Biology subjects

Aziz, A.

Publications and source records attributed to Aziz, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Gamma-frequency firing persistently enhances intrinsic excitability in retinal ganglion cells

Experience-dependent plasticity is usually attributed to synaptic changes, but neuronal output also depends on changes in intrinsic excitability. Whether intrinsic excitability is persistently modified at the retinal output stage is unknown. Using whole-cell recordings from retinal ganglion cells (RGCs) of juvenile rats, we found that 40-Hz firing produced sustained potentiation of intrinsic excitability in low-input-resistance A-type RGCs and rapid potentiation of intrinsic excitability in high-input-resistance B-type RGCs. In A-type bursting RGCs, long-term potentiation of intrinsic excitability (LTP-IE) required Cav1 calcium channels for its induction. LTP-IE was associated with hyperpolarization of spike threshold and reduction of spike time jitter, due to reduced Kv1 potassium-family channel function. Potentiation also increased the probability that visually-evoked synaptic events triggered action potentials. Patterned firing therefore persistently reconfigures RGC input-output transformation through the Cav1-dependent regulation of Kv1 channels, revealing intrinsic plasticity at the retinal output stage.

neuroscience↗

bioRxiv2026

Predictive dendrites as a foundation for biological learning

A fundamental challenge for neuroscience is to identify laws of synaptic plasticity that are consistent with experimental observations at the level of individual neurons, whilst also explaining the ability of neural networks to learn complex tasks. Here we investigate a candidate law in which neurons adjust synaptic strengths to minimize the mismatch between somatic and dendritic activity. We demonstrate that models based on this rule can effectively adjust synaptic weights across network layers to learn non-linear tasks. Moreover, minimizing mismatch between spiking activity and dendritic inputs leads to integrate-and-fire dynamics and spike-timing-dependent plasticity. The model reproduces the experimentally observed dependencies of plasticity upon initial synaptic weights and spike patterns, whilst also generating a series of testable predictions. Our results show that a single principle - minimization of somato-dendritic mismatch - links learning at the network level with fundamental properties of individual neurons, including membrane potential dynamics and canonical features of synaptic plasticity.

neuroscience↗

bioRxiv2026

Voluntary engagement predicts recovery across rehabilitation time points after experimental spinal cord injury

Rehabilitation is the cornerstone of clinical care following spinal cord injury (SCI) and is frequently incorporated into preclinical studies to evaluate emerging therapies. However, the variables that influence the effectiveness of rehabilitation interventions in rodent models remain poorly characterized, limiting the translational value of preclinical research. Here, we performed a meta-analysis of 150 preclinical studies comprising more than 3000 rodents and 292 effect sizes to identify such factors associated with successful rehabilitation after SCI. Rehabilitation improved functional outcomes across multiple behavioral domains, with larger effects observed in thoracic than cervical injury models. Meta-regression identified environmental enrichment as the most effective strategy, particularly when combined with task-specific training. Longer rehabilitation duration was associated with improved recovery, whereas greater daily exposure to forced rehabilitation was associated with smaller gains. In contrast, prolonged access to voluntary rehabilitation did not show this relationship. Rehabilitation improved outcomes when initiated at all time points after injury, with greater benefits when initiated during the late subacute and intermediate phases. Rehabilitation approaches associated with higher stress burden produced reduced benefits, suggesting that stress may limit rehabilitation-induced recovery. Collectively, these findings identify rehabilitation type, duration, and delivery context as important determinants of recovery after SCI and support a broad therapeutic window for intervention. Our results favor low-stress, voluntary rehabilitation strategies that promote sustained engagement and provide principles for designing effective and biologically appropriate rehabilitation strategies, potentially improving translational success for emerging SCI therapies. One Sentence SummarySustained voluntary rehabilitation promotes functional recovery across stages of experimental spinal cord injury, whereas prolonged forced training may reduce its benefits.

neuroscience↗

bioRxiv2026

LRP-1 promotes tumor progression of triple negative breast cancers by coordinating extracellular matrix remodeling and immune cell infiltration

Structural AbstractO_ST_ABSBackgroundC_ST_ABSTriple-negative breast cancer (TNBC) represents a major clinical challenge due to its aggressiveness, heterogeneity and limited availability of effective targeted therapy. We investigated whether LRP-1, a multifunctional cell-surface endocytic and signaling receptor, contributes to TNBC progression. MethodsUsing CRISPR-Cas9, LRP-1-deficient murine 4T1 and human HS578-T TNBC cells were used. Functional consequences were assessed through migration, invasion, and 3D spheroid assays, imaging of focal adhesions and actin organization, atomic force microscopy, and plasmin activity assays. Global molecular reprogramming was analyzed by label-free quantitative proteomics and secretomics. LRP-1-deficient or proficient 4T1 cells were implanted orthotopically in immunocompetent mice; tumor progression was monitored longitudinally while peritumoral collagen architecture and immune microenvironment composition were characterized by second harmonic generation imaging and immunohistochemistry. ResultsWe show that LRP-1 loss reduces TNBC aggressiveness, as reflected by decreased migration and invasive capacity, reduced spheroid evasion, and significant morphological changes in focal adhesion and actin structure. LRP-1-deficient cells became stiffer and showed lower LOXL-4 levels, while pericellular proteolytic activity remained unchanged, suggesting other proteases mechanism. Multi-omic analysis revealed alterations in extracellular matrix (ECM), epithelial-mesenchymal transition, and inflammatory pathways. In vivo, LRP-1-deficiency reduced tumor progression and peritumoral collagen deposition, while increasing CD8+ T and Natural Killer cell infiltration, together with a cytokine profiling compatible with a more immune-permissive microenvironment. ConclusionsLRP-1 act as a key contributor in TNBC progression through matrix remodeling, mechano-adaptation, and immune exclusion. Positioning it as a candidate biomarker for TNBC patients who are likely to benefit from stroma-targeting therapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/732906v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1b595c2org.highwire.dtl.DTLVardef@7b208aorg.highwire.dtl.DTLVardef@1956e54org.highwire.dtl.DTLVardef@17e55d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cancer Biology↗

bioRxiv2026

Homeostatic regulation of intrinsic neuronal excitability in visual thalamic relay cells induced by brief monocular deprivation

Homeostatic plasticity of intrinsic excitability (IE) in the visual system has been essentially shown at the cortical level but whether thalamic nuclei also express homeostatic plasticity of IE is unknown. We show here that 4 days of monocular deprivation (MD) at eye opening induces a homeostatic change in IE in dorsal lateral geniculate nucleus (dLGN) neurons. Neurons recorded in the dLGN region activated by the deprived eye are more excitable than neurons recorded in the dLGN region activated by the open eye. No significant changes were observed following 7 days of MD, however. Enhanced excitability in neurons from the deprived side after 4 days of MD was associated with a reduced Kv1-dependent LTP-IE, a smaller voltage ramp, and a reduced inter-spike interval, suggesting that Kv1 channels are down-regulated in deprived dLGN neurons. Furthermore, the ankyrin G signal of the axon initial segment was larger in deprived dLGN neurons compared with open ones, indicating that Nav1 channel number also undergoes homeostatic regulation, and Kv1.1 channel signals were lower in deprived neurons compared to open ones. In addition, electrical coupling was found to be strengthened in neurons displaying enhanced IE following either brief (4 days) or long (10 days) MD. These results suggest that homeostatic and Hebbian plasticity in the dLGN share common expression mechanisms involving the regulation of Kv1 channels, Nav1 channels and electrical coupling between relay neurons.

neuroscience↗

bioRxiv2026

Systematic Evaluation Defines the Limits of Ferroptosis in Cancer Therapy

Ferroptosis is a cell death mechanism characterized by the accumulation of iron-catalyzed lipid peroxides in membrane lipid acyl chains and subsequent loss of membrane integrity.1 Despite thorough investigation of its mechanisms in cultured cells, induction of ferroptosis has unresolved clinical utility in cancer therapy. Here, we systematically evaluate ferroptosis induction via multiple mechanisms, in both cell and tumor models, using focused genetic screens, genetic loss-of-function systems, and pharmacological perturbations. Through this analysis we identify cancer cell line subsets with distinct responses to canonical ferroptosis inducers and suppressors and define the underpinnings of each. Inhibition of central in vitro ferroptosis suppressors GPX4, GCLC, or SLC7A11 across these multiple models fails to impact established tumor growth. In contrast, deficiency in the cytosolic thioredoxin reductase and pharmacologic GCLC inhibition potently induces tumor regression and triggers a form of non-ferroptotic cell death regulated by cystine availability and translation. These analyses further reveal that the principal essential function of environmental cystine in cultured cells is to support selenoprotein function, identified through investigating our finding that {beta}-mercaptoethanol supports exponential growth in cystine-free conditions. Thus, while ferroptosis activation may be efficacious alone or in combination with other therapies in specific tumor contexts, cell culture systems greatly overestimate the potential anti-cancer effects of ferroptosis induction via the GPX4 axis.

cancer biology↗

bioRxiv2025

Pantoea ananatis-triggered systemic resistance requires root sensing through the LORE receptor kinase in Arabidopsis

Systemic immunity induced by beneficial bacteria helps plants to cope with subsequent pathogen attacks. However, how these bacteria are sensed by plants and how this sensing results in a systemic response is not well understood. Recently, the Brassicaceae LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION (LORE) receptor kinase was identified as the direct sensor of bacterial medium-chain-length 3-hydroxy fatty acids (mc-3-OH-FAs) and 3-(3-hydroxyalkanoyloxy)alkanoic acids (HAAs), which activate systemic Brassicaceae immunity. Here, we show that the bacterium Pantoea ananatis BRT175, which produces HAAs, can colonize Arabidopsis thaliana roots independently of the production of these compounds. P. ananatis triggers induced systemic resistance (ISR) to the necrotrophic pathogen Botrytis cinerea, but not to the hemibiotrophic pathogen Pseudomonas syringae pv. tomato. Importantly, this ISR can be mimicked by HAAs or 3-hydroxy-decanoic acid (3-OH-C10). Both P. ananatis-triggered and 3-OH-C10-triggered ISR against B. cinerea are mediated by LORE sensing, involve salicylic acid, jasmonic acid and ethylene signaling pathways, and activate the expression of similar defense genes in infected leaves. Thus, 3-OH-C10 and HAAs are perceived by a pattern recognition receptor (PRR) in the root and activate a local immune response in roots as well as systemic immunity in leaves. Our study demonstrates that these lipidic microbe-associated molecular patterns (MAMPs), produced by beneficial microorganisms, are necessary and sufficient to trigger rhizobacteria-driven ISR. It further highlights the role of these MAMPs in differentially activating systemic resistance against biotrophic and necrotrophic pathogens.

plant biology↗

bioRxiv2025

Magnetically Controlled Microrobots for In Vivo Non-Invasive Embryo Transfer

Infertility affects millions worldwide and is often linked to factors such as poor sperm quality and female reproductive organ disorders. Despite significant advancements in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), implantation rates remain low, ranging from 17 to 21% after three days of incubation, mainly due to stress, lifestyle factors, and uterine conditions. Extended embryo culture techniques have shown promise in improving pregnancy rates. However, the availability of high-quality blastocysts remains a major challenge. Intrafallopian transfer techniques, such as gamete/zygote intrafallopian transfer (GIFT/ZIFT), were introduced to improve fertilization and early embryo development, particularly for patients with repeated embryo implantation failure (10-30% of assisted reproduction technology (ART) cases, particularly in women >35). However, these methods have declined due to advancements in IVF and the variability in laparoscopy procedures used for GIFT/ZIFT. To address these challenges, we propose a non-invasive microrobotic embryo transfer ({micro}ET) technique using remotely controlled microcarriers comparable in size to embryos. We demonstrate the capabilities of magnetically actuated spiral microrobots, fabricated using laser direct writing for capturing, transporting, and releasing embryos into murine uteri. Additionally, we characterize their motion performance and implement image-guided closed-loop control and dual ultrasound (US)/photoacoustic (PA) tracking for deep-tissue interventions. Recognizing the importance of clinical translation, we present preliminary studies on gelatin-based microrobots, a biodegradable alternative, and explore endometrial remodeling after the in vivo transfer of microrobots carrying embryo-like structures. Our findings show that these microrobots can effectively transport embryos, support their development, and enable minimally invasive delivery, providing a more natural, targeted, and non-invasive strategy for in vivo assisted reproduction. One-Sentence SummaryWe propose a non-invasive {micro}ET technique using magnetically actuated microcarriers to improve embryo cargo-delivery in assisted reproduction, addressing challenges in infertility treatments by enabling precise, image-guided embryo delivery with minimal invasiveness.

bioengineering↗

bioRxiv2024

U1 snRNP-Specific U1C Acts as the Gatekeeper of the Survival of Motor Neurons (SMN) Complex in snRNP Biogenesis

The stability and abundance of spliceosomal snRNPs are determined by the assembly of an Sm protein ring (Sm core) on each snRNA, a process facilitated by the survival of motor neuron (SMN) complex. Whereas the SMN complexs role as a chaperone is well-established, the mechanisms that regulate its activity remain unclear. Our study identifies U1C, a U1 snRNP-specific protein, as a key regulator of the SMN complex. U1C together with U1-70K facilitates U1 snRNP formation, rendering the SMN complex accessible for other snRNAs to assemble Sm cores. Remarkably, a prevalent cancer-associated mutation in U1 snRNA near the U1C binding site not only disrupts Sm core assembly but also sequesters the SMN complex, inhibiting canonical snRNP formation. Our findings provide mechanistic insights into how snRNP-specific proteins regulate the SMN complex and suggest that U1 snRNA mutations in numerous cancers disrupt the SMN complex, leading to perturbation in various RNA metabolism pathways. HighlightsO_LIU1C facilitates the formation of Sm core not only on U1 snRNA but also on other snRNAs. C_LIO_LIU1C together with U1-70K promotes U1 snRNP formation, enabling the SMN complex to recruit Gemin5/other snRNAs complex. C_LIO_LIThe divalent binding of U1C to the SMN complex is mediated by U1Cs N-terminus helix, interacting with U1-70K, and its arginine-methylated C-terminus domain, binding to the SMN protein. C_LIO_LIMultiple U1 snRNA mutations in cancer patients defect in Sm core assembly and potentially sequester the SMN complex, thereby inhibiting canonical snRNP formation. C_LI

biochemistry↗

bioRxiv2024

A unified model of hippocampal spatial and object cells involving bidirectionally coupled Lateral and Medial Entorhinal Cortical layers

Popularly referred to as the GPS of the brain, the hippocampus has a variety of neurons that encode spatial properties of the environment. These spatial cells of the hippocampus may be broadly placed under two categories - those that encode spatial locations (e.g. place cells, grid cells etc) and those that encode spatial objects (eg. Object-sensitive cells. Object-trace cells etc). There are computational models that explain emergence of specific types of spatial cells, but it is challenging to construct integrative models that can demonstrate the emergence of the complete range of spatial cells both space and object type. We present a simple, unified computational model that explains the emergence of a wide variety of object- and spatially-sensitive neurons in the hippocampus. The model is essentially a deep neural network that combines visual and path integration information. The visual information is received by a part of the model that is analogous to Lateral Entorhinal Cortex (LEC) and path integration information is received by a layer analogous to Medial Entorhinal Cortex (MEC). In order to arrive at a consistent estimate of position, LEC and MEC in the model are connected laterally using a Graph Neural Network. The model is trained to predict position, orientation and reward of a simulated agent. The agent explores a box-like environment with colored walls and objects on the floor and is rewarded based on its encounters with objects. The model demonstrates the emergence of the following 7 types of spatial and object cells - place, grid, border, object, object-sensitive, object-vector and, object-trace cells. The model findings compare favorably with a large body of experimental literature on hippocampal spatial cells.

neuroscience↗

bioRxiv2024

High Throughput Screening with a Primary Human Mucociliary Airway Model Identifies a Small Molecule with Anti-SARS-CoV-2 Activity

Respiratory viruses (e.g. influenza, RSV, SARS etc.) attack the proximal airway and cause a wide spectrum of diseases for which we have limited therapies. To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. Here we present a microscale, primary human stem cell-based proximal airway model of SARS-CoV-2 infection, which is amenable to moderate-to-high throughput drug screening. The model recapitulates the heterogeneity of infection seen among different patients and with different SARS-CoV-2 variants. We applied this model to screen 2100 compounds from targeted drug libraries using an image-based quantification method. While there were heterogeneous responses across variants for host factor targeting compounds, the direct acting antivirals showed a consistent response and we characterized a new antiviral drug that is effective against both the parental strain and the Omicron variant.

cell biology↗

bioRxiv2024

A conserved lysine/arginine-rich motif in potyviral 6K1 protein is key in engaging autophagy-mediated self-degradation for completing pepper veinal mottle virus infection

Potyviruses possess one positive-sense single-stranded RNA genome mainly with polyprotein processing as their gene expression strategy. The resulting polyproteins are proteolytically processed by three virus-encoded proteases into 11 or 12 mature proteins. One of such, 6-kDa peptide 1 (6K1), is an understudied viral factor. Its function in viral infection remains largely mysterious. This study is to reveal part of its roles by using pepper veinal mottle virus (PVMV) as a model virus. Alanine substitution screening analysis revealed that 15 out of 17 conserved residues across potyviral 6K1 sequences are essential for PVMV infection. However, 6K1 protein is less accumulated in virus-infected cells, even though P3-6K1 junction is efficiently processed by NIa-Pro for its release, indicating that 6K1 undergoes a self-degradation event. Mutating the cleavage site to prevent NIa-Pro processing abolishes viral infection, suggesting that the generation of 6K1 along with its degradation might be important for viral multiplication. We corroborated that cellular autophagy is engaged in 6K1s degradation. Individual engineering of the 15 6K1 variants into PVMV was performed to allow for their expression along with viral infection. Five of such variants, D30A, V32A, K34A, L36A, and L39A, significantly interfere with viral infection. The five residues are enclosed in a conserved lysine/arginine-rich motif; four of them appear to be crucial in engaging autophagy-mediated self-degradation. Based on these data, we envisaged a scenario that potyviral 6K1s interact with an unknown anti-viral component to be co-degraded by autophagy to promote viral infection. IMPORTANCEPotyvirus is the largest genus of plant-infecting RNA viruses, which encompasses socio-economically important virus species, such as Potato virus Y, Plum pox virus, and Soybean mosaic virus. Like all picorna-like viruses, potyviruses express their factors mainly via polyprotein processing. Theoretically, viral factors P3 through CP, including 6K1, should share an equivalent number of molecules. The 6K1 is small in size ([~]6 kDa) and conserved across potyviruses, but less accumulated in virus-infected cells. This study demonstrates that cellular autophagy is engaged in the degradation of 6K1 to promote viral infection. In particular, we found a conserved lysine/arginine-rich motif in 6K1s across potyviruses that is engaged in this degradation event. This finding reveals one facet of a small protein that help understand the pro-viral role of cellular autophagy in viral infection.

microbiology↗

bioRxiv2024

Investigating the Structural Impact and Conformational Dynamics of a Sequence Variant (c.242G>A) in TMIE Gene Provoking Usher Syndrome

Usher syndrome (USH) is a retinal autosomal recessive genetic disorder, characterized by congenital severe-to-profound sensorineural hearing loss, retinitis pigmentosa (RP), and rarely vestibular dysfunction. A transmembrane inner ear gene TMIE causing autosomal recessive usher syndrome hearing loss, which may open up interesting perspectives into the function of this protein in inner ear. This disease is linked with mutations in TMIE gene. In this study delineates the pathogenic association, miss-fold aggregation, and conformational paradigm of a missense variant (c.242G>A) resulting into (p.Arg81His) in TMIE gene segregating usher syndrome through a molecular dynamics simulations approach. The transmembrane inner ear expressed protein assumes a critical role as its helices actively engage in binding with specific target DNA base pairs. The alteration observed in the mutant protein, characterized by an outward repositioning of the proximal helical portion, which is attributed to the absence of preceding beta-hairpins in the C-terminal region. This structural modification results in the loss of hydrogen bonds, exposure of hydrophobic residues to the solvent, and a consequential transformation of helices into loops, ultimately leading to functional impairment in the TMIE protein. These notable modifications in the stability and conformation of the mutant protein were verified through essential dynamics analysis, revealing that a point mutation induces distinct overall motions and correlations between proteins, ultimately resulting in usher syndrome. The current study provides insilico evidences of Usher syndrome hearing loss disease as protein folding disorder. The energy calculation also revealed that there is a difference of -251.211Kj/mol which also indicates that the SNP has significantly decreased the stability of protein consequently folding into Usher syndrome. This study contributes molecular insights into the structural correlation between the TMIE protein and usher syndrome. The docking analysis highlight various interaction between wild and mutant structure emphasizing key residues involved in hydrogen and hydrophobic interaction.

bioinformatics↗

bioRxiv2024

Mutating the arginine residue within the FRNK motif of HC-Pro yield highly attenuated strains that confer complete cross protection against telosma mosaic virus (TelMV) in passion fruit (Passiflora edulis)

Telosma mosaic virus (TelMV, Potyvirus, Potyviridae) is an emerging viral pathogen causing a major global threat to passion fruit plantations. However, an efficient strategy for controlling such viruses is not yet available. Cross protection is a phenomenon in which pre-infection of a plant with one virus prevents or delays superinfection with the same or closely related virus. HC-Pro is the potyviral encoded multifunctional protein involved in several steps of viral infection, including multiplication, movement, transmission and RNA silencing suppression. The main hypothesis we tested in this study was whether it is possible to generate attenuated viral strains capable of conferring protection against severe TelMV infection by manipulating the HC-Pro gene. By introducing point mutation into the potyviral conserved motif FRNK of HC-Pro, we have successfully obtained three highly attenuated mutants of TelMV (R181K, R181D and R181E, respectively) that can systemically infect passion fruit plants without any noticeable symptoms. Importantly, these mutants confer complete protection against subsequent infection of severe recombinant virus TelMV-GFP, evidenced by no detection of viral RNA or protein of the superinfection virus in the systemic leaves of passion fruit plants in both early and late stages. Lastly, we demonstrated that the HC-Pros harbored by the highly attenuated mutants exhibited reduced RNA silencing suppression activity in Nicotiana benthamiana leaves. Altogether, this study provides the first demonstration of the generation of highly attenuated strains for TelMV and highlights key amino acid residue involved in complete cross protection against TelMV, opening a new avenue to fight TelMV in the field.

pathology↗

bioRxiv2023

Visual activity enhances neuronal excitability in thalamic relay neurons

The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a basic relay for visual information travelling from the retina to cortical areas, but recent findings suggest a largely underestimated functional plasticity of dLGN neurons. However, the cellular mechanisms supporting this functional plasticity have not been yet explored. In particular, it remains to elucidate whether intrinsic neuronal excitability change upon visual stimuli. We show here that monocular deprivation for 10 days reduces the intrinsic excitability of dorsal LGN relay cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 Hz or when spikes are induced with direct somatic current injection to reproduce patterns of retinal activity. LTP-IE is observed after eye opening and requires calcium influx mediated by L-type calcium channels. It involves activation of PKA and is expressed through the down-regulation of Kv1 potassium channels. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN relay cells, thus further pointing the role of thalamic neurons in activity-dependent visual plasticity and amblyopia.

neuroscience↗

bioRxiv2022

A simplified, amplicon-based method for whole genome sequencing of human respiratory syncytial viruses

Human Respiratory Syncytial Virus (RSV) infections pose a significant risk to human health worldwide, especially for young children. Whole genome sequencing (WGS) provides a useful tool for global surveillance to better understand the evolution and epidemiology of RSV and provide essential information that may impact on antibody treatments, antiviral drug sensitivity and vaccine effectiveness. Here we report the development of a rapid and simplified amplicon-based one-step multiplex reverse-transcription polymerase chain reaction (mRT-PCR) for WGS of both human RSV-A and RSV-B viruses. The method requires only two reactions for each sample, which significantly reduces the cost and time compared to other commonly used RSV WGS methods. In silico analysis and laboratory testing revealed that the primers used in the new method covered most of the currently circulating RSV-A and RSV-B. Amplicons generated were suitable for both Illumina and Oxford Nanopore Technologies (ONT) NGS platforms. This new method was tested on 200 clinical samples collected in Australia in 2020 and 2021 with RSV Ct values between 10 and 32. A success rate of 88% with a full coverage for the genome of 99 RSV-A and 77 RSV-B was achieved. This assay is simple to set up, robust, easily scalable in sample preparation and relatively inexpensive, and as such, provides a valuable addition to existing NGS RSV WGS methods.

genomics↗

bioRxiv2022

Modeling Hippocampal Spatial Cells in Rodents navigating in 3D environments

Studies on the neural correlates of navigation in 3D environments are plagued by several unresolved issues. For example, experimental studies show markedly different place cell responses in rats and bats, both navigating in 3D environments. In an effort to understand this divergence, we propose a deep autoencoder network to model the place cells and grid cells in a simulated agent navigating in a 3D environment. We also explore the possibility of a vital role that Head Direction (HD) tuning plays in determining the isotropic or anisotropic nature of the observed place fields in different species. The input layer to the autoencoder network model is the HD layer which encodes the agents HD in terms of azimuth ({theta}) and pitch angles ({phi}). The output of this layer is given as input to the Path Integration (PI) layer, which integrates velocity information into the phase of oscillating neural activity. The output of the PI layer is modulated and passed through a low pass filter to make it purely a function of space before passing it to an autoencoder. The bottleneck layer of the autoencoder model encodes the spatial cell like responses. Both grid cell and place cell like responses are observed. The proposed model is verified using two experimental studies with two 3D environments in each. This model paves the way for a holistic approach of using deep networks to model spatial cells in 3D navigation.

neuroscience↗

bioRxiv2022

Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

Current concepts regarding the biology of aging are based on studies aimed at identifying factors regulating natural lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific sets of pathologies, rather than by general physiological decline. Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans. We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging. HighlightsO_LIPhenotyping at scale defines lifetime trajectories of age-dependent changes in C57BL/6J mice C_LIO_LICentral genetic and environmental lifespan regulators (putative anti-aging interventions; PAAIs) influence age-sensitive phenotypes (ASPs) often long before the appearance of age-dependent changes in these ASPs C_LIO_LICorresponding genetic variants in humans also have age-independent effects C_LIO_LIMany PAAI effects shift the baseline of ASPs rather than slowing their rate of change C_LI

physiology↗