bluuebunny/crossref_metadata_2025 huggingface dataset:
Artoo-Detoo: What imitating a Star Wars droid reveals on allospecific vocal imitation in parrots and starlings
Authors: Dam Nick C.P. , Honing Henkjan , Spierings Michelle J.
Published: October 2024

Vocal production learning is a widespread and remarkable phenomenon. However, the underlying mechanisms of allospecific vocal imitation are poorly understood. Parrots and corvids are well known for their imitation abilities, but imitation accuracy has not yet been studied across species in a comparative context. We compared imitation accuracy between nine parrot species and European starlings based on imitation of monophonic and multiphonic sounds, produced by the Star Wars droid R2-D2. Our results show that starlings were better at imitating multiphonic sounds than parrots. However, no difference in imitation accuracy was found between parrots and starlings when imitating monophonic sounds. The differences in imitating accuracy are likely based on a physiological difference in syrinx anatomy, rather than on perceptual or cognitive differences between starlings and parrots. Between our nine tested parrot species, we found that parrots with larger brains (e.g., African greys and amazon parrots) were less accurate at imitating monophonic sounds than smaller brained budgerigars and cockatiels. The use of citizen science in our study shows the great potential this has to expand data collection beyond traditional studies. These findings contribute to a deeper understanding of the evolution of communication complexity in vocal learners.

Significance Statement

Vocal imitation is a hallmark of complex communication in animals, yet the mechanisms driving species differences remain poorly understood. By comparing vocal imitation across nine parrot species and European starlings, we demonstrate, for the first time, that differences in syrinx anatomy, rather than cognitive or perceptual capacities, underlie species-specific variation in imitation accuracy. Contrary to traditional expectations, smaller-brained parrots outperformed larger-brained species in monophonic sound imitation. These findings challenge assumptions that brain size is directly linked to imitation accuracy and offer insights into the evolution of complex communication. We used citizen science to create a uniquely large dataset of species imitating the same source, demonstrating the powerful potential of this approach to broaden research in comparative cognition and vocal learning.
The ratio between experimental and theoretical localization precision of single molecules is sensor-dependent and typically larger than one
Authors: Brenlla-Lopez Alfonso , Deen Laila , Annibale Paolo
Published: October 2024

Since the advent of stochastic localization microscopy approaches in 2006, the number of studies employing this strategy to investigate the sub-diffraction limit features of fluorescently labeled structures in biology, biophysics and solid state samples has increased exponentially. Underpinning all these approaches is the notion that the position of single molecules can be determined to high precision, provided enough photons are collected. The determination of exactly how precisely, has been demanded to formulas that try to approximate the so-called Cramer Rao Lower Bound based on input parameters such as the number of photons collected from the molecules, or the size of the camera pixel. These estimates should however be matched to the experimental localization precision, which can be easily determined if instead of looking at single beads, we study the distance between a pair. We revisit here a few key works, observing how these theoretical determinations tend to routinely underestimate the experimental localization precision, of the order of a factor two. A software-independent metric to determine, based on each individual setup, the appropriate value to set on the localization error of individual emitters is provided.
A direct computational assessment of vinculin-actin unbinding kinetics reveals catch bonding behavior
Authors: Ccoa Willmor J Peña , Mukadum Fatemah , Ramon Aubin , Stirnemann Guillaume , Hocky Glen M
Published: October 2024

Vinculin forms a catch bond with the cytoskeletal polymer actin, displaying an increased bond lifetime upon force application. Notably, this behavior depends on the direction of the applied force, which has significant implications for cellular mechanotransduction. In this study, we present a comprehensive molecular dynamics simulation study, employing enhanced sampling techniques to investigate the thermodynamic, kinetic, and mechanistic aspects of this phenomenon at physiologically relevant forces. We dissect a catch bond mechanism in which force shifts vinculin between either a weakly- or strongly-bound state. Our results demonstrate that models for these states have unbinding times consistent with those from single-molecule studies, and suggest that both have some intrinsic catch bonding behavior. We provide atomistic insight into this behavior, and show how a directional pulling force can promote the strong or weak state. Crucially, our strategy can be extended to capture the difficult-to-capture effects of small mechanical forces on biomolecular systems in general, and those involved in mechanotransduction more specifically.
Context-dependent Rhythmicity in Chimpanzee Displays
Authors: van der Vleuten Bas , Hovenkamp Veerle , Varkevisser Judith , Spierings Michelle
Published: October 2024

Rhythm is an important component of human language and music production. Rhythms like isochrony (intervals spaced equally in time), are also present in vocalisations of certain non-human species, including several birds and mammals. This study aimed to identify rhythmic patterns with music-based methods within display behaviour of chimpanzees (Pan troglodytes), humans’ closest living relatives. Behavioural observations were conducted on individuals from two zoo-housed colonies. We found isochronous rhythms in vocal (e.g. pants, grunts and hoots), as well as in motoric (e.g. swaying and stomping) behavioural sequences. Among individuals, variation was found in the duration between onsets of behavioural elements, resulting in individual-specific tempi. Despite this variation in individual tempi, display sequences were consistently structured with stable, isochronous rhythms. Overall, directed displays, targeted at specific individuals, were less isochronous than undirected displays. The presence of rhythmic patterns across two independent colonies of chimpanzees, suggests that underlying mechanisms for rhythm production may be shared between humans and non-human primates. This shared mechanism indicates that the cognitive requirements for rhythm production potentially preceded human music and language evolution.
Recovery from Spreading Depolarization is slowed by aging and accelerated by antioxidant treatment in locusts
Authors: Robertson R. Meldrum , Wang Yuyang
Published: October 2024

Spreading depolarization (SD) temporarily shuts down neural processing in nervous systems with effective blood brain barriers. In mammals this is usually pathological in response to energetic stress. In insects a very similar process is induced by abiotic environmental stressors and can be beneficial by conserving energy. Age is a critical factor for predicting the consequences of SD in humans. We investigated the effect of aging on SD in an insect model of SD and explored the contribution of oxidative stress. Aging slowed the recovery of intact locusts from asphyxia by water submersion. In semi-intact preparations we monitored SD by recording the DC potential across the blood brain barrier in response to bath application of the Na+/K+-ATPase inhibitor, ouabain. Treatment with ouabain induced changes to the DC potential that could be separated into two distinct components: a slow, permanent negative shift, similar to the negative ultraslow potential recorded in mammals and human patients, as well as rapid, reversible negative DC shifts (SD events). Aging had no effect on the slow shift but increased the duration of SD events from ∼0.6 minutes in young locusts to ∼0.9 minutes in old ones. This was accompanied by a decrease in the rate of recovery of DC potential at the end of the SD event, from ∼1.5 mV/s (young) to ∼0.6 mV/s (old). An attempt to generate oxidative stress using rotenone was unsuccessful, but pretreatment with the antioxidant, N-acetylcysteine amide, had opposite effects to those of aging, reducing duration (control ∼1.1 minutes, NACA ∼0.7 minutes) and increasing rate of recovery (control ∼0.5 mV/s, NACA ∼1.0 mV/s) suggesting that it prevented oxidative damage occurring during the ouabain treatment. The antioxidant also reduced the rate of the slow negative shift. We propose that the aging locust nervous system is more vulnerable to stress due to a prior accumulation of oxidative damage. Our findings also strengthen the notion that insects provide useful models for the investigation of cellular and molecular mechanisms underlying SD in mammals.

Significance Statement

Anoxia and similar energetic crises trigger a shutdown of central neural processing in a process of spreading depolarization (SD) which is generally pathological in mammals and protective in insects. We show that some variability in the consequences of SD in an insect model can be attributed to age, such that older animals are slower to recover. Moreover, preventing oxidative stress with an antioxidant speeds recovery. These findings demonstrate a role for oxidative stress in contributing to the vulnerability of the aging insect CNS in energetic emergencies.

Abstract Figure

Graphical Abstract of Robertson and Wang - Locust Spreading Depolarization
Astrocytic HIV-1 Nef expression decreases glutamate transporter expression in the nucleus accumbens and increases cocaine-seeking behavior in rats
Authors: Pla-Tenorio Jessalyn , Velazquez-Perez Bethzaly , Mendez-Borrero Yainira , Cruz-Rentas Myrella , Sepulveda-Orengo Marian , Noel Richard J.
Published: October 2024

Cocaine use disorder is an intersecting issue in populations with HIV-1, further exacerbating the clinical course of the disease, contributing to neurotoxicity and neuroinflammation. Cocaine and HIV neurotoxins play roles in neuronal damage during neuroHIV progression by disrupting glutamate homeostasis in the brain. Even with cART, HIV-1 Nef, an early viral protein expressed in approximately 1% of infected astrocytes, remains a key neurotoxin. This study investigates the relationship that exists between Nef, glutamate homeostasis, and cocaine in the NAc, a critical brain region associated with drug motivation and reward. Using a rat model, we compared the effects of astrocytic Nef and cocaine by molecular analysis of glutamate transporters in the NAc. We further conducted behavioral assessments for cocaine self-administration to evaluate cocaine-seeking behavior. Our findings indicate that both cocaine and Nef independently decrease the expression of the glutamate transporter GLT-1 in the NAc. Additionally, rats with astrocytic Nef expression exhibited increased cocaine-seeking behavior but demonstrated sex dependent molecular differences after behavioral paradigm. In conclusion, our results suggest the expression of Nef intensifies cocaine-induced alterations in glutamate homeostasis in the NAc, potentially underlying increased cocaine-seeking. Understanding these interactions better may inform therapeutic strategies for managing cocaine use disorder in HIV-infected individuals.
Balance performance in aged mice is dependent on unipolar brush cells
Authors: Kizeev Gabrielle , Witteveen Isabelle , Balmer Timothy
Published: October 2024

The vestibular processing regions of the cerebellum integrate vestibular information with other sensory modalities and motor signals to regulate balance, gaze stability, and spatial orientation. A class of excitatory glutamatergic interneurons known as unipolar brush cells (UBCs) are highly concentrated within the granule cell layer of these regions. UBCs receive vestibular signals directly from primary vestibular afferents and indirectly from mossy fibers. Each UBC excites numerous granule cells and could contribute to computations necessary for balance-related motor function. Prior research has implicated UBCs in motor function, but their influence on balance performance remains unclear, especially in aged mice that have age-related impairment. Here we tested whether UBCs contribute to motor coordination and balance by disrupting their activity with chemogenetics in aged and young mice. Age-related balance deficits were apparent in mice > 6 months old. Disrupting the activity of a subpopulation of UBCs caused aged mice to fall off a balance beam more frequently and altered swimming behaviors that are sensitive to vestibular dysfunction. These effects were not seen in young (7-week-old) mice. Thus, disrupting the activity of UBCs impairs mice with age-related balance issues and suggest that UBCs are essential for balance and vestibular function in aged mice.
A piRNA regulating oogenesis and embryo development in cockroaches
Authors: Gonzalvo Judit , Farrus Nuria , Escudero Jorge , Pujal David , Bau Josep , Piulachs Maria-Dolors
Published: October 2024

The PIWI-interacting RNAs (piRNAs) are small non-coding RNAs ranging from 26 to 31 nucleotides. Initially, piRNA functions were associated with repressing transposable elements as part of a mechanism that maintains genomic stability across evolution. However, in the last years, new regulatory functions for piRNAs have been identified. Now, we investigated the regulatory role of piRNAs in insect oogenesis and embryo development. We studied the expression and function of piRNA-83679, one the most abundantly expressed piRNA inBlattella germanicaadult ovaries. piRNA-83679 is expressed in germinal and somatic cells in adult ovaries during the gonadotropic cycle, and is maternally provided to the egg. Using an antisense oligonucleotide (ASO), we reduced piRNA-83679 levels inB. germanicaadult females, enabling the study of its functions. piRNA-83679 depletion affected the expression of different ecdysone and chorion genes in the ovary, and the organization of the F-actin fibers in the basal pole of the follicle cells of the basal ovarian follicle. As a result, the eggs were not correctly encapsulated in the ootheca. Moreover, piRNA-83679 depletion delayed oviposition and affected embryo development, especially in the early stages.
Weak magnetic field effects in biology are measurable—acceleratedXenopusembryogenesis in the absence of the geomagnetic field
Authors: Lodesani Alessandro , Anders Geoff , Bougas Lykourgos , Lins Tobias , Budker Dmitry , Fierlinger Peter , Aiello Clarice D.
Published: October 2024

Despite decades of reports of weak magnetic field effects in biology across the tree of life and on a broad range of cell types, the evidence to date remains met with skepticism. To remedy this, we present open-data, large-scale, and varied morphological evidence thatXenopus laevisembryo development is accelerated in a well-engineered, environmentally-calibrated hypomagnetic field of less than 1 nT. These data imply that basal tadpole physiology can sense and react to the absence of Earth’s minute magnetic field of approximately 50µT. The effect is significant, as demonstrated by a variety of statistical measures. As no definitive biophysical mechanism has been identified to account for its occurrence, this study raises the question of which mechanism provides the most plausible explanation. How that question is answered may have implications in a variety of fields, including human health, behavioral ecology, and space exploration.
Early experience affects foraging behavior of wild fruit-bats more than their original behavioral predispositions
Authors: Rachum Adi , Harten Lee , Assa Reut , Goldshtein Aya , Chen Xing , Gonceer Nesim , Yovel Yossi
Published: October 2024

There are immense consistent inter-individual differences in animal behavior. While many studies have documented such behavioral differences, often referred to as individual personalities, little research has focused on the underlying causes and on determining whether they are innate or based on individual experience. Moreover, most studies on animal personalities have described consistent differences in behavior under laboratory conditions. We aimed to examine the impact of the early experienced environment on individual animal behavior, and to compare it to that of the individual’s original genetic predisposition. Additionally, we explored the correlation between personality traits measured indoors and the animal’s outdoor behavior. We studied Egyptian fruit bats, in which vast behavioral variability and plasticity have already been demonstrated. We raised bats in a captive colony under either enriched or impoverished environments and assessed their personality under controlled laboratory conditions. We then released the bats into the wild and tracked their foraging using GPS. Bats that had experienced an enriched environment during early life displayed increasing boldness and exploratory behavior when foraging outdoors, demonstrating how early-life experience can affect adult behavior. The individuals’ original predispositions did not predict their later foraging behavior. Our findings shed new light on the interplay between innate and experienced-based effects on individual behavior.
HEXIM1 homodimer binds two sites on 7SK RNA to release autoinhibition for P-TEFb inactivation
Authors: Yang Yuan , Murrali Maria Grazia , Wang Yaqiang , Galvan Sabrina , Ajjampore Neha , Feigon Juli
Published: October 2024

Hexim proteins are RNA-dependent regulators whose main target is 7SK long non-coding RNA, a major regulator of eukaryotic mRNA transcription. 7SK RNPs control available intracellular concentrations of the kinase P-TEFb (Cdk9–CyclinT1/2) by sequestering it in an inactive form. Active P-TEFb phosphorylates NELF, DSIF, and the RNA polymerase II CTD to transition it from promoter-proximal pausing to productive elongation. P-TEFb associates with 7SK RNP via Hexim, which directly binds 7SK RNA. However, free Hexim is in an autoinhibited state that cannot inactivate P-TEFb, and how Hexim autoinhibition is released by 7SK remains unknown. Here, we show that one Hexim1 homodimer binds two sites on linear 7SK RNA in a manner that exposes the Cdk9 binding sites, which are otherwise masked within the autoinhibited dimer. These results provide mechanistic insights into Hexim–RNA specificity and explain how P-TEFb can be effectively regulated to respond to changing levels of transcriptional signaling.
Spinal cerebrospinal fluid contacting neurons are a conserved sensory neuronal population along the mouse spinal cord
Authors: Elysa Crozat , Edith Blasco , Jorge Ramirez-Franco , Priscille Riondel , Nina Jurčić , Riad Seddik , Caroline Michelle , Jérôme Trouslard , Nicolas Wanaverbecq
Published: October 2024

Cerebrospinal Fluid contacting neurons (CSF-cNs) are present in all vertebrates around the medullo-spinal central canal. They are GABAergic, selectively express PKD2L1, a member of the TRP channel superfamily, and are thought to represent a novel sensory system intrinsic to the central nervous system. Using histology, we found that CSF-cNs form a homogeneous population, distributed along the whole spinal cord and mainly located in the ventral region of the central canal. Patch-clamp recordings reveal conserved intrinsic properties and voltage-dependent conductance expression. Spinal CSF-cNs express PKD2L1 channels and ASICs, acting as sensory receptors for extracellular pH changes. They express both inhibitory (GABAA, glycine) and excitatory (glutamate, cholinergic) synaptic receptors as well as functional GABABand muscarinic receptors, but not glutamatergic metabotropic ones, to modulate Ca2+channels.

CSF-cNs represent a functionally homogeneous population that might integrates sensory signals along the central canal to modulate body functions by regulating local spinal networks. Demonstrating such a function represents the future challenge in the field.
Time-Space Resolved Fluorescence Spectroscopy in LiveChlamydomonasCells under Light-Harvesting Regulation
Authors: Fujita Yuki , Zhang Xianjun , Ye Shen , Shibata Yutaka
Published: October 2024

We report here a technical advancement that enables time-resolved fluorescence spectroscopy in spatially resolved domains of a living cell at low temperatures. The technique is based on a combination of the self-developed cryo-confocal microscope system and the streak-camera technology. An instrumental response time of ca. 24 ps was achieved. This technique was applied to reveal the light-harvesting dynamics in local domains within singleChlamydomonas reinhardtiicells. Organisms performing oxygenic photosynthesis, likeChlamydomonas, have evolved a regulation mechanism called state transitions (ST), which maintains the excitation balance between PSI and PSII. ST relies on the shuttling of light-harvesting chlorophyll protein complex II (LHCII) between the two PSs. In the present experiment, cells were induced either to state1, where LHCII is bound to PSII, or state2, where LHCII moved and is bound to PSI. After the induction of ST, cells were immediately cooled to ca. 80 K, where PSI and PSII show clearly separated fluorescence emission bands, enabling the visualization of these components separately. Based on kinetic analyses of the time-resolved fluorescence spectra in both PSI-rich and PSII-rich local domains, we concluded that (1) the intracellular inhomogeneity in the PSII/PSI fluorescence ratio comes from that in the PSII/PSI stoichiometry, not from that in the antenna sizes of the PSs, and (2) the antenna size of PSI in state2 cells may larger in intact cells than that of the isolated PSI-LHCI-LHCII super-complex reported so far.
Data-Driven Equation-Free Dynamics Applied to Many-Protein Complexes: The Microtubule Tip Relaxation
Authors: Wu Jiangbo , Dasetty Siva , Beckett Daniel , Wang Yihang , Xue Weizhi , Skóra Tomasz , Bidone Tamara C. , Ferguson Andrew L. , Voth Gregory A.
Published: October 2024

Microtubules (MTs) constitute the largest components of the eukaryotic cytoskeleton and play crucial roles in various cellular processes, including mitosis and intracellular transport. The property allowing MTs to cater to such diverse roles is attributed to dynamic instability, which is coupled to the hydrolysis of GTP (guanosine-5’-triphosphate) to GDP (guanosine-5’-diphosphate) within theβ-tubulin monomers. Understanding the equilibrium dynamics and the structural features of both GDP- and GTP-complexed MT tips, especially at an all-atom level, remains challenging for both experimental and computational methods because of their dynamic nature and the prohibitive computational demands of simulating large, many-protein systems. This study employs the “equation-free” multiscale computational method to accelerate the relaxation of all-atom simulations of MT tips toward their putative equilibrium conformation. Using large MT lattice systems (14 protofilaments × 8 heterodimers) comprising ∼21-38 million atoms, we applied this multiscale approach to leapfrog through time and nearly double the computational efficiency in realizing relaxed all-atom conformations of GDP- and GTP-complexed MT tips. Commencing from an initial 4 μs unbiased all-atom simulation, we interleave coarse projective “equation-free” jumps with short bursts of all-atom molecular dynamics simulation to realize an additional effective simulation time of 1.875 μs. Our 5.875 μs of effective simulation trajectories for each system expose the subtle yet essential differences in the structures of MT tips as a function of whetherβ-tubulin monomer is complexed with GDP or GTP, as well as the lateral interactions within the MT tip, offering a refined understanding of features underlying MT dynamic instability. The approach presents a robust and generalizable framework for future explorations of large biomolecular systems at atomic resolution.

SIGNIFICANCE

The dynamic instability of microtubules (MTs) is essential for a plethora of biological functions, from cell division to intracellular transport. Despite their importance, current computational models often struggle to handle the large-scale, long-term dynamics of all-atom simulations. This computational study employs the “equation-free” method to accelerate relaxation of the all-atom structures of MT tips in both GDP and GTP states which nearly halves the computational demands of simulating very large biomolecular systems. Our findings expose subtle but crucial structural differences between GDP-bound and GTP-bound MTs, particularly in the number of protofilament clusters, and is consistent with a relatively stronger lateral interactions in GTP-bound MT tips.
Distinct cortical spatial representations learned along disparate visual pathways
Authors: Lian Yanbo , LaChance Patrick A. , Malmberg Samantha , Hasselmo Michael E. , Burkitt Anthony N.
Published: October 2024

Recent experimental studies have discovered diverse spatial properties, such as head direction tuning and egocentric tuning, of neurons in the postrhinal cortex (POR) and revealed how the POR spatial representation is distinct from the retrosplenial cortex (RSC). However, how these spatial properties of POR neurons emerge is unknown, and the cause of distinct cortical spatial representations is also unclear. Here, we build a learning model of POR based on the pathway from the superior colliculus (SC) that has been shown to have motion processing within the visual input. Our designed SC-POR model demonstrates that diverse spatial properties of POR neurons can emerge from a learning process based on visual input that incorporates motion processing. Moreover, combining SC-POR model with our previously proposed V1-RSC model, we show that distinct cortical spatial representations in POR and RSC can be learnt along disparate visual pathways (originating in SC and V1), suggesting that the varying features encoded in different visual pathways contribute to the distinct spatial properties in downstream cortical areas.

Conflict of interest statement

The authors declare no competing financial interests.
X-Tracker: Automated Analysis of Xenopus Tadpole Visual Avoidance Behavior
Authors: McKeown Caroline R. , Ta Aaron C. , Marshall Christopher L. , McLain Natalie J. , Archuleta Kailey J. , Cline Hollis T.
Published: October 2024

Xenopus laevistadpoles exhibit an avoidance behavior when they encounter a moving visual stimulus. A visual avoidance event occurs when a moving object approaches the eye of a free-swimming animal at an approximately 90-degree angle and the animal turns in response to the encounter. Analysis of this behavior requires tracking both the free-swimming animal and the moving visual stimulus both prior to and after the encounter. Previous automated tracking soft-ware does not discriminate the moving animal from the moving stimulus, requiring time-consuming manual analysis. Here we present X-Tracker, an automated behavior tracking code that can detect and discriminate moving visual stimuli and free-swimming animals and score encounters and avoidance events. X-Tracker is as accurate as human analysis without the human time commitment. We also present software improvements to our previous visual stimulus presentation and image capture that optimize videos for automated analysis, and hardware improvements that increase the number of animal-stimulus encounters. X-Tracker is a high throughput, unbiased, and significant time-saving analysis system that will greatly facilitate visual avoidance behavior analysis ofXenopus laevistadpoles, and potentially other free-swimming organisms. The tool is available athttps://github.com/ClineLab/Tadpole-Behavior-Automation.
Hippocampal-cortical interactions in the consolidation of social memory
Authors: Park Gaeun , Kim Min Seok , Lee Young-Beom , Shin Soonho , Lee Doyun , Kim Sang Jeong , Lee Yong-Seok
Published: October 2024

Episodic memories are initially encoded in the hippocampus and subsequently undergo systems consolidation into the neocortex. The nature of memory stored in the hippocampus and neocortex also differs, with the cortex shown to encode memories in more generalized forms. Although several brain regions are known to encode social information, the specific cortical regions and circuits involved in the consolidation of social memory and the nature of the information encoded in the cortex remain unclear. Usingin vivoCa2+imaging and optogenetic manipulations, we found that infralimbic (IL) neurons projecting to the nucleus accumbens shell (IL→NAcSh) neurons store consolidated social memory. Inactivating IL→NAcShneurons that responded to a familiar conspecific impaired the recognition of other familiar mice including littermates, demonstrating that these neuronal activities support social familiarity. Furthermore, inactivating hippocampal ventral CA1 neurons projecting to the IL disrupted the consolidation of memory for newly familiarized mice while sparing the recognition of littermates. These findings demonstrate the critical role of hippocampal-cortical interactions in the consolidation of social memory.
Learning good therapeutic targets in ALS, neurodegeneration, using observational studies
Authors: Alidoost Mohammadali , Huang Jeremy Y. , Dermentzaki Georgia , Blazier Anna S. , Gaglia Giorgio , Hammond Timothy R. , Frau Francesca , Mccorry Mary Clare , Ofengeim Dimitry , Wilson Jennifer L.
Published: October 2024

Analysis of real-world data (RWD) is attractive for its applicability to real-world scenarios but RWD is typically used for drug repurposing and not therapeutic target discovery. Repurposing studies have identified few effective options in neuroinflammatory diseases with relatively few patients such as amyotrophic lateral sclerosis (ALS), which is characterized by progressive muscle weakness and death with no disease-modifying treatments available. We previously reclassified drugs by their simulated effects on proteins downstream of drug targets and observed class-level effects in the EHR, implicating the downstream protein as the source of the effect. Here, we developed a novel ALS-focused pathways model using data from patient samples, the public domain, and consortia. With this model, we simulated drug effects on ALS and measured class effects on overall survival in retrospective EHR studies. We observed an increased but non-significant risk of death for patients taking drugs associated with the complement system downstream of their targets and experimentally validated drug effects on complement activation. We repeated this for six protein classes, three of which, including multiple chemokine receptors, were associated with a significant increased risk for death, suggesting that targeting proteins such as chemokine receptors could be advantageous for these patients. We recovered effects for drugs associated with complement activation and chemokine receptors in Parkinson’s and Myasthenia Gravis patients. We demonstrated the utility of network medicine for testing novel therapeutic effects using RWD and believe this approach may accelerate target discovery in neuroinflammatory diseases, addressing the critical need for new therapeutic options.
The impact of differentiated service delivery (DSD) on retention in care and viral suppression in South Africa: A target trial emulation of routine care data
Authors: Huber Amy N. , Jamieson Lise , Fox Matthew P , Manganye Musa , Malala Lufuno , Chidarikire Thato , Khoza Nthabiseng , Nichols Brooke E , Rosen Sydney , Pascoe Sophie
Published: October 2024

Introduction Replacing conventional, facility-based HIV treatment with less intensive differentiated service delivery (DSD) models could benefit DSD clients and the health system, but its value depends on maintaining or improving clinical outcomes. We compared retention and viral suppression between antiretroviral therapy (ART) clients enrolled in DSD models to those eligible for but not enrolled in DSD models in South Africa. Methods We applied a target trial emulation (TTE) methodology to data from South Africa’s electronic medical record system (TIER.Net) for 18 clinics across 3 provinces and estimated retention in care (attended clinic visit within 12 months) and viral suppression (<400 copies/ml3) at 12, 24, and 36 months after follow-up start date, defined as DSD enrollment date for the intervention arm and the first trial enrollment period clinic visit for the comparison arm. Clients were eligible for DSD models if they were ≥18 years old, on ART ≥12 months, and had two suppressed viral load (VL) measurements, per prevailing national guidelines. For the TTE, we designated eight 6-month target trial enrolment periods between 1 July 2017 and 1 July 2021. For each period, we estimated the risk differences for retention in care and viral suppression by comparing those enrolled in DSD models to those not enrolled, using a Poisson distribution with an identity link function. We report adjusted and unadjusted risk differences for clients enrolled in DSD models and for DSD-eligible clients not enrolled in a DSD model. Results and discussion 49,595 unique individuals were eligible for DSD enrolment over eight target trials, contributing to a total of 148,943 trial-clients, of whom 17% (25,775) were enrolled in DSD models. The pooled adjusted risk difference for retention in care between clients enrolled in DSD and those not enrolled in DSD was 3.2% (95% confidence interval (CI) 1.6%; 4.7%) at 12 months, 4.2% (2.4%; 6.0%) at 24 months, and 4.4% (2.0%; 6.8%) at 36 months. For viral suppression, the adjusted risk difference comparing DSD to non-DSD was estimated to be 1.4% (-0.5%; 3.2%) at 12 months, 1.7% (-0.5%; 4.0%) at 24 months, and 1.4% (-0.6%; 4.4%) at 36 months. Results remained consistent across target trials. Clients who were younger, lived in urban settings, or had less ART experience at trial enrolment had lower retention.  Conclusions Clients enrolled in DSD models in South Africa had slightly better retention in care and similar viral suppression to those who were eligible for but not enrolled in DSD. With better or equivalent outcomes, DSD models can be assessed on the basis of non-clinic costs and benefits, such as changes in quality of care and resource utilization.
Discovering Subtypes with Imaging Signatures in the Motoric Cognitive Risk Syndrome Consortium using Weakly-Supervised Clustering
Authors: Nallapu Bhargav Teja , Ezzati Ali , Blumen Helena M. , Petersen Kellen K. , Lipton Richard B. , Ayers Emmeline , Kumar V G Pradeep , Velandai Srikanth , Beare Richard , Beauchet Olivier , Doi Takehiko , Shimada Hiroyuki , Milman Sofiya , Aleksic Sandra , Verghese Joe
Published: October 2024

STRUCTURED ABSTRACT

INTRODUCTION

Understanding the heterogeneity of brain structure in individuals with the Motoric Cognitive Risk Syndrome (MCR) may improve the current risk assessments of dementia.

METHODS

We used data from 6 cohorts from theMCR consortium(N=1987). A weakly- supervised clustering algorithm called HYDRA was applied to volumetric MRI measures to identify distinct subgroups in the population with gait speeds lower than one standard deviation (1SD) above mean.

RESULTS

Three subgroups (Groups A, B & C) were identified through MRI-based clustering with significant differences in regional brain volumes, gait speeds, and performance on Trail Making (Part-B) and Free and Cued Selective Reminding Tests.

DISCUSSION

Based on structural MRI, our results reflect heterogeneity in the population with moderate and slow gait, including those with MCR. Such a data-driven approach could help pave new pathways toward dementia at-risk stratification and have implications for precision health for patients.
Associations of perceived discrimination with health outcomes and health disparities in theAll of Uscohort
Authors: Lam Vincent , Gupta Sonali , Jordan I. King , Mariño-Ramírez Leonardo
Published: October 2024

Objective

The goal of this study was to investigate the association of perceived discrimination with health outcomes and disparities.

Materials and Methods

The study cohort consists of 60,180 participants from the four largest SIRE groups in theAll of UsResearch Program participant body: Asian (1,291), Black (4,726), Hispanic (5,336), and White (48,827). A perceived discrimination index (PDI) was derived from participant responses to the “Social Determinants of Health” survey, and theAll of UsResearcher Workbench was used to analyze associations and mediation effects of PDI and self-identified race and ethnicity (SIRE) with 1,755 diseases.

Results

The Black SIRE group has the greatest median PDI, followed by the Asian, Hispanic, and White groups. The Black SIRE group shows the greatest number of diseases with elevated risk relative to the White reference group, followed by the Hispanic and Asian groups. PDI was found to be positively and significantly associated with 489 out of 1,755 (27.86%) diseases. ‘Mental Disorders’ is the disease category with the greatest proportion of diseases positively and significantly associated with PDI: 59 out of 72 (81.94%) diseases. Mediation analysis showed that PDI mediates 69 out of 351 (19.66%) Black-White disease disparities.

Discussion

Perceived discrimination is significantly associated with risk for numerous diseases and mediates Black-White disease disparities in theAll of Usparticipant cohort.

Conclusion

This work highlights the role of discrimination as an important social determinant of health and provides a means by which it can be quantified and modeled on theAll of Usplatform.
APOE4 carriers display loss of anticipatory cerebral vascular regulation over AD progression
Authors: Palmer Jacqueline A. , Kaufman Carolyn S. , Whitaker-Hilbig Alicen A. , Billinger Sandra A.
Published: October 2024

INTRODUCTION

Maintenance of cerebral blood flow during orthostasis is impaired with aging and associated with cognitive decline, but the effect of Apolipoprotein L4-allele (APOE4) is unknown.

METHODS

Older adults (n=108) (APOE4carriers, n=47; noncarriers, n=61) diagnosed as cognitively-normal (NC), MCI, or AD participated. Middle cerebral artery blood velocity (MCAv), assessed using Transcranial Doppler ultrasound, and beat-to-beat mean arterial blood pressure (MAP) were continuously recorded during a sit-to-stand transition. Anticipatory and orthostatic-induced MCAv and MAP responses were compared between genotypes and across disease progression.

RESULTS

Cognitively-normalAPOE4carriers showed greater anticipatory MCAv increase, greater MCAv decrease with orthostasis, and shorter latency of peripheral MAP responses to orthostasis compared to noncarriers. MCAv and MAP responses were delayed and attenuated across theAPOE4disease progression, with no differences between genotypes in MCI and AD.

DISCUSSION

APOE4carriers and noncarriers present with distinct phenotypes of cerebral vascular dysfunction during hemodynamic orthostatic challenge. Unique cerebral and peripheral vascular compensation observed inAPOE4carriers may be lost as AD progresses.
Unraveling Interoceptive Processing and Action Dynamics: Exploring Neural and Psychological Responses to Food Cues Using fMRI
Authors: Malmir Nastaran , Ekhtiari Hamed , Farhoudian Ali , Robatmili Somaye , Nistche Michael
Published: October 2024

Interoception, the perception of body signals, which is crucial for maintaining metabolic homeostasis, is asserted to play a vital role in obesity. Despite conceptual assumptions that impaired insular interoceptive processing contributes to overeating behaviors predominantly through modulating motor cortices, this link has not been extensively explored. Therefore, to further investigate neural mechanisms underlying insula-based interoceptive processing, this pre-registered (PMC9003175) study assessed blood oxygenation level-dependent (BOLD) responses via functional magnetic resonance tomography (fMRI) in 45 healthy participants (31 females/14 males, age 35.78 ± 10 years, BMI 29.52 ± 3.5 kg/m2) during a block-designed food cue reactivity task. Region of interest (insula) and whole brain voxel-wise correlation analyses explored neural correlates of visceral interoception. Furthermore, group factor analysis (GFA) unveiled coherence patterns between neural (fMRI) and psychological/behavioral measures. At the psychological level, self-reported hunger (P < 0.01, d = 0.82) and food craving (P < 0.01, d = 0.68) significantly increased, while craving control (P = 0.04, d = 0.37) decreased after cue exposure. Voxel-wise correlation analysis identified positive correlations (P < 0.01) between visceral interoception and activation of the precentral gyrus (PrG or motor cortex), insula, inferior frontal gyrus (IFG), posterior cingulate cortex (PCC), and superior parietal lobule (SPL). Moreover, altered functional connectivity dynamics were noted within the insula-PrG-IFG network during food cue exposure, with a significant reduction of IFG-PrG connections (P = 0.05). Interestingly, GFA identified a cross-unit latent factor across neural and psychological/behavioral measures. Overall, our findings indicate that altered interoceptive processing (insula activity), motor planning (motor cortex activity), and diminished inhibitory control (negative IFG-PrG connectivity) collectively contribute to food craving generation and potentially subsequent actions toward food consumption.
ReducedBacille Calmette-Guérin-specific IgG titres among babies born to mothers with Active Tuberculosis Disease in Uganda
Authors: Sitenda Diana , Ssekamatte Phillip , Nakavuma Rose , Kyazze Andrew Peter , Bongomin Felix , Baluku Joseph , Nabatanzi Rose , Kibirige Davis , Nakimuli Annette , Cose Stephen , Andia-Biraro Irene
Published: October 2024

Background

Babies born to mothers with active tuberculosis disease (ATB) are at risk of poor clinical outcomes such as low birth weight and perinatal mortality. However, little is known about the influence of maternal ATB exposure on their vaccine responses during infancy. The study aimed to explore how maternal ATB affects infants’ vaccine responses, hypothesising reduced responses to BCG and other infant vaccines.

Methods

This was a case-control study with a longitudinal component of babies born to mothers with bacteriologically confirmed ATB (cases) and babies born to mothers without ATB (controls) carried out between September 2021 and June 2022. Quantitative BCG, diphtheria, tetanus, and measles-specific IgG ELISA assays were performed on infant plasma harvested from lithium-heparin blood collected on first encounter after birth (0), at 3, 6, and 9 months. We used prism v10.1.2, Mixed-effects modelling, and Tukey’s multiple comparison testing to determine mean differences (MD) between the cases and controls at all time points.

Results

Infants cases had reduced IgG titres to BCG at baseline compared to the controls (p=0.04), with a mean of 125.8/141.1 IU/mL, respectively. This difference was, however, not sustained at the other time points. Similarly, we demonstrated strong trends of reduced responses to tetanus, diphtheria, and measles vaccines among infant cases at baseline and three-month time points and weakly at months six and nine. The mean titres for tetanus at baseline and 3 months for cases versus controls are 1.744/2.917 IU/mL and 1.716/2.344 IU/mL (p<0.0001/0.018), respectively. The mean titres for diphtheria at 3 months were 0.022/0.075 IU/mL (p=0.006), respectively.

Conclusion

We have demonstrated that maternal TB disease influences vaccine responses to BCG and other infant vaccines. This has implications for increased risk of childhood TB and other preventable diseases.
Single Cell Integration Characterises Metaplasia in Inflammatory Intestinal Diseases
Authors: Oliver Amanda J. , Huang Ni , Li Ruoyan , Bartolome-Casado Raquel , Nilsen Hogne R. , Gudino Victoria , Melon-Ardanaz Centro de Investigacion Biomedica e , Fitzpatrick Michael E. B. , Provine Nicholas M. , Polanski Krzysztof , Koplev Simon , Milchsack Lisa Marie , Dann Emma , Predeus Alexander V. , Cakir Batuhan , To Ken , Prete Martin , Chapman Jonathan A. , Masi Andrea C. , Stephenson Emily , Engelbert Justin , Lobentanzer Sebastian , Perera Shani , Richardson Laura , Kapuge Rakeshlal , Wilbrey-Clark Anna , Semprich Claudia I. , Moy Madelyn , Ellams Sophie , Tudor Catherine L. , Joseph Philomeena , Garrido-Trigo Alba , Corraliza Centro de Investigacion Biomedica e , Oliver Thomas R.W. , Hook C. Elizabeth , Saez-Rodriguez Julio , James Kylie R. , Meyer Kerstin B. , Mahbubani Krishnaa T. , Saeb-Parsy Kourosh , Zilbauer Matthias , Hoivik Marte Lie , Baekkevold Espen S. , Salas Centro de Investigacion Biomedica e , Stewart Christopher J. , Berrington Janet E. , Klenerman Paul , Haniffa Muzlifah , Jahnsen Frode L. , Elmentaite Rasa , Teichmann Sarah A.
Published: October 2024

The gastrointestinal (GI) tract consists of connected organs, from the oral cavity to rectum, which function to ensure efficient nutrient uptake and barrier immunity. Diseases of the GI tract affect millions worldwide and as such there are now over 25 published single cell RNA-sequencing (scRNAseq) datasets surveying the GI tract, profiling specific anatomical regions, cell lineages, ages and diseases. To consolidate these efforts, we harmonised and integrated scRNAseq datasets across the whole GI tract from developing and adult human tissues, as well as newly generated data from preterm gut. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated QC approach (scAutoQC). In total, our healthy reference contains ~1.1 million cells which we annotated to a total of 137 fine-grained cell states. We anchor 13 published and 1 unpublished GI disease datasets covering gastric and colorectal (CRC) cancers, celiac disease, ulcerative colitis (UC) and Crohn's disease (CD) to this reference, taking our atlas to a total of 1.6 million cells. We provide our atlas as a valuable resource to the community (available at gutcellatlas.org). Using this resource, we discover epithelial cell metaplasia arising from stem cells across intestinal inflammatory diseases (celiac, UC and CD) and CRC with transcriptional similarity to cells of the gastric and Brunner's glands. Whilst previously linked to mucosal healing, we now implicate these cells in inflammation through recruitment of immune cells including T cells and neutrophils, and through direct interactions with T cells. Overall, we discover a shift in paradigm whereby changes in stem cells during inflammation lead to altered mucosal tissue architecture, which in turn contributes to ongoing inflammation. These findings highlight that in addition to barrier function, epithelial cells actively contribute to progression of inflammation which may be a function applicable to other tissues and diseases.