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Biology subjects

Wood, M.

Publications and source records attributed to Wood, M..

At least 19 recordsLinked to original sources

Four genome assemblies of new wild Gossypium hirsutum accessions from the Yucatan Peninsula, the center of domestication

Gossypium hirsutum is a leading source of natural cotton fiber, accounting for most of the market share. While domestication and improvement have led to significant gains in fiber quantity and quality, the narrow germplasm base of modern cultivars creates vulnerabilities, including to emerging pests. Wild populations provide a reservoir for genetic diversity that may be valuable in identifying and transferring resistance or stress-adaptation alleles to modern breeding lines. Here we report four new genome assemblies of G. hirsutum representing distinct populations from its center of diversity in Yucatan, Mexico. These chromosome-level assemblies are highly contiguous and structurally similar to existing G. hirsutum genomes; however, comparative analyses highlight their distinctiveness, suggesting they form a valuable reservoir of untapped diversity. Preliminary analyses of nucleotide-binding leucine-rich repeat (NLR) immune receptor genes underscore this variation, suggesting presence-absence variation may exist among populations. These findings demonstrate the potential of these new genomic resources for discovery of novel disease resistance alleles and, generally, for expanding the narrow germplasm base of the modern cotton cultivars.

genomics↗

Cell-resolved pharmacodynamic profiling reveals tissue- and cell-population-specific activity of antisense oligonucleotide chemical conjugates in vivo

Chemical conjugation can modulate antisense oligonucleotide (ASO) pharmacology and improve organ-specific delivery, yet whole-tissue measurements provide limited information on cell-specific activity. Here, we used metastasis-associated lung adenocarcinoma transcript 1 (Malat1) knockdown as a pharmacodynamic readout to compare whole-tissue and cell-resolved activity of chemically conjugated ASOs in platelet-derived growth factor receptor alpha-enhanced green fluorescent protein (PDGFR-eGFP) mouse model to assess their in vivo uptake in PDGFR-expressing (GFP+) cells. This reporter mouse model uses PDGFR as an exemplar cellular marker and provides an accessible tool for evaluating ASO conjugate activity within mesenchymal stromal and progenitor populations, mainly tissue fibroblasts. Following subcutaneous administration, Malat1 was quantified in whole tissues and cell-sorted PDGFR+/GFP or PDGFR-/GFP- populations. ASO-mediated Malat1 reduction varied by tissue and conjugate chemistry, with palmitate conjugation producing the broadest extrahepatic activity and pronounced whole-tissue activity in heart and skeletal muscle. Cell-resolved analysis further revealed preferential palmitate-ASO activity within PDGFR skeletal-muscle populations. Preliminary safety assessment also showed conjugate-dependent differences, with body-weight loss and ALT elevation in tocopherol-ASO-treated male mice and spleen enlargement in both sexes. These findings present an in vivo modelling system for evaluating cell-specific ASO activity and demonstrate the advantages of cell-resolved assessment over whole-tissue measurements.

molecular biology↗

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

The androgen receptor polyglutamine tract sets the transcriptional balance between muscle growth and atrophy

The androgen receptor (AR) mediates the potent anabolic effects of testosterone and other androgens on skeletal muscle, yet the transcriptional mechanisms coupling this hormonal signal to muscle growth remain unresolved. AR is a ligand-inducible transcription factor whose N-terminal transactivation domain (NTD) harbours a polymorphic polyglutamine (polyQ) tract that, when pathologically expanded, causes spinal and bulbar muscular atrophy (SBMA). To define how the NTD and its polyQ tract shape muscle transcription, we combined an engineered AR allelic series in human myogenic cells with super-resolution and single-molecule imaging, genome-wide binding and expression maps, and human population genetics. Under physiological conditions, androgen-activated AR assembles into dynamic transcriptional condensates and drives an anabolic programme in skeletal muscle through activation of the AP-1 pathway. Progressive expansion of the polyQ tract destabilises AR chromatin binding and shifts its occupancy from promoters to low-affinity distal enhancers, tracking with imaging signatures of muscle aging. In SBMA, this culminates in aberrant transactivation of ectodysplasin A2 receptor (EDA2R), a marker of senescence and inflammation, which engages non-canonical NF-{kappa}B signalling to drive muscle atrophy. Silencing Eda2r attenuated muscle wasting in SBMA mice, establishing this axis as therapeutically actionable. Together, these findings reveal a fundamental mechanism of skeletal-muscle homeostasis and open therapeutic avenues for the many conditions in which muscle atrophy is central.

molecular biology↗

Identification of a sequence motif of the rice Pho1 L80 that potentially modulates grain starch metabolism and floral timing

Plastidial phosphorylase (Pho1) regulates starch metabolism and also modulates photosystem I (PSI) activity. In rice, Pho1 contains an 80 amino acid intrinsically disordered region (IDR), L80, that acts as a negative regulator. While total removal of the IDR boosts seedling growth, flowering time, overall biomass, and grain yield and alters PSI redox properties, the precise underlying regulatory basis remains unclear. To pinpoint IDR regulatory elements, four Pho1 partial-IDR deletion variants ({delta}N, {delta}C, {delta}M, and {delta}N{delta}C) were evaluated. Lines carrying {delta}M and {delta}C exhibited enhanced starch metabolism, yielding larger, heavier grains, and flowered 5 to10 days earlier than wild type. Both d{delta}M and {delta}C share an acidic motif, (E/V)SEEV, identifying it as a primary negative regulator of starch synthesis and floral timing. By contrast, no partial deletion fully mirrored the PSI redox modifications of Pho1{delta}L80. These results demonstrate that starch biosynthesis and flowering are governed by one or more discrete sequence motifs within the middle and C-terminal regions, whereas PSI modulation likely requires the structural integrity of the intact IDR.

plant biology↗

Click Chemistry-Based Strategy for Modular Ligand Attachment to siRNAs: Toward Extrahepatic RNAi

Efficient extrahepatic delivery of siRNAs remains a major limitation for broadening their therapeutic potential. Using a modular, orthogonal click chemistry platform, we generated 28 siRNA conjugates varying in ligand class, valency, and spatial arrangement. Following systemic administration, fatty acid conjugates - particularly palmitic acid (C16) - outperformed sterol- and phospholipid-based designs in promoting extrahepatic gene silencing, with preferential activity observed in heart and skeletal muscle. Increasing ligand valency through 3',5'-bis-conjugation generally enhanced activity compared to 5-mono conjugation. Nevertheless, bis-C22 conjugates showed increased hepatic activity, suggesting a shift in tissue distribution linked to hydrophobicity. Architectural parameters further modulated outcomes: Branched 5' C16 conjugates, bearing two lipids on one terminus, were markedly less active than their bis counterparts and required short PEG spacers to restore activity. Notably, bis-lipid conjugation strategies that enhanced extrahepatic activity for an siRNA did not translate to an ASO gapmer, underscoring modality-specific constraints. Together, these findings delineate structure-activity relationships and establish bis-fatty-acid conjugation as a robust design principle for achieving extrahepatic RNAi. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/726808v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@b7af11org.highwire.dtl.DTLVardef@146b9c6org.highwire.dtl.DTLVardef@4e8948org.highwire.dtl.DTLVardef@16fa07_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

Inhibition of histone lysine demethylase restores learning and memory in aged mice

Chromatin undergoes dramatic changes during the ageing process. In the brain, these chromatin changes are thought to underlie age-associated deficits in the activity-dependent gene transcription necessary for memory consolidation. Here, we show that the levels of a specific histone post-translational modification (PTM), trimethylation of lysine 4 on histone 3 (H3K4me3) is markedly increased in the hippocampus of aged mice and that the activity-induced increase in H3K4me3 that is observed in response to a learning stimulus in young mice, is severely blunted in the aged hippocampus. H3K4me3 typically marks open, accessible chromatin at the transcriptional start sites (TSSs) of actively transcribed genes. We identify altered H3K4me3 peaks at TSSs and show that ca. 90% of the activity-induced H3K4me3 changes at TSSs are either absent or reduced in the aged hippocampus. To understand the biological significance of these age-associated changes, we screened a library of pharmacological compounds for compounds that can alter H3K4me3 levels in hippocampal neurons. We show that treatment of aged mice with one of these, the LSD1 inhibitor ORY-1001, restored normal learning and memory in object location and recognition tasks. Furthermore, we show that ORY-1001 treatment increased long-term potentiation (LTP), a form of synaptic plasticity deficient in the aged hippocampus. These findings suggest that targeting the epigenetic machinery that regulates activity-dependent gene transcription may represent an avenue for treating age-associated cognitive impairment. HighlightsO_LIH3K4me3 levels are elevated in the naive aged mouse hippocampus C_LIO_LIActivity-dependent H3K4me3 induction is impaired in the aged mouse hippocampus C_LIO_LILSD1 inhibition restores learning and memory in aged mice C_LIO_LILSD1 inhibition restores activity-dependent Arc induction and increases LTP in the aged hippocampus C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/695858v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@fccd92org.highwire.dtl.DTLVardef@11c4d93org.highwire.dtl.DTLVardef@128f8b8org.highwire.dtl.DTLVardef@e1341f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Engineered AAV Capsids with Enhanced Extracellular Vesicle Loading via Rational Design and Directed Evolution

Overcoming immune responses and ensuring efficient delivery remain key obstacles to advancing adeno-associated virus (AAV)-based genetic medicines into the clinic. Encapsulating AAVs within naturally secreted extracellular vesicles (EV-AAV) can shield them from neutralising antibodies and increase transduction efficiency; however, wild-type AAV capsids are incorporated into EVs inefficiently, with the percentage of total AAV genomes in the EV-AAV fraction ranging from 0.5% to 12%, depending on AAV serotype. Here, we establish a high-throughput screening platform that links AAV capsid genotype to EV encapsulation phenotype to improve encapsulation efficiency. We combined rational design with directed evolution to engineer AAV9 variants that preferentially sort into EVs. A library of 392,550 AAV9 capsid mutants was generated by inserting Late (L) domains, established EV-sorting motifs, and fully random amino acid inserts in a surface-exposed region of the AAV9 capsid protein. Screening data were analysed using a statistical model-assisted protein selection (SMAPS) workflow - developed as a novel quantitative modelling and selection strategy for protein engineering challenges of this kind. SMAPS functions as a digital twin of the protein variants in our high-throughput screen, allowing us to monitor uncertainty in copy numbers over multiple steps in the experimental workflow. Using SMAPS, we identified five lead hits, which showed up to threefold increased EV-AAV yield compared to wild-type, without altering particle size. Moreover, in vitro transduction experiments demonstrated that the lead AAV9 capsid exhibits substantially higher transduction efficiency compared to wild-type AAV9 and retained functional activity in the presence of neutralising anti-AAV9 antibodies. Collectively, our study: (i) delivers a scalable high-throughput screen for EV-AAV engineering, (ii) introduces the fields first statistical model-guided quality-control framework for directed evolution, and (iii) provides best-in-class capsids for EV encapsulation.

synthetic biology↗

Microbiota/gut/neuron axis promotes Drosophila ageing via Acetobacter, Tachykinin, and TkR99D

Gut microbiota exert an evolutionarily conserved influence on ageing, from invertebrates to humans. How do microbes that are physically confined to the gut lumen affect the systemic physiological process of ageing? In female Drosophila, we show that microbiota increase expression of the peptide hormone Tachykinin (Tk), which corresponds to reduced lifespan. Tk is required for microbiota to shorten lifespan, with knockdown rendering flies constitutively long-lived even in the presence of an intact microbiota. This lifespan extension does not come with canonical costs to fecundity or feeding, but impacts on triacylglyceride (TAG) storage suggest adaptive functions in metabolic homeostasis. In flies with defined (gnotobiotic) microbiotas, we show that we can model Tk-dependent effects of microbiota on lifespan and TAG by monoassociation with Acetobacter pomorum. These effects require Tk in the midgut, and the cognate TK receptor TkR99D in neurons, implicating a microbiota-gut-neuron relay. This relay also appears to compromise gut barrier function in aged flies, indicating roles in healthspan as well as lifespan. However, the effect of TkR99D is independent of its reported role in insulin signalling and adipokinetic hormone signalling which, respectively, are canonical regulators of lifespan and TAG metabolism, suggesting a non-canonical role for TkR99D elsewhere in the nervous system. Altogether our results implicate a microbiota-gut-neuron axis in ageing, via a specific bacterium modulating activity of a specific and evolutionarily-conserved hormone.

genetics↗

Systemic Inflammation Modulates Clearance and drives Extra-Hepatic Distribution of Extracellular Vesicles

Extracellular vesicles (EVs) are promising vehicles for targeted therapeutic delivery, capable of encapsulating and transporting biomolecules to specific cells and tissues. Given that inflammation is central to many acute and chronic diseases, understanding EV biodistribution under inflammatory conditions is essential for therapeutic optimization. This study examines how acute systemic inflammation influences EV biodistribution, clearance, and plasma half-life, with a focus on the role of macrophages and their polarization states. Using a lipopolysaccharide (LPS)-induced inflammation model in wild-type mice and bioluminescent and fluorescent labelling of EVs, we observed that inflammation extends the plasma half-life of EVs by over 600-fold within 2 hours and 900-fold at 24 hours post-administration, leading to significant enrichment in inflamed organs, particularly the liver and spleen. Enhanced accumulation in specific tissues translated to increased targeting of immune- and epithelial cells within those organs, with notable uptake by hepatocytes in the liver. This prolonged half-life was attributed to the altered EV protein corona in inflamed tissues, which facilitates cellular association. These findings underscore the complex dynamics between EVs and immune cells under inflammatory conditions and provide critical insights for advancing EV-based therapies in chronic inflammatory diseases.

bioengineering↗

IL-18 metabolically reprograms CAR-expressing natural killer T cells and enhances their antitumor activity against neuroblastoma

Invariant natural killer T cells (NKTs) have intrinsic anti-tumor properties that make them promising candidates for chimeric antigen receptor (CAR)-based immunotherapies. Transgenic cytokine expression has been shown to enhance the potency of cellular immunotherapies, and we hypothesized that co-expressing IL-18 alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this hypothesis, we generated retroviral constructs expressing IL-15 and/or IL-18 with the inducible caspase 9 (iC9) safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased GD2.CAR-NKT in vitro cytotoxicity, proliferation, and cytokine secretion compared to IL-15 alone. In a metastatic neuroblastoma model, GD2.CAR-NKTs expressing constructs with IL-18 controlled tumor growth better than cells expressing IL-15 only, but mice in the IL-15/IL-18 group developed severe toxicities not observed in the IL-18-only group. Mechanistically, we found that IL-18 drives a distinct transcriptional profile from IL-15 in CAR-NKTs marked by lower expression of exhaustion gene signatures and enrichment of metabolism-related processes. Finally, targeted metabolomics revealed that IL-18 induces broad metabolic reprogramming in CAR-NKTs including enhancement of oxidative phosphorylation, glycolysis, glutaminolysis and purine metabolism. These results support the use of IL-18 in developing the next generation of cytokine-armed CAR-NKT cancer immunotherapy.

immunology↗

Targeted BDNF upregulation via upstream open reading frame disruption

To understand the relative contributions of 5' UTR elements to translation, we performed a comprehensive analysis of upstream open reading frames (uORFs) across a representative 5' UTR. We selected the neurotrophin BDNF (Brain derived neurotrophic factor) as an exemplar as upregulation of this protein is a potential therapeutic approach for a plethora of neurodevelopmental, neurodegenerative, and neuropsychiatric disorder indications. Predicted uORFs were identified in 14 out of 17 BDNF RefSeq transcript isoforms, and experimentally confirmed to be exerting translation repression effects for five of these transcripts. These findings suggest that uORF elements play an important role in shaping the protein output from this locus. We explored several approaches to disrupt BDNF uORF function. Deletion of a 5' UTR exon in BDNF v11 (containing eight predicted uORFs), in order to simulate an exon skipping outcome, resulted in pronounced upregulation in a reporter construct system. This effect was found to be partially uORF-dependent, but was also dependent on the disruption of an RNA secondary structure element. However, this transcript variant was found to not be expressed in human brain. Conversely, direct disruption of a single uORF start codon in the widely expressed BDNF v4 transcript variant using an adenine base editing approach resulted in a [~]1.8-fold upregulation of endogenous BDNF protein expression in cell culture. This study describes novel BDNF regulatory mechanisms, and potential uORF-targeted modalities for therapeutic gene activation.

molecular biology↗

Robust CRISPR/dCas13 RNA blockers specifically perturb miRNA-target interactions and rescue type 1 myotonic dystrophy pathology

While RNA-targeting strategies are powerful tools for disease therapy, challenges, including low target engagement and off-target collateral effects, currently limit their efficacy. Here, we report the engineering and optimisation of a CRISPR/dCas13 RNA steric blocker (CRISPR-Lock) that prevents mRNA translation, shields mRNAs from miRNA-mediated silencing, and blocks RNA-protein interactions. By tuning the spatial resolution and mismatch tolerance of CRISPR-Lock, we develop a high-resolution perturbation approach that employs genetically encoded CRISPR-Lock as a miRNA target protector. This system enables precise spatiotemporal control of miRNA:mRNA interactions, offering broader applicability compared to phosphorodiamidate mor-pholino (PMO) target protectors. Moreover, we demonstrate the potential therapeutic application of CRISPR-Lock for blocking pathological RNA-protein interactions in type 1 myotonic dystro-phy (DM1). Optimising CRISPR-Lock to target expanded repeat RNAs corrects approximately 85% of clinically relevant splicing biomarkers in patient-derived myotubes and significantly out-performs third-generation PMO antisense oligonucleotides. Finally, by delivering a miniaturised AAV-encoded CRISPR-Lock system into an established DM1 mouse model, we demonstrate the dose-dependent correction of intranuclear foci and splicing dysregulation, underscoring the potential therapeutic application of this technology.

bioengineering↗

Tissue-specific modulation of CRISPR activity by miRNA-sensing guide RNAs

Nucleic acid nanostructures offer unique opportunities for biomedical applications due to their sequence-programmable structures and functions, which enable the design of complex responses to molecular cues. Control of the biological activity of therapeutic cargoes based on endogenous molecular signatures holds the potential to overcome major hurdles in translational research: cell specificity and off-target effects. Endogenous microRNAs can be used to profile cell type and cell state and are ideal inputs for RNA nanodevices. Here we present CRISPR MiRAGE (miRNA-activated genome editing), a tool comprising a dynamic single-guide RNA that senses miRNA complexed with Argonaute proteins and controls downstream CRISPR activity based on the detected miRNA signature. We study the operation of the miRNA-sensing single-guide RNA and attain muscle-specific activation of gene editing through CRISPR MiRAGE in models of Duchenne muscular dystrophy. By enabling RNA-controlled gene editing activity, this technology creates opportunities to advance tissue-specific CRISPR treatments for human diseases.

bioengineering↗

uORF-targeting steric block antisense oligonucleotides do not reproducibly activate RNASEH1 expression

Upstream open reading frames (uORFs) are cis-regulatory motifs that are predicted to occur in the 5' untranslated region (UTR) of the majority of human protein-coding transcripts. uORFs are typically associated with repression of the downstream primary open reading frame (pORF) at either the level of translation, or by promoting mRNA turnover via the nonsense-mediated decay pathway. Interference with uORF activity provides a potential mechanism for targeted upregulation of the expression of specific transcripts. It was recently reported that steric block antisense oligonucleotides (ASOs) can bind to and mask uORF start codons in order to inhibit translation initiation, and thereby disrupt uORF-mediated gene regulation. Given the relative maturity of the oligonucleotide field, such a uORF blocking mechanism might have widespread therapeutic utility. Here, we re-synthesised three of the most potent ASOs targeting the RNASEH1 uORF described in the study by Liang et al. and investigated their potential for RNASEH1 protein upregulation. No upregulation (of endogenous or reporter protein expression) was observed with any of the oligonucleotides tested at doses ranging from 25 nM to 300 nM. Conversely, we observed downregulation of expression in some instances, consistent with well-established mechanisms of blocking ribosome procession. Experiments were performed using multiple transfection protocol setups, with care taken to replicate the conditions of the original study. Transfection efficiency was confirmed using a MALAT1-targeting gapmer ASO as a positive control. We conclude that previously-described RNASEH1 uORF-targeting steric block ASOs are incapable of upregulating pORF protein expression in our hands.

biochemistry↗

A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints

PurposeUltra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions. MethodsWe previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters. In this study, we compared the outcome of FLASH and CONV 10 Gy whole brain irradiation on female adult mice at both institutions to evaluate the reproducibility and temporal evolution of multiple endpoints. ResultsFLASH sparing of behavioral performance on novel object recognition (4 months post-irradiation) and electrophysiologic long-term potentiation (LTP, 5-months post-irradiation) was reproduced between institutions. Interestingly, differences between FLASH and CONV on the endpoints of hippocampal neurogenesis (Sox2, doublecortin), neuroinflammation (microglial activation), and electrophysiology (LTP) at late times were not observed at early times. ConclusionsIn summary, we demonstrated reproducible FLASH sparing effects between two beams and two institutions with validated dosimetry. FLASH sparing effects on the endpoints evaluated manifested at late but not early time points.

cancer biology↗

Systemic delivery of a splice-switching oligonucleotide heteroduplex corrects splicing in central nervous system and muscle in spinal muscular atrophy mice

Oligonucleotide therapeutics are an established class of drugs for the treatment of genetic disorders. Their clinical development is challenging, however, as they typically distribute poorly to extra-hepatic tissues after systemic injection. Here we tested the heteroduplex oligonucleotide (HDO) platform for systemic delivery of SMN2 splice-switching oligonucleotides of 2-O-methoxyethyl phosphorothioate or phosphorodiamidate morpholino oligomer chemistries. We first showed that splice-switching HDO cargoes correct SMN2 splicing in cells derived from spinal muscular atrophy (SMA) patients, and validated extra-hepatic activity in spinal cord and muscle in a mouse model of SMA following systemic delivery. Our study raises prospects for delivery of nusinersen, the 2-O-methoxylethyl phosphorothioate oligonucleotide therapy approved for SMA and currently delivered by intrathecal injection, by systemic injection exploiting the HDO chemistry platform. Our findings also suggest that oligonucleotide drugs lacking convincing in vivo efficacy in muscle tissue could be delivered effectively by the HDO technology.

molecular biology↗

High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons

Dendritic computations have a central role in rodent neocortical circuit function, which are signaled into neuronal output by the initiation and propagation of regenerative dendritic spikes. However, it remains poorly explored whether these mechanisms are operational in the human neocortex. To directly examine the dendritic computational properties of the most numerous class of pyramidal neuron in the human and rat neocortex we made simultaneous electrical recordings from the soma and apical dendrites of layer 2/3 pyramidal neurons maintained in acute brain slices of analogous cortical areas under identical experimental conditions. In both species correlated dendritic excitatory input led to the initiation of sodium channel-mediated dendritic spikes with conserved biophysical properties. Dendritic sodium spikes in human and rat layer 2/3 pyramidal neurons could be generated across a similar wide input range, exhibited a similar frequency range of activation, and forward propagated with high fidelity to drive neuronal output to implement stereotyped computations. Our findings therefore reveal that the dendritic computational properties of human layer 2/3 pyramidal neurons are phylogenetically conserved.

neuroscience↗