bluuebunny/crossref_metadata_2025 huggingface dataset:
Karyopherin mimicry explains how the HIV capsid penetrates nuclear pores
Authors: Dickson C.F. , Hertel S. , Ruan J. , Ariotti N. , Tuckwell A. , Li N. , Al-Izzi S.C. , Sierecki E. , Gambin Y. , Morris R.G. , Towers G.J. , Böcking T. , Jacques D.A.
Published: March 2023

Summary Paragraph

HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus. Remarkably, the intact HIV capsid is over one thousand times greater than the size-limit prescribed by the nuclear pore’s diffusion barrier. This barrier is a phase-separated condensate in the central channel of the nuclear pore and is comprised of intrinsically-disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG-interactions, cellular karyopherins and their bound cargoes solubilise in this phase to drive nucleocytoplasmic transport. By performing anin vitrodissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG-motifs from multiple nucleoporins and that this interaction licenses capsids to penetrate nucleoporin condensates. This karyopherin mimicry model resolves a key conceptual challenge for the role of the HIV capsid in nuclear entry, and explains how an exogenous entity much larger than any known cellular cargo can non-destructively breach the nuclear envelope.
Environmental modulators of algae-bacteria interactions at scale
Authors: Gopalakrishnappa Chandana , Li Zeqian , Kuehn Seppe
Published: March 2023

Photosynthetic microbes associated with non-photosynthetic, heterotrophic, bacteria play a key role in the global primary production. Understanding these phototroph-heterotroph associations is therefore important, but remains challenging because they reside in chemically complex aquatic and terrestrial environments. We do not understand how the myriad of environmental parameters from nutrient availability to pH impact interactions between phototrophs and their heterotrophic partners. Here, we leverage a massively parallel droplet microfluidic platform that enables us to interrogate algae-bacteria interactions in>100,000 communities across ∼525 environmental conditions with varying pH, carbon availability and phosphorous availability. By developing a statistical framework to dissect interactions in this complex dataset, we reveal that dependance of algae-bacteria interactions on nutrient availability is strongly modulated by pH and buffering capacity. Furthermore, we show that the chemical identity of the available organic carbon source controls how pH, buffering capacity, and nutrient availability modulate algae-bacteria interactions. By leveraging a high-throughput platform, our study reveals the previously underappreciated role of pH in modulating phototroph-heterotroph interactions.
Elevated ENO2 Disrupts VSMCs Homeostasis Facilitating the Development of Aortic Dissection
Authors: Cai Weixing , Zhang Li , Lin Jing-Jing , Zou Qiuying , Wang Chaoyun , Yang Xi , Wu Xiaohui , Ye Jianqiang , Zheng Hui , Zhang Lin , Zhong Lin , Li Xinyao , Chen Keyuan , Wu Jiangbin , Chen Liangwan , Li Yumei
Published: March 2023

OBJECTIVE

Aortic dissection (AD) is a dangerous cardiovascular disease. However, its regulatory mechanism remains poorly understood. Autophagy is an important pathway for maintaining cellular homeostasis. Recent studies have shown that glycolysis and autophagy are essential for the development of AD. Elevated glycolysis can promote cells autophagy, but the relationship between the two is unclear. Enolase 2 (ENO2) is a glycolytic enzyme. Here, we investigated whether ENO2 can regulate autophagy in vascular smooth muscle cells (VSMCs) involved in the progression of AD.

APPROACH AND RESULTS

The levels of ENO2 and autophagy-related proteins in aortic tissues from AD patients were identified by qRT-PCR, Western blot and IHC. We found that autophagosome clearance was impaired in aortic tissues and positively correlated with elevated ENO2 expression. Furthermore, aortic application of smooth muscle-specific adeno-associated virus (AAV) inhibiting ENO2 expression attenuated the development of AD in mice. in vitro experiments, downregulation of ENO2 partially restored PDGF-BB-induced impairment of autophagic flux, as evidenced by reduced expression of Beclin-1, SQSTM1, LC3BII/I and increased levels of LAMP2 in human aortic vascular smooth muscle cells (HAVSMCs). Similarly, increased levels of ENO2 exacerbated the autophagic dysfunction in HAVSMCs. Mechanistically, ENO2 may block autophagic flux through the ENO2-GAP43-ATF4 pathway and disrupt cellular homeostasis.

CONCLUSIONS

Our data reveal a perturbing role of ENO2 in the homeostasis of VSMCs, suggesting ENO2 as a potential target for intervention in AD.
“Comparison of antibiotic protein binding in human plasma vs. rabbit plasma”
Authors: Pesta Maximilian , Datler Philip , Scheriau Georg , Wohlrab Peter , Eberl Sabine , Lackner Edith , Franz Claudia , Jäger Walter , Maier-Salamon Alexandra , Zeitlinger Markus , Tschernko Edda
Published: March 2023

Rabbits are frequently used for the examination of the pharmacokinetics and effectiveness of antibiotic substances. However, antibiotics vary substantially in protein binding affecting the concentration of the antimicrobially effective unbound drug. We hypothesized that the binding properties of vancomycin, meropenem and ceftriaxone might vary between human and rabbit plasma. In an in-vitro study we observed dose dependent variability in protein binding of antibiotics between species. Thus, in-vitro-pre-studies are required to guarantee for translational conditions.
Serine peptidases and increased amounts of soluble proteins contribute to heat priming of the plant pathogenic fungusBotrytis cinerea
Authors: Zhang Mingzhe , Trushina Naomi Kagan , Lang Tabea , Hahn Matthias , Chor Metsada Pasmanik , Sharon Amir
Published: March 2023

Botrytis cinereacauses grey mold disease in leading crop plants. The disease develops only at cool temperatures, but the fungus remains viable in warm climates and can survive periods of extreme heat. We discovered a strong heat priming effect in which the exposure ofB. cinereato moderately high temperatures greatly improves its ability to cope with subsequent, potentially lethal temperature conditions. We showed that priming promotes protein solubility during heat stress and discovered a group of priming-induced serine-type peptidases. Several lines of evidence, including transcriptomics, proteomics, pharmacology, and mutagenesis data, link these peptidases to theB. cinereapriming response, highlighting their important roles in regulating priming-mediated heat adaptation. By imposing a series of sub-lethal temperature pulses that subverted the priming effect, we managed to eliminate the fungus and prevent disease development, demonstrating the potential for developing temperature-based plant protection methods by targeting the fungal heat priming response.

Importance

Priming is a general and important stress adaptation mechanism. Our work highlights the importance of priming in fungal heat adaptation, reveals novel regulators and aspects of heat adaptation mechanisms, and demonstrates the potential of affecting microorganisms, including pathogens through manipulations of the heat adaptation response.
Low circulating adropin concentrations predict increased risk of cognitive decline in community-dwelling older adults
Authors: Aggarwal Geetika , Morley John E. , Vellas Bruno , Nguyen Andrew D. , Butler Andrew A. ,   the MAPT/DSA Group
Published: March 2023

The secreted peptide adropin is highly expressed in human brain tissues and correlates with RNA and proteomic risk indicators for dementia. Here we report that plasma adropin concentrations predict risk for cognitive decline in the Multidomain Alzheimer Preventive Trial (ClinicalTrials.govIdentifier,NCT00672685; mean age 75.8y, SD=4.5y, 60.2% female, n=452). Cognitive ability was evaluated using a composite cognitive score (CCS) that assessed four domains: memory, language, executive function, and orientation. Relationships between plasma adropin concentrations and changes in CCS (ΔCCS) were examined using Cox Proportional Hazards Regression, or by grouping into tertiles ranked low to high by adropin values and controlling for age, time between baseline and final visits, baseline CCS, and other risk factors (e.g., education, medication, APOE4 status). Risk of cognitive decline (defined as a ΔCCS of -0.3 or more) decreased with increasing plasma adropin concentrations (hazard ratio = 0.873, 95%CI 0.780-0.977, P=0.018). Between adropin tertiles, ΔCCS was significantly different (P=0.01; estimated marginal mean±SE for the 1st-to 3rd-tertile, -0.317±0.064; -0.275±0.063; -0.042±0.071; n=133,146, and 130, respectively; P<0.05 for 1stvs. 2ndand 3rdadropin tertiles). Normalized plasma Aβ42/40ratio and plasma neurofilament light chain, indicators of neurodegeneration, were significantly different between adropin tertile. These differences were consistent with reduced risk of cognitive decline with higher plasma adropin levels. Overall, these results suggest cognitive decline is reduced in community-dwelling older adults with higher circulating adropin levels. Further studies are needed to determine the underlying causes of the relationship and whether increasing adropin levels can delay cognitive decline.
Dementia Risk Analysis Using Temporal Event Modeling on a Large Real-World Dataset
Authors: Taylor Richard Andrew , Gilson Aidan , Chi Ling , Haimovich Adrian D. , Crawford Anna , Brandt Cynthia , Magidson Phillip , Lai James , Levin Scott , Mecca Adam P. , Hwang Ula
Published: March 2023

The objective of the study is to identify healthcare events leading to a diagnosis of dementia from a large real-world dataset. This study uses a data-driven approach to identify temporally ordered pairs and trajectories of healthcare codes in the electronic health record (EHR). This allows for discovery of novel temporal risk factors leading to an outcome of interest that may not otherwise be obvious. We identified several known (Down syndrome RR: 116.1, thiamine deficiency RR: 76.1, and Parkinson’s disease RR: 41.1) and unknown (Brief psychotic disorder RR: 68.6, Toxic effect of metals RR: 40.4, and Schizoaffective disorders RR: 40.0) factors for a specific dementia diagnosis. The associations with the greatest risk for any dementia diagnosis were found to be primarily related to mental health (Brief psychotic disorder RR: 266.5, Dissociative and conversion disorders RR: 169.8), or neurologic conditions or procedures (Dystonia RR: 121.9, Lumbar Puncture RR: 119.0). Trajectory and clustering analysis identified factors related to cerebrovascular disorders, as well as diagnoses which increase the risk of toxic imbalances. The results of this study have the ability to provide valuable insights into potential patient progression towards dementia and improve recognition of patients at risk for developing dementia.
Dietary and metabolic factors contributing to Barrett’s esophagus: a univariate and multivariate Mendelian randomization study
Authors: Li Zijie , Zhuang Weitao , Wu Junhan , Xu Haijie , Tang Yong , Qiao Guibin
Published: March 2023

Background

Dietary and metabolic factors have been associated with the risk of Barrett’s esophagus (BE) in observational epidemiological studies. However, the aforementioned associations may be influenced by confounding bias. The present study aimed to evaluate these causal relationships through univariate and multivariate Mendelian randomization (MR) analysis.

Methods

Genetic instruments associated with dietary and metabolic factors were obtained in the large-scale genome-wide association studies (GWAS), respectively. Summary data for BE were available from a GWAS of 13,358 cases and 43,071 controls of European descent. Univariable MR analysis was initially performed to estimate the causal relationship between exposures and BE. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis. Multivariate MR analysis was further conducted to evaluate the independent effects of exposures on BE.

Results

In univariate MR analysis, BE was causally associated with higher body mass index (odds ratio (OR) = 2.575, 95% confidence interval (CI): 2.301-2.880, P = 7.369E-61), larger waist circumference (OR = 2.028, 95% CI: 1.648-2.496, P = 2.482E-11), and smoking per day (OR = 1.241, 95% CI: 1.085-1.419, P = 0.002). Dried fruit intake showed a protective effect on BE (OR = 0.228, 95% CI: 0.135-0.384, P = 2.783E-08), whereas alcohol drinking, coffee intake, tea intake, fresh fruit intake, and type 2 diabetes mellitus were not associated with BE (P = 0.351, P = 0.458, P = 0.125, P = 0.847, P = 0.413, respectively). No pleiotropy was found in the sensitivity analysis. The relationships of obesity, smoking, and dried fruit intake with BE risk remained strong after adjustment.

Conclusions

Our study provided MR evidence supporting obesity and smoking were independent risk factors for BE. Conversely, dried fruit intake was a protective factor for BE.
Improving Medication Prescribing-Related Outcomes for Vulnerable Elderly In Transitions on High Risk Medications (IMPROVE-IT HRM): A Pilot Randomized Trial Protocol
Authors: Holbrook Anne , Perri Dan , Levine Mitch , Jarmain Sarah , Thabane Lehana , Tarride Jean-Eric , Dolovich Lisa , Hyland Sylvia , Forster Alan , Nieuwstraten Carmine
Published: March 2023

Rationale

Transitions in, through, and out of hospital define the highest risk periods for patient safety. Hospitalized senior high-cost health care users taking high risk medications, are a large group of patients, usually highly complex with polypharmacy, and at high risk of serious adverse medication events. We will assess whether an expert Clinical Pharmacology Toxicology (CPT) medication management intervention during hospitalization with follow-up post-discharge and communication with circle of care, is feasible and can decrease drug therapy problems amongst this group.

Design

Pragmatic pilot randomized trial at SJHH with 1:1 patient-level concealed randomization with blinded outcome assessment and data analysis.

Participants

Adults 65 years of age and older, admitted to Internal Medicine services for more than 2 days, who are high-cost users defined as at least one other hospitalization in the prior year, taking 5 or more chronic medications including at least one high risk medication.

Intervention

CPT consult service identifies medication target(s), completes consult, including priorities for improving prescribing negotiated with the patient, starts the care plan, ensures a detailed discharge medication reconciliation and circle-of-care communication, and sees the patient at least twice after hospital discharge via integrated virtual visits to consolidate the care plan in the community. Control group receives usual care as provided by admitting services.

Outcomes

Include a) Feasibility Outcomes and b) Clinical Outcomes including the number of drug therapy problems improved, medication appropriateness and safety, the quality and coordination of transitions in care, quality of life, and health care utilization and costs by 3-month follow-up.

Impact

If results support feasibility of ramp-up and promising clinical outcomes, a follow-up definitive trial will be organized using a developing national platform and medication appropriateness network.

RESEARCH QUESTION

Our detailed research question is ‘In a randomized pilot trial, can an expert Clinical Pharmacology team coordinate and improve medication management during the very high-risk transition period from hospitalization through post-hospital discharge follow-up for senior high-cost users of healthcare taking high risk medications, meeting key feasibility outcomes while improving patient-important outcomes and health care costs sufficiently to warrant a large subsequent trial?’
Reduction, removal or replacement of sodium nitrite in a model of cured and cooked meat: a joint evaluation of consequences on microbiological issues in food safety, colon ecosystem and colorectal carcinogenesis
Authors: Guéraud Françoise , Buisson Charline , Promeyrat Aurélie , Naud Nathalie , Fouché Edwin , Bézirard Valérie , Dupuy Jacques , Plaisancié Pascale , Héliès-Toussaint Cécile , Trouilh Lidwine , Martin Jean-Luc , Jeuge Sabine , Keuleyan Eléna , Petit Noémie , Aubry Laurent , Théodorou Vassilia , Frémaux Bastien , Olier Maïwenn , Caderni Giovanna , Kostka Tina , Nassy Gilles , Santé-Lhoutellier Véronique , Pierre Fabrice
Published: March 2023

Scope

Epidemiological and experimental evidence reported that processed meat consumption is associated with colorectal cancer (CRC) risk. Several studies suggest the involvement of nitrite or nitrate additivesvia N-nitroso-compound formation (NOCs).

Methods and results

Compared to the reference level (120 mg/kg of ham), the effects of sodium nitrite reduction (90 mg/kg of ham), removal and replacement were analysed on ham characteristics and in a CRC rat model. Sodium nitrite removal and reduction induced a similar decrease in CRC preneoplastic lesions, but only reduction led to (i) an inhibitory effect onListeria monocytogenesgrowth comparable to that obtained using the reference nitrite level of 120 mg/kg and (ii) an effective control of lipid peroxidation. Among the three alternatives tested, none led to a significant gain when compared to the 120 mg/kg ham reference level: vegetable stock, due to nitrate presence, was very similar to this reference nitrite level, yeast extract induced a strong luminal peroxidation and no decrease in preneoplastic lesions despite the absence of NOCs, and polyphenol rich extract induced the clearest downward trend on preneoplastic lesions but the concomitant presence of nitrosyl iron in feces. Except vegetable stock, other alternatives were less efficient than sodium nitrite (≥ 90 mg/kg) in reducingL. monocytogenesgrowth.

Conclusion

Nitrite reduction (90mg/kg) effectively reduced CRC risk through limiting NOC formation and lipid peroxidation, while mitigatingL. monocytogenesrisks from cooked hams. Going further in reduction should be possible if accompanied by antioxidants to limit lipid peroxidation and appropriate use-by dates.
Distance-dependent reconfiguration of hubs in Alzheimer’s disease: a cross-tissue functional network study
Authors: Zhang Xingxing , Li Yingjia , Guan Qing , Dong Debo , Zhang Jianfeng , Meng Xianghong , Chen Fuyong , Luo Yuejia , Zhang Haobo ,   Alzheimer’s Disease Neuroimaging Initiative
Published: March 2023

The hubs of the intra-grey matter (GM) network were sensitive to anatomical distance and susceptible to neuropathological damage. However, few studies examined the hubs of cross-tissue distance-dependent networks and their changes in Alzheimer’s disease (AD). Using resting-state fMRI data of 30 AD patients and 37 normal older adults (NC), we constructed the cross-tissue networks based on functional connectivity (FC) between GM and white matter (WM) voxels. In the full-ranged and distance-dependent networks (characterized by gradually increased Euclidean distances between GM and WM voxels), their hubs were identified with weight degree metrics (frWD and ddWD). We compared these WD metrics between AD and NC; using the resultant abnormal WDs as the seeds, we performed seed-based FC analysis. With increasing distance, the GM hubs of distance-dependent networks moved from the medial to lateral cortices, and the WM hubs spread from the projection fibers to longitudinal fascicles. Abnormal ddWD metrics in AD were primarily located in the hubs of distance-dependent networks around 20-100mm. Decreased ddWDs were located in the left corona radiation (CR), which had decreased FCs with the executive network’s GM regions in AD. Increased ddWDs were located in the posterior thalamic radiation (PTR) and the temporal-parietal-occipital junction (TPO), and their FCs were larger in AD. Increased ddWDs were shown in the sagittal striatum, which had larger FCs with the salience network’s GM regions in AD. The reconfiguration of cross-tissue distance-dependent networks possibly reflected the disruption in the neural circuit of executive function and the compensatory changes in the neural circuits of visuospatial and social-emotional functions in AD.
Multiscale Computational Framework to Investigate Integrin Mechanosensing and Cell Adhesion
Authors: Montes Andre R. , Gutierrez Gabriela , Tepole Adrian Buganza , Mofrad Mohammad R.K.
Published: March 2023

Integrin mechanosensing plays an instrumental role in cell behavior, phenotype, and fate by transmitting mechanical signals that trigger downstream molecular and cellular changes. For instance, force transfer along key amino acid residues can mediate cell adhesion. Disrupting key binding sites withinα5β1integrin’s binding partner, fibronectin (FN) diminishes adhesive strength. While past studies have shown the importance of these residues in cell adhesion, the relationship between the dynamics of these residues and how integrin distributes force across the cell surface remains less explored. Here, we present a multiscale mechanical model to investigate the mechanical coupling between integrin nanoscale dynamics and whole-cell adhesion mechanics. Our framework leverages molecular dynamics simulations to investigate residues withinα5β1-FN during stretching and the finite element method to visualize the whole-cell adhesion mechanics. The forces per integrin across the cell surface of the whole-cell model were consistent with past atomic force microscopy and Förster resonance energy transfer measurements from literature. The molecular dynamics simulations also confirmed past studies that implicate two key sites within FN that maintain cell adhesion: the synergy site and RGD motif. Our study contributed to our understanding of molecular mechanisms by which these sites collaborate to mediate whole-cell integrin adhesion dynamics. Specifically, we showed how FN unfolding, residue binding/unbinding, and molecular structure contribute toα5β1-FN’s nonlinear force-extension behavior during stretching. Our computational framework could be used to explain how the dynamics of key residues influence cell differentiation or how uniquely designed protein structures could dynamically limit the spread of metastatic cells.
Long-term citizen science data reveals environmental controls on tropical tree flowering at the regional scale
Authors: Anujan Krishna , Mardian Jacob , Luo Carina , Ramraj R ,   SeasonWatch Citizen Scientist Network, Tasic Hana , Akseer Nadia , Ramaswami Geetha
Published: March 2023

Abstract

Tropical tree reproductive phenology is sensitive to changing climate, but inter-individual and interannual variability at the regional scale is poorly understood. While large-scale and long-term datasets of environmental variables are available, reproductive phenology needs to be measured in-site, limiting the spatiotemporal scales of the data. We leveraged a unique dataset assembled by SeasonWatch, a citizen-science phenology monitoring programme in India to assess the environmental correlates of flowering in three ubiquitous and economically important tree species - jackfruit, mango and tamarind - in the south-western Indian state of Kerala. We explored the possibility of predicting (i) the flowering status of a tree at any given time, knowing recent environmental conditions, (ii) the environmental conditions that predict the onset of flowering and (iii) explored spatiotemporal patterns in these predictors to aid future hypotheses for changing phenology patterns. We used 165006 phenology observations spread over 19591 individual trees over 9 years, environmental predictors for the fortnight preceding each observation derived from remotely sensed observations (ERA5-LAND) to model the environmental correlates of flowering using two statistical approaches - machine learning and generalised linear mixed models. We found strong influences of temperature and rainfall variables on phenophase presence - soil moisture and minimum temperature had high importance values under machine learning models of presence/absence and had strong effects in the onset of flowering. The effect of time-varying environmental factors, minimum temperature, soil moisture and solar radiation, were also modified by static predictors like elevation, aspect, and urbanisation. Taken together, our results show the pervasive influence of climate on tropical tree reproductive phenology and its variability among years and individuals. Our results become increasingly important in the face of large heterogenous change in the climate of this landscape and other tropical regions. We demonstrate the potential and limitations of citizen-science observations in making and testing predictions at scale for predictive climate science in tropical landscapes.

OpenResearchStatement

Data are already published and publicly available, with those items properly cited in this submission. SeasonWatch data is publicly archived as Ramaswami (2022).
An intact oculomotor neural circuit in congenital blindness
Authors: Koba Cemal , Crimi Alessandro , Collignon Olivier , Ricciardi Emiliano , Hasson Uri
Published: March 2023

In the past three decades, multiple studies revealed that congenital blindness is associated with functional and structural reorganization in early visual areas and its interaction with other neural systems. Among the most reproducible findings is the weaker connectivity between the visual and sensorimotor cortices, which in sighted individuals plays a role in eye-motor coordination. Here we demonstrate an important exception to this reorganization phenomena: we find that in congenitally blind individuals (as for normally sighted ones), spontaneous, non-controlled eye movements correlate with connectivity between visual and sensorimotor cortices. Furthermore, using time-lagged regression, we show that eye movements drive activity in the visual cortex, which subsequently drives sensorimotor activity. Remarkably, this phenomenon persists even though blind participants often exhibit unsynchronized eye movements and cannot sense or regulate their eye positions. These findings provide evidence of a preserved, “non-functional” connectivity in congenitally blind individuals and reveal a firm, hard-wired constraint on connectivity that remains immune to any reorganization phenomena produced by lack of visual experience and oculomotor control.
Cortical contributions to the perception of loudness and hyperacusis
Authors: McGill Matthew , Kremer Caroline , Stecyk Kamryn , Clayton Kameron , Skerleva Desislava , Hancock Kenneth , Kujawa Sharon G. , Polley Daniel B.
Published: March 2023

Sound perception is closely linked to the spatiotemporal patterning of neural activity in the auditory cortex (ACtx). Inhibitory interneurons sculpt the patterns of excitatory ACtx pyramidal neuron activity, and thus play a central role in sculpting the perception of sound. Reduced inhibition from parvalbumin-expressing (PV) inhibitory interneurons and the associated increased gain of sound-evoked pyramidal neuron spike rates are well-established consequences of aging and sensorineural hearing loss. Here, we reasoned that changes in PV-mediated inhibition would directly impact the perception of loudness. We hypothesized that ACtx PV activity could function as a perceptual volume knob, where reduced or elevated PV activity would increase or decrease the perceived loudness of sound, respectively. To test these hypotheses, we developed a two-alternative forced-choice loudness classification task for head-fixed mice and demonstrated that noise-induced sensorineural hearing loss directly caused a ∼10 dB loudness hyperacusis that begins hours after noise-induced sensorineural hearing loss and persists for at least several weeks. Conversely, sounds were perceived as ∼10 dB softer during optogenetic activation of ACtx PV neurons without having any effect on the overall detectability of sound. These data suggest that ACtx PV neurons can bi-directionally control the perceived loudness of sound, presumably via the strength of their inhibition onto local pyramidal neurons. Further, these data identify cortical PV neurons as a target for hyperacusis therapies and demonstrate a direct link between acquired sensorineural hearing loss and loudness hyperacusis.
Transformations of sensory information in the brain reflect a changing definition of optimality
Authors: Manning Tyler S. , Alexander Emma , Cumming Bruce G. , DeAngelis Gregory C. , Huang Xin , Cooper Emily A.
Published: March 2023

Neurons throughout the brain modulate their firing rate lawfully in response to changes in sensory input. Theories of neural computation posit that these modulations reflect the outcome of a constrained optimization: neurons aim to efficiently and robustly represent sensory information under resource limitations. Our understanding of how this optimization varies across the brain, however, is still in its infancy. Here, we show that neural responses transform along the dorsal stream of the visual system in a manner consistent with a transition from optimizing for information preservation to optimizing for perceptual discrimination. Focusing on binocular disparity – the slight differences in how objects project to the two eyes – we re-analyze measurements from neurons characterizing tuning curves in macaque monkey brain regions V1, V2, and MT, and compare these to measurements of the natural visual statistics of binocular disparity. The changes in tuning curve characteristics are computationally consistent with a shift in optimization goals from maximizing the information encoded about naturally occurring binocular disparities to maximizing the ability to support fine disparity discrimination. We find that a change towards tuning curves preferring larger disparities is a key driver of this shift. These results provide new insight into previously-identified differences between disparity-selective regions of cortex and suggest these differences play an important role in supporting visually-guided behavior. Our findings support a key re-framing of optimal coding in regions of the brain that contain sensory information, emphasizing the need to consider not just information preservation and neural resources, but also relevance to behavior.

Significance

A major role of the brain is to transform information from the sensory organs into signals that can be used to guide behavior. Neural activity is noisy and can consume large amount of energy, so sensory neurons must optimize their information processing so as to limit energy consumption while maintaining key behaviorally-relevant information. In this report, we re-examine classically-defined brain areas in the visual processing hierarchy, and ask whether neurons in these areas vary lawfully in how they represent sensory information. Our results suggest that neurons in these brain areas shift from being an optimal conduit of sensory information to optimally supporting perceptual discrimination during natural tasks.
Pulmonary vein flow split effects in patient-specific simulations of left atrial flow
Authors: Durán E. , García-Villalba M. , Martinez-Legazpi P. , Gonzalo A. , McVeigh E. , Kahn A.M. , Bermejo J. , Flores O. , del Álamo J.C.
Published: March 2023

Disruptions to left atrial (LA) blood flow, such as those caused by atrial fibrillation (AF), can lead to thrombosis in the left atrial appendage (LAA) and an increased risk of systemic embolism. LA hemodynamics are influenced by various factors, including LA anatomy and function, and pulmonary vein (PV) inflow conditions. In particular, the PV flow split can vary significantly among and within patients depending on multiple factors. In this study, we investigated how changes in PV flow split affect LA flow transport, focusing on blood stasis in the LAA, using a high-fidelity patient-specific computational fluid dynamics (CFD) model. We analyzed LA anatomies from eight patients with varying atrial function, including three with AF and either a LAA thrombus or a history of TIAs. Using four different flow splits (60/40% and 55/45% through right and left PVs, even flow rate, and same velocity through each PV), we found that flow patterns are sensitive to PV flow split variations, particularly in planes parallel to the mitral valve. Changes in PV flow split also had a significant impact on blood stasis and could contribute to increased risk for thrombosis inside the LAA, particularly in patients with AF and previous LAA thrombus or a history of TIAs. Our study highlights the importance of considering patient-specific PV flow split variations when assessing LA hemodynamics and identifying patients at increased risk for thrombosis and stroke.
Ocular following responses of the marmoset monkey are dependent on post-saccadic delay, spatiotemporal frequency and saccade direction
Authors: Ken Yip Hoi Ming , Allison-Walker Timothy John , Cloherty Shaun Liam , Hagan Maureen Ann , Chiang Price Nicholas Seow
Published: March 2023

Ocular following is a short-latency, reflexive eye movement that tracks wide-field visual motion. It has been studied extensively in humans and macaques and is an appealing behaviour for studying sensory-motor transformations in the brain due to its rapidity and rigidity. We explored ocular following in the marmoset, an emerging model in neuroscience because their lissencephalic brain allows direct access to most cortical areas for imaging and electrophysiological recordings. In three experiments, we tested ocular following responses in three adult marmosets. First, we varied the gap between saccade end and stimulus motion onset (post-saccadic delay), from 10 to 300 ms. As in other species, tracking had shorter onset latencies and higher eye speeds with shorter post-saccadic delays. Second, using sine-wave grating stimuli we explored the dependence of eye speed on spatiotemporal frequency. The highest eye speed was evoked at ∼16 Hz and ∼0.16 cycles per degree (cpd), however, the highest gain was elicited at ∼1.6 Hz and ∼1.2 cpd. The highest eye speed for each spatial frequency was observed at a different temporal frequency, but this interdependence was not consistent with complete speed tuning of the ocular following response. Finally, we found the highest eye speeds when saccade and stimulus motion directions were congruent, although latencies were unaffected by direction congruence. Our results showed comparable ocular following in marmosets, humans and macaques, despite over an order of magnitude variation in body and eye size across species. This characterization will help future studies examining the neural basis of sensory-motor transformations.

New & Noteworthy

Previous ocular following studies focused on humans and macaques. We examined the properties of ocular following responses in marmosets in three experiments, in which post-saccadic delay, spatial-temporal frequency of stimuli and congruency of saccade and motion directions were manipulated. We have demonstrated short-latency ocular following in marmosets, and discuss the similarities across three species that vary markedly in eye and head size. Our findings will help future studies examining the neural mechanism of sensory-motor transformations.
Structure-function relationships underpin disulfide loop cleavage-dependent activation ofLegionella pneumophilalysophosholipase A PlaA
Authors: Hiller Miriam , Diwo Maurice , Wamp Sabrina , Gutsmann Thomas , Lang Christina , Blankenfeldt Wulf , Flieger Antje
Published: March 2023

Legionella pneumophila,the causative agent of a life-threatening pneumonia, intracellularly replicates in a specialized compartment in lung macrophages, theLegionella-containing vacuole (LCV). Secreted proteins of the pathogen govern important steps in the intracellular life cycle including bacterial egress. Among these is the type II secreted PlaA which, together with PlaC and PlaD, belongs to the GDSL phospholipase family found inL. pneumophila. PlaA shows lysophospholipase A (LPLA) activity which increases after secretion and subsequent processing by the zinc metalloproteinase ProA at residue E266/L267 located within a disulfide loop. Activity of PlaA contributes to the destabilization of the LCV in the absence of the type IVB-secreted effector SdhA. We here present the 3D structure of PlaA which shows a typical α/β hydrolase fold and reveals that the uncleaved disulfide loop forms a lid structure covering the catalytic triad S30/D278/H282. This leads to reduction of both substrate access and membrane interaction before activation; however, the catalytic and membrane interaction site gets more accessible when the disulfide loop is processed. After structural modelling, a similar activation process is suggested for the GDSL hydrolase PlaC, but not for PlaD. Furthermore, the size of the PlaA substrate binding site indicated preference towards phospholipids comprising ~16 carbon fatty acid residues which was verified by lipid hydrolysis, suggesting a molecular ruler mechanism. Indeed, mutational analysis changed the substrate profile with respect to fatty acid chain length. In conclusion, our analysis revealed the structural basis for the regulated activation and substrate preference of PlaA.
Fibroblast-induced mammary epithelial branching depends on fibroblast contractility
Authors: Sumbal Jakub , Fre Silvia , Koledova Zuzana Sumbalova
Published: March 2023

Epithelial branching morphogenesis is an essential process in living organisms, through which organ-specific epithelial shapes are created. Interactions between epithelial cells and their stromal microenvironment instruct branching morphogenesis but remain incompletely understood. Here we employed fibroblast-organoid or fibroblast-spheroid co-culture systems and time-lapse imaging to reveal that physical contact between fibroblasts and epithelial cells and fibroblast contractility are required to induce mammary epithelial branching. Pharmacological inhibition of ROCK or non-muscle myosin II, or fibroblast-specific knock-out ofMyh9abrogate fibroblast-induced epithelial branching. Furthermore, fibroblast-induced branching requires epithelial proliferation and is associated with distinctive epithelial patterning of YAP and ERK activity along organoid branches, which is dependent on fibroblast contractility. Together, we identify fibroblast contractility as a novel stromal factor driving mammary epithelial morphogenesis. Our study contributes to comprehensive understanding of overlapping but divergent employment of mechanically active fibroblasts in developmental versus tumorigenic programs.
Total RNA sequencing reveals gene expression and microbial alterations shared by oral pre-malignant lesions and cancer
Authors: Khan Mohammed Muzamil , Frustino Jennifer , Villa Alessandro , Nguyen Bach-Cuc , Woo Sook-Bin , Johnson William Evan , Varelas Xaralabos , Kukuruzinska Maria , Monti Stefano
Published: March 2023

Head and neck cancers are a complex malignancy comprising multiple anatomical sites, with cancer of the oral cavity ranking among the deadliest and most disfiguring cancers globally. Oral cancer (OC) constitutes a subset of head and neck cancer cases, presenting primarily as tobacco-and alcohol-associated oral squamous cell carcinoma (OSCC), with a 5-year survival rate of ∼65%, partly due to the lack of early detection and effective treatments. OSCC arises from premalignant lesions (PMLs) in the oral cavity through a multi-step series of clinical and histopathological stages, including varying degrees of epithelial dysplasia. To gain insights into the molecular mechanisms associated with the progression of PMLs to OSCC, we profiled the whole transcriptome of 66 human PMLs comprising leukoplakia with dysplasia and hyperkeratosis non-reactive (HkNR) pathologies, alongside healthy controls and OSCC. Our data revealed that PMLs were enriched in gene signatures associated with cellular plasticity, such as partial EMT (p-EMT) phenotypes, and with immune response. Integrated analyses of the host transcriptome and microbiome further highlighted a significant association between differential microbial abundance and PML pathway activity, suggesting a contribution of the oral microbiome towards PML evolution to OSCC. Collectively, this study reveals molecular processes associated with PML progression that may help early diagnosis and disease interception at an early stage.

AUTHOR SUMMARY

Patients harboring oral premalignant lesions (PMLs) have an increased risk of developing oral squamous cell carcinoma (OSCC), but the underlying mechanisms driving transformation of PMLs to OSCC remain poorly understood. In this study, Khan et al., analyzed a newly generated dataset of gene expression and microbial profiles of oral tissues from patients diagnosed with PMLs from differing histopathological groups, including hyperkeratosis not reactive (HkNR) and dysplasia, comparing these profiles with OSCC and normal oral mucosa. Significant similarities between PMLs and OSCC were observed, with PMLs manifesting several cancer hallmarks, including oncogenic and immune pathways. The study also demonstrates associations between the abundance of multiple microbial species and PML groups, suggesting a potential contribution of the oral microbiome to the early stages of OSCC development. The study offers insights into the nature of the molecular, cellular and microbial heterogeneity of oral PMLs and suggests that molecular and clinical refinement of PMLs may provide opportunities for early disease detection and interception.
A soft tick vector ofBabesiasp. YLG in Yellow-legged gull (Larus michahellis) nests
Authors: Bonsergent Claire , Vittecoq Marion , Leray Carole , Jouglin Maggy , Buysse Marie , McCoy Karen D. , Malandrin Laurence
Published: March 2023

Babesiasp. YLG has recently been described in Yellow-legged gull (Larus michahellis) chicks and belongs to the Peircei clade in the new classification of Piroplasms. Here, we studiedBabesiasp. YLG vectorial transmission by ticks in the simplified environment of a single seabird breeding colony where the Yellow-legged gull is the sole vertebrate host,Ornithodoros maritimus(syn.Alectorobius maritimus) the sole tick species, andBabesiasp. YLG is the only blood parasite species detected in chicks of the colony. We collected ticks over four years, maintained certain individuals through moulting or oviposition, and dissected fresh ticks to isolate different organs and test for the presence of the parasite using molecular assays. We report the first strong evidence of a Piroplasmidae transmitted by a soft tick. Indeed,Babesiasp. YLG DNA was detected in the salivary glands of nymphs, females and males, a necessary organ to infect for transmission to a new vertebrate host. Parasite DNA was also found in tick ovaries, which could indicate possible transovarial transmission. Our detection ofBabesiasp. YLG DNA in several male testes and in endospermatophores, and notably in a parasite-free female (uninfected ovaries and salivary glands), raise the interesting possibility of sexual transmission from infected males to uninfected females. Future work in this system will now need to focus on the degree to which the parasite can be maintained locally by ticks and the epidemiological consequences of infection for bothO. maritimusand its avian host.
Immune cell type signature discovery and random forest classification for analysis of single cell gene expression datasets
Authors: Aybey Bogac , Zhao Sheng , Brors Benedikt , Staub Eike
Published: March 2023

Background

Robust immune cell gene expression signatures are central to the analysis of single cell studies. Nearly all known sets of immune cell signatures have been derived by making use of only single gene expression datasets. Utilizing the power of multiple integrated datasets could lead to high-quality immune cell signatures which could be used as superior inputs to machine learning-based cell type classification approaches.

Results

We established a novel gene expression similarity-based workflow for the discovery of immune cell type signatures that leverages multiple datasets, here four single cell expression datasets from three different cancer types. We used our immune cell signatures to train random forest classifiers for immune cell type assignment of single-cell RNA-seq datasets. We obtained similar or better prediction results compared to commonly used methods for cell type assignment in two independent benchmarking datasets. Our gene signature set yields higher prediction scores than other published immune cell type gene sets in our random forest approach.

Discussion and conclusion

We demonstrated the quality of our immune cell signatures and their strong performance in a random forest-based cell typing approach. We argue that classifying cells based on our comparably slim sets of genes accompanied by a random forest-based approach not only matches or outperforms widely used published approaches. It also facilitates unbiased downstream statistical analyses of differential gene expression between cell types for 90% of all genes whose expression profiles have not been used for cell type classification.
Absence of Telomerase Leads to Immune Response and Tumor Regression in Zebrafish Melanoma
Authors: Lopes-Bastos Bruno , Nabais Joana , Ferreira Tânia , El Maï Mounir , Bird Malia , Targen Seniye , Kang Da , Yue Jia-Xing , Carvalho Tânia , Ferreira Miguel Godinho
Published: March 2023

Most cancers reactivate telomerase to maintain telomere length to acquire immortality. The importance of this process is well illustrated by the fact that telomerase promoter mutations are found at a high frequency in many cancer types, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. Here, we show that melanoma can occur in the absence of telomerase but is required to sustain later growth and to avoid tumor regression. We combined telomerase mutant zebrafish (tert-/-) with two established melanoma models and found equal melanoma incidence and invasiveness as tumors became visible. Later, however, whiletert+/+fish develop increasing larger tumors,tert-/-tumors stagnate growth and regress.tert-/-tumors showed lower cell proliferation, higher apoptosis and melanocyte differentiation. We also detected an immune response directed attert-/-tumors.tert-/-tumors exhibited increased immune cell infiltrates and resume growth when transplanted into immunocompromised hosts. We propose that telomerase is required for melanoma in zebrafish, albeit at later stages of progression, to sustain growth while avoiding immune rejection and regression. Thus, absence of telomerase restricts melanoma through tumor-autonomous mechanisms (cell cycle arrest, apoptosis and melanocyte differentiation) and a non-tumor-autonomous mechanisms (immune rejection).