they would exhibit different trait responses to urban environments, particularly in dispersal-related traits.

In this study, we compared seed dispersal-related traits betweenYoungia japonicasubsp.japonica (Y.j. japonica), which is expanding its range in urban areas and its closely-relativeY.j. elstonii, which is contracting its range in urban areas along an urban-rural gradient of the Osaka-Kobe megacity area. We also examined relationships between seed traits and terminal velocity which influences seed dispersal ability.

We found that achene length increased with the degree of urbanisation only inY.j. japonica, while pappus length decreased only inY.j. elstonii. The terminal velocity had a significant relationship only with pappus length inY. japonica.

Seed traits of two subspecies with different urban distributions showed different responses to urbanisation. Our results suggest that species expanding their distribution in urban areas has increased seed competitiveness while maintaining dispersal ability. In contrast, species that has shrunk in urban areas likely showed a passive response to urban fragmentation, indicating a loss of seed dispersal ability.
Neural Speech-Tracking During Selective Attention: A Spatially Realistic Audiovisual Study
Authors: Har-shai Yahav Paz , Rabinovitch Eshed , Korisky Adi , Vaknin Harel Renana , Bliechner Martin , Zion Golumbic Elana
Published: December 2023

Paying attention to a target talker in multi-talker scenarios is associated with its more accurate neural-tracking relative to competing non-target speech. This “neural-bias” to target speech has largely been demonstrated in experimental setups where target and non-target speech are acoustically controlled and interchangeable. However, in real-life situations this is rarely the case. For example, listeners often look at the talker they are paying attention to while non-target speech is heard (but not seen) from peripheral locations. To enhance the ecological-relevance of attention research, here we studied whether neural-bias towards target speech is observed in a spatially realistic audiovisual context, and how this is affected by switching the identity of the target talker.

Group-level results show robust neural-bias towards target speech, an effect that persisted and generalized after switching the identity of the target talker. In line with previous studies, this supports the utility of the speech-tracking approach for studying speech processing and attention in spatially realistic settings. However, a more nuanced picture emerges when inspecting data of individual participants. Although reliable neural speech-tracking could be established in most participants, this was not correlated with neural-bias or with behavioral performance, and >50% of participant showed similarly robust neural tracking of both target and non-target speech.

These results indicate that neural-bias toward the target is not a ubiquitous, or necessary, marker of selective attention (at least as measured from scalp-EEG), and suggest that individuals diverge in their internal prioritization among concurrent speech, perhaps reflecting different listening strategies or capabilities under realistic conditions.

Significance Statement

This work contributes to ongoing efforts to study the neural mechanisms involved in selective attention to speech under ecologically relevant conditions, emulating the type of speech materials, multisensory experience, and spatial realism of natural environments. Group-level results show that under these more realistic conditions, the hallmark signature of selective attention – namely the modulation of sensory representation, and its robustness to switches in target-identity – is conserved, at least at the group level. At the same time, results point to an underlying diversity among participants in how that this modulation manifests, raising the possibility that differences in listening strategies, motivation or personal traits lead to differences in the way that individuals encode and process competing stimuli, under ecological conditions.
Microscopy-guided subcellular proteomic discovery by high-speed ultra-content photo-biotinylation
Authors: Chen Yi-De , Chang Chih-Wei , Cheung Chantal Hoi Yin , Chang Hsiao-Jen , Sie Yong-Da , Chung Chia-Wen , Huang Chun-Kai , Huang Chien-Chang , Chong Weng Man , Liu You-Pi , Lin Yu-Chih , Kai Hsiang-Ju James , Wang Pei-Jie , Liao Jung-Chi
Published: December 2023

Microscopy-guided proteomics at an organelle-dimension resolution is desired for revealing unknown protein constituents at specific disease- or functional-associated regions at the molecular-molecular interactions level. Here, we achieve protein spatial purification by introducing a firmware-integrated microscopy platform that triggersin situsubcellular photo-biotinylation of proteins at user-defined regions of interest (ROIs) one field of view (FOV) at a time for thousands of FOVs fully automatically. An illumination pattern at the analogous ROIs of each FOV is calculated on the fly by either machine learning or traditional image processing. Photoactivatable amino acid crosslinkers are activated by a two-photon focal light one spot at a time at a sub-millisecond illumination duration per spot. Imaging, pattern generation, targeted illumination, and FOV movement are coordinated and cycled with high-speed mechatronic control to complete illumination on millions of ROI spots within hours. Once enough proteins are biotinylated in a cell or tissue sample, the sample is scraped and lysed, and avidin pulldown is used to enrich proteins to achieve spatial protein scooping at a 240-nm precision. Subsequent LC-MS/MS is implemented to reveal the subcellular proteome in high sensitivity, specificity, and resolution. Using this technology termed optoproteomics, we have revealed novel stress granule-localized and amyloid β-localized proteins validated by immunostaining. Together, spatial purification by ultra-content, high-speed microscopy-targeted photo-biotinylation enables unprecedented subcellular spatial proteomics discovery in any microscopically recognizable regions.
A Modified Tseng Algorithm Approach to Restoring Thoracic Diseases’ Computerized Tomography Images
Authors: Umar Huzaifa , Adamu Abubakar , Hijaz Ahmad , Ozsahin Dilber Uzun
Published: December 2023

It is well-known that the Tseng algorithm and its modifications have been successfully employed in approximating zeros of the sum of monotone operators. In this study, we restored various thoracic diseases’ computerized tomography (CT) images, which were degraded with a known blur function and additive noise, using a modified Tseng algorithm. The test images used in the study depict calcification of the Aorta, Subcutaneous Emphysema, Tortuous Aorta, Pneumomediastinum, and Pneumoperitoneum. Additionally, we employed well-known image restoration tools to enhance image quality and compared the quality of restored images with the originals. Finally, the study demonstrates the potential to advance monotone inclusion problem-solving, particularly in the field of medical image recovery.
The placental protein NRK promotes cell death through its plasma membrane-localizing CNH domain
Authors: Lestari Beni , Soda Kohei , Moritsugu Kei , Kidera Akinori , Suenaga Yusuke , Hippo Yoshitaka , Meiyanto Edy , Komada Masayuki , Wahyuningsih Mae Sri Hartati , Fukushima Toshiaki
Published: December 2023

Placental development is regulated by the balance between cell proliferation and death. The placental protein NRK (NIK-related kinase) plays a role in preventing excessive placenta growth. We previously demonstrated that NRK underwent rapid molecular evolution in the ancestor of placental mammals and acquired the functional regions, including the phospholipid-binding citron homology (CNH) domain, by which NRK inhibits cell proliferation. NRK is also potentially responsible for cell death; caspases cleave NRK during apoptosis, releasing theC-terminal fragment that promotes cell death. Here, we explored the molecular mechanisms underlying the cell death-promoting effects of NRK. Our experimental data using HeLa, placenta trophoblast BeWo (human), and Rcho-1 (rat) cells indicated that the CNH domain of NRK was required and sufficient to promote cell death.In vitroandin silicostudies showed the NRK CNH domain bound to phospholipids via its polybasic clusters and remains at the plasma membrane (PM) during apoptosis. Evolutional analyses indicated that these clusters formed in the ancestor of placental mammals. Mutations in these clusters (CNH-18A) hindered the cell death-promoting activity of the CNH domain. We concluded that NRK promotes cell death through its plasma membrane-localizing CNH domain and suggested its active role in PM-associated events during cell death.
p23-FKBP51 chaperone complex regulates tau aggregation
Authors: Chakraborty Pijush , Zweckstetter Markus
Published: December 2023

The pathological deposition of tau into insoluble amyloid fibrils is a pathological hallmark of tauopathies. Molecular chaperones are important cellular factors contributing to the regulation of tau misfolding and aggregation. Here we reveal an Hsp90-independent modulation of tau aggregation by a molecular complex of the two Hsp90 co-chaperones p23 and FKBP51. Integrating NMR spectroscopy, SAXS, molecular docking, and site-directed mutagenesis we reveal the structural basis of the p23-FKBP51 complex. We show that p23 specifically recognizes the TPR domain of FKBP51 and interacts with tau through its C-terminal disordered tail. We further show that the p23-FKBP51 complex binds tau to form a dynamic p23-FKBP51-tau trimeric complex that inhibits tau aggregation and thus may counteract Hsp90-FKBP51 mediated toxicity. Taken together, our findings reveal a co-chaperone mediated Hsp90-independent chaperoning of tau protein.
A yeast love triangle: multiple hybridizations shape genome evolution in thePichia cactophilaspecies complex
Authors: Mixão Verónica , Saus Ester , Hagen Ferry , Boekhout Teun , Stevens Ryan R. , Gabaldón Toni
Published: December 2023

Hybrids are chimeric organisms carrying genetic material from at least two divergent parental lineages. Hybridization can contribute to the emergence of novel lineages with unique phenotypic traits that may facilitate their adaptation to new environments. In recent years, genomic analyses have revealed the hybrid nature of several opportunistic human pathogenic yeasts. One of them isCandida inconspicua,a member of thePichia cactophilaspecies complex, for which all sequenced strains are hybrids isolated from Europe with so far unknown parentals. It has been recently proposed thatC. inconspicuaandP. cactophilas.s. should be ranked as the same species due to their genetic similarity. To obtain a better understanding of the evolution of this clade, we sequenced the genomes of theP. cactophilatype strain, of its close-relativePichia pseudocactophila, and of a putativeC. inconspicuaclinical isolate from Alaska and compared them with the previously sequenced genomes ofPichia norvegensis, C. inconspicuaand the recently describedPichia galeolata. Our results show evidence for the existence of distinct hybrid lineages within this clade and suggest an intricate scenario of recurrent hybridizations in this species complex, some of them giving rise to lineages with the ability to infect humans. Given their different hybridization histories, we propose thatC. inconspicua, P. cactophila,and the new clinical isolate from Alaska should represent three distinct species and suggest the namePichia alaskaensisfor the new taxon. Moreover, the nameC. inconspicuais recombined in the genusPichiaasP. inconspicua. Our results clarify the evolutionary relationships within theP. cactophilaspecies complex and underscore the importance of non-vertical evolution.
From Inhibition to Excitation and Why: The Role of Temporal Urgency in Modulating Corticospinal Activity
Authors: McInnes Aaron N. , Smithers Benjamin , Lipp Ottmar V. , Tresilian James R. , Vallence Ann-Maree , Rothwell John C. , Marinovic Welber
Published: December 2023

Previous research on movement preparation identified a period of corticospinal suppression about 200 ms prior to movement initiation. This phenomenon has been observed for different types of motor tasks typically used to investigate movement preparation (e.g., reaction time, self-initiated, and anticipatory actions). However, we recently discovered that this phenomenon is not observed when actions must be initiated under time pressure. In the present study, we investigated urgency effects on corticospinal suppression throughout the time course of an anticipatory timing task. Participants were required to perform timing actions under two urgency scenarios, high and low, and we applied single-pulse transcranial magnetic stimulation at different times during the time course of preparation. We analysed the time course of excitability under high and low scenarios in relation to expected and actual movement onset times. Our results confirmed our earlier findings that corticospinal suppression is not observed when participants perform actions under high urgency scenarios. In addition, we found no evidence that this preparatory suppression could be shifted in time to occur later under high urgency scenarios. Moreover, we found evidence that responses prepared under high urgency are more likely to be disrupted by external events (e.g., TMS pulses). These results suggest that preparatory suppression might be a strategy employed by the central nervous system to shield motor actions from interference of external events (e.g., loud sounds) when time allows. Given these data, we propose conceptual models that could account for the absence of preparatory suppression under time pressure to act.
Comparative genomics ofCryptococcusandKwoniellareveals pathogenesis evolution and contrasting karyotype dynamics via intercentromeric recombination or chromosome fusion
Authors: Coelho Marco A. , David-Palma Márcia , Shea Terrance , Bowers Katharine , McGinley-Smith Sage , Mohammad Arman W. , Gnirke Andreas , Yurkov Andrey M. , Nowrousian Minou , Sun Sheng , Cuomo Christina A. , Heitman Joseph
Published: December 2023

A large-scale comparative genomic analysis was conducted for the global human fungal pathogens within theCryptococcusgenus, compared to non-pathogenicCryptococcusspecies, and related species from the sister genusKwoniella. Chromosome-level genome assemblies were generated for multiple species of both genera, resulting in a dataset encompassing virtually all of their known diversity. AlthoughCryptococcusandKwoniellahave comparable genome sizes (about 19.2 and 22.9 Mb) and similar gene content, hinting at pre-adaptive pathogenic potential, our analysis found evidence in pathogenicCryptococcusspecies of specific examples of gene gain (via horizontal gene transfer) and gene loss, which might represent evolutionary signatures of pathogenic development. Genome analysis also revealed a significant variation in chromosome number and structure between the two genera. By combining synteny analysis and experimental centromere validation, we found that mostCryptococcusspecies have 14 chromosomes, whereas mostKwoniellaspecies have fewer (11, 8, 5 or even as few as 3). Reduced chromosome number inKwoniellais associated with formation of giant chromosomes (up to 18 Mb) through repeated chromosome fusion events, each marked by a pericentric inversion and centromere loss. While similar chromosome inversion-fusion patterns were observed in allKwoniellaspecies with fewer than 14 chromosomes, no such pattern was detected inCryptococcus. Instead,Cryptococcusspecies with less than 14 chromosomes, underwent chromosome reductions primarily through rearrangements associated with the loss of repeat-rich centromeres. Additionally,Cryptococcusgenomes exhibited frequent interchromosomal translocations, including intercentromeric recombination facilitated by transposons shared between centromeres. Taken together, our findings advance our understanding of genomic changes possibly associated with pathogenicity inCryptococcusand provide a foundation to elucidate mechanisms of centromere loss and chromosome fusion driving distinct karyotypes in closely related fungal species, including prominent global human pathogens.
Delineating markers of disease-disease interaction: a systematic methodology and its application to multiple diabetes-helminth cohorts
Authors: Subramanian Nilesh Anantha , Philip Philge , Rajamanickam Anuradha , Kumar Nathella Pavan , Babu Subash , Narayanan Manikandan
Published: December 2023

Understanding how the molecules in our body respond to the co-occurrence of two diseases in an individual (comorbidity) could lead to mechanistic insights into novel treatments for comorbid conditions. Studies have shown for instance that responses of our immune system to comorbid conditions could be more complex than the union of immune responses to each disease occurring separately, but a data-driven quantification of this complexity is lacking. In this study, we present a systematic methodology to quantify the interaction effect of two diseases on marker variables of interest (using a chronic inflammatory disease diabetes and parasitic infection helminth as illustrative disease pairs to identify cytokines or other immune markers that respond distinctively under a comorbid condition). To perform this systematic comorbidity analysis, we (i) collected and preprocessed data measurements from multiple single- and double-disease cohorts, (ii) extended differential expression analysis of such data to identify disease-disease interaction (DDI) markers (such as cytokines that respond antagonistically or synergistically to the double-disease condition relative to single-disease states), and (iii) interpreted the resulting DDI markers in the context of prior cytokine/immune-cell knowledgebases. We applied this three-step DDI methodology to multiple cohorts of helminth and diabetes (specifically, helminth-infected and helminth treated individuals in diabetic and non-diabetic conditions, and non-disease control individuals), and identified cytokines such as IFN-gamma, TNF-alpha, and IL-2 to be DDI markers acting at the interface of both diseases in data collected prior to helminth treatment. Validating our expectations, for these cytokines and other T helper Th-2 cytokines like IL-13 and IL-4, their DDI statuses were lost after treatment for helminth infection. For instance, the relative contribution of the DDI term in explaining the individual-to-individual variation of IFN-gamma and TNF-alpha cytokines were 67.68% and 48.88% respectively before anthelmintics treatment and dropped to 6.09% and 14.56% respectively after treatment. Furthermore, signaling pathways like IL-10 and IL-4/IL-13 were found to be significantly enriched for genes targeted by certain DDI markers, thereby suggesting mechanistic hypotheses on how these DDI markers influence both diseases. Our results quantified the extent of helminth-diabetes DDI exhibited by various tested cytokine markers, and thereby delineated their role in the pathogenesis of both diseases. These results are promising and encourage the application of our DDI methodology (https://github.com/BIRDSgroup/DDI) to dissect the interaction between any two diseases, provided multi-cohort measurements of markers are available.
Hippocampal sequences span experience relative to rewards
Authors: Sosa Marielena , Plitt Mark H. , Giocomo Lisa M.
Published: December 2023

Hippocampal place cells fire in sequences that span spatial environments and non-spatial modalities, suggesting that hippocampal activity can anchor to the most behaviorally salient aspects of experience. As reward is a highly salient event, we hypothesized that sequences of hippocampal activity can anchor to rewards. To test this, we performed two-photon imaging of hippocampal CA1 neurons as mice navigated virtual environments with changing hidden reward locations. When the reward moved, the firing fields of a subpopulation of cells moved to the same relative position with respect to reward, constructing a sequence of reward-relative cells that spanned the entire task structure. The density of these reward- relative sequences increased with task experience as additional neurons were recruited to the reward- relative population. Conversely, a largely separate subpopulation maintained a spatially-based place code. These findings thus reveal separate hippocampal ensembles can flexibly encode multiple behaviorally salient reference frames, reflecting the structure of the experience.
Phosphatases of regenerating liver balance F-actin rearrangements during T cell activation through WD repeat containing protein 1
Authors: Aguilar-Sopeña Óscar , Carrasco-Padilla Carlos , Gomez-Moron Álvaro , Castro-Sánchez Patricia , Estarás-Hermosel Matías , Valvo Salvatore , Alegre-Gómez Sergio , Redondo-Muñoz Javier , Torres Raúl , Rodríguez-Perales Sandra , Ismail Shehab , Sánchez-Madrid Francisco , Martín-Cófreces Noa B. , Dustin Michael L. , Roda-Navarro Pedro
Published: December 2023

Phosphatases of regenerating liver (PRLs) have been proposed to regulate actin dynamics in lymphoid cells. However, the mechanism mediating this role remained unknown. Here we showed the interaction of the PRLs with the actin regulator WD repeat containing protein 1 (WDR1). The interaction of the PRLs with WDR1 was dependent on F-actin integrity and the proper recruitment of the PRLs to cell membranes through the CAAX motif. Endogenous PRLs and WDR1 were distributed to the Immunological Synapse (IS) and perturbed expression of PRL-1 or PRL-2 by CRISPR/Cas9 mediated genome editing showed that the PRLs were required for proper distribution of WDR1 to filamentous (F)-actin at the IS. Further, perturbed expression of the PRLs or WDR1 resulted in defective IS assembly with deregulated F-actin rearrangements, altered positioning of LFA-1, and reduced IL-2 production. Interestingly, balanced expression of PRLs was required for accumulation of CD3ε at the IS and early activating signalling. We propose that PRLs regulate early T cell signalling and are required for proper F-actin dynamics by regulating the WDR1 access to F-actin networks. As a consequence, PRLs regulate LFA-1 positioning at the IS and proper cytokine secretion.
Identification of a myofibroblast differentiation program during neonatal lung development
Authors: Yin Yongjun , Koenitzer Jeffrey R. , Patra Debabrata , Dietmann Sabine , Bayguinov Peter , Hagan Andrew S. , Ornitz David M.
Published: December 2023

Alveologenesis is the final stage of lung development in which the internal surface area of the lung is increased to facilitate efficient gas exchange in the mature organism. The first phase of alveologenesis involves the formation of septal ridges (secondary septae) and the second phase involves thinning of the alveolar septa. Within secondary septa, mesenchymal cells include a transient population of alveolar myofibroblasts (MyoFB) and a stable but poorly described population of lipid rich cells that have been referred to as lipofibroblasts or matrix fibroblasts (MatFB). Using a uniqueFgf18CreERlineage trace mouse line, cell sorting, single cell RNA sequencing, and primary cell culture, we have identified multiple subtypes of mesenchymal cells in the neonatal lung, including an immature progenitor cell that gives rise to mature MyoFB. We also show that the endogenous and targeted ROSA26 locus serves as a sensitive reporter for MyoFB maturation. These studies identify a myofibroblast differentiation program that is distinct form other mesenchymal cells types and increases the known repertoire of mesenchymal cell types in the neonatal lung.

Summary Statement

During primary alveologenesis, alveolar myofibroblasts comprise a distinct proliferative mesenchymal lineage that matures and populates emerging secondary septa.
Functional characterization of allCDKN2Amissense variants and comparison to in silico models of pathogenicity
Authors: Kimura Hirokazu , Lahouel Kamel , Tomasetti Cristian , Roberts Nicholas J.
Published: December 2023

Interpretation of variants identified during genetic testing is a significant clinical challenge. In this study, we developed a high-throughput CDKN2A functional assay and characterized all possibleCDKN2Amissense variants. We found that 17.7% of all missense variants were functionally deleterious. We also used our functional classifications to assess the performance of in silico models that predict the effect of variants, including recently reported models based on machine learning. Notably, we found that all in silico models performed similarly when compared to our functional classifications with accuracies of 39.5-85.4%. Furthermore, while we found that functionally deleterious variants were enriched within ankyrin repeats, we did not identify any residues where all missense variants were functionally deleterious. Our functional classifications are a resource to aid the interpretation ofCDKN2Avariants and have important implications for the application of variant interpretation guidelines, particularly the use of in silico models for clinical variant interpretation.
ADMET-AI: A machine learning ADMET platform for evaluation of large-scale chemical libraries
Authors: Swanson Kyle , Walther Parker , Leitz Jeremy , Mukherjee Souhrid , Wu Joseph C. , Shivnaraine Rabindra V. , Zou James
Published: December 2023

The emergence of large chemical repositories and combinatorial chemical spaces, coupled with high-throughput docking and generative AI, have greatly expanded the chemical diversity of small molecules for drug discovery. Selecting compounds for experimental validation requires filtering these molecules based on favourable druglike properties, such as Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET). We developed ADMET-AI, a machine learning platform that provides fast and accurate ADMET predictions both as a website and as a Python package. ADMET-AI has the highest average rank on the TDC ADMET Benchmark Group leaderboard, and it is currently the fastest web-based ADMET predictor, with a 45% reduction in time compared to the next fastest ADMET web server. ADMET-AI can also be run locally with predictions for one million molecules taking just 3.1 hours.

Availability and Implementation

The ADMET-AI platform is freely available both as a web server atadmet.ai.greenstonebio.comand as an open-source Python package for local batch prediction atgithub.com/swansonk14/admet_ai(also archived on Zenodo atdoi.org/10.5281/zenodo.10372930). All data and models are archived on Zenodo atdoi.org/10.5281/zenodo.10372418.