title: Sequence diversity in the 3' untranslated region of alphavirus modulates IFIT2-dependent restriction in a cell type-dependent manner

abstract: Alphaviruses (family Togaviridae) are a diverse group of positive-sense RNA (+ssRNA) viruses that are transmitted by arthropods and are the causative agent of several significant human and veterinary diseases. Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFITs) are a family of RNA-binding IFN stimulated genes (ISGs) that are highly upregulated following viral infection, and have been identified as potential restrictors of alphaviruses. The mechanism by which IFIT1 restricts RNA viruses is dependent on self and non-self-discrimination of RNA, and alphaviruses evade this recognition via their 5UTR. However, the role of IFIT2 during alphavirus replication and the mechanism of viral replication inhibition is unclear. In this study, we identify IFIT2 as a restriction factor for Venezuelan equine encephalitis virus (VEEV) and show that IFIT2 binds the 3 untranslated region (3UTR) of the virus. We investigated the potential role of variability in the 3UTR of the virus affecting IFIT2 antiviral activity by studying infection with VEEV. Comparison of recombinant VEEV clones containing 3UTR sequences derived from epizootic and enzootic isolates exhibited differential sensitivity to IFIT2 restriction in vitro infection studies, suggesting that the alphavirus 3UTR sequence may function in part to evade IFIT2 restriction. In vitro binding assays demonstrate that IFIT2 binds to the VEEV 3UTR, however in contrast to previous studies VEEV restriction did not appear to be dependent on the ability of IFIT2 to inhibit translation of viral RNA, suggesting a novel mechanism of IFIT2 restriction. Our study demonstrates that IFIT2 is a restriction factor for alphaviruses and variability in the 3UTR of VEEV can modulate viral restriction by IFIT2. Ongoing studies are exploring the biological consequences of IFIT2-VEEV RNA interaction in viral pathogenesis and defining sequence and structural features of RNAs that regulate IFIT2 recognition.


title: Chloride-dependent mechanisms of multimodal sensory discrimination and neuropathic sensitization in Drosophila

abstract: Individual sensory neurons can be tuned to many stimuli, each driving unique, stimulus-relevant behaviors, and the ability of multimodal nociceptor neurons to discriminate between potentially harmful and innocuous stimuli is broadly important for organismal survival. Moreover, disruptions in the capacity to differentiate between noxious and innocuous stimuli can result in neuropathic pain. Drosophila larval Class III (CIII) neurons are peripheral noxious cold nociceptors and gentle touch mechanosensors; high levels of activation drive cold-evoked contraction (CT) behavior, while low levels of activation result in a suite of touch-associated behaviors. However, it is unknown what molecular factors underlie CIII multimodality. Here, we show that the TMEM16/anoctamins subdued and white walker (wwk; CG15270) are required for cold-evoked CT, but not for touch-associated behavior, indicating a conserved role for anoctamins in nociception. We also evidence that CIII neurons make use of atypical depolarizing chloride currents to encode cold, and that overexpression of ncc69--a fly homologue of NKCC1--results in phenotypes consistent with neuropathic sensitization, including behavioral hypersensitization and spontaneous nociceptor activity, making Drosophila CIII neurons a candidate system for future studies of the basic mechanisms underlying neuropathic pain.

category: neuroscience


title: Entorhinal cortex directs learning-related changes in CA1 representations

abstract: Learning-related changes in brain activity are thought to underlie adaptive behaviors1,2. For instance, the learning of a reward site by rodents requires the development of an over-representation of that location in the hippocampus3-6. However, how this learning-related change occurs remains unknown. Here we recorded hippocampal CA1 population activity as mice learned a reward location on a linear treadmill. Physiological and pharmacological evidence suggests that the adaptive over-representation required behavioral timescale synaptic plasticity (BTSP)7. BTSP is known to be driven by dendritic voltage signals that we hypothesized were initiated by input from entorhinal cortex layer 3 (EC3). Accordingly, the CA1 over-representation was largely removed by optogenetic inhibition of EC3 activity. Recordings from EC3 neurons revealed an activity pattern that could provide an instructive signal directing BTSP to generate the over-representation. Consistent with this function, exposure to a second environment possessing a prominent reward-predictive cue resulted in both EC3 activity and CA1 place field density that were more elevated at the cue than the reward. These data indicate that learning-related changes in the hippocampus are produced by synaptic plasticity directed by an instructive signal from the EC3 that appears to be specifically adapted to the behaviorally relevant features of the environment.


title: Ion channel distributions in cortical neurons are optimized for energy-efficient active dendritic computations

abstract: The mammalian brain has an enormous demand for energy, which is thought to impose strong selective pressure by which the neurons evolve in ways that ensure robust function at minimal energy cost. However, which principles drive the ion channel distributions in the dendrites to implement different neuronal functions is yet unclear. Here we found that an energy-efficient generation of dendritic calcium action potentials in cortical pyramidal neurons requires a low expression of slow inactivating potassium channels. We demonstrate that this relationship between energy cost and neuronal function is independent of the dendritic morphology and the expression patterns of other ion channels that implement additional perisomatic and dendritic functions. Moreover, we found that calcium action potentials can arise from a wide spectrum of ion channel expression patterns, including configurations with high potassium channel densities in the dendrites. These configurations can account equally well for the characteristic intrinsic physiology of the pyramidal neurons. However, only configurations with low potassium channel densities in the distal dendrites are observed empirically. Thus, our findings indicate that cortical neurons do not utilize all theoretically possible ways to implement their functions, but instead select those optimized for energy-efficient active dendritic computations.


title: Disruption in structural-functional network repertoire and time resolved subcortical-frontoparietal connectivity in disorders of consciousness

abstract: Understanding recovery of consciousness and elucidating its underlying mechanism is believed to be crucial in the field of basic neuroscience and medicine. Ideas such as the global neuronal workspace and the mesocircuit theory hypothesize that failure of recovery in conscious states coincide with loss of connectivity between subcortical and frontoparietal areas, a loss of the repertoire of functional networks states and metastable brain activation. We adopted a time-resolved functional connectivity framework to explore these ideas and assessed the repertoire of functional network states as a potential marker of consciousness and its potential ability to tell apart patients in the unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). In addition, prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, i.e. so-called eigenmodes, were supplemented as potential markers. By analysing time-resolved functional connectivity from fMRI data, we demonstrated a reduction of metastability and functional network repertoire in UWS compared to MCS patients. This was expressed in terms of diminished dwell times and loss of nonstationarity in the default mode network and fronto-parietal subcortical network in UWS compared to MCS patients. We further demonstrated that these findings co-occurred with a loss of dynamic interplay between structural eigenmodes and emerging time-resolved functional connectivity in UWS. These results are, amongst others, in support of the global neuronal workspace theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness.


title: Insights into bear evolution from a Pleistocene polar bear genome

abstract:
The polar bear (Ursus maritimus) has become a symbol of the threat to biodiversity from climate change. Understanding polar bear evolutionary history may provide insights into apex carnivore responses and prospects during periods of extreme environmental perturbations. In recent years, genomic studies have examined bear speciation and population history, including evidence for ancient admixture between polar bears and brown bears (Ursus arctos). Here, we extend our earlier studies of a 130,000-115,000-year-old polar bear from the Svalbard Archipelago using a 10X coverage genome sequence and ten new genomes of polar and brown bears from contemporary zones of overlap in northern Alaska. We demonstrate a dramatic decline in effective population size for this ancient polar bears lineage, followed by a modest increase just before its demise. A slightly higher genetic diversity in the ancient polar bear suggests a severe genetic erosion over a prolonged bottleneck in modern polar bears. Statistical fitting of data to alternative admixture graph scenarios favors at least one ancient introgression event from brown bears into the ancestor of polar bears, possibly dating back over 150,000 years. Gene flow was likely bidirectional, but allelic transfer from brown into polar bear is the strongest detected signal, which contrasts with other published works. These findings may have implications for our understanding of climate change impacts: polar bears, a specialist Arctic lineage, may not only have undergone severe genetic bottlenecks, but also been the recipient of generalist, boreal genetic variants from brown bear during critical phases of Northern Hemisphere glacial oscillations.

SignificanceInterspecific hybridization is a widespread phenomenon, but measuring its extent, directionality, and adaptive importance remains challenging. Ancient genomes, however, can help illuminate the history of modern organisms. Here, we present a genome retrieved from a 130,000-115,000-year-old polar bear and perform genome analyses of modern polar and brown bears throughout their geographic range. We find that the principal direction of ancient allele sharing was from brown bear into polar bear, although gene flow between them has likely been bidirectional. This inverts the current paradigm of unidirectional gene flow from polar into brown bear, and it suggests that polar bears were recipients of external genetic variation prior to their extensive population decline.

category: evolutionary biology


title: Multiple genes in cis mediate the effects of a single chromatin accessibility variant on aberrant synaptic development and function in human neurons

abstract: Despite hundreds of risk loci from genome-wide association studies of neuropsychiatric disorders, causal variants/genes remain largely unknown. Here, in NEUROG2-induced human neurons, we identified 31 risk SNPs in 26 schizophrenia (SZ) risk loci that displayed allele-specific open chromatin (ASoC) and were likely to be functional. Editing the strongest ASoC SNP rs2027349 near vacuolar protein sorting 45 homolog (VPS45) altered the expression of VPS45, lncRNA AC244033.2, and a distal gene, C1orf54, in human neurons. Notably, the global gene expression changes in neurons were enriched for SZ risk and correlated with post-mortem brain gene expression signatures of neuropsychiatric disorders. Neurons carrying the risk allele exhibited increased dendritic complexity, synaptic puncta density, and hyperactivity, which were reversed by knocking-down distinct cis-regulated genes (VPS45, AC244033.2, or C1orf54), suggesting a phenotypic contribution from all three genes. Interestingly, transcriptomic analysis of knockdown cells suggested a non-additive effects of these genes. Our study reveals a compound effect of multiple genes at a single SZ locus on synaptic development and function, providing a mechanistic link between a non-coding SZ risk variant and disease-related cellular phenotypes.

category: genetics


title: The human thalamus orchestrates neocortical oscillations during NREM sleep.

abstract: A hallmark of non-rapid eye movement (NREM) sleep is the coordinated interplay of slow oscillations (SOs) and sleep spindles. Traditionally, a cortico-thalamo-cortical loop is suggested to coordinate these rhythms: neocortically-generated SOs trigger spindles in the thalamus that are projected back to neocortex. Here, we used direct intrathalamic recordings from human epilepsy patients to test this canonical interplay. We show that SOs in the anterior thalamus precede neocortical SOs, whereas concurrently-recorded SOs in the mediodorsal thalamus are led by neocortical SOs. Furthermore, sleep spindles, detected in both thalamic nuclei, preceded their neocortical counterparts and were initiated during early phases of thalamic SOs. Our findings indicate an active role of the anterior thalamus in organizing the cardinal sleep rhythms in the neocortex and highlight the functional diversity of specific thalamic nuclei in humans. The concurrent coordination of sleep oscillations by the thalamus could have broad implications for the mechanisms underlying memory consolidation.


title: The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

abstract: Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one  and one {beta} chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR  and {beta} chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses. The TCR responses broadly presaged the antibody responses. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

category: immunology


title: Identification of novel Ebola virus inhibitors using biologically contained virus

abstract: Despite recent advancements in the development of vaccines and monoclonal antibody therapies for Ebola virus disease, treatment options remain limited. Moreover, management and containment of Ebola virus outbreaks is often hindered by the remote nature of the locations in which the outbreaks originate. Small-molecule compounds offer the advantage of being relatively cheap and easy to produce, transport and store, making them an interesting modality for the development of novel therapeutics against Ebola virus disease. Furthermore, the repurposing of small-molecule compounds, previously developed for alternative applications, can aid in reducing the time needed to bring potential therapeutics from bench to bedside. For this purpose, the Medicines for Malaria Venture provides collections of previously developed small-molecule compounds for screening against other infectious diseases. In this study, we used biologically contained Ebola virus to screen over 4,200 small-molecule drugs and drug-like compounds provided by the Medicines for Malaria Venture (i.e., the Pandemic Response Box and the COVID Box) and the Centre for Drug Design and Discovery (CD3, KU Leuven, Belgium). In addition to confirming known Ebola virus inhibitors, illustrating the validity of our screening assays, we identified eight novel selective Ebola virus inhibitors. Although the inhibitory potential of these compounds remains to be validated in vivo, they represent interesting compounds for the study of potential interventions against Ebola virus disease and might serve as a basis for the development of new therapeutics.

category: microbiology


title: Microtubule-associated IQD9 guides cellulose synthase velocity to shape seed mucilage

abstract:
O_LIArabidopsis seeds release large capsules of mucilaginous polysaccharides, which are shaped by an intricate network of cellulosic microfibrils. Cellulose synthase complexes is guided by the microtubule cytoskeleton, but it is unclear which proteins mediate this process in the seed coat epidermis (SCE).
C_LIO_LIUsing reverse genetics, we identified IQ67 DOMAIN 9 (IQD9) and KINESIN LIGHT CHAIN-RELATED 1 (KLCR1) as two highly expressed genes during seed development and comprehensively characterized their roles for cell wall polysaccharide biosynthesis and cortical microtubule (MT) organization.
C_LIO_LIMutations in IQD9 as well as in KLCR1 lead to compact mucilage capsules with aberrant cellulose distribution, which can be rescued by transgene complementation. Double mutant analyses revealed that their closest paralogs (IQD10 and KLCR2, respectively) are not required for mucilage biosynthesis. IQD9 physically interacts with KLCR1 and localizes to cortical MTs to maintain their organization in SCE cells. Similar to the previously identified TONNEAU1 (TON1) RECRUITING MOTIF 4 (TRM4) protein, IQD9 is required to maintain the velocity of cellulose synthases.
C_LIO_LIOur results demonstrate that IQD9, KLCR1 and TRM4 are MT-associated proteins that are required for seed mucilage architecture. This study provides the first direct evidence that members of the IQD, KLCR and TRM families have overlapping roles in guiding the distribution of cell wall polysaccharides. Therefore, SCE cells provide an attractive system to further decipher the complex genetic regulation of polarized cellulose deposition.
C_LI

category: biochemistry


title: NFE2L1-mediated proteasome function protects from ferroptosis

abstract:
ObjectiveFerroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood.

Methods and ResultsHere we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4-deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis.

ConclusionOur data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.

Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

HighlightsO_LIProteasome function is diminished during ferroptosis
C_LIO_LINFE2L1-mediated proteasomal activity protects from ferroptosis
C_LIO_LIThe ubiquitination of the GPX4-glutathione pathway is implicated in Nfe2l1 deficiency
C_LIO_LINFE2L1 deficiency in brown fat is associated with hallmarks of ferroptosis
C_LI


title: ClusTRace, a bioinformatic pipeline for analyzing clusters in virus phylogenies

abstract:
SummarySARS-CoV-2 is the highly transmissible etiologic agent of coronavirus disease 2019 (COVID-19) and has become a global scientific and public health challenge since December 2019. Several new variants of SARS-CoV-2 have emerged globally raising concern about prevention and treatment of COVID-19. Early detection and in depth analysis of the emerging variants allowing pre-emptive alert and mitigation efforts are thus of paramount importance.

Here we present ClusTRace, a novel bioinformatic pipeline for a fast and scalable analysis of sequence clusters or clades in large viral phylogenies. ClusTRace offers several high level functionalities including outlier filtering, aligning, phylogenetic tree reconstruction, cluster or clade extraction, variant calling, visualization and reporting. ClusTRace was developed as an aid for COVID-19 transmission chain tracing in Finland and the main emphasis has been on fast and unsupervised screening of phylogenies for markers of super-spreading events and other features of concern, such as high rates of cluster growth and/or accumulation of novel mutations.

AvailabilityAll code is freely available from https://bitbucket.org/plyusnin/clustrace/

category: bioinformatics


title: A two-component protein condensate of EGFR and Grb2 regulates Ras activation at the membrane

abstract: We reconstitute a phosphotyrosine-mediated protein condensation phase transition of the [~]200 residue cytoplasmic tail of the epidermal growth factor receptor (EGFR) and the adaptor protein, Grb2, on a membrane surface. The phase transition depends on phosphorylation of the EGFR tail, which recruits Grb2, and the dimerization of Grb2, which provides the crosslinking element for condensation with EGFR. The Grb2 Y160 residue plays a structurally critical role in dimer formation, and phosphorylation or mutation of Y160 prevents EGFR:Grb2 condensation. By extending the reconstitution experiment to include the guanine nucleotide exchange factor, SOS, and its substrate Ras, we further find that EGFR condensation controls the ability of SOS to activate Ras. These results identify an EGFR:Grb2 protein condensation phase transition as a regulator of signal propagation from EGFR to the MAPK pathway.

category: biophysics


title: Metabolic potentials of Liquorilactobacillus nagelii AGA58 isolated from Shalgam based on genomic and functional analysis

abstract: The aim of present study was to perform functional and genomic characterization of a novel Liquorilactobacillus nagelii AGA58 isolated from Shalgam to understand its metabolic potentials. AGA58 is gram-positive, catalase-negative and appears as short-rods under light-microscope. The AGA58 chromosome composed of a single linear chromosome of 2,294,535 bp that is predicted to carry 2151 coding sequences, including 45 tRNA genes, 4 rRNA operons. Genome has a GC content of 36.9% includes 45 pseudogenes, 32 transposases and one intact-prophage. AGA58 is micro-anaerobic owing to shorter doubling time and faster growth rate achieved compared microaerofilic condition. It carries flagellar biosynthesis protein-encoding genes predicting motile behavior. AGA58 is an obligatory homofermentative where hexose sugars such as galactose, glucose, fructose, sucrose, mannose, N-acetyl glucosamine, maltose, trehalose are fermented to lactate thru glycolysis and no acid production from pentose sugars achieved due to lack of key enzyme namely phosphoketolase in pentose phosphate pathway. Carbohydrate fermentation tests showed AGA58 cannot ferment pentoses which was also confirmed in silico. Putative pyruvate metabolism revealed formate, malate, oxaloacetate, acetate, acetaldehyde, acetoin and lactate forms from pyruvate. AGA58 predicted to carry bacteriocin genes for type A2 lantipeptide, Blp family class II bacteriocins showing antimicrobial potential of this bacterium which can be linked to antagonism tests that AGA58 can inhibit E. coli O157:H7, S. Typhimurium ATCC14028, and K. pneumonia ATCC13883. Moreoever, AGA58 is tolerant to acid and bile concentrations simulating the human gastrointestinal conditions. L. nagelii AGA58 depicting the probiotic potential of AGA58 as a first report in literature within same species.


title: In silico and functional characterisation of an ultra-rare CFTR mutation identifies novel lasso motif interactions regulating channel gating

abstract: Characterisation of I37R - a novel mutation in the lasso motif of ABC-transporter CFTR, a chloride channel - was conducted by theratyping using CFTR potentiators which increase channel gating activity and correctors which repair protein trafficking defects. I37R-CFTR function was characterised using intestinal current measurements (ICM) in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids and short circuit current measurements (Isc) in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype. We demonstrated that the I37R-CFTR mutation results in a residual function defect amenable to treatment with potentiators and type III, but not to type I, correctors. Molecular dynamics of I37R-CFTR using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavourable strengthening of the interactions between the lasso motif, the regulatory (R) domain and the transmembrane domain two (TMD2). In conclusion, structural and functional characterisation of the I37R-CFTR mutation increases understanding of CFTR channel regulation and provides a potential pathway to access CFTR modulator treatments for individuals with CF caused by ultra-rare CFTR mutations.

category: molecular biology


title: Ubiquitin proteomics reveals critical targets of the Nse1 RING domain in rDNA and genome stability

abstract: Ubiquitination controls numerous cellular processes, and its deregulation is associated to many pathologies. The Nse1 subunit in the Smc5/6 complex contains a RING domain with ubiquitin E3 ligase activity and important functions in genome integrity. However, Nse1-dependent ubiquitin targets remain largely unknown. Here, we use label-free quantitative proteomics to analyse the nuclear ubiquitinome of nse1-C274A RING mutant cells. Our results show that Nse1 impacts on the ubiquitination of several proteins involved in DNA damage tolerance, ribosome biogenesis and metabolism that, importantly, extend beyond canonical functions of the Smc5/6 complex in chromosome segregation. In addition, our analysis uncovers an unexpected connection between Nse1 and RNA polymerase I (RNAP I) ubiquitination. Specifically, Nse1 promotes the ubiquitination of K408 and K410 in A190, the largest subunit of RNAP I, to induce its degradation. We propose that this mechanism contributes to Smc5/6-dependent rDNA disjunction in response to transcriptional elongation defects.


title: Regulation of mitochondrial proteostasis by the proton gradient

abstract: Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multi-proteomic approach to demonstrate regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+/H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.


title: Glycine targets NINJ1-mediated plasma membrane rupture to provide cytoprotection

abstract:
First recognized 35 years ago, glycine is known to protect cells against plasma membrane rupture from diverse types of tissue injury. This robust and widely observed effect has been speculated to target a late downstream process common to multiple modes of tissue injury. The molecular target of glycine cytoprotection, however, remains entirely elusive. We hypothesized that glycine targets ninjurin-1 (NINJ1), a newly identified executioner of plasma membrane rupture in pyroptosis, necrosis, and post-apoptotic cell death. NINJ1 is thought to cluster within the plasma membrane to cause cell rupture. Here, we first demonstrate that NINJ1 knockout functionally and morphologically phenocopies glycine cytoprotection in mouse and human macrophages stimulated to undergo lytic cell death. Next, we show that glycine treatment prevents NINJ1 clustering thereby preserving cellular integrity. By identifying NINJ1 as a glycine target, our data help resolve a long-standing mechanism of glycine cytoprotection. This new understanding will inform the development of cell preservation strategies to counter pathologic lytic cell death pathways.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/471765v2_ufig1.gif" ALT="Figure 1">
View larger version (30K):
org.highwire.dtl.DTLVardef@b9c3d9org.highwire.dtl.DTLVardef@1e903f0org.highwire.dtl.DTLVardef@1018498org.highwire.dtl.DTLVardef@a819b9_HPS_FORMAT_FIGEXP  M_FIG C_FIG SummaryGlycine is known to protect cells against plasma membrane rupture from diverse types of tissue injury by an unknown mechanism. The authors demonstrate that NINJ1, a newly identified executioner of plasma membrane rupture across lytic cell death pathways, is a glycine target and resolve a longstanding mechanism of glycine cytoprotection.

category: cell biology


title: Plant morphometry matches beetle diversity: effects of natural adjacent vegetation on grain Amaranth crop under small-holder conditions

abstract: Grain Amaranth, Amaranthus hypochondriacus L., is an emerging arable crop cultivated worldwide. One way to obtain resources from the crop, other than grain, is to grow Amaranths in the dry season and harvest only the leaves. In this environmental condition the response of an Amaranth agroecosystem to the presence of natural and semi-natural habitats or other crops has not been studied yet. We analysed the response of (1) Amaranth morphometry and (2) alpha and beta diversity of beetles to the nearness of adjacent vegetation and natural habitats (such as deciduous forest) at the small-holder conditions. Our results showed that A. hypochondriacus crop plants responded positively to the presence of an ecotone (adjacent vegetation) and the natural habitat (deciduous forest), i.e., A. hypochondriacus plants grew bigger in the section nearest to adjacent vegetation, which was a pattern consistent in time. Moreover, for beetles (considered as a bioindicator group), richness was different amongst the study areas and negatively followed the gradient of perturbation. These results suggest that Amaranth crop is sensitive to the presence of natural and semi-natural habitats but not to other crops in the dry season. In addition, beetles match the response of Amaranth plants. This is the first time that this type of data is recorded in grain Amaranth agroecosystem and it will help to understand the interaction amongst grain Amaranth agroecosystems, biodiversity, and natural adjacent vegetation to boost ecosystem services.

category: ecology


title: Extreme drought triggers transition to an alternative soil microbial state

abstract: Soil microbial communities play a pivotal role in regulating ecosystem functioning1 but they are increasingly threatened by human-driven perturbations, including climate extremes, which are predicted to increase in frequency and intensity with climate change2. It has been demonstrated that soil microbial communities are sensitive to climate extremes, such as drought3,4, and that effects can be long-lasting5,6. However, considerable uncertainties remain concerning the response of soil microbial communities to increases in the intensity and frequency of climate extremes, and their potential to trigger transitions to alternative, and potentially deleterious, taxonomic and functional states7. Here we demonstrate that extreme, frequent drought induces a shift to an alternative soil microbial state characterised by strongly altered bacterial and fungal community structure of reduced complexity and functionality. Moreover, we found that this drought-induced alternative microbial state persisted after returning soil to its previous moisture status. However, bacterial communities were able to adapt by increasing their growth capacity, despite being of reduced diversity. Abrupt transitions to alternative states are well documented in aquatic and terrestrial plant communities in response to human-induced perturbations, including climate extremes8,9. Our results provide experimental evidence that such transitions also occur in soil microbial communities in response to extreme drought with potentially deleterious consequences for soil health.


title: Tabula Microcebus: A transcriptomic cell atlas of mouse lemur, an emerging primate model organism

abstract: Mouse lemurs are the smallest, fastest reproducing, and among the most abundant primates, and an emerging model organism for primate biology, behavior, health and conservation. Although much has been learned about their physiology and their Madagascar ecology and phylogeny, little is known about their cellular and molecular biology. Here we used droplet- and plate-based single cell RNA-sequencing to profile 226,000 cells from 27 mouse lemur organs and tissues opportunistically procured from four donors clinically and histologically characterized. Using computational cell clustering, integration, and expert cell annotation, we defined and biologically organized over 750 mouse lemur molecular cell types and their full gene expression profiles. These include cognates of most classical human cell types, including stem and progenitor cells, and the developmental programs for spermatogenesis, hematopoiesis, and other adult tissues. We also described dozens of previously unidentified or sparsely characterized cell types and subtypes. We globally compared cell type expression profiles to define the molecular relationships of cell types across the body, and explored primate cell type evolution by comparing mouse lemur cell profiles to those of the homologous cells in human and mouse. This revealed cell type specific patterns of primate cell specialization even within a single tissue compartment, as well as many cell types for which lemur provides a better human model than mouse. The atlas provides a cellular and molecular foundation for studying this primate model organism, and establishes a general approach for other emerging model organisms.


title: A Dual-reporter Platform for Screening Tumor-targeted Extracellular Vesicles

abstract: Extracellular vesicle (EV)-mediated transfer of biomolecules plays an essential role in intercellular communication and may improve targeted drug delivery. In the past decade, various approaches to EV surface modification for targeting specific cells or tissues have been proposed, including genetic engineering of parental cells or postproduction EV engineering. However, due to technical limitations, targeting moieties of engineered EVs have not been thoroughly characterized. Here, we report the bioluminescence resonance energy transfer (BRET) EV reporter, PalmReNL-based dual-reporter platform for characterizing the cellular uptake of tumor homing peptide (THP)-engineered EVs, targeting PDL1, uPAR, or EGFR proteins expressed in MDA-MB-231 breast cancer cells, simultaneously by bioluminescence measurement and fluorescence microscopy. Bioluminescence analysis of cellular EV uptake revealed the highest binding efficiency of uPAR-targeted EVs, whereas PDL1-targeted EVs showed slower cellular uptake. EVs engineered with two known EGFR-binding peptides via lipid nanoprobes did not increase cellular uptake, indicating that designs of EGFR-binding peptide conjugation to the EV surface are critical for functional EV engineering. Fluorescence analysis of cellular EV uptake allowed us to track individual PalmReNL-EVs bearing THPs in recipient cells. These results demonstrate that the PalmReNL-based EV assay platform can be a foundation for high-throughput screening of tumor-targeted EVs.

category: bioengineering


title: Prolonged XPO1 inhibition is essential for optimal anti-leukemic activity in NPM1-mutated AML

abstract: NPM1 encodes for a nucleolar multifunctional protein and is the most frequently mutated gene in adult acute myeloid leukemia (AML). NPM1 mutations cause the aberrant accumulation of mutant NPM1 (NPM1c) in the cytoplasm of leukemic cells, that is mediated by the nuclear exporter Exportin-1 (XPO1). Recent work has demonstrated that the interaction between NPM1c and XPO1 promotes high homeobox (HOX) genes expression, which is critical for maintaining the leukemic state of NPM1-mutated cells. However, the XPO1 inhibitor Selinexor administered once or twice/week in early-phase clinical trials did not translate into clinical benefit for NPM1-mutated AML patients. Here, we demonstrate that this dosing strategy results in only temporary disruption of the XPO1-NPM1c interaction and transient HOX genes downregulation, limiting the efficacy of Selinexor in the context of NPM1-mutated AML. Since second-generation XPO1 inhibitors can be administered more frequently, we compared intermittent (twice/week) versus prolonged (5 days/week) XPO1 inhibition in NPM1-mutated AML models. Integrating in vitro and in vivo data, we show that only prolonged XPO1 inhibition results in stable HOX downregulation, cell differentiation and remarkable anti-leukemic activity. This study lays the groundwork for the accurate design of clinical trials with second-generation XPO1 inhibitors in NPM1-mutated AML.

category: cancer biology


title: De-novo generation of novel phenotypically active molecules for Chagas disease from biological signatures using AI-driven generative chemistry

abstract: Designing novel molecules with targeted biological activities and optimized physicochemical properties is a challenging endeavor in drug discovery. Recent developments in artificial intelligence have enhanced the early steps of de novo drug design and compound optimization. Herein, we present a generative adversarial network trained to design new chemical matter that satisfies a given biological signature. Our model, called pqsar2cpd, is based on the activity of compounds across multiple assays obtained via pQSAR (profile-quantitative structure-activity relationships). We applied pqsar2cpd to Chagas disease and designed a novel molecule that was experimentally confirmed to inhibit growth of parasites in vitro at low micromolar concentrations. Altogether, this approach bridges chemistry and biology into one single framework for the design of novel molecules with promising biological activity.

category: pharmacology and toxicology


title: Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo

abstract: The eIF2 initiation complex is central to maintaining a functional translation machinery. Extreme stress such as life-threatening sepsis exposes vulnerabilities in this tightly regulated system, resulting in an imbalance between the opposing actions of kinases and phosphatases on the main regulatory subunit eIF2. Here, we report that translation shutdown is a hallmark of established sepsis-induced kidney injury brought about by excessive eIF2 phosphorylation and sustained by blunted expression of the counterregulatory phosphatase subunit Ppp1r15a. We determined that the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic approaches enabled the derepression of Ppp1r15a, salvaged translation and improved kidney function in an endotoxemia model. We also found that the loss of this uORF has broad effects on the composition and phosphorylation status of the immunopeptidome that extended beyond the eIF2 axis. Collectively, our findings define the breath and potency of the highly conserved Ppp1r15a uORF and provide a paradigm for the design of uORF-based translation rheostat strategies. The ability to accurately control the dynamics of translation during sepsis will open new paths for the development of therapies at codon level precision.

category: physiology


title: Food Restriction Augmented Alpha1 Adrenergic Mediated Contraction in Mesenteric Arteries

abstract: Food restriction (FR) enhances the sensitivity to cardiopulmonary reflexes and 1- adrenoreceptors in the female, despite hypotension. The effect of male FR on cardiopulmonary and systemic vascular function is not well understood. This study examines the effects of FR on cardiopulmonary, isolated mesenteric arterial function and potential underlying mechanisms. We hypothesized that FR decreased eNOS activity in mesenteric arteries. Male Sprague Dawley (SD) rats were randomly divided into three groups: (1) control (n=30), (2) 20 percent of food reduction (FR20, n=30), and (3) 40 percent of food reduction (FR40, n=30) for five weeks. Non-invasive blood pressure was measured twice a week. Pulmonary arterial pressure (PAP) was measured using isolated/perfused lungs in rats. The isolated vascular reactivity was assessed in double-wire myograph. After five weeks, food restricted rats exhibited a lower mean arterial pressure and heart rate, however, only FR40 groups exhibited statistically significant differences. The basal tone of PAP and various vasoconstrictors did not show significant differences in pulmonary circulation between each group. We observed that food restriction were enhanced the sensitivity (EC50) in response to 1-adrenoreceptors (phenylephrine, PhE)-induced vasoconstriction, but not to serotonin, U46619, and high K+ in the mesenteric arteries. FR reduced endothelium-dependent relaxation via decreased function of endothelial nitric oxide synthase (eNOS)-nitric oxide (NO) pathway in the mesenteric arteries. PhE-mediated vasoconstriction in mesenteric arteries was eliminated in the presence of eNOS inhibitor (L-NAME). In addition, incubation with NOX2/4 inhibitors (apocynin, GKT137831, VAS2870) and reactive oxygen species (ROS) scavenger inhibitor (Tiron) were eliminated the differences of PhE-mediated vasoconstriction but not to cyclooxygenase inhibitor (indomethacin) in the mesenteric artery. Augmentation of 1-adrenergic mediated contraction via inhibition of eNOS-NO pathway by increased activation of ROS through NOX2/4 in response to FR. Reduced eNOS-NO signaling might be a pathophysiological counterbalance to prevent hypovolemic shock in response to FR.


title: Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion

abstract: TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization. How TMEM16F is activated during cell fusion is unclear. Here, we used trophoblasts as a model for cell fusion and demonstrated that Ca2+ influx through Ca2+ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. Patch-clamp electrophysiology demonstrated that TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in human trophoblasts. Pharmacological inhibition or gene silencing of TRPV4 hindered TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and a physiological activation mechanism of TMEM16F in human trophoblasts, thus providing us with novel strategies to regulate CaPLSase activity as a critical checkpoint of physiologically- and disease-relevant cell fusion events.


title: IGF1 Receptor Regulates Upward Firing Rate Homeostasis via the Mitochondrial Calcium Uniporter

abstract: Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca2+ has long been hypothesized to be a feedback control signal, the molecular machinery enabling network-wide homeostatic response remains largely unknown. Here we show that deletion of insulin-like growth factor-1 receptor (IGF1R), a well-known regulator of neurodevelopment and ageing, limits firing rate homeostasis in response to inactivity, without altering the baseline firing rate distribution. Disruption of both synaptic and intrinsic homeostatic plasticity contributed to deficient firing rate homeostatic response. At the cellular level, a fraction of IGF1Rs was localized in mitochondria with the mitochondrial calcium uniporter complex (MCUc). IGF1R deletion suppressed spike burst-evoked mitochondrial Ca2+ (mitoCa2+) by weakening mitochondria-to-cytosol Ca2+ coupling. MCUc overexpression in IGF1R-deficient neurons rescued the deficits in spike-to-mitoCa2+ coupling and firing rate homeostasis. Our findings highlight IGF1R as a key regulator of the integrated homeostatic response by tuning mitochondrial temporal filtering. Decline in mitochondrial reliability for burst transfer may drive dysregulation of firing rate homeostasis in ageing and brain disorders associated with aberrant IGF1R / MCUc signaling.


title: Coral larvae suppress the heat stress response during the onset of symbiosis thereby decreasing their odds of survival

abstract: The endosymbiosis between most corals and their photosynthetic dinoflagellate partners begins early in the host life history, when corals are larvae or juvenile polyps. The capacity of coral larvae to buffer climate-induced stress while in the process of symbiont acquisition could come with physiological trade-offs that alter larval behavior, development, settlement and survivorship. Here we examined the joint effects of thermal stress and symbiosis onset on colonization dynamics, survival, metamorphosis and host gene expression of Acropora digitifera larvae. We found that thermal stress decreased symbiont colonization of hosts by 50% and symbiont density by 98.5% over two weeks. Temperature and colonization also influenced larval survival and metamorphosis in an additive manner, where colonized larvae fared worse or prematurely metamorphosed more often than non-colonized larvae under thermal stress. Transcriptomic responses to colonization and thermal stress treatments were largely independent, while the interaction of these treatments revealed contrasting expression profiles of genes that function in the stress response, immunity, inflammation and cell cycle regulation. The combined treatment either canceled or lowered the magnitude of expression of heat-stress responsive genes in the presence of symbionts, revealing a physiological cost to acquiring symbionts at the larval stage with elevated temperatures. In addition, host immune suppression, a hallmark of symbiosis onset under ambient temperature, turned to immune activation under heat stress. Thus, by integrating the physical environment and biotic pressures that mediate pre-settlement event in corals, our results suggest that colonization may hinder larval survival and recruitment creating isolated, genetically similar populations under projected climate scenarios.


title: Phylogenomics unravels the early diversification of fungi

abstract: Phylogenomic analyses have boosted our understanding of the evolutionary trajectories of all living forms by providing continuous improvements to the tree of life1-5. Within this tree, fungi represent an ancient eukaryote group6, having diverged from the animals [~]1.35 billion years ago7. Estimates of the number of extant species range between 1.5 and 3.8 million8,9. Recent reclassifications and the discovery of the deep-branching Sanchytriomycota lineage10 have brought the number of proposed phyla to 2011; 21 if the Microsporidia are included12-14. Uncovering how the diverse and globally distributed fungi are related to each other is fundamental for understanding how their lifestyles, morphologies, and metabolic capacities evolved. To date, many of the proposed relationships among the phyla remain controversial and no phylogenomic study has examined the entire fungal tree using a taxonomically comprehensive data set and suitable models of evolution. We assembled and curated a 299-protein data set with a taxon sampling broad enough to encompass all recognised fungal diversity with available data, but selective enough to run computationally intensive analyses using best-fitting models. Using a range of reconstruction methods, we were able to resolve many contested nodes, such as a sister-relationship of Chytridiomyceta to all other non-Opisthosporidia fungi (with Chytridiomycota being sister to Monoblepharomycota + Neocallimastigomycota), a branching of Blastocladiomycota + Sanchytriomycota after the Chytridiomyceta but before other non-Opisthosporidia fungi, and a branching of Glomeromycota as sister to the Dikarya. Our most up-to-date fungal tree of life will serve as a springboard for future investigations on the evolution of fungi.


title: Sensitizing solid tumors to CAR-mediated cytotoxicity using synthetic antigens

abstract: CAR T cell immunotherapy relies on CAR targeting of tumor-associated antigens, yet heterogenous antigen expression, interpatient variation, and off-tumor expression by healthy cells remain barriers. Here, we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by viral vectors. Using the RSV-F camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of VHH CAR T cells to mice bearing VHH expressing tumors reduced tumor burden in multiple syngeneic mouse models of cancer, improved survival, induced epitope spread, and protected against tumor rechallenge. Our work supports in situ delivery of synthetic antigens to treat antigen low or negative tumors with CAR T cells.


title: Characterization of individual HIV-1 budding event using ultra-fast atomic force microscopy reveals a multiplexed role for VPS4

abstract: The assembly and budding of newly formed human immunodeficiency virus-1 (HIV-1) particles occur at the plasma membrane of infected cells. Whereas the molecular basis for viral budding has been studied extensively, investigation of its spatiotemporal characteristics has been limited by the small dimensions (< 100 nm) of HIV particles and the fast kinetics of the process (a few minutes from bud formation to virion release). Here we applied ultra-fast atomic force microscopy to achieve real-time visualization of individual HIV-1 budding events from wildtype (WT) cell lines as well as from mutated lines lacking vacuolar protein sorting-4 (VPS4) or visceral adipose tissue-1 protein (VTA1). Using single-particle analysis, we show that HIV-1 bud formation follows two kinetic pathways (fast and slow) with each composed of three distinct phases (growth, stationary, decay). Notably, approximately 30% of events did not result in viral release and were characterized by the formation of short (rather than tall) particles that slowly decayed back into the cell membrane. These non-productive events became more abundant in VPS4 knockout cell lines. Strikingly, the absence of VPS4B, rather than VPS4A, increased the production of short viral particles, suggesting a role for VPS4B in earlier stages of HIV-1 budding than traditionally thought.


title: Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size.

abstract: Cellular competition for limiting hematopoietic factors is a physiologically regulated but poorly understood process. Here, we studied this phenomenon by hampering hematopoietic progenitor access to Leptin receptor+ mesenchymal stem/progenitor cells (MSPCs) and endothelial cells (ECs). We show that HSC numbers increased by 2-fold when multipotent and lineage-restricted progenitors failed to respond to CXCL12 produced by MSPCs and ECs. HSCs were qualitatively normal, and HSC expansion only occurred when early hematopoietic progenitors but not differentiated hematopoietic cells lacked CXCR4. Furthermore, the MSPC and EC transcriptomic heterogeneity was remarkably stable, suggesting that it is impervious to dramatic changes in hematopoietic progenitor interactions. Instead, HSC expansion was caused by increased availability of membrane-bound stem cell factor (mSCF) on MSPCs and ECs due to reduced consumption by cKit-expressing hematopoietic progenitors. These studies revealed an intricate homeostatic balance between HSCs and proximal hematopoietic progenitors regulated by cell competition for limited amounts of mSCF.


title: Clonal hematopoiesis is driven by aberrant activation of TCL1A

abstract: A diverse set of driver genes, such as regulators of DNA methylation, RNA splicing, and chromatin remodeling, have been associated with pre-malignant clonal expansion of hematopoietic stem cells (HSCs). The factors mediating expansion of these mutant clones remain largely unknown, partially due to a paucity of large cohorts with longitudinal blood sampling. To circumvent this limitation, we developed and validated a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate). Applying PACER to 5,071 persons with clonal hematopoiesis accurately recapitulated the known fitness effects due to different driver mutations. A genome-wide association study of PACER revealed that a common inherited polymorphism in the TCL1A promoter was associated with slower clonal expansion. Those carrying two copies of this protective allele had up to 80% reduced odds of having driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 by CRISPR editing led to aberrant expression of TCL1A and expansion of HSCs in vitro. These effects were abrogated in HSCs from donors carrying the protective TCL1A allele. Our results indicate that the fitness advantage of multiple common driver genes in clonal hematopoiesis is mediated through TCL1A activation. PACER is an approach that can be widely applied to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues.


title: 21/2-minute 3D 7T 31P-MRSI of the human heart using concentric rings (CRT)

abstract:
A 3D density-weighted concentric ring trajectory (CRT) MRSI sequence is implemented for cardiac 31P-MRS at 7T.

The point-by-point k-space sampling of traditional phase-encoded CSI sequences severely restricts the minimum scan time at higher spatial resolutions. Our proposed CRT sequence implements a stack of concentric rings trajectory, with a variable number of rings and planes spaced to optimise the density of k-space weighting. This creates flexibility in acquisition time, allowing acquisitions substantially faster than traditional phase-encoded CSI sequences, while retaining high SNR.

We first characterise the signal-to-noise ratio and point spread function of the CRT sequence in phantoms. We then evaluate it at five different acquisition times and spatial resolutions in the hearts of five healthy participants at 7T. These different sequence durations are compared with existing published 3D acquisition-weighted CSI sequences with matched acquisition times and spatial resolutions. To minimise the effect of noise on the short acquisitions, low-rank denoising of the spatio-temporal data was also performed after acquisition.

The proposed sequence measures 3D localised PCr/ATP ratios of the human myocardium in 2.5 minutes, 2.6 times faster than the minimum scan time for the acquisition-weighted phase-encoded CSI. Alternatively, in the same scan time a 1.7-times smaller nominal voxel volume can be achieved. Low-rank denoising reduced the variance of measured PCr/ATP ratios by 11% across all protocols. The faster acquisitions permitted by 7T CRT 31P-MRSI could make cardiac stress protocols or creatine kinase rate measurements (which involve repeated scans) more tolerable for patients without sacrificing spatial resolution.


title: Reliability of transcranial magnetic stimulation evoked potentials to detect the effects of theta-burst stimulation of the prefrontal cortex

abstract:
BackgroundTranscranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) is a novel method for assessing cortical properties outside the motor region. Theta burst stimulation (TBS), a form of repetitive TMS, can non-invasively modulate cortical excitability and has been increasingly used to treat psychiatric disorders by targetting the dorsolateral prefrontal cortex (DLPFC). The TMS-evoked potentials (TEPs) analysis has been used to evaluate cortical excitability changes after TBS. However, it remains unclear whether TEPs can detect the neuromodulatory effects of TBS.

ObjectivesTo confirm the reliability of TEP components within and between sessions and to measure changes in neural excitability induced by intermittent (iTBS) and continuous TBS (cTBS) applied to the left DLPFC.

MethodsTest-retest reliability of TEPs and TBS-induced changes in cortical excitability were assessed in twenty-four healthy participants by stimulating the DLPFC in five separate sessions, once with sham and twice with iTBS and cTBS. EEG responses were recorded of 100 single TMS pulses before and after TBS, and the reproducibility measures were quantified with the concordance correlation coefficient (CCC).

ResultsThe N100 and P200 components presented substantial reliability within the baseline block (CCCs>0.8) and moderate concordance between sessions (CCCmax{approx}0.7). Both N40 and P60 TEP amplitudes showed little concordance between sessions. Changes in TEP amplitudes after iTBS were marginally reliable for N100 (CCCmax=0.52), P200 (CCCmax=0.47) and P60 (CCCmax=0.40), presenting only fair levels of concordance at specific time points.

ConclusionsThe present findings show that only the N100 and P200 components had good concordance between sessions. The reliability of earlier components may have been affected by TMS-evoked artefacts. The poor reliability to detect changes in neural excitability induced by TBS indicates that TEPs do not provide a precise estimate of the changes in excitability in the DLPFC or, alternatively, that TBS did not induce consistent changes in neural excitability.


title: Test-retest reproducibility of in vivo magnetization transfer ratio and saturation index in mice at 9.4 Tesla

abstract:
BackgroundMagnetization transfer saturation (MTsat) imaging was developed to reduce T1 dependence and improve specificity to myelin compared to the widely used MT ratio (MTR), while maintaining a feasible scan time. Knowledge of MTsat reproducibility is necessary to apply MTsat in preclinical neuroimaging.

PurposeTo assess the test-retest reproducibility of MTR and MTsat in the mouse brain at 9.4 T and calculate sample sizes required to detect various effect sizes.

Study TypeProspective

Animal ModelC57Bl/6 Mouse Model (6 females and 6 males, aged 12 - 14 weeks)

Field Strength/SequenceMagnetization Transfer Imaging at 9.4 T

AssessmentAll mice were scanned at two timepoints (5 days apart). MTR and MTsat maps were analyzed using mean region-of-interest (ROI), and whole brain voxel-wise analysis.

Statistical TestsBland-Altman plots assessed biases between test and retest measurements. Test-retest reproducibility was evaluated via between and within-subject coefficients of variation (CV). Sample sizes required were calculated (at a 95 % significance level and power of 80 %), given various minimum detectable effect sizes, using both between and within-subject approaches.

ResultsBland-Altman plots showed negligible biases between test and retest sessions. ROI-based and voxel-wise CVs revealed high reproducibility for both MTR (ROI: CVs < 8 %) and MTsat (ROI: CVs < 10 %). With a sample size of 6, changes on the order of 15% can be detected in MTR and MTsat, both between and within subjects, while smaller changes (6 - 8 %) require sample sizes of 10 - 15 for MTR, and 15 - 20 for MTsat.

Data ConclusionMTsat exhibits comparable reproducibility to MTR, while providing sensitivity to myelin with less T1 dependence than MTR. Our findings suggest both MTR and MTsat can detect moderate changes, common in pathologies, with feasible preclinical sample sizes.


title: Predicting proprioceptive cortical anatomy and neural coding with topographic autoencoders

abstract: Proprioception is one of the least understood senses yet fundamental for the control of movement. Even basic questions of how limb pose is represented in the somatosensory cortex are unclear. We developed a variational autoencoder with topographic lateral connectivity (topo-VAE) to compute a putative cortical map from a large set of natural movement data. Although not fitted to neural data, our model reproduces two sets of observations from monkey centre-out reaching: 1. The shape and velocity dependence of proprioceptive receptive fields in hand-centered coordinates despite the model having no knowledge of arm kinematics or hand coordinate systems. 2. The distribution of neuronal preferred directions (PDs) recorded from multi-electrode arrays. The model makes several testable predictions: 1. Encoding across the cortex has a blob-and-pinwheel-type geometry PDs. 2. Few neurons will encode just a single joint. Topo-VAE provides a principled basis for understanding of sensorimotor representations, and the theoretical basis of neural manifolds, with applications to the restoration of sensory feedback in brain-computer interfaces and the control of humanoid robots.


title: ForestScanner: A mobile application for measuring and mapping trees with LiDAR-equipped iPhone and iPad

abstract:
O_LIGround-based light detection and ranging (LiDAR) is becoming increasingly popular as an alternative means to conventional forest inventory methods. By gauging the distances to multiple points on the surrounding object surfaces, LiDAR acquires 3D point clouds from which tree sizes and spatial distributions can be rapidly estimated. However, the high cost and specialized skills associated with LiDAR technologies have put them out of reach for many potential users.
C_LIO_LIWe here introduce ForestScanner, a free, mobile application that allows LiDAR-based forest inventories by means of iPhone or iPad with a built-in LiDAR sensor. ForestScanner does not require any manual analysis of 3D point clouds. As the user scans trees with an iPhone/iPad, ForestScanner estimates the stem diameters and spatial coordinates based on real-time instance segmentation and circle fitting. The users can visualize, check, and share the scanning results in situ.
C_LIO_LIBy using ForestScanner, we measured the stem diameters and spatial coordinates of 672 trees within a 1 ha plot in 1 h 39 min with an iPhone and in 1 h 38 min with an iPad (diameter [≥]5 cm; detection rate = 100%). The diameters measured by ForestScanner and a diameter tape were in good agreement; R2=0.963 for iPhone and R2=0.961 for iPad. ForestScanner and a conventional surveying system showed almost identical results for tree mapping (assessed by the spatial distances among trees within 0.04 ha subplots); Mantel R2=0.999 for both iPhone and iPad. ForestScanner reduced the person-hours required for measuring diameters to 25.7%, mapping trees to 9.3%, and doing both to 6.8% of the person-hours taken using a dimeter tape and the conventional surveying system.
C_LIO_LIOur results indicate that ForestScanner enables cost-, labor-, and time-efficient forest inventories. The application can increase the accessibility to LiDAR for non-experts (e.g., students, citizen scientists) and enhance resource assessments and biodiversity monitoring in forests worldwide.
C_LI


title: The economic burden of protecting islands from invasive alien species

abstract: Biological invasions represent a key threat to island ecosystems, with pronounced impacts across environments and economies. The ecological impacts have received substantial focus, but the economic costs have lacked synthesis at spatial and temporal scales. Here we utilise the InvaCost database, the most comprehensive global assessment of published economic costs of invasive species, to assess reported spend by cost types and socioeconomic sectors, and to examine temporal trends in spending, across islands that differ in their political geography - nation states, overseas territories or offshore islands of continental countries. We based this assessment on 1473 unique cost entries comprising 2914 annual costs totalling almost US$100 million in area-corrected costs between 1965-2020. We find that offshore islands of continental countries incur the greatest total and management costs. However, nation states incurred the greatest damage costs whilst substantially financing management actions, and spent an overall greater proportion of their GDP. In contrast, spending within overseas territories was significantly lower in all respects. The most impacted sector was authorities and stakeholders, demonstrating the key role of government in addressing island invasions. Temporal trends revealed continual increases in spending across all island types. This likely reflects ongoing introduction rates globally alongside an increased recognition of the importance of islands as biodiversity hotspots, and an appetite to tackle invasive species at larger and more socially complex scales. However, the high economic costs of invasions on islands substantiates the need to prevent them in order to avoid this dire threat to biodiversity and its burden on limited conservation resources.


title: Developing an empirical model for spillover and emergence: Orsay virus host range in Caenorhabditis

abstract: A lack of tractable experimental systems in which to test hypotheses about the ecological and evolutionary drivers of disease spillover and emergence has limited our understanding of these processes. Here we introduce a promising system: Caenorhabditis hosts and Orsay virus, a positive-sense single-stranded RNA virus that naturally infects C. elegans. We assayed the susceptibility of species across the Caenorhabditis tree and found 21 of 84 wild strains belonging to 14 of 44 species to be susceptible to Orsay virus. Confirming patterns documented in other systems, we detected effects of host phylogeny on susceptibility. We then tested whether susceptible strains were capable of transmitting Orsay virus by transplanting exposed hosts and determining whether they transmitted infection to conspecifics during serial passage. We found no evidence of transmission in 10 strains (virus undetectable after passaging), evidence of low-level transmission in 5 strains (virus lost between passage 1 and 5), and evidence of sustained transmission in 6 strains (including all 3 experimental C. elegans strains). Transmission was associated with host phylogeny and with viral amplification in exposed populations. Variation in Orsay virus susceptibility and transmission among Caenorhabditis species suggests that the system could be powerful for studying spillover and emergence.


title: Measuring drift by mean deviation: unequal breeding sex ratio revisited

abstract: With the growing amount and diversity of intermediate omics data complementary to genomics (e.g., DNA methylation, gene expression, and protein abundance), there is a need to develop methods to incorporate intermediate omics data into conventional genomic evaluation. The omics data helps decode the multiple layers of regulation from genotypes to phenotypes, thus forms a connected multi-layer network naturally. We developed a new method named NN-LMM to model the multiple layers of regulation from genotypes to intermediate omics features, then to phenotypes, by extending conventional linear mixed models ("LMM") to multi-layer artificial neural networks ("NN"). NN-LMM incorporates intermediate omics features by adding middle layers between genotypes and phenotypes. Linear mixed models (e.g., pedigree-based BLUP, GBLUP, Bayesian Alphabet, single-step GBLUP, or single-step Bayesian Alphabet) can be used to sample marker effects or genetic values on intermediate omics features, and activation functions in neural networks are used to capture the nonlinear relationships between intermediate omics features and phenotypes. NN-LMM had significantly better prediction performance than the recently proposed single-step approach for genomic prediction with intermediate omics data. Compared to the single-step approach, NN-LMM can handle various patterns of missing omics measures, and allows nonlinear relationships between intermediate omics features and phenotypes. NN-LMM has been implemented in an open-source package called "JWAS".


title: Climate Change, Crop Wild Relatives and Genomic Data: The persistence and agronomic utility of five Vitis species

abstract: Crop wild relatives (CWRs) have the capacity to contribute novel traits to agriculture. Given climate change, these contributions may be especially vital for perennial crops, because perennials are often clonally propagated and consequently do not evolve rapidly. By studying the landscape genomics of five Vitis CWRs (V. arizonica, V. mustangensis, V. riparia, V. berlandieri and V. girdiana) in the context of projected climate change, we addressed two goals. The first was assessing the relative potential of different CWRs to persist in the context of climate change. By integrating species distribution models with adaptive genetic variation, additional genetic features such as genomic load, and a phenotype (resistance to Pierces Disease), we predicted that accessions of V. mustangensis are particularly well-suited to persist. The second goal was identifying candidate CWRs to contribute to bioclimatic adaptation for grapevine (V. vinifera) cultivation. To do so, we first estimated that [~]40% of current viticulture sites in the United States will be vulnerable to climate change, based on species distribution models projected to 2070. We then predicted which CWRs have the genomic profile to contribute to bioclimatic adaptation at these vulnerable sites. We identified rootstock candidates from V. mustangensis, V. riparia and V. girdiana and hypothesized that they may prove useful for mitigating climate impacts on viticulture. By identifying candidate germplasm, this work takes a conceptual step toward mitigating the climate impacts on crops by utilizing the genomic and bioclimatic characteristics of CWRs.


title: A Transcriptomic and Proteomic Atlas of Obesity and Type 2 Diabetes in Cynomolgus Monkeys

abstract: Obesity and type 2 diabetes (T2D) remain major global healthcare challenges and developing therapeutics necessitate using nonhuman primate models. Here, we present transcriptomic and proteomic analyses of all the major organs of cynomolgus monkeys with spontaneous obesity or T2D in comparison to healthy controls. Molecular changes occur predominantly in the adipose tissues of individuals with obesity, while extensive expression perturbations among T2D individuals are observed in many tissues, such as the liver, kidney, brain, and heart. Immune response-related pathways are upregulated in obesity and T2D, whereas metabolism and mitochondrial pathways are downregulated. Incorporating human single-cell RNA sequencing findings corroborates the role of macrophages and monocytes in obesity. Moreover, we highlight some potential therapeutic targets including SLC2A1 and PCSK1 in obesity as well as SLC30A8 and SLC2A2 in T2D. Our findings provide insights into tissue-specific molecular foundations of obesity and T2D and reveal the mechanistic links between these two metabolic disorders.


title: Computer Modeling of Radiofrequency Cardiac Ablation including Heartbeat-Induced Electrode Displacement

abstract:
BackgroundThe state of the art in computer modeling of radiofrequency catheter ablation (RFCA) only considers a static model, i.e. it does not allow modeling ablation electrode displacements induced by tissue movement due to heartbeats. This feature is theoretically required, since heartbeat-induced changes in contact force can be detected during this clinical procedure.

MethodsWe built a 2D RFCA model coupling electrical, thermal and mechanical problems and simulated a standard energy setting (25 W - 30 s). The mechanical interaction between the ablation electrode and tissue was dynamically modeled to reproduce heartbeat-induced changes in the electrode insertion depth from 0.86 to 2.05 mm, which corresponded with contact forces between 10 and 30 g when cardiac tissue was modeled by a hyperelastic Neo-Hookean model with a Youngs modulus of 75 kPa and Poissons ratio of 0.49.

ResultsThe dynamic model computed a lesion depth of 5.86 mm, which is within the range of previous experimental results based on a beating heart for a similar energy setting and contact force (5.6-6.7 mm). Lesion size was practically identical (differences less than 0.02 mm) to that using a static model with the electrode inserted to an average depth (1.46 mm, equivalent to 20 g contact force).

ConclusionsThe RFCA dynamic model including heartbeat-induced electrode displacement predicts lesion depth reasonably well compared to previous experimental results based on a beating heart model, however this is true only at a standard energy setting and moderate contact force.


title: A single latent channel is sufficient for biomedical image segmentation

abstract: Glottis segmentation is a crucial step to quantify endoscopic footage in laryngeal high-speed videoendoscopy. Recent advances in using deep neural networks for glottis segmentation allow a fully automatic workflow. However, exact knowledge of integral parts of these segmentation deep neural networks remains unknown. Here, we show using systematic ablations that a single latent channel as bottleneck layer is sufficient for glottal area segmentation. We further show that the latent space is an abstraction of the glottal area segmentation relying on three spatially defined pixel subtypes. We provide evidence that the latent space is highly correlated with the glottal area waveform, can be encoded with four bits, and decoded using lean decoders while maintaining a high reconstruction accuracy. Our findings suggest that glottis segmentation is a task that can be highly optimized to gain very efficient and clinical applicable deep neural networks. In future, we believe that online deep learning-assisted monitoring is a game changer in laryngeal examinations.


title: Discrete Protein Metric (DPM): A new image similarity metric to calculate accuracy of deep learning-generated cell focal adhesion predictions

abstract: Understanding cell behaviors can provide new knowledge on the development of different pathologies. Focal adhesion (FA) sites are important sub-cellular structures that are involved in these processes. To better facilitate the study of FA sites, deep learning (DL) can be used to predict FA site morphology based on limited datasets (e.g., cell membrane images). However, calculating the accuracy score of these predictions can be challenging due to the discrete/point pattern like nature of FA sites. In the present work, a new image similarity metric, discrete protein metric (DPM), was developed to calculate FA prediction accuracy. This metric measures differences in distribution (d), shape/size (s), and angle (a) of FA sites between the predicted image and its ground truth image. Performance of the DPM was evaluated by comparing it to three other commonly used image similarity metrics: Pearson correlation coefficient (PCC), feature similarity index (FSIM), and Intersection over Union (IoU). A sensitivity analysis was performed by comparing changes in each metric value due to quantifiable changes in FA site location, number, aspect ratio, area, or orientation. Furthermore, accuracy score of DL-generated predictions was calculated using all four metrics to compare their ability to capture variation across samples. Results showed better sensitivity and range of variation for DPM compared to the other metrics tested. Most importantly, DPM had the ability to determine which FA predictions were quantitatively more accurate and consistent with qualitative assessments. The proposed DPM hence provides a method to validate DL-generated FA predictions and can be extended to evaluating other predicted or segmented discrete structures of biomedical relevance.


title: OptDesign: Identifying Optimum Design Strategies in Strain Engineering for Biochemical Production

abstract: Computational tools have been widely adopted for strain optimisation in metabolic engineering, contributing to numerous success stories of producing industrially relevant biochemicals. However, most of these tools focus on single metabolic intervention strategies (either gene/reaction knockout or amplification alone) and rely on hypothetical optimality principles (e.g., maximisation of growth) and precise gene expression (e.g., fold changes) for phenotype prediction. This paper introduces OptDesign, a new two-step strain design strategy. In the first step, OptDesign selects regulation candidates that have a noticeable flux difference between the wild type and production strains. In the second step, it computes optimal design strategies with limited manipulations (combining regulation and knockout) leading to high biochemical production. The usefulness and capabilities of OptDesign are demonstrated for the production of three biochemicals in E. coli using the latest genome-scale metabolic model iML1515, showing highly consistent results with previous studies while suggesting new manipulations to boost strain performance. Source code is available at https://github.com/chang88ye/OptDesign.


title: robustica: customizable robust independent component analysis

abstract:
BackgroundIndependent Component Analysis (ICA) allows the dissection of omic datasets into modules that help to interpret global molecular signatures. The inherent randomness of this algorithm can be overcome by clustering many iterations of ICA together to obtain robust components. Existing algorithms for robust ICA are dependent on the choice of clustering method and on computing a potentially biased and large Pearson distance matrix.

ResultsWe present robustica, a Python-based package to compute robust independent components with a fully customizable clustering algorithm and distance metric. Here, we exploited its customizability to revisit and optimize robust ICA systematically. From the 6 popular clustering algorithms considered, DBSCAN performed the best at clustering independent components across ICA iterations. After confirming the bias introduced with Pearson distances, we created a subroutine that infers and corrects the components signs across ICA iterations to enable using Euclidean distance. Our subroutine effectively corrected the bias while simultaneously increasing the precision, robustness, and memory efficiency of the algorithm. Finally, we show the applicability of robustica by dissecting over 500 tumor samples from low-grade glioma (LGG) patients, where we define a new gene expression module with the key modulators of tumor aggressiveness downregulated upon IDH1 mutation.

Conclusionrobustica brings precise, efficient, and customizable robust ICA into the Python toolbox. Through its customizability, we explored how different clustering algorithms and distance metrics can further optimize robust ICA. Then, we showcased how robustica can be used to discover gene modules associated with combinations of features of biological interest. Taken together, given the broad applicability of ICA for omic data analysis, we envision robustica will facilitate the seamless computation and integration of robust independent components in large pipelines.

Contactmiquel.anglada@crg.eu

category: systems biology


title: Sensory convergence in the world s largest cavefish diversification: patterns of neuromast evolution, distribution and associated behaviour in Sinocyclocheilus

abstract: The genus Sinocyclocheilus represents the largest freshwater cavefish genus in the world. This emerging model system is endemic to the southern Chinese karstic landscape, and demonstrates multiple adaptations for caves (troglomorphism), with eye-degeneration being the most pronounced. The less-apparent lateral line system, which is often expanded in cave-dwellers, has been studied in other cavefish systems, but never in the context of this diversification. Here we investigated the distribution and evolution of cephalic neuromasts in 26 Sinocyclocheilus species. We used live-staining and behavioural assays, and interpreted results in a phylogenetic context. We show that asymmetry in neuromast features and the rate of evolution is greater in cave-adapted species. Ancestral state reconstructions show that most Sinocyclocheilus are right-biased with some scatter, and show convergence of neuromast phenotypes. There is substantial variation in cephalic neuromast distribution patterns between and (to a lesser extent) within species. Behavioural assays show blind species have a distinctive wall-following behaviour. We explain these patterns in the context of the deep evolutionary history associated with this karstic region, other organismal traits, and habitat occupation of these remarkable diversifications of fishes. Interestingly, some of these neuromast patterns and behaviour show convergence with other phylogenetically distant cavefish systems.

category: zoology


title: High-speed, multi-Z confocal microscopy for voltage imaging in densely labeled neuronal populations

abstract: Genetically encoded voltage indicators (GEVIs) hold great promise for monitoring neuronal population activity, but GEVI imaging in dense neuronal populations remains difficult due to a lack of contrast and/or speed. To address this challenge, we developed a novel confocal microscope that allows simultaneous multiplane imaging with high-contrast at near-kHz rates. This approach enables high signal-to-noise ratio voltage imaging in densely labeled populations and minimizes optical crosstalk during concurrent optogenetic photostimulation.

category: neuroscience


title: Evaluating denoising strategies in resting-state fMRI in traumatic brain injury (EpiBioS4Rx)

abstract:
ObjectiveResting-state functional MRI is increasingly used in the clinical setting and is now included in some diagnostic guidelines for severe brain injury patients. However, to ensure high-quality data, one should mitigate fMRI-related noise typical of this population. Therefore, we aimed to evaluate the ability of different preprocessing strategies to mitigate noise-related signal (i.e., in-scanner movement and physiological noise) in functional connectivity of traumatic brain injury patients.

MethodsWe applied nine commonly used denoising strategies, combined into 17 pipelines, to 88 traumatic brain injury patients from the Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy clinical trial (EpiBioS4Rx). Pipelines were evaluated by three quality control metrics across three exclusion regimes based on the participants head movement profile.

ResultsWhile no pipeline eliminated noise effects on functional connectivity, some pipelines exhibited relatively high effectiveness depending on the exclusion regime. Once high-motion participants were excluded, the choice of denoising pipeline becomes secondary - although this strategy leads to substantial data loss. Pipelines combining spike regression with physiological regressors were the best performers, whereas pipelines that used automated data driven methods performed comparatively worse.

ConclusionIn this study, we report the first large-scale evaluation of denoising pipelines aimed at reducing noise-related functional connectivity in a clinical population known to be highly susceptible to in-scanner motion and significant anatomical abnormalities. If resting-state functional magnetic resonance is to be a successful clinical technique, it is crucial that procedures mitigating the effect of noise be systematically evaluated in the most challenging populations, such as traumatic brain injury datasets.


title: Theta and gamma hippocampal-neocortical oscillations during the episodic-like memory test: impairment in epileptogenic rats

abstract: Cortical oscillations in different frequency bands have been shown to be intimately involved in exploration of environment and cognition. Here, the local field potentials in the hippocampus, the medial prefrontal cortex (mPFC), and the medial entorhinal cortex (mEC) were recorded simultaneously in rats during the execution of the episodic-like memory task. The power of hippocampal theta (~4-10 Hz), slow gamma (~25-50 Hz), and fast gamma oscillations (~55-100 Hz) was analyzed in all structures examined. Particular attention was paid to the theta coherence between three mentioned structures. The modulation of the power of gamma rhythms by the phase of theta cycle during the execution of the episodic-like memory test by rats was also closely studied. Healthy rats and rats one month after kainate-induced status epilepticus (SE) were examined. Paroxysmal activity in the hippocampus (high amplitude interictal spikes), excessive excitability of animals, and the death of hippocampal and dentate granular cells in rats with kainate-evoked SE were observed, which indicated the development of seizure focus in the hippocampus (epileptogenesis). One month after SE, the rats exhibited a specific impairment of episodic memory for the what-where-when triad: unlike healthy rats, epileptogenic SE animals did not identify the objects during the test. This impairment was associated with the changes in the characteristics of theta and gamma rhythms and specific violation of theta coherence and theta/gamma coupling in these structures in comparison with the healthy animals. We believe that these disturbances in the cortical areas play a role in episodic memory dysfunction in kainate-treated animals. These findings can shed light on the mechanisms of cognitive deficit during epileptogenesis.


title: Passive inertial damping improves high-speed gaze stabilization in hoverflies

abstract:
Gaze stabilization reflexes reduce motion blur and simplify the processing of visual information by keeping the eyes level. These reflexes typically depend on estimates of the rotational motion of the body, head, and eyes, acquired by visual or mechanosensory systems. During rapid movements, there can be insufficient time for sensory feedback systems to estimate rotational motion, requiring additional mechanisms. Solutions to this common problem are likely to be adapted to an animals behavioral repertoire. Here, we examine gaze stabilization in three families of dipteran flies, each with distinctly different flight behaviors. Through frequency response analysis based on tethered-flight experiments, we demonstrate that fast roll oscillations of the body lead to a stable gaze in hoverflies, whereas the reflex breaks down at the same speeds in blowflies and horseflies. Surprisingly, the high-speed gaze stabilization of hoverflies does not require sensory input from the halteres, their low-latency balance organs. Instead, we show how the behavior is explained by a hybrid control system that combines a sensory-driven, active stabilization component mediated by neck muscles, and a passive component which exploits physical properties of the animals anatomy--the mass and inertia of its head. This adaptation requires hoverflies to have specializations of the head-neck joint that can be employed during flight. Our comparative study highlights how species-specific control strategies have evolved to support different visually-guided flight behaviors.

SIGNIFICANCE STATEMENTAcross the animal kingdom, reflexes are found which stabilize the eyes to reduce the impact of motion blur on vision--analogous to the image stabilization functions found in modern cameras. These reflexes can be complex, often combining predictions about planned movements with information from multiple sensory systems which continually measure self-motion and provide feedback. The processing of this information in the nervous system incurs time delays which impose limits on performance when fast stabilization is required. Hoverflies overcome the limitations of sensory-driven stabilization reflexes by exploiting the passive stability provided by the head during roll perturbations with particularly high rotational kine-matics. Integrating passive and active mechanisms thus extends the useful range of vision and likely facilitates distinctive aspects of hoverfly flight.


title: Neural mechanisms to exploit positional geometry for collision avoidance

abstract: Visual motion provides rich geometrical cues about the three-dimensional configuration the world. However, how brains decode the spatial information carried by motion signals remains poorly understood. Here, we study a collision avoidance behavior in Drosophila as a simple model of motion-based spatial vision. With simulations and psychophysics, we demonstrate that walking Drosophila exhibit a pattern of slowing to avoid collisions by exploiting the geometry of positional changes of objects on near-collision courses. This behavior requires the visual neuron LPLC1, whose tuning mirrors the behavior and whose activity drives slowing. LPLC1 pools inputs from object- and motion-detectors, and spatially biased inhibition tunes it to the geometry of collisions. Connectomic analyses identified circuitry downstream of LPLC1 that faithfully inherits its response properties. Overall, our results reveal how a small neural circuit solves a specific spatial vision task by combining distinct visual features to exploit universal geometrical constraints of the visual world.


title: A somatosensory computation that unifies bodies and tools

abstract: It is often claimed that tools are embodied by the user, but whether the brain actually repurposes its body-based computations to perform similar tasks with tools is not known. A fundamental computation for localizing touch on the body is trilateration. Here, the location of touch on a limb is computed by integrating estimates of the distance between sensory input and its boundaries (e.g., elbow and wrist of the forearm). As evidence of this computational mechanism, tactile localization on a limb is most precise near its boundaries and lowest in the middle. We show that the brain repurposes trilateration to localize touch on a tool. In a large sample of participants, we found that localizing touch on a tool produced the signature of trilateration, with highest precision close to the base and tip of the tool. A computational model of trilateration provided a good fit to the observed localization behavior. To further demonstrate the computational plausibility of repurposing trilateration, we implemented it in a three-layer neural network that was based on principles of probabilistic population coding. This network determined hit location in tool-centered coordinates by using a tools unique pattern of vibrations when contacting an object. Simulations demonstrated the expected signature of trilateration, in line with the behavioral patterns. Our results have important implications for how trilateration may be implemented by somatosensory neural populations. We conclude that trilateration is a fundamental spatial computation that unifies limbs and tools.


title: A somatosensory computation that unifies limbs and tools


title: Presence and the global implications of plastics in wild commercial fish in the Alboran Sea

abstract: The presence of plastic in the environment has become a major problem for marine megafauna. The identification of the global micro and mesoplastic uptake by commercial fish populations may allow for a better understanding of their impact. This study aims to: (i) determine the presence and composition of plastic in two pelagic fish (Engraulis encrasicolus and Scomber scombrus) and two demersal species (Scyliorinus canicula and Mullus barbatus) from the Alboran Sea (western Mediterranean) to quantify the relationship between plastic prevalence and habitat and feeding behavior in the selected fish species, (ii) compare local measurements made of the presence of plastics ingested by these four fish species with published values from a across their range literature review, and (iii) identify the methodologies used in similar studies of plastic pollution in fish. Across their range, the highest occurrence of plastics was found in E. encrasicolus, which contrasts to that found in S. scombrus at the Alboran sea. Material analysis of the collected data showed the most predominant fiber color was black and the predominant plastic polymer was polyethylene. The increasing emerging risk of plastics and the levels of macro- and micro-plastic ingested by seafood in this study support the suggest that quantifying plastic presence and composition may be essential as a food safety measure.


title: Human and wildlife use of mountain glacier habitat in western North America

abstract:
ContextThe global recession of glaciers and perennial snowfields is reshaping mountain ecosystems. Beyond physical changes to the landscape and altered downstream hydrology, the implications of glacier decline for biodiversity are poorly known. Before predictions can be made about how climate change will affect wildlife in glacier-associated ecosystems, a more thorough accounting of the role that glaciers play in species life histories is needed. However, typical approaches for documenting wildlife presence and behavior--remote camera traps--are difficult to use in glaciated terrain due to limited options for securing them (e.g., no trees) and dramatic seasonal changes in snowpack.

AimsIn this study, we sought to test a novel camera trap designed for glaciated mountain ecosystems. We also aimed to use this approach to gain insight into wildlife and human usage of a mountain glacier in western North America.

MethodsWe deployed an elevational transect of uniquely designed camera traps along the western margin of the Paradise Glacier, a rapidly receding mountain glacier on the south side of Mount Rainier, WA, USA. Our simple camera trap design consisted of a wildlife camera attached to a camouflaged cylindrical cooler filled with snow and rocks.

Key resultsOur camera design proved ideal for a mountain glacier ecosystem and from June to September 2021, we detected at least 16 vertebrate species (seven birds, nine mammals) over 770 trap nights using glacier-associated habitats. Humans, primarily skiers, were the most common species detected, but we also recorded 99 observations of wildlife (birds and mammals). These included three species of conservation concern in Washington: wolverine (Gulo gulo), Cascade red fox (Vulpes vulpes cascadensis), and white-tailed ptarmigan (Lagopus leucura).

ConclusionsCollectively, our results provide proof-of-concept for a novel camera trap design that is ideal for treeless, perennially snow-covered landscapes and revealed a rich diversity of wildlife using mountain glacier habitat in the Pacific Northwest. We highlight the global need for similar studies to better understand the true scale of biodiversity that will be impacted by glacier recession in mountain ecosystems.


title: A novel camera trap design for studying wildlife in mountain glacier ecosystems yields new insight for glacier biodiversity in the Pacific Northwest, USA