Neeraj Soni

Tsetse flies locate vertebrate hosts largely by smell, and odor-baited devices are central to tsetse and trypanosomiasis control. A published electrophysiological survey of the Glossina morsitans antenna defined seven classes of olfactory sensilla, but descriptive clustering cannot reveal how much information these classes carry or which odors they distinguish. We reanalyzed responses of 182 sensilla to 16–17 odorants using Fisher–Rao information geometry, bias-corrected mutual information, Bayesian decoding, and signal detection theory. In the fruit fly Drosophila melanogaster , trichoid sensilla are largely dedicated to pheromones. In tsetse, the three trichoid classes carried more information about odor identity than the four basiconic classes (1.92 vs. 1.14 bits, of a possible 4), a difference of 0.78 bits (95% confidence interval 0.44–1.10), and were strongly excited by the host attractant 1-octen-3-ol. Adding trichoid to basiconic sensilla raised decoding accuracy from 32% to 70% (23% to 55% for decoders tested on held-out sensilla) and identified 1-octen-3-ol on 98% of trials (92% held out). The basiconic code was nearly one-dimensional (participation ratio 1.71), organized along an axis of response strength with 1-octen-3-ol at its extreme. The CO ₂ -sensitive ab4 class was the most sensitive detector for 11 of 16 odorants, whereas ab2 carried no detectable odor information. Classes shared up to 0.41 bits of their information with one another, an overlap only weakly predicted by the similarity of their mean tuning. On a shared odor panel, Drosophila receptors carried twice the information per channel and, with channel number matched, spanned about 1.5-fold more dimensions. These conclusions held in simulations at the real sample sizes, under alternative noise models, and when classes were defined on independent odorants. The tsetse antenna thus combines redundant, detection-oriented basiconic channels with trichoid sensilla that carry host-odor identity, principles relevant to the design of odor baits. Author summary: Tsetse flies spread sleeping sickness in people and a related wasting disease in cattle, and they find the animals they bite largely by smell. Traps and targets baited with odors are among the most effective tools for controlling these flies, so knowing what the fly’s nose can and cannot tell apart could help us design better baits. Several years ago we recorded how the different smell-sensing hairs on the tsetse antenna respond to a panel of odors. Here we returned to those recordings with a different question: not which hairs respond to which odors, but how much information each type of hair actually carries about which odor is present. Using tools from information theory, we found that one type of hair, which in the fruit fly serves mainly to detect the scents of other flies, carries most of the tsetse antenna’s information about the identity of host odors, including the classic tsetse attractant 1-octen-3-ol. The other hair types act mainly as sensitive alarms that signal that a host odor is present. These results suggest which sensory channels odor baits should be designed to engage.

Antiseizure medications, such as levetiracetam, are commonly used in glioma patients. Retrospective analyses evaluating effects of antiseizure medications on glioma patient survival have yielded inconsistent results, probably due to confounding factors of glioma subtype and drug class. Here we present retrospective real-world clinical data that demonstrate longer overall survival for children with diffuse midline glioma (DMG) who were taking levetiracetam, which was not evident in pediatric patients with hemispheric high-grade glioma. In preclinical models, levetiracetam reduces glioma proliferation and tumor burden, extending survival of mice bearing DMG orthotopic xenografts. These beneficial effects were not found in hemispheric high-grade glioma patient-derived orthotopic xenograft models. The subtype-specificity of this antiproliferative effect of levetiracetam is congruent with recent findings that GABAergic neuron-to-glioma synapses promote glioma growth in DMG but not hemispheric high-grade glioma. We demonstrate here that levetiracetam attenuates low-frequency GABAergic synaptic transmission in a glioma-specific manner, reducing GABAergic synaptic currents in DMG but not in healthy neurons. This effect is independent of action on SV2A, the chief mechanism by which levetiracetam functions to prevent and treat seizures. Taken together, these findings indicate a promising approach to target GABAergic synapses in DMG and suggest that use of levetiracetam in DMG should be further studied in future prospective clinical studies.

Glioblastoma (GBM), a high-grade glioma, is the most common primary brain tumor in adults, with a dismal prognosis and a very high recurrence rate. Major challenges to effective treatment arise from the tumor’s locally aggressive, diffusely infiltrative nature and extensive intratumoral heterogeneity. Recent advances in cancer neuroscience have uncovered bidirectional neuron-glioma interactions including the formation of functional neuron-glioma synapses (NGS). Neuronal activity drives tumor growth and its synaptic integration into neural circuits; tumor-induced circuit remodeling reciprocally influences neural activity. In parallel, emerging evidence implicates the immunological synapse- a dynamic interface between T cells and antigen-presenting cells analogous to its neural counterpart- as a key driver of GBM pathogenesis and progression. The tumor microenvironment (TME) in GBM is characterized by local immunosuppression, immune evasion, and resistance to immunotherapy. Notably, neural and immune synapses share fundamental architectural and functional principles–spatial confinement of signaling, receptor clustering and adhesion-mediated stabilization, directional information transfer, and use-dependent plasticity–and an expanding catalog of molecular hubs operates across both interfaces. In this context, glioblastoma can be reconceptualized as a disease of coupled neural and immune synaptic networks cooperating to drive tumor progression. Therapeutic strategies targeting these hubs may offer advantages over current approaches by simultaneously disrupting tumor-promoting neuronal input and enhancing antitumor immunity, providing a “double hit” with the potential to dismantle the network architecture sustaining tumor growth and resilience.

High-grade gliomas (HGGs) are the leading cause of brain cancer-related death. HGGs include clinically, anatomically and molecularly distinct subtypes that stratify into diffuse midline gliomas (DMGs), such as H3K27M-altered diffuse intrinsic pontine glioma, and hemispheric HGGs, such as IDH wild-type glioblastoma. Neuronal activity drives glioma progression through paracrine signalling^1,2 and neuron-to-glioma synapses^3–6. Glutamatergic AMPA receptor-dependent synapses between neurons and glioma cells have been demonstrated in paediatric³ and adult⁴ high-grade gliomas, and early work has suggested heterogeneous glioma GABAergic responses⁷. However, neuron-to-glioma synapses mediated by neurotransmitters other than glutamate remain understudied. Using whole-cell patch-clamp electrophysiology, in vivo optogenetics and patient-derived orthotopic xenograft models, we identified functional, tumour-promoting GABAergic neuron-to-glioma synapses mediated by GABA_A receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 chloride transporter function and consequently elevated intracellular chloride concentration in DMG malignant cells. As membrane depolarization increases glioma proliferation^3,6, we found that the activity of GABAergic interneurons promotes DMG proliferation in vivo. The benzodiazepine lorazepam enhances GABA-mediated signalling, increases glioma proliferation and growth, and shortens survival in DMG patient-derived orthotopic xenograft models. By contrast, only minimal depolarizing GABAergic currents were found in hemispheric HGGs and lorazepam did not influence the growth rate of hemispheric glioblastoma xenografts. Together, these findings uncover growth-promoting GABAergic synaptic communication between GABAergic neurons and H3K27M-altered DMG cells, underscoring a tumour subtype-specific mechanism of brain cancer neurophysiology.

The world is grappling with the coronavirus disease 2019 (COVID-19) pandemic, the causative agent of which is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 symptoms are similar to the common cold, including fever, sore throat, cough, muscle and chest pain, brain fog, dyspnoea, anosmia, ageusia, and headache. The manifestation of the disease can vary from being asymptomatic to severe life-threatening conditions warranting hospitalization and ventilation support. Furthermore, the emergence of mutecated variants of concern (VOCs) is paramount to the devastating effect of the pandemic. This highly contagious virus and its emergent variants challenge the available advanced viral diagnostic methods for high-accuracy testing with faster result yields. This review is to shed light on the natural history, pathology, molecular biology, and efficient diagnostic methods of COVID-19, detecting SARS-CoV-2 in collected samples. We reviewed the gold standard RT-qPCR method for COVID-19 diagnosis to confer a better understanding and application to combat the COVID-19 pandemic. This comprehensive review may further develop awareness about the management of the COVID-19 pandemic.

Significance: Almost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate ∼24-h oscillations in gene expression and control much of our behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of core clock proteins and genes over the circadian cycle and its critical role in circadian clock function. We show that Drosophila clock proteins are concentrated in a few discrete foci and that they play a key role in positioning the core clock genes close to the nuclear envelope precisely during the repression phase to control circadian rhythms. These studies provide fundamental insights into cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian rhythms.

Circadian clocks regulate ∼24 hour oscillations in gene expression, behavior, and physiology. While the molecular and neural mechanisms of circadian rhythms are well characterized, how cellular organization of clock components controls circadian clock regulation remains poorly understood. Here, we elucidate how clock proteins regulate circadian rhythms by controlling the spatiotemporal organization of clock genes. Using high-resolution live imaging techniques we demonstrate that Drosophila clock proteins are concentrated in a few discrete foci and are organized at the nuclear envelope; these results are in contrast to longstanding expectations that clock proteins are diffusely distributed in the nucleus. We also show that clock protein foci are highly dynamic and change in number, size, and localization over the circadian cycle. Further, we demonstrate that clock genes are positioned at the nuclear periphery by the clock proteins precisely during the circadian repression phase, suggesting that subnuclear localization of clock genes plays an important role in the control of rhythmic gene expression. Finally, we show that Lamin B receptor, a nuclear envelope protein, is required for peripheral localization of clock protein foci and clock genes and for normal circadian rhythms. These results reveal that clock proteins form dynamic nuclear foci and play a hitherto unexpected role in the subnuclear reorganization of clock genes to control circadian rhythms, identifying a novel mechanism of circadian regulation. Our results further suggest a new role for clock protein foci in the clustering of clock-regulated genes during the repression phase to control gene co-regulation and circadian rhythms. SIGNIFICANCE: Almost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate ∼24-hour oscillations in gene expression, behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of clock proteins and clock genes and its critical role in circadian clock function. We show, in contrast to current expectations, that clock proteins are concentrated in a few discrete, dynamic nuclear foci at the nuclear envelope during the repression phase. Further, we uncovered several unexpected features of clock protein foci, including their role in positioning the clock genes at the nuclear envelope precisely during the repression phase to enable circadian rhythms. These studies provide fundamental new insights into the cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian clocks.