Exploration of genome organization and function in the HIV infected brain is critical to aid in the understanding and development of treatments for HIV-associated neurocognitive disorder (HAND). Here, we applied a multiomic approach, including single nuclei transcriptomics, cell-type specific Hi-C 3D genome mapping, and viral integration site sequencing (IS-seq) to frontal lobe tissue from HIV-infected individuals with encephalitis (HIVE) and without encephalitis (HIV+). We observed reorganization of open/repressive (A/B) compartment structures in HIVE microglia encompassing 6.4% of the genome with enrichment for regions containing interferon (IFN) pathway genes. 3D genome remodeling was associated with transcriptomic reprogramming, including down-regulation of cell adhesion and synapse-related functions and robust activation of IFN signaling and cell migratory pathways, and was recapitulated by IFN-g stimulation of cultured microglial cells. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 integration sites in the brain that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Viral transcription, which was detected in 0.003% of all nuclei in HIVE brain, occurred in a subset of highly activated microglia that drove differential expression in HIVE. Thus, we observed a dynamic interrelationship of interferon-associated 3D genome and transcriptome remodeling with HIV integration and transcription in the brain.

After more than 4 million deaths worldwide, the ongoing vaccination to conquer the COVID-19 disease is now competing with the emergence of increasingly contagious mutations, repeatedly supplanting earlier strains. Following the near-absence of historical examples of the long-time evolution of infectious diseases under similar circumstances, models are crucial to exemplify possible scenarios. Accordingly, in the present work we systematically generalize the popular susceptible-infected-recovered model to account for mutations leading to repeatedly occurring new strains, which we coarse grain based on tools from statistical mechanics to derive a model predicting the most likely outcomes. The model predicts that mutations can induce a super exponential growth of infection numbers at early times, which self-amplify to giant infection waves which are caused by a positive feedback loop between infection numbers and mutations and lead to a simultaneous infection of the majority of the population. At later stages -- if vaccination progresses too slowly -- mutations can interrupt an ongoing decrease of infection numbers and can cause infection revivals which occur as single waves or even as whole wave trains featuring alternative periods of decreasing and increasing infection numbers. Our results might be useful for discussions regarding the importance of a release of vaccine-patents to reduce the risk of mutation-induced infection revivals but also to coordinate the release of measures following a downwards trend of infection numbers.

COVID-19 non-pharmaceutical intervention (NPI) policies have been one of the most important and contentious decisions of our time. Beyond even the "normal" inherent difficulties in impact evaluation with observational data, COVID-19 NPI policy evaluation is complicated by additional challenges related to infectious disease dynamics and lags, lack of direct observation of key outcomes, and a multiplicity of interventions occurring on an accelerated time scale. Randomized controlled trials also suffer from what is feasible and ethical to randomize as well as the sheer scale, scope, time, and resources required for an NPI trial to be informative (or at least not misinformative). In this talk, Dr. Haber will discuss the challenges in generating useful evidence for COVID-19 NPIs, the landscape of the literature, and highlight key controversies in several high profile studies over the course of the pandemic. Chasing after unknowables poses major problems for the metascience/replicability movement, institutional research science, and decision makers. If the only choices for informing an important topic are "weak study design" vs "do nothing," when is "do nothing" the best choice?

Repeat-rich sequence blocks are considered major determinants for 3D folding and structural genome organization in the cell nucleus in all higher eukaryotes. Here, we discuss how megabase-scale chromatin domain and chromosomal compartment organization in adult mouse cerebral cortex is linked, in highly cell type-specific fashion, to multiple retrotransposon superfamilies which comprise the vast majority of mobile DNA elements in the murine genome. We show that neuronal megadomain architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, unleashes proviruses from the Long Terminal Repeat (LTR) Endogenous Retrovirus family that exhibit strong tropism in mature neurons. Furthermore, we mapped, in the human brain, cell type-specific genomic integration patterns of the human pathogen and exogenous retrovirus, HIV, together with changes in genome organization and function of the HIV infected brain. Our work highlights the critical importance of chromosomal conformations and the ‘spatial genome’ for neuron- and glia-specific regulatory mechanisms and defenses aimed at exogenous and endogenous retrotransposons in the brain

The main transmission mode of the COVID-19 disease is through virus-laden aerosols and droplets generated by expiratory events, such as breathing and sneezing. Patients with respiratory diseases are typically treated with oxygenation devices in hospitals, homes, and other settings where they increase the risk of spreading the disease to caregivers and first responders. Here, I will discuss a systematic study of aerosol and droplet dispersal through the air and their final deposition on surfaces. Through laser and fluorescent imaging techniques, we measure the volumetric spatial-temporal dynamics of droplet dispersal while varying rheological properties of the mucosaliva. We then demonstrate that a standard nose and mouth mask reduces the amount of mucosaliva dispersed by a factor of at least a hundred. Our ongoing collaborations with doctors and respiratory therapists from the Baystate Medical Hospital are developing new guidelines to help mitigate disease spread in a hospital setting.

We made a low-cost centrifuge that can be useful for carrying out low-cost LAMP based detection of SARS-Cov2 virus in saliva. The 3D printed centrifuge (Mobilefuge) is portable, robust, stable, safe, easy to build and operate. The Mobilefuge doesn’t require soldering or programming skills and can be built without any specialised equipment, yet practical enough for high throughput use. More importantly, Mobilefuge can be powered from widely available USB ports, including mobile phones and associated power supplies. This allows the Mobilefuge to be used even in off-grid and resource limited settings. Website: https://www.cappa.ie/chinna-devarapu/

The vIRt nucleus in the medulla, composed of mainly inhibitory neurons, is necessary for whisking rhythm generation. It innervates motoneurons in the facial nucleus (FN) that project to intrinsic vibrissa muscles. The nearby pre-Bötzinger complex (pBötC), which generates inhalation, sends inhibitory inputs to the vIRt nucleus which contribute to the synchronization of vIRt neurons. Lower-amplitude periodic whisking, however, can occur after decay of the pBötC signal. To explain how vIRt network generates these “intervening” whisks by bursting in synchrony, and how pBötC input induces strong whisks, we construct and analyze a conductance-based (CB) model of the vIRt circuit composed of hypothetical two groups, vIRtr and vIRtp, of bursting inhibitory neurons with spike-frequency adaptation currents and constant external inputs. The CB model is reduced to a rate model to enable analytical treatment. We find, analytically and computationally, that without pBötC input, periodic bursting states occur within a certain ranges of network connectivities. Whisk amplitudes increase with the level constant external input to the vIRT. With pBötC inhibition intact, the amplitude of the first whisk in a breathing cycle is larger than the intervening whisks for large pBötC input and small inhibitory coupling between the vIRT sub-populations. The pBötC input advances the next whisk and shortens its amplitude if it arrives at the beginning of the whisking cycle generated by the vIRT, and delays the next whisks if it arrives at the end of that cycle. Our theory provides a mechanism for whisking generation and reveals how whisking frequency and amplitude are controlled.

Biomolecular condensation is a mechanism for controlling cell organization. Many condensates are rich in nuclei acids such as RNA. The role of specific RNA sequences and structures in promoting the molecular identity of condensates formed for cell polarity and division and by the SARS CoV-2 virus will be discussed.

The SARS-CoV-2 pandemic is awash in data, including daily, spatially-resolved COVID case data, virus sequence data, patients `omics data, and mobility data. Journals are now also awash in studies that make use of quantitative modeling approaches to gain insight into the geographic spread of SARS-CoV-2 and its temporal dynamics, as well as studies that predict the impact of control strategies on SARS-CoV-2 circulation. Some, but by no means all, of these studies are informed by the massive amounts of available data. Some, but by no means all, of these studies have been useful — in that their predictions revealed something beyond simple back of the envelope calculations. To summarize some of these findings, in this symposium, we will address questions such as: What do we want from models of disease spread? What can and should be predicted? Which data are the most useful for predictions? When do we need mechanistic models? What have we learned about how to model disease spread from unmet and/or conflicting predictions? The workshop speakers will explore these questions from different perspectives on what data need to be considered and how models can be evaluated. As at other TMLS workshops, each speaker will deliver a 10-minute talk with ample time set aside for moderated questions/discussion. We expect the talks to be provocative and bold, while respecting different perspectives.

Much of the science underpinning the global response to the COVID-19 pandemic lies in the soft matter domain. Coronaviruses are composite particles with a core of nucleic acids complexed to proteins surrounded by a protein-studded lipid bilayer shell. A dominant route for transmission is via air-borne aerosols and droplets. Viral interaction with polymeric body fluids, particularly mucus, and cell membranes controls their infectivity, while their interaction with skin and artificial surfaces underpins cleaning and disinfection and the efficacy of masks and other personal protective equipment. The global response to COVID-19 has highlighted gaps in the soft matter knowledge base. I will survey these gaps, especially as pertaining to the transmission of the disease, and suggest questions that can (and need to) be tackled, both in response to COVID-19 and to better prepare for future viral pandemics.

Adolescence is a period of life characterised by heightened sensitivity to social stimuli, an increased need for peer interaction and peer acceptance, and development of the social brain. Lockdown and social distancing measures intended to mitigate the spread of COVID-19 are reducing the opportunity to engage in face-to-face social interaction with peers. The consequences of social distancing on human social brain and social cognitive development are unknown, but animal research has shown that social deprivation and isolation have unique effects on brain and behaviour in adolescence compared with other stages of life. It is possible that social distancing might have a disproportionate effect on an age group for whom peer interaction is a vital aspect of development.

The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain and mediates various forms of synaptic plasticity. We recently discovered that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestral to retroviruses such as HIV. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system that may underlie cognition and memory.

COVID -19 has affected social interaction and healthcare worldwide. This talk will focus on the impact of the pandemic and “lockdown” on mental health services, community physical health services, and patient mortality in Cambridgeshire and Peterborough, based on the analysis of de-identified data from the primary NHS provider of secondary care mental health services to this population (~0.86 million)

The SARS-CoV-2 virus has rapidly evolved into a pandemic that is threatening public health, economics, and quality of life worldwide. The gold-standard for testing individuals for COVID-19 is using traditional RT-qPCR, which is expensive and can take up to several hours. Expanding surveillance across a global scale will call for new strategies and tests that are inexpensive, require minimal reagents, decrease assay time, and allow for simple point-of-care (POC) monitoring without need of trained personnel and with quick turnaround time. To expand the speed of COVID-19 surveillance, we are working on a point-of-care microfluidic chip to enable significantly faster and easier testing. This is based upon digital drop loop-mediated isothermal amplification that will allow for rapid testing of large populations at a reasonable cost. The device will employ a nucleic-acid based test called reverse transcriptase LAMP (RT- LAMP) that operates at a temperature of 60-65°C. RT-LAMP removes the bottleneck of thermal cycling and high temperatures required by traditional RT-qPCR thermocycling. The simplicity, speed, and sensitivity will enable early treatment and response to infection.

This seminar is part of our “Emergent Scientists” series, an initiative that provides a platform for scientists at the critical PhD/postdoc transition period to share their work with a broad audience and network. Summary: These talks cover Alzheimer’s disease (AD) research in both mice and humans. Christiana will discuss in particular the translational aspects of applying mouse work to humans and the importance of timing in disease pathology and intervention (e.g. timing between AD biomarkers vs. symptom onset, timing of therapy, etc.). Siddharth will discuss a rare variant of Alzheimer’s disease called “Logopenic Progressive Aphasia”, which presents with temporo-parietal atrophy yet relative sparing of hippocampal circuitry. Siddharth will discuss how, despite the unusual anatomical basis underlying this AD variant, degeneration of the angular gyrus in the left inferior parietal lobule contributes to memory deficits similar to those of typical amnesic Alzheimer’s disease. Christiana’s abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that causes severe deterioration of memory, cognition, behavior, and the ability to perform daily activities. The disease is characterized by the accumulation of two proteins in fibrillar form; Amyloid-β forms fibrils that accumulate as extracellular plaques while tau fibrils form intracellular tangles. Here we aim to translate findings from a commonly used AD mouse model to AD patients. Here we initiate and chronically inhibit neuropathology in lateral entorhinal cortex (LEC) layer two neurons in an AD mouse model. This is achieved by over-expressing P301L tau virally and chronically activating hM4Di DREADDs intracranially using the ligand dechloroclozapine. Biomarkers in cerebrospinal fluid (CSF) is measured longitudinally in the model using microdialysis, and we use this same system to intracranially administer drugs aimed at halting AD-related neuropathology. The models are additionally tested in a novel contextual memory task. Preliminary findings indicate that viral injections of P301L tau into LEC layer two reveal direct projections between this region and the outer molecular layer of dentate gyrus and the rest of hippocampus. Additionally, phosphorylated tau co-localize with ‘starter cells’ and appear to spread from the injection site. Preliminary microdialysis results suggest that the concentrations of CSF amyloid-β and tau proteins mirror changes observed along the disease cascade in patients. The disease-modifying drugs appear to halt neuropathological development in this preclincial model. These findings will lead to a novel platform for translational AD research, linking the extensive research done in rodents to clinical applications. Siddharth’s abstract: A distributed brain network supports our ability to remember past events. The parietal cortex is a critical member of this network, yet, its exact contributions to episodic remembering remain unclear. Neurodegenerative syndromes affecting the posterior neocortex offer a unique opportunity to understand the importance and role of parietal regions to episodic memory. In this talk, I introduce and explore the rare neurodegenerative syndrome of Logopenic Progressive Aphasia (LPA), an aphasic variant of Alzheimer’s disease presenting with early, left-lateralized temporo-parietal atrophy, amidst relatively spared hippocampal integrity. I then discuss two key studies from my recent Ph.D. work showcasing pervasive episodic and autobiographical memory dysfunction in LPA, to a level comparable to typical, amnesic Alzheimer’s disease. Using multimodal neuroimaging, I demonstrate how degeneration of the angular gyrus in the left inferior parietal lobule, and its structural connections to the hippocampus, contribute to amnesic profiles in this syndrome. I finally evaluate these findings in the context of memory profiles in other posterior cortical neurodegenerative syndromes as well as recent theoretical models underscoring the importance of the parietal cortex in the integration and representation of episodic contextual information.

Chemotherapeutic drugs (used for treating cancer), HIV infection and antiretroviral therapy (ART) can independently cause difficult-to-manage painful neuropathy. Paclitaxel, a chemotherapeutic drug, for example is associated with high incidence of peripheral neuropathy, around 71% of the patients of which 27% of these develop neuropathic pain. Use of cannabis or phytocannabinoids has been reported to improve pain measures in patients with neuropathic pain, including painful HIV-associated sensory neuropathy and cancer pain. Phytocannabinoids and endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), produce their effects via cannabinoid (CB) receptors, which are present both in the periphery and central nervous system. Endocannabinoids are synthesized in an “on demand” fashion and are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Various studies, including those from our group, suggest that there are changes in gene and protein expression of endocannabinoid molecules during chemotherapy-induced neuropathic pain (CINP), HIV and antiretroviral-induced neuropathic pain. Analysis of endocannabinoid molecule expression in the brain, spinal cord and paw skin using LC-MS/MS show that there is a specific deficiency of the endocannabinoids 2-AG and/or anandamide in the periphery during CINP. Various drugs including endocannabinoids, cannabidiol, inhibitors of FAAH and MGL, CB receptor agonists, desipramine and coadministered indomethacin plus minocycline have been found to either prevent the development and/or attenuate established CINP, HIV and antiretroviral-induced neuropathic pain in a CB receptor-dependent manner. The results available suggest that targeting the endocannabinoid system for prevention and treatment of CINP, HIV-associated neuropathic pain and antiretroviral-induced neuropathic pain is a plausible therapeutic option.

Recently a powerful example of a replicating nano-machine entered our society. In principle, it’s just a normal disease, that one attempts to model with 3 or 4 simple coupled equations with 2 important parameters: a timescale, and a replication factor (the famous R0). Then one tries to guess how changes in society change R0 and perhaps adopt some more or less strong lock-down measures. However, this virus has more “personality” than that. It behaves differently in different persons, and persons behave differently. Presumably, only a few of us infect a lot, while most do not infect so much. This assumption is supported by the observation that couples living together only infect each other with about 15 percent probability, indicating that most infected people are not really infectious. I will discuss this and other aspects of Covid-19 in the perspective of models that describe heterogeneous individuals in a society. In particular, we suggest that limiting superspreading opportunities is a cost-effective strategy to mitigate Covid-19.