bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperactive PI3Kinase delta enables long distance regeneration of the rat corticospinal tract
Authors: Karova Kristyna , Polcanova Zuzana , Suchankova Stepanka , Knight Lydia , Nieuwenhuis Bart , Holota Radovan , Herynek Vit , Urdzikova Lucia Machova , Turecek Rostislav , Kwok Jessica C.F. , Verhaagen Joost , Eva Richard , Fawcett James W , Jendelova Pavla
Published: November 2023

Maturation of central nervous system neurons leads to loss of their intrinsic regeneration potential. In particular after injury of the adult spinal cord there is minimal regeneration of corticospinal axons, which control gait and fine movement. Previous work has shown that knockdown of PTEN to increase PIP3 levels can promote regeneration in young animals, but the effect is much less in adults probably due to low PIP3 production. Here, we have transduced sensorimotor cortex neurons with a hyperactive form of PI3K, PI3Kδ, which increases PIP3 in mature neurons. This enables cortical neurons to regenerate corticospinal axons and improve behavioural outcomes.

We used a C4 dorsal column lesion model in adult rats and injected the right motor cortex at 4 sites concurrently with a mixture AAV1-PIK3CD and AAV1-eGFP or titre matched AAV1-eGFP only. We allowed rats to survive for 6, 9, 12 or 16 weeks. Immunostaining showed 70 - 80% co-expression in cortical neurons which remained stable at both 12 and 16 weeks. We counted GFP labelled axons in 20 μm spinal cord sections. In PI3KCD-treated animals many axons were seen to have regenerated around the margins of lesions, collecting into a knot of axons with the typical appearance of regeneration at the caudal end. Tracing down the cord, and excluding axons and neurites that could have come from unlesioned ventral CST, we found axons extending up to 1 cm below lesions, numbers decreasing with distance from the lesion. After 16 weeks there were circa 200 axons at the caudal end of lesions with a regeneration index of 0.2, with half this number at 12 weeks. Behavioural testing for 16 weeks revealed functional improvements in skilled paw reaching, grip strength and ladder rung walking in rats treated with PIK3CD compared to GFP only controls. In addition to behavioural testing, functional recovery of PIK3CD treated rats was confirmed with electrophysiological recordings during which we stimulated the right pyramid. Cord dorsum potentials (CDPs) above and below lesion and EMG forepaw distal flexor muscles showed greatly increased connectivity compared with GFP only controls, lesion only controls and uninjured shams. We conclude that forcing upregulation of PI3Kδ in cortical neurons leads to robust regeneration after spinal cord injury that results in functional restoration.
Genome-wide DNA methylation changes in human spermatogenesis
Authors: Siebert-Kuss Lara M. , Dietrich Verena , Persio Sara Di , Bhaskaran Jahnavi , Stehling Martin , Cremers Jann-Frederik , Sandmann Sarah , Varghese Julian , Kliesch Sabine , Schlatt Stefan , Vaquerizas Juan M. , Neuhaus Nina , Laurentino Sandra
Published: November 2023

Sperm production and function require the correct establishment of DNA methylation patterns in the germline. Here, we examined the genome-wide DNA methylation changes during human spermatogenesis and its alterations in disturbed spermatogenesis. We found that spermatogenesis is associated with remodeling of the methylome, comprising a global-decline in DNA methylation in primary spermatocytes followed by selective remethylation, resulting in a spermatid-specific methylome. Hypomethylated regions in spermatids were enriched in specific transcription factor binding sites for DMRT and SOX family members and spermatid-specific genes. Intriguingly, while SINEs displayed differential methylation throughout spermatogenesis, LINEs appeared to be protected from changes in DNA methylation. In disturbed spermatogenesis, germ cells exhibited considerable DNA methylation changes, which were significantly enriched at transposable elements and genes involved in spermatogenesis. We detected hypomethylation in SVA and L1HS in disturbed spermatogenesis, suggesting an association between the abnormal programming of these regions and failure of germ cells progressing beyond meiosis.
A human pluripotent stem cell-based somitogenesis model using microfluidics
Authors: Liu Yue , Kim Yung Su , Xue Xufeng , Kobayashi Norio , Sun Shiyu , Yang Qiong , Pourquié Olivier , Fu Jianping
Published: November 2023

Emerging human pluripotent stem cell (hPSC)-based embryo models are useful for studying human embryogenesis. Particularly, there are hPSC-based somitogenesis models using free-floating culture that recapitulate somite formation. Somitogenesisin vivoinvolves intricately orchestrated bio-chemical and -mechanical events. However, none of the current somitogenesis models controls biochemical gradients or biomechanical signals in the culture, limiting their applicability to untangle complex biochemical-biomechanical interactions that drive somitogenesis. Here we report a new human somitogenesis model by confining hPSC-derived presomitic mesoderm (PSM) tissues in microfabricated trenches. Exogenous microfluidic morphogen gradients imposed on PSM cause axial patterning and trigger spontaneous rostral-to-caudal somite formation. A mechanical theory is developed to explain the size dependency between somites and PSM. The microfluidic somitogenesis model is further exploited to reveal regulatory roles of cellular and tissue biomechanics in somite formation. This study presents a useful microengineered, hPSC-based model for understanding the bio-chemical and -mechanical events that guide somite formation.
Nano-pulling stimulates axon regeneration in dorsal root ganglia by inducing stabilization of axonal microtubules and activation of local translation
Authors: Falconieri Alessandro , Folino Pietro , Palmata Lorenzo Da , Raffa Vittoria
Published: November 2023

Axonal plasticity is a phenomenon strongly related to neuronal development as well as regeneration. Recently, it has been demonstrated that active mechanical tension, intended as an extrinsic factor, is a valid contribution to the modulation of axonal plasticity. In previous publications, our team validated a method, the “nano-pulling”, for applying mechanical forces on developing axons of isolated primary neurons using magnetic nanoparticles (MNP) actuated by static magnetic fields. This method was found to promote axon growth and synaptic maturation. Here, we explore the possibility to use nano-pulling as an extrinsic factor to promote axon regeneration in a neuronal tissue explant. Having this in mind, whole dorsal root ganglia (DRG) have been dissected from mouse spinal cord, incubated with MNPs, and then stretched. We found that particles were able to penetrate the ganglion and to localise both into the somas and in sprouting axons. Our results point that the nano-pulling doubles the regeneration rate, documented by an increase in the arborizing capacity of axons, and an accumulation of cellular organelles related to mass addition (endoplasmic reticulum and mitochondria) with respect to spontaneous regeneration. In line with the previous results on isolated hippocampal neurons, we observed an increase in the density of stable microtubules and activation of local translation in stretched ganglions. The collected data demonstrate that the nano-pulling is able to enhance axon regeneration in whole spinal ganglia exposed to MNPs and external magnetic fields. The preliminary data represent an encouraging starting point for proposing the nano-pulling as biophysical tool to design novel therapies based on the use of force as an extrinsic factor for promoting nerve regeneration.
The mindful brain at rest: neural oscillations and aperiodic activity in experienced meditators
Authors: McQueen Brittany , Murphy Oscar W , Fitzgerald Paul B , Bailey Neil W.
Published: November 2023

Objectives

Previous research has demonstrated that mindfulness meditation is associated with a variety of benefits, including improved mental health. Researchers have suggested these benefits may be underpinned by differences in neural oscillations. However, previous studies measuring neural oscillations have not controlled for non-oscillatory neural activity, the power spectrum of which follows a 1/f distribution and contributes to power measurements within oscillation frequencies of interest. In this study, we applied recently developed methods to determine if past findings related to neural oscillations in meditation are present even after controlling for non-oscillatory 1/f activity.

Methods

48 experienced meditators and 44 non-meditators provided resting electroencephalography (EEG) recordings. Whole scalp EEG comparisons (topographical ANOVAs) were used to test for differences between meditators and non-meditators in the distribution or global power of activity for theta, alpha, beta, and gamma oscillations, and for the 1/f components slope and intercept.

Results

Results indicated that meditators showed differences in theta, alpha, and gamma oscillatory power compared to non-meditators (allp< 0.05). Post-hoc testing suggested that the oscillatory differences were primarily driven by differences in the distribution of neural activity between meditators and non-meditators, rather than differences in the overall power across all scalp electrodes.

Conclusion

Our results suggest that experience with meditation is associated with higher oscillatory power and altered distributions of theta, alpha and gamma oscillations, even after controlling for non-oscillatory 1/f activity. Band-specific differences in oscillatory activity may be a mechanism through which meditation leads to neurophysiological benefits.
Multimodal mismatch responses in mouse auditory cortex
Authors: Solyga Magdalena , Keller Georg B.
Published: November 2023

Our movements result in predictable sensory feedback that is often multimodal. Based on deviations between predictions and actual sensory input, primary sensory areas of cortex have been shown to compute sensorimotor prediction errors. How prediction errors in one sensory modality influence the computation of prediction errors in another modality is still unclear. To investigate multimodal prediction errors in mouse auditory cortex (ACx), we used a virtual environment to experimentally couple running to both self-generated auditory and visual feedback. Using two-photon microscopy, we first characterized responses of layer 2/3 (L2/3) neurons to sounds, visual stimuli, and running onsets and found responses to all three stimuli. Probing responses evoked by audiomotor mismatches, we found that they closely resemble visuomotor mismatch responses in visual cortex (V1). Finally, testing for cross modal influence on audiomotor mismatch responses by coupling both sound amplitude and visual flow speed to the speed of running, we found that audiomotor mismatch responses were amplified when paired with concurrent visuomotor mismatches. Our results demonstrate that multimodal and non-hierarchical interactions shape prediction error responses in cortical L2/3.
Inferring therapeutic vulnerability within tumors through integration of pan-cancer cell line and single-cell transcriptomic profiles
Authors: Zhang Weijie , Maeser Danielle , Lee Adam , Huang Yingbo , Gruener Robert F. , Abdelbar Israa G. , Jena Sampreeti , Patel Anand G. , Huang R. Stephanie
Published: November 2023

Single-cell RNA sequencing greatly advanced our understanding of intratumoral heterogeneity through identifying tumor subpopulations with distinct biologies. However, translating biological differences into treatment strategies is challenging, as we still lack tools to facilitate efficient drug discovery that tackles heterogeneous tumors. One key component of such approaches tackles accurate prediction of drug response at the single-cell level to offer therapeutic options to specific cell subpopulations. Here, we present a transparent computational framework (nicknamed scIDUC) to predict therapeutic efficacies on an individual-cell basis by integrating single-cell transcriptomic profiles with large, data-rich pan-cancer cell line screening datasets. Our method achieves high accuracy, with predicted sensitivities easily able to separate cells into their true cellular drug resistance status as measured by effect size (Cohen’s d > 1.0). More importantly, we examine our method’s utility with three distinct prospective tests covering different diseases (rhabdomyosarcoma, pancreatic ductal adenocarcinoma, and castration-resistant prostate cancer), and in each our predicted results are accurate and mirrored biological expectations. In the first two, we identified drugs for cell subpopulations that are resistant to standard-of-care (SOC) therapies due to intrinsic resistance or effects of tumor microenvironments. Our results showed high consistency with experimental findings from the original studies. In the third test, we generated SOC therapy resistant cell lines, used scIDUC to identify efficacious drugs for the resistant line, and validated the predictions with in-vitro experiments. Together, scIDUC quickly translates scRNA-seq data into drug response for individual cells, displaying the potential as a first-line tool for nuanced and heterogeneity-aware drug discovery.
Walking (and talking) the plank: Dual-task performance costs in a virtual balance-threatening environment
Authors: Raffegeau Tiphanie E. , Brinkerhoff Sarah A. , Clark Mindie , McBride Ashlee D. , Williams A. Mark , Fino Peter C. , Fawver Bradley
Published: November 2023

We evaluated the effects of engaging in extemporaneous speech while walking in virtual environments meant to elicit low or high levels of mobility-related anxiety. We expected that mobility-related anxiety imposed by a simulated balance threat (i.e. virtual high elevation) would impair walking behavior and lead to greater dual-task costs. Altogether, 15 adults (age = 25.6 ± 4.7 yrs, 7 women) walked at their self-selected speed within low (ground) and high elevation (15 meters) VR settings while speaking extemporaneously (dual-task) or not speaking (single-task). Likert-scale ratings of cognitive and somatic anxiety, confidence, and mental effort were evaluated after experiencing each condition, and gait speed, step length, and step width, and the variability of each, was calculated for each trial using the position of trackers attached to participants’ ankles. Silent speech pauses (>150ms) were determined from audio recordings to infer the cognitive costs of extemporaneous speech planning at low and high virtual elevation. The presence of a balance threat and the inclusion of a concurrent speech task both perturbed gait kinematics, but only the virtual height illusion increased anxiety and mental effort while decreasing confidence. Extemporaneous speech pauses were longer on average when walking, but no effects of virtual elevation were reported. Trends toward interaction effects arose in self-reported responses, participants reported more comfort walking at virtual heights if they engaged in extemporaneous speech. Walking at virtual elevation and walking while talking have independent and significant effects on gait; both effects were robust and did not support an interaction when combined (i.e., walking and talking at virtual heights). Rather than additive cognitive-motor demands, the nature of extemporaneous speech may have distracted participants from the detrimental effects of walking in anxiety-inducing settings.
Efficient coding explains neural response homeostasis and stimulus-specific adaptation
Authors: Young Edward James , Ahmadian Yashar
Published: November 2023

In the absence of adaptation, the average firing rate of neurons would rise or drop when changes in the environment make their preferred stimuli more or less prevalent. However, by adjusting the responsiveness of neurons, adaptation can yield firing rate homeostasis and stabilise the average rates of neurons at fixed levels, despite changes in stimulus statistics. In sensory cortex, adaptation is typically also stimulus specific, in that neurons reduce their responsiveness to over-represented stimuli, but maintain or even increase their responsiveness to stimuli far from over-represented ones. Here, we present a normative explanation of firing rate homeostasis grounded in the efficient coding principle, showing that this homeostasis yields an optimal trade-off between coding fidelity and the metabolic cost of neural firing. Unlike previous efficient coding theories, we formulate the problem in a computation-agnostic manner, enabling our framework to apply far from the sensory periphery. We then apply this general framework to Distributed Distributional Codes, a specific computational theory of neural representations serving Bayesian inference. We demonstrate how homeostatic coding, combined with such Bayesian neural representations, provides a normative explanation for stimulus-specific adaptation, widely observed across the brain, and how this coding scheme can be accomplished by divisive normalisation with adaptive weights. Further, we develop a model within this combined framework, and by fitting it to previously published experimental data, quantitatively account for measures of stimulus-specific and homeostatic adaption in the primary visual cortex.
Within-species floral evolution reveals convergence in adaptive walks during incipient pollinator shift
Authors: Wenzell Katherine E. , Neequaye Mikhaela , Paajanen Pirita , Hill Lionel , Brett Paul , Byers Kelsey J.R.P.
Published: November 2023

Understanding how evolution proceeds from molecules to organisms to interactions is critical for evolutionary biology and requires integrative studies that span biological levels. By linking phenotypic changes with associated genes and fitness implications, we gain insight on the repeatability of evolution and how adaptive walks move organisms between fitness peaks, which remains poorly understood at intermediate stages,e.g.potential fitness valleys. Floral trait evolution can proceed rapidly, confer reproductive isolation, and provides numerous examples of convergent evolution associated with pollinator guilds. Within the monkeyflowers (Mimulussect.Erythranthe), intraspecific shifts to yellow flowers within red hummingbird-pollinated species have arisen at least twice and may represent incipient shifts between optima of pollinator adaptation. Here, we compare two natural yellow-flowered forms ofM. cardinalisandM. verbenaceusto their red conspecifics in floral phenotypes, biochemistry, transcriptomic and genomic variation, and interactions with pollinators. We find convergent evolution in the adaptive walks of yellow morphs in both species, with consistent changes in traits of large effect (floral pigments and associated gene expression), which result in strong preference for yellow flowers by bumblebees. Shifts in additional traits (scent emissions and floral opening size) are also consistent with bee pollination, which may represent smaller-effect steps in an ongoing walk from hummingbird to bee pollination. By examining intraspecific variation representing incipient pollinator shifts in two related species, this work elucidates how adaptive walks proceed at early stages by highlighting how convergent large effect mutations (floral color) may drive pollinator attraction, preceding smaller effect changes controlling pollinator fit and reward access. This work integrates phenotypic, biochemical, genomic, and behavioral evidence to shed light on how repeated steps in adaptive walks to new fitness optima may impact reproductive isolation and incipient speciation via convergent evolution.
Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds
Authors: Alonso-Matilla Roberto , Provenzano Paolo P. , Odde David J.
Published: November 2023

Despite recent experimental progress in characterizing cell migration mechanics, our understanding of the mechanisms governing rapid cell movement remains limited. To effectively limit tumor growth, antitumoral T cells need to rapidly migrate to find and kill cancer cells. To investigate the upper limits of cell speed, we developed a new hybrid stochastic-mean field model of bleb-based cell motility. We first examined the potential for adhesion-free bleb-based migration and show that cells migrate inefficiently in the absence of adhesion-based forces, i.e., cell swimming. While no cortical contractility oscillations are needed for cells to swim in viscoelastic media, high-to-low cortical contractility oscillations are necessary for cell swimming in viscous media. This involves a high cortical contractility phase with multiple bleb nucleation events, followed by an intracellular pressure buildup recovery phase at low cortical tensions, resulting in modest net cell motion. However, our model suggests that cells can employ a hybrid bleb- and adhesion-based migration mechanism for rapid cell motility and identifies conditions for optimality. The model provides a momentum-conserving mechanism underlying rapid single-cell migration and identifies factors as design criteria for engineering T cell therapies to improve movement in mechanically complex environments.
Electrophysiological properties of the medial mammillary bodies across the sleep-wake cycle
Authors: Dillingham Christopher M. , Wilson Jonathan J. , Vann Seralynne D.
Published: November 2023

The medial mammillary bodies (MB) play an important role in the formation of spatial memories. Dense anatomical connectivity with hippocampal, brainstem, and thalamic structures, positions them as a focal point for the integration of movement-related and spatial information that is extended to the anterior thalamic nuclei and beyond to cortex. While their anatomical connectivity has been well-studied, much less is known about the physiological properties of the medial MBs, particularly in freely moving animals. We therefore carried out a comprehensive characterization of medial MB electrophysiology across arousal states by concurrently recording from the medial MB and the CA1 field of the hippocampus. In agreement with previous studies, we found medial MB neurons to have firing rates modulated by running speed and angular head velocity, as well as theta-entrained firing. We extended the characterization of MB neuron electrophysiology in three key ways: 1) we identified a subset of neurons (25%) that exhibit dominant bursting activity; 2) we show that ∼30% of theta-entrained neurons exhibit robust theta cycle skipping, a firing characteristic that implicates them in a network for prospective coding of position; 3) A considerable proportion of medial MB units show sharp wave-ripple (SWR) responsive firing (∼37%). The functional heterogeneity of MB electrophysiology reinforces their role as an integrative node for mnemonic processing and identifies potential roles for the MBs in memory consolidation through propagation of SWR-responsive activity to the anterior thalamus and prospective coding in the form of theta-cycle skipping.

Significance Statement

While the medial mammillary bodies (MBs) are important for memory, it is still not clear how they support memory formation. Through conjoint medial MB and hippocampal recordings across different arousal states we identified a population of medial MB units with diverse and often conjunctive physiological properties, including theta-entrained cells, cells modulated by running speed and angular head velocity, complex bursting, theta cycle skipping activity, and hippocampal sharp-wave ripple-responsive firing. These properties likely support a role for the medial MBs in mnemonic processing, enabling the integration of separate sensory streams and the propagation of information to the thalamus.
Adenosine triggers early astrocyte reactivity that provokes microglial activation and drives the pathogenesis of sepsis-associated encephalopathy
Authors: Guo Qilin , Gobbo Davide , Zhao Na , Liu Qing , Fang Li-Pao , Gampfer Tanja M. , Meyer Markus R. , Bai Xianshu , Bian Shan , Scheller Anja , Kirchhoff Frank , Huang Wenhui
Published: November 2023

Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial activation, ameliorating blood-brain barrier disruption, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as a novel pathway driving SAE.
Efficient semi-supervised semantic segmentation of electron microscopy cancer images with sparse annotations
Authors: Pagano Lucas , Thibault Guillaume , Bousselham Walid , Riesterer Jessica L. , Song Xubo , Gray Joe W.
Published: November 2023

Electron microscopy (EM) enables imaging at nanometer resolution and can shed light on how cancer evolves to develop resistance to therapy. Acquiring these images has become a routine task; however, analyzing them is now the bottleneck, as manual structure identification is very time-consuming and can take up to several months for a single sample. Deep learning approaches offer a suitable solution to speed up the analysis. In this work, we present a study of several state-of-the-art deep learning models for the task of segmenting nuclei and nucleoli in volumes from tumor biopsies. We compared previous results obtained with the ResUNet architecture to the more recent UNet++, FracTALResNet, SenFormer, and CEECNet models. In addition, we explored the utilization of unlabeled images through semi-supervised learning with Cross Pseudo Supervision. We have trained and evaluated all of the models on sparse manual labels from three fully annotated in-house datasets that we have made available on demand, demonstrating improvements in terms of 3D Dice score. From the analysis of these results, we drew conclusions on the relative gains of using more complex models, semi-supervised learning as well as next steps for the mitigation of the manual segmentation bottleneck.
Investigating the role of mitochondrial membrane potential in paternal inheritance of mitochondria
Authors: Pouliot-Drouin Ariane , Niaison Thierry , Breton Sophie , Bettinazzi Stefano
Published: November 2023

The process of oxidative phosphorylation (OXPHOS) in mitochondria depends on an electrochemical gradient known as the mitochondrial membrane potential (Δψm). Reflecting high functionality, elevated Δψm usually depicts healthy mitochondria and contribute to organelle selection. This study investigates whether mitochondrial properties linked with bioenergetics, such as Δψm, may play a role in paternal inheritance of mitochondria. More specifically, how sperm Δψm responds to egg chemoattractants in bivalves characterized by distinct mitochondrial inheritance patterns: strict maternal inheritance (SMI) and doubly uniparental inheritance (DUI), the latter displaying sex-specific transmission of paternal mitochondrial DNA (mtDNA). Sperm Δψm was examined in four bivalve species:Mytilus edulisandRuditapes philippinarum(DUI), plusMercenaria mercenariaandMya arenaria(SMI). In absence of oocytes, sperm Δψm did not vary between the two groups. However, we revealed an increase in Δψm following egg detection only in sperm bearing paternally-derived mitochondria (DUI). This suggests, along with bioenergetic changes, that Δψm modulation might be a specific property of DUI paternal mitochondria, possibly implicated in their unique ability to be sex-specifically transmitted.
Metapopulations, the inflationary effect, and consequences for public health
Authors: Kortessis Nicholas , Glass Gregory , Gonzalez Andrew , Ruktanonchai Nick W. , Simon Margaret W. , Singer Burton , Holt Robert D.
Published: November 2023

The metapopulation perspective is an important conceptual framework in ecology and evolutionary ecology. Metapopulations are spatially distributed populations linked by dispersal. Both metapopulation models and their community and ecosystem level analogues, metacommunity and meta-ecosystem models, tend to be more stable regionally than locally and display enhanced abundance because of the interplay of spatiotemporal heterogeneity and dispersal (an effect that has been called the “inflationary effect”). We highlight the essential role of spatiotemporal heterogeneity in metapopulation biology, sketch empirical demonstrations of the inflationary effect, and provide a mechanistic interpretation of how the inflationary effect arises and impacts population growth and abundance. We illustrate the effect with examples from the spread of infectious disease. Namely, failure to recognize the full possible effects of spatiotemporal heterogeneity likely enhanced the spread of COVID-19, a failure based on lack of understanding of emergent population processes at large scales which may hamper control and eradication of other infectious diseases. We finish by noting how the effects of spatiotemporal heterogeneity have implicitly played roles in the history of ecology, ranging across subdisciplines as diverse as natural enemy-victim dynamics, species coexistence, and conservation biology. Seriously confronting the complexity of spatiotemporal heterogeneity could push many of these subdisciplines forward.
Carbonized Tetracycline: a new class of nanomaterial with tuneable antioxidant, reduced cytotoxicity, immunomodulatory, and osteogenic properties
Authors: Mandal Saptarshi , Annamalai Ramkumar T
Published: November 2023

Tetracycline (TET), a broad-spectrum antibiotic, also possesses different non-antibiotic activities such as inhibition of metalloproteinase (MMP), anti-inflammatory, antioxidant, high bone affinity, etc. However, the comparatively low efficacy of these non-antibiotic properties along with adverse effects such as hyperpigmentation, phototoxicity, long-term skeletal retention, etc. have not helped their broad utilization similar to their use as an antibiotic. In a unique attempt to improve the non-antibiotic properties while reducing the adverse effects, we converted the TET to nano-carbons through partial carbonization. After sorting out two water-dispersible C-TETs (C-TETHT- hydrothermal and C-TETHP- hot plate) based on their improved antioxidant activity, they have been characterized through a host of analytical techniques that showed distinct differences in morphology, size, shape, and surface functionality. Excitingly, the C-TETHTand C-TETHPhave shown differential biological activity in a dosage and time-dependent manner in terms of cytotoxicity, immunomodulation, and osteogenic activity that was found to be associated with their carbonized parameters. Overall, the carbonized nano-drugs, C-TETHTand C-TETHPhave presented substantial early promises on their non-antibiotic properties that could be further explored to develop into some effective therapeutics.
Proteomic insights into the pathophysiology of hypertension-associated albuminuria: Pilot study in a South African cohort
Authors: Govender Melanie A. , Stoychev Stoyan H. , Brandenburg Jean-Tristan , Ramsay Michèle , Fabian June , Govender Ireshyn S.
Published: November 2023

Background

Hypertension is an important public health priority with a high prevalence in Africa. It is also an independent risk factor for kidney outcomes. We aimed to identify potential proteins and pathways involved in hypertension-associated albuminuria by assessing urinary proteomic profiles in black South African participants with combined hypertension and albuminuria compared to those who have neither condition.

Methods

The study included 24 South African cases with both hypertension and albuminuria and 49 control participants who had neither condition. Protein was extracted from urine samples and analysed using ultra-high-performance liquid chromatography coupled with mass spectrometry. Data was generated using data-independent acquisition (DIA) and processed using Spectronaut™ 15. Statistical and functional data annotation were performed on Perseus and Cytoscape to identify and annotate differentially abundant proteins. Machine learning was applied to the dataset using the OmicLearn platform.

Results

Overall, a mean of 1,225 and 915 proteins were quantified in the control and case groups, respectively. Three hundred and thirty-two differentially abundant proteins were constructed into a network. Pathways associated with these differentially abundant proteins included the immune system (q-value [false discovery rate]=1.4×10-45), innate immune system (q=1.1×10-32), extracellular matrix (ECM) organisation (q=0.03) and activation of matrix metalloproteinases (q=0.04). Proteins with high disease scores (76–100% confidence) for both hypertension and CKD included angiotensinogen (AGT), albumin (ALB), apolipoprotein L1 (APOL1), and uromodulin (UMOD). A machine learning approach was able to identify a set of 20 proteins, differentiating between cases and controls.

Conclusions

The urinary proteomic data combined with the machine learning approach was able to classify disease status and identify proteins and pathways associated with hypertension and albuminuria.
Cultivated Robusta coffee meets wildCoffea canephora: Evidence of cultivated-wild hybridisation in the Democratic Republic of the Congo
Authors: Lauren Verleysen , Jonas Depecker , Robrecht Bollen , Justin Asimonyio , Yves Hatangi , Jean-Léon Kambale , Ithe Mwanga Mwanga , Tshimi Ebele , Benoit Dhed’a , Piet Stoffelen , Tom Ruttink , Filip Vandelook , Olivier Honnay
Published: November 2023

Background and aims

Plant breeders are increasingly turning to crop wild relatives (CWRs) to ensure global food security amidst a rapidly changing environment. However, CWR populations are confronted with various human-induced threats, including hybridisation with their nearby cultivated crops, posing a significant threat to the wild gene pool. Here, we focussed on Robusta coffee in the Yangambi region in the DR Congo, where cultivated Robusta coffee coexists with its wild relative (Coffea canephora), creating ample opportunity for genetic exchange. We examined the geographical distribution of cultivated Robusta coffee plants and the incidence of hybridisation between cultivated and wild individuals within the rainforest.

Methods

We used Genotyping-by-Sequencing data from 471 C. canephora individuals across various locations, including natural rainforests, home gardens, and the INERA Coffee Collection, a Robusta coffee field genebank. Our analyses involved establishing robust diagnostic fingerprints that differentiate cultivated from wild coffee, identifying cultivated-wild hybrids and mapping their geographical position.

Key results

We identified cultivated genotypes and cultivated-wild hybrids in zones with clear anthropogenic activity, and where Robusta coffee cultivated in the home gardens may serve as a source for crop-to-wild gene flow. We found relatively few hybrids and backcrosses in the rainforests, which is so far likely not sufficient for the stable incorporation of alleles from the cultivated gene pool into the CWR gene pool.

Conclusions

The cultivation of Robusta coffee in close proximity to its wild gene pool has led to cultivated genotypes and cultivated-wild hybrids appearing within the natural habitats of C. canephora. Yet, given the high overlap between the cultivated and wild gene pool, together with the relatively low frequency of hybridisation, our results indicate that the overall impact in terms of risk of introgression remains limited so far. Nevertheless, it is important to continue monitoring crop-to-wild gene flow to safeguard the wild gene pool of C. canephora.
Spatio-temporal brain invasion pattern ofStreptococcus pneumoniaeand dynamic changes of the cellular environment in meningitis pathogenesis
Authors: Farmen Kristine , Tofiño-Vian Miguel , Wellfelt Katrin , Olson Lars , Iovino Federico
Published: November 2023

Streptococcus pneumoniae(the pneumococcus) is the major cause of bacterial meningitis globally, and pneumococcal meningitis is associated with increased risk of long-term neurological sequelae. These include several sensorimotor functions that are controlled by specific brain regions which, during bacterial meningitis, are damaged by the vast neuroinflammation and bacterial toxins. Little is known about the invasion pattern of the pneumococcus into the brain. Using a bacteremia-derived meningitis mouse model, we combined 3D whole brain imaging with brain microdissection to show that all brain regions were equally affected during disease progression, with pneumococci in close association to the microvasculature. In the hippocampus, the invasion provoked a dynamic microglial response, while the dentate gyrus showed a significant loss of neuroblasts. Our results indicate that, even before symptom occur, the bacterial load throughout the brain causes neuroinflammation and cell death, a pathological scenario which ultimately leads to a failing regeneration of new neurons.
Digitoids: a novel computational platform for mimicking oxygen-dependent firing dynamics inin vitroneuronal networks
Authors: Fabbri Rachele , Ahluwalia Arti , Magliaro Chiara
Published: November 2023

In vitromodels of neural tissues are crucial to gain new insights on the pathophysiology of the brain. However, cell cultures are associated with many drawbacks and difficulties, e.g., technical complexities, ethical problems and high cost. Computational model-based solutions could represent an important tool to support the study of neuron function. In this work we present a novel computational platform where digital neuronal networks, i.e., Digitoids, can be developed with different size and layouts. The Digitoids rely on a novel firing model where the dependence on oxygen concentration is introduced, since it is a crucial limiting factor in cell cultures. To validate the performance of the platform, Digitoids were developed with the same morphological arrangement as observed in neuron monolayersin vitro. The comparison between the functional output of the Digitoids and the experimental data are not statistically different. The platform delivers a flexible digital tool that can easily be adapted for mimickingin vitromodels with increasing complexity and can be exploited to optimize the laboratory experiments involving neuron cultures.

Author Summary

The use of cell models within laboratories is crucial to gain new understandings of the functioning of neuronal assemblies. However, culturing cells requires highly skilled personnel, a huge quantity of disposable materials and is thus associated with elevated costs. To overcome these limitations, the use of computer-based systems that reproduce the electrical behaviour of neurons can be employed. Sincein vitromodels are vessel-free, we present a novel computational model of neuron electrophysiology, where we introduce the dependence on local oxygen concentration Indeed, oxygen affects the metabolism and the function of cultured neurons. Thanks to our model and platform, we are able to reproduce the morphology of the cultured networks of neurons and build the so-calledDigitoids. We then simulate theDigitoidsand obtain their electrophysiological output. We compared theDigitoids’output with experimental data from neurons cultured on microelectrode arrays. We did not find any differences between the electrophysiological output of theDigitoidsand the experimental data, therefore we conclude that our novel oxygen-dependent model can be used to develop more physiologically relevant tools for simulating the activity of cultured neurons.
Sea anemone MACPF proteins demonstrate an evolutionary transitional state between venomous and developmental functions
Authors: Surm Joachim M. , Landau Morani , Columbus-Shenkar Yaara Y. , Moran Yehu
Published: November 2023

Gene duplication is a major force driving evolutionary innovation. A classic example is generating new animal toxins via duplication of physiological protein-encoding genes and recruitment into venom. While this process drives the innovation of many animal venoms, reverse-recruitment of toxins into non-venomous cells remains unresolved. Using comparative genomics, we find members of the Membrane Attack Complex and Perforin Family (MACPF) have been recruited into venom-injecting cells (cnidocytes), in soft and stony corals and sea anemones, suggesting that the ancestral MACPF was a cnidocyte expressed toxin. Further investigation into the model sea anemoneNematostella vectensis,reveals that three members have undergoneNematostella-specific duplications leading to their reverse-recruitment into mesoendodermal cells. Furthermore, simultaneous knock-down of all three mesoendodermally-expressed MACPFs leads to mis-development, supporting that these paralogs have non-venomous function. By resolving the evolutionary history and function of MACPFs inNematostella, we provide the first proof for reverse-recruitment from venom to organismal development.

Significance statement

In this study, we reveal how a gene can gain a new function, even from a most unexpected origin. Specifically, we report that in the last common ancestor of corals and sea anemones a member of the Membrane Attack Complex and Perforin Family (MACPF), which is commonly associated with the immune system, was recruited into venom-injecting cells called cnidocytes. Using the sea anemoneNematostella vectensiswe find repeated gene duplication has occurred leading to the new copies adopting divergent functions including being retained in cnidocytes but also recruited into non-venomous mesoendodermal cells. Furthermore, when we depleteNematostellaof mesoendodermally-expressed MACPFs we disrupt normal embryonic development, supporting that these copies have indeed been recruited from venom into the developmental plan.
Adolescent social anxiety is associated with diminished discrimination of anticipated threat and safety in the bed nucleus of the stria terminalis
Authors: Hur Juyoen , Tillman Rachael M. , Kim Hyung Cho , Didier Paige , Anderson Allegra S. , Islam Samiha , Stockbridge Melissa D. , De Los Reyes Andres , DeYoung Kathryn A. , Smith Jason F. , Shackman Alexander J.
Published: November 2023

Social anxiety—which typically emerges in adolescence—lies on a continuum and, when extreme, can be devastating. Socially anxious individuals are prone to heightened fear, anxiety, and the avoidance of contexts associated with potential social scrutiny. Yet most neuroimaging research has focused on acute social threat. Much less attention has been devoted to understanding the neural systems recruited during the uncertain anticipation of potential encounters with social threat. Here we used a novel fMRI paradigm to probe the neural circuitry engaged during the anticipation and acute presentation of threatening faces and voices in a racially diverse sample of 66 adolescents selectively recruited to encompass a range of social anxiety and enriched for clinically significant levels of distress and impairment. Results demonstrated that adolescents with more severe social anxiety symptoms experience heightened distress when anticipating encounters with social threat, and reduced discrimination of uncertain social threat and safety in the bed nucleus of the stria terminalis (BST), a key division of the central extended amygdala (EAc). Although the EAc—including the BST and central nucleus of the amygdala—was robustly engaged by the acute presentation of threatening faces and voices, the degree of EAc engagement was unrelated to the severity of social anxiety. Together, these observations provide a neurobiologically grounded framework for conceptualizing adolescent social anxiety and set the stage for the kinds of prospective-longitudinal and mechanistic research that will be necessary to determine causation and, ultimately, to develop improved interventions for this often-debilitating illness.
Isolating Small Extracellular Vesicles from Small Volumes of Blood Plasma using size exclusion chromatography and density gradient ultracentrifugation: A Comparative Study
Authors: Kong Fang , Upadya Megha , Weng Andrew See Wong , Dalan Rinkoo , Dao Ming
Published: November 2023

Small extracellular vesicles (sEVs) are heterogeneous biological vesicles released by cells under both physiological and pathological conditions. Due to their potential as valuable diagnostic and prognostic biomarkers in human blood, there is a pressing need to develop effective methods for isolating high-purity sEVs from the complex milieu of blood plasma, which contains abundant plasma proteins and lipoproteins. Size exclusion chromatography (SEC) and density gradient ultracentrifugation (DGUC) are two commonly employed isolation techniques that have shown promise in addressing this challenge. In this study, we aimed to determine the optimal combination and sequence of SEC and DGUC for isolating sEVs from small plasma volumes, in order to enhance both the efficiency and purity of the resulting isolates. To achieve this, we compared sEV isolation using two combinations: SEC-DGUC and DGUC-SEC, from unit volumes of 500μlplasma. Both protocols successfully isolated high-purity sEVs; however, the SEC-DGUC combination yielded higher sEV protein and RNA content. We further characterized the isolated sEVs obtained from the SEC-DGUC protocol using flow cytometry and mass spectrometry to assess their quality and purity. In conclusion, the optimized SEC-DGUC protocol is efficient, highly reproducible, and well-suited for isolating high-purity sEVs from small blood volumes.
Concurrent response and action effect representations across the somatomotor cortices during novel task preparation
Authors: Palenciano Ana F. , González-García Carlos , De Houwer Jan , Liefooghe Baptist , Brass Marcel
Published: November 2023

Instructions allow us to fulfill novel and complex tasks on the first try. This skill has been linked to preparatory brain signals that encode upcoming demands in advance, facilitating novel performance. To deepen insight into these processes, we explored whether instructions pre-activated task-relevant motoric and perceptual neural states. Critically, we addressed whether these representations anticipated activity patterns guiding overt sensorimotor processing, which could reflect that internally simulating novel tasks facilitates the preparation. To do so, we collected functional magnetic resonance imaging data while female and male participants encoded and implemented novel stimulus-response associations. Participants also completed localizer tasks designed to isolate the neural representations of the mappings-relevant motor responses, perceptual consequences, and stimulus categories. Using canonical template tracking, we identified whether and where these sensorimotor representations were pre-activated. We found that response-related templates were encoded in advance in regions linked with action control, entailing not only the instructed responses but also their somatosensory consequences. This result was particularly robust in primary motor and somatosensory cortices. While, following our predictions, we found a systematic decrease in the irrelevant stimulus templates’ representational strength compared to the relevant ones, this difference was due to below-zero estimates linked to the irrelevant category activity patterns. Overall, our findings reflect that instruction processing relies on the sensorimotor cortices to anticipate motoric and kinesthetic representations of prospective action plans, suggesting the engagement of motor imagery during novel task preparation. More generally, they stress that the somatomotor system could participate with higher-level frontoparietal regions during anticipatory task control.