Biology subjects

Tan, H.

Publications and source records attributed to Tan, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Background and AimsHexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell-type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis. Approach and ResultsWe found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models and, molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3{beta} to stabilize {beta}-catenin, leading to enhanced stemness of HCC cells. ConclusionsOverall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.

cancer biology↗

bioRxiv2024

Evoked Resonant Neural Activity Long-Term Dynamics can be Reproduced by a Computational Model with Vesicle Depletion

Subthalamic deep brain stimulation (DBS) robustly generates high-frequency oscillations known as evoked resonant neural activity (ERNA). Recently the importance of ERNA has been demonstrated through its ability to predict the optimal DBS contact in the subthalamic nucleus in patients with Parkinsons disease. However, the underlying mechanisms of ERNA are not well understood, and previous modelling efforts have not managed to reproduce the wealth of published data describing the dynamics of ERNA. Here, we therefore aim to present a minimal model capable of reproducing the characteristics of the slow ERNA dynamics published to date. We make biophysically-motivated modifications to the Kuramoto model and fit its parameters to the slow dynamics of ERNA obtained from data. We further validate the model against experimental data from Parkinsons disease patients by simulating variable stimulation and medication states, as well as the response of individual neurons. Our results demonstrate that it is possible to reproduce the slow dynamics of ERNA with a single neuronal population, and, crucially, with vesicle depletion as the key mechanism behind the ERNA frequency decay. We provide a series of predictions from the model that could be the subject of future studies for further validation. Author SummaryERNA is a high amplitude response to stimulation of deep brain structures, with a frequency over twice that of the frequency of stimulation. While the underlying mechanisms of ERNA are still unclear, recent findings have demonstrated its importance as the best indicator of which stimulation contact to select for DBS therapy in patients with Parkinsons disease. Previous modelling studies of ERNA focus on the immediate responses to stimulation (<200ms) and rely on interconnected neural structures and delays. Our work shows that the long-term (on the scale of one or more seconds) ERNA response to continuous stimulation can be modelled using a single neural structure. The proposed model also captures the long-term frequency and amplitude characteristics of ERNA with variable stimulation and medication paradigms. The key features of the model, in particular the depletion of vesicles carrying neurotransmitters between neurons by high-frequency stimulation, may provide insights into the underlying mechanisms of ERNA and inform future investigations into this neural response.

neuroscience↗

bioRxiv2024

AnnoView enables large-scale analysis, comparison, and visualization of microbial gene neighborhoods

The analysis and comparison of gene neighborhoods is a powerful approach for exploring microbial genome structure, function, and evolution. Although numerous tools exist for genome visualization and comparison, genome exploration across large genomic databases or user-generated datasets remains a challenge. Here, we introduce AnnoView, a web server designed for interactive exploration of gene neighborhoods across the bacterial and archaeal tree of life. Our server offers users the ability to identify, compare, and visualize gene neighborhoods of interest from 30,238 bacterial genomes and 1,672 archaeal genomes, through integration with the comprehensive GTDB and AnnoTree databases. Identified gene neighborhoods can be visualized using pre-computed functional annotations from different sources such as KEGG, Pfam, and TIGRFAM, or clustered based on similarity. Alternatively, users can upload and explore their own custom genomic datasets in GBK, GFF, or CSV format, or use AnnoView as a genome browser for relatively small genomes (e.g., viruses and plasmids). Ultimately, we anticipate that AnnoView will catalyze biological discovery by enabling user-friendly search, comparison, and visualization of genomic data. AnnoView is available at http://annoview.uwaterloo.ca

bioinformatics↗

bioRxiv2023

Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. In this study, we designed and synthesized 85 noncovalent PLpro inhibitors that bind to the newly discovered Val70Ub site and the known BL2 groove pocket. Potent compounds inhibited PLpro with inhibitory constant Ki values from 13.2 to 88.2 nM. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 {micro}M. Oral treatment with Jun12682 significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates. One-Sentence SummaryStructure-guided design of SARS-CoV-2 PLpro inhibitors with in vivo antiviral efficacy in a mouse model.

microbiology↗

bioRxiv2023

GTExome: Modeling commonly expressed missense mutations in the human genome

A web application, GTExome, is described that quickly identifies, classifies, and models missense mutations in commonly expressed human proteins. GTExome can be used to categorize genomic mutation data with tissue specific expression data from the Genotype-Tissue Expression (GTEx) project. Commonly expressed missense mutations in proteins from a wide range of tissue types can be selected and assessed for modeling suitability. Information about the consequences of each mutation is provided to the user including if disulfide bonds, hydrogen bonds, or salt bridges are broken, buried prolines introduced, buried charges are created or lost, charge is swapped, a buried glycine is replaced, or if the residue that would be removed is a proline in the cis configuration. Also, if the mutation site is in a binding pocket the number of pockets and their volumes are reported. The user can assess this information and then select from available experimental or computationally predicted structures of native proteins to create, visualize, and download a model of the mutated protein using Fast and Accurate Side-chain Protein Repacking (FASPR). For AlphaFold modeled proteins, confidence scores for native proteins are provided. Using this tool, we explored a set of 9,666 common missense mutations from a variety of tissues from GTEx and show that most mutations can be modeled using this tool to facilitate studies of proteinprotein and protein-drug interactions. The open-source tool is freely available at https://pharmacogenomics.clas.ucdenver.edu/gtexome/ Author SummaryGTExome greatly simplifies the process of studying the three-dimensional structures of proteins containing missense mutations that are critical to understanding human health. In contrast to current state-of-the-art methods, users with no external software or specialized training can rapidly produce three-dimensional structures of any possible mutation in nearly any protein in the human exome. Accomplishing this requires reliance on AlphaFold based structural models. We therefore compared the protein models created by GTExome where possible to known experimental structures. We find that by avoiding specific mutations, the majority of proteins are amenable to being modeled by GTExome with similar results to the direct use of AlphaFold.

bioinformatics↗

bioRxiv2023

Tuning the brakes: Modulatory role of transcranial random noise stimulation on inhibition

BackgroundEveryday decision-making requires the ability to flexibly modify and sometimes terminate our actions, such as avoiding a tempting slice of cake to hitting the brakes in an emergency. Neural oscillations, such as beta-band rhythms observed over the medial prefrontal cortex(mPFC), help regulate these context-dependent behaviours. However, how random noise stimulation would modulate neural rhythms and corresponding inhibitory behaviors remain understudied. ObjectivesTo target the mPFC using random noise stimulation and modulate neural activity underlying inhibitory behaviours. MethodsUsing a single-blinded within-subject design, fifteen participants received random noise or sham stimulation in a pseudo-randomized order while performing a Go/Conflict/No-Go task. We measured neural activity and behavior before and after stimulation. ResultsWe show that random noise stimulation significantly improved inhibitory behaviors (4.6{+/-}4.42percent) by reducing the number of errors in No-Go trials. This improvement was a function of participants impulsivity-levels and baseline performance, i.e., impulsive individuals who made more baseline errors improved more after receiving stimulation. At the neural level, we show that random noise stimulation increases low-beta power at stimulation site, mediated by an increase in the duration of intermittent beta-bursts. ConclusionWe show for the first time that random noise stimulation improves the ability to withhold response to unexpected inhibitory cues as a function of an individuals impulsivity level. This improvement could be attributed to increased low-beta band power and intermittent-burst duration. These results suggest that random noise stimulation of the mPFC could potentially be used as a neuromodulatory intervention to target maladaptive behaviors in impulse control disorders.

neuroscience↗

bioRxiv2023

Auditory cues modulate the short timescale dynamics of STN activity during stepping in Parkinson's disease

BackgroundGait impairment has a major impact on motor performance and quality of life in patients with Parkinsons disease (PD). The neurophysiological mechanisms of gait impairment remain poorly understood, meaning that treatment options are currently limited. It is believed that basal ganglia oscillatory activity at {beta} frequencies (15-30 Hz) may be a contributor to gait impairment in PD, but the precise dynamics of this oscillatory activity during gait remain unclear. Auditory cues are known to lead to improvements in gait kinematics in PD. If the neurophysiological mechanisms of this cueing effect were better understood they could be leveraged to treat gait impairments using brain-computer interface (BCI) technologies. ObjectiveWe aimed to characterize the dynamics of subthalamic nucleus (STN) oscillatory activity during stepping movements in PD and to establish the neurophysiological mechanisms by which auditory cues modulate gait. MethodsWe used local field potentials (LFPs) to study STN oscillatory activity in eight PD patients while stepping in place with auditory cueing. Hidden Markov Models (HMMs) were used to discover dynamic brain states that occurred pre-sound, on-sound, and post-sound cues. ResultsThe occurrence of {beta} bursts was suppressed during and after auditory cues. This manifested as a decrease in their fractional occupancy and state lifetimes. Interestingly, transients showed the opposite effect, with fractional occupancy and state lifetimes increasing during and after auditory cues. ConclusionsWe found transient oscillatory states in the STN LFP during stepping and showed that and {beta} oscillations are differentially modulated by auditory cues during stepping in PD.

neuroscience↗

bioRxiv2023

Neurophysiological Features of STN LFP underlying Sleep Fragmentation in Parkinson's Disease

BackgroundSleep fragmentation is a persistent problem throughout the course of Parkinsons disease (PD). However, the related neurophysiological patterns and the underlying mechanisms remained unclear. MethodWe recorded subthalamic nucleus (STN) local field potentials (LFPs) using DBS with real-time wireless recording capacity from thirteen PD patients undergoing a one-night polysomnography recording, one month after DBS surgery before initial programming and when the patients were Off-Medication. The STN LFP features that characterized different sleep stages, correlated with arousal and sleep fragmentation index, and preceded stage transitions during N2 and REM sleep were analyzed. ResultsBoth beta and low gamma oscillations in NREM sleep increased with the severity of sleep disturbance (arousal index (ArI)-betaNREM: r=0.9,p=0.0001) and sleep fragmentation index (SFI)-betaNREM: r=0.6,p=0.0301; SFI-gammaNREM: r=0.6,p=0.0324). We next examined the low-to-high power ratio, which was the power ratio of theta oscillations to beta and low gamma oscillations, and found it to be an indicator of sleep fragmentation (ArI-LHPRNREM: r=-0.8,p=0.0053; ArI-LHPRREM: r=-0.6,p=0.0373; SFI-LHPRNREM: r=-0.7,p=0.0204; SFI-LHPRREM: r=-0.6,p=0.0428). In addition, long beta bursts (>0.25s) during NREM stage 2 were found preceding the completion of transition to stages with more cortical activities (towards Wake/N1/REM compared with towards N3 (p<0.01)) and negatively correlated with STN spindles, which were detected in STN LFPs with peak frequency distinguishable from long beta bursts (STN spindle: 11.5Hz, STN long beta bursts: 23.8Hz), in occupation during NREM sleep ({beta} = -0.24,p<0.001). ConclusionFeatures of STN LFPs help explain neurophysiological mechanisms underlying sleep fragmentations in PD, which can inform new intervention for sleep dysfunction. What is already known on this topicBeta oscillation, which is a biomarker for rigidity and bradykinesia during awake, significantly reduced during NREM sleep compared to REM or awake. Researches from MPTP non-human primate model suggested increased beta oscillation in basal ganglia contributed to insomnia in PD, however evidence in human patients is still lacking. What this study addsBeta and low gamma band activities in STN LFPs during sleep recorded from human PD patients correlated with severity of sleep impairment. The low-high power ratio can serve as a biomarker for sleep fragmentation. Besides, pathological beta bursts and physiological sleep spindles can be detected in STN LFP during NREM sleep and distinguishable from each other. How this study might affect research, practice or policyThese findings enhance our understanding of the electrophysiological mechanisms that underlie sleep fragmentation in Parkinsons disease. The study also has implications on the design of closed-loop DBS: we may need to take multiple frequency band activities into consideration and differentiate pathological beta oscillation from the sleep spindles.

physiology↗

bioRxiv2023

Theranostic Bottle-Brush Polymers Tailored for Universal Solid-Tumour Targeting

Nanomedicines involving nanotechnologies and engineering of nanomaterials for medicines have shown great promise in diagnosis and treatment of diseases including cancers. A major hurdle that limits the successful clinical translation of nanomedicines, however, is how to overcome the cascaded biological barriers and improve the delivery efficacy towards the disease sites and minimize the toxicity against healthy tissues and cells. Here, we report a type of bottle-brush-like polymers systematically optimized in their chemical structures, sizes, and surface charges that lead to their outstanding pharmacokinetics and tumour-targeting performances in a variety of both subcutaneous and orthotopic tumour models. The potential mechanism has been studied by revealing the structure-activity relationship of these polymers in overcoming the biological barriers, including their avoidance by the immune system and deep tumour infiltration. Our study may offer insight for a rational design of highly efficient delivery platform of polymeric nanomedicines that could effectively overcome the cascaded biological barriers and thus lead to high tumour-targeting efficacy and low toxicity.

bioengineering↗

bioRxiv2023

SoMAS: Finding somatic mutations associated with alternative splicing in human cancers

Aberrant alternative splicing is prevalent in cancer and affects most cancer hallmarks involving proliferation, angiogenesis, and invasion. Somatic point mutations can exert their cancer-driving functions via splicing disruption. We propose "SoMAS" (Somatic Mutation associated with Alternative Splicing), an efficient computational pipeline based on principal component analysis techniques, to explore the role of somatic mutations in shaping the landscape of alternative splicing via both cis- and trans-acting mechanisms. Applying SoMAS to 33 cancer types consisting of 9,738 tumor samples in The Cancer Genome Atlas, we identified 908 somatically mutated genes significantly associated with altered isoform expression in three or more cancer types. These genes include many well-known oncogenes/suppressor genes, RNA binding protein and splicing factor genes with both biological and clinical significance. Many of our identified SoMAS genes were corroborated to affect gene splicing by independent cohorts and/or methodologies. With SoMAS, we for the first time demonstrate the potential network of somatic mutations associated with the overall splicing profiles of cancer transcriptomes, bridging the genetic and epigenetic regulation of human tumorigenesis in an innovative way.

cancer biology↗

bioRxiv2023

Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor

Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a "molecular glue" that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

cancer biology↗

bioRxiv2023

Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse

Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 (RRM2) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B. Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.

cancer biology↗

bioRxiv2023

The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis

Severe lower respiratory infection (sLRI) are a major cause of infant morbidity and mortality, and predispose to later chronic respiratory diseases such as asthma. Poor maternal diet during pregnancy is a risk factor for sLRI in the offspring. Here we demonstrate in mice that a maternal low-fibre diet (LFD) disrupts plasmacytoid and conventional dendritic cell (DC) hematopoiesis in the offspring, predisposing to sLRI and subsequent asthma. The LFD alters the composition of the maternal milk microbiome and assembling infant gut microbiome, ablating the induction of a developmental wave of the non-redundant DC growth factor Flt3L by neonatal intestinal epithelial cells. Therapy with a propionate-producing bacteria isolated from the milk of high-fibre diet-fed mothers, or supplementation with propionate, confers protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that regulates pDC hematopoiesis in early life and confers disease resistance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=51 SRC="FIGDIR/small/522516v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1a39990org.highwire.dtl.DTLVardef@1b6fe67org.highwire.dtl.DTLVardef@f8440dorg.highwire.dtl.DTLVardef@13bc67e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

A plant virus causes symptoms through the deployment of a host-mimicking protein domain to attract the insect vector

Viruses are obligate intracellular parasites with limited proteomes that heavily rely on the cell molecular machinery for their multiplication and spread. Plant viruses frequently cause symptoms through interference with host developmental programs. Despite the agricultural relevance of symptom development in virus-infected crops, the molecular mechanisms underlying these viral effects remain elusive. Here, we show that the symptoms triggered by tomato yellow leaf curl virus (TYLCV) depend on the physical interaction between the host-mimicking domain of a virus-encoded protein, C4, and a plant-specific family of RCC1-like domain-containing (RLD) proteins. C4 outcompetes endogenous interactors of RLDs, disrupting RLD function in the regulation of endomembrane trafficking and polar auxin transport, ultimately leading to the developmental alterations recognized as symptoms of the viral infection. Importantly, symptoms do not have a detectable effect on the performance of the virus in the plant host, but they serve as attractants for the viral insect vector, the whitefly Bemisia tabaci, hence promoting pathogen spread. Our work uncovers the molecular underpinnings of the viral manipulation that leads to symptom development in the TYLCV-tomato pathosystem, and suggests that symptoms have evolved as a strategy to promote viral transmission by the insect vector. Given that most plant viruses are insect-transmitted, the principles described here might have broad applicability to crop-virus interactions.

plant biology↗

bioRxiv2022

Integrated proteomics reveals the landscape of autophagy degradation in human neurons and autophagy receptors regulating neuronal activity

Autophagy is a catabolic and self-degradative process crucial for maintaining cellular homeostasis. Malfunctional autophagy is implicated in neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we reported a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and LC3-interactome uncovers a role of neuronal autophagy in targeting primarily endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) proteins, and cAMP-PKA pathway, for degradation. Tubular ER and specific SV proteins are significant autophagy cargos in the axons. Functional validation identified calumenin as an ER resident autophagy receptor and illuminated a role of autophagy in regulating PKA and neuronal activity through AKAP11-mediated degradation. Our study thus reveals the landscape of autophagy degradation in human neurons and offers molecular insight into mechanisms of neurological disorders linked to autophagy deficiency. HighlightO_LIIntegrated proteomics reveals the landscape of autophagy degradation in human neurons C_LIO_LIAutophagy clears tubular ER and selective ER and synaptic vesicle proteins in neurons C_LIO_LICalumenin is an ER resident autophagy receptor C_LIO_LIAutophagy controls PKA pathway and neuronal activity through autophagy receptor AKAP11 C_LI

neuroscience↗

bioRxiv2022

Dispersal provides trophic-level dependent insurance against a heatwave in freshwater ecosystems

Climate change-related heatwaves are major recent threats to biodiversity and ecosystem functioning. However, our current understanding of the mechanisms governing community resilience (resistance and recovery) to extreme temperature events is still rudimentary. The spatial insurance hypothesis postulates that diverse regional species pools can buffer ecosystem functioning against local disturbances through immigration of better adapted taxa. However, experimental evidence for such predictions from multi-trophic communities and pulse-type disturbances, like heatwaves, are largely missing. We performed an experimental mesocosm study with alpine lake plankton to test whether a dispersal event from natural lakes prior to a simulated heatwave could increase resistance and recovery of local communities. As the buffering effect of dispersal may differ among trophic groups, we independently manipulated dispersal of organisms from lower (microorganisms) and higher (zooplankton) trophic levels. The experimental heatwave suppressed total community biomass by having a strong negative effect on zooplankton biomass, probably due to a heat-induced increase in metabolic costs that in turn caused mortality. Heating thus resulted in weaker top-down control and a subsequent shift to bottom-heavy food webs. While zooplankton dispersal did not alleviate the negative heatwave effects on zooplankton biomass, dispersal of microorganism enhanced biomass recovery at the level of phytoplankton, thereby providing evidence for spatial insurance. The different response of trophic groups may be related to the timing of dispersal, which happened under strongly monopolized resource conditions by zooplankton, creating limited opportunity for competitors to establish. At the same time, the heatwave released phytoplankton from grazing pressure and increased nutrient recycling, which may have facilitated the establishment of new phytoplankton taxa. Our findings clearly show that even a short heatwave can strongly alter energy flow in aquatic ecosystems. Although dispersal can enhance community resilience, the strength of its buffering effects depends on the trophic level.

ecology↗

bioRxiv2022

The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism: a cross-species study in vivo

AO_SCPLOWBSTRACTC_SCPLOWPeriodic features of neural time series data, such as local field potentials (LFP), are often quantified using power spectra. While the aperiodic exponent of spectra is typically disregarded, it is nevertheless modulated in a physiologically-relevant manner and was recently hypothesised to reflect excitation/inhibition (E/I) balance in neuronal populations. Here, we used a cross-species in vivo electrophysiological approach to test the E/I hypothesis in the context of experimental and idiopathic Parkinsonism. We demonstrate in dopamine-depleted rats that aperiodic exponents and power at 30-100 Hz in subthalamic nucleus (STN) LFPs reflect defined changes in basal ganglia network activity; higher aperiodic exponents tally with lower levels of STN neuron firing and a balance tipped towards inhibition. Using STN-LFPs recorded from awake Parkinsons patients, we show that higher exponents accompany dopaminergic medication and deep brain stimulation (DBS) of STN, consistent with untreated Parkinsons manifesting as reduced inhibition and hyperactivity of STN. These results suggest that the aperiodic exponent of STN-LFPs in Parkinsonism reflects E/I balance, and might be a candidate biomarker for adaptive DBS.

neuroscience↗

bioRxiv2022

Identification of divergent botulinum neurotoxin homologs in Paeniclostridium ghonii

Botulinum neurotoxins (BoNTs) are the most potent family of toxins known to science. Bioinformatic studies in recent years have revealed that they are members of a broader toxin family, with an increasing number of divergent homologs identified in genomes of organisms outside of the Clostridium genus. Here, we report the identification of two putative divergent BoNT-like homologs in the genomes of two strains of Paeniclostridium ghonii. We designated them PG-toxin 1 (PGT1) and PG-toxin 2 (PGT2), which share ~54% protein sequence identity. Unlike any other known BoNT homologs, PGT1 and PGT2 are composed of two separate subunits encoded on two neighboring genes: one encoding the protease domain (light chain, LC) with a conserved HExxH motif, and the second encoding the heavy-chain (HC) containing the putative translocation domain and receptor-binding domain. Phylogenetic analysis of both the LC and HC reveal that it is a divergent member of the lineage of BoNT that also includes BoNT/X, BoNT/En and the insecticidal PMP1. The gene clusters harboring PGT1 and PGT2 also include a putative insecticidal delta-endotoxin, Cry8Ea1, as well as putative endolysin and bacteriocin genes that may facilitate lytic toxin secretion, suggesting a possibility that this gene cluster might serve an insecticidal purpose.

bioinformatics↗