bluuebunny/crossref_metadata_2025 huggingface dataset:
A high-performance speech neuroprosthesis
Authors: Willett Francis R. , Kunz Erin M. , Fan Chaofei , Avansino Donald T. , Wilson Guy H. , Choi Eun Young , Kamdar Foram , Hochberg Leigh R. , Druckmann Shaul , Shenoy Krishna V. , Henderson Jaimie M.
Published: January 2023

Speech brain-computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speaking movements into text1,2or sound3,4. Early demonstrations, while promising, have not yet achieved accuracies high enough for communication of unconstrainted sentences from a large vocabulary1–7. Here, we demonstrate the first speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant, who can no longer speak intelligibly due amyotrophic lateral sclerosis (ALS), achieved a 9.1% word error rate on a 50 word vocabulary (2.7 times fewer errors than the prior state of the art speech BCI2) and a 23.8% word error rate on a 125,000 word vocabulary (the first successful demonstration of large-vocabulary decoding). Our BCI decoded speech at 62 words per minute, which is 3.4 times faster than the prior record for any kind of BCI8and begins to approach the speed of natural conversation (160 words per minute9). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for using intracortical speech BCIs to restore rapid communication to people with paralysis who can no longer speak.
Towards Reduced Order Models via Robust Proper Orthogonal Decomposition to Capture Personalised Aortic Haemodynamics
Authors: Chatpattanasiri Chotirawee , Franzetti Gaia , Bonfanti Mirko , Diaz-Zuccarini Vanessa , Balabani Stavroula
Published: January 2023

Data driven, reduced order modelling has shown promise in tackling the challenges associated with computational and experimental hemodynamic models. In this work, we explore the use of Reduced Order Models (ROMs) to capture the main flow features in a patient-specific dissected aorta. We apply Proper Orthogonal Decomposition (POD) and Robust Principle Component Analysis (RPCA) on in vitro, hemodynamic data acquired by Particle Image Velocimetry and compare the decomposed flows to those derived from Computational Fluid Dynamics (CFD) data for the same geometry and flow conditions. The flow is reconstructed using different numbers of POD modes and the flow features obtained throughout the cardiac cycle are compared to the original Full Order Models (FOMs).

RPCA has been found to enhance the quality of PIV data and to capture most of the kinetic energy of the flow in just two modes similar to the numerical data that are free from measurement noise. The reconstruction errors differ along the cardiac cycle with diastolic flows requiring more modes for accurate reconstruction. In general, modesΦ1-10 are found sufficient to represent the flow field. The results demonstrate that the coherent structures that characterise this aortic dissection flow are described by the first few POD modes suggesting that it is possible to represent the macroscale behaviour of aortic flow in a low-dimensional space; thus significantly simplifying the problem, and allowing for more computationally efficient flow simulations that can pave the way for translation of such models to the clinic.
Interoceptive and metacognitive facets of fatigue in multiple sclerosis
Authors: Rouault Marion , Pereira Inês , Galioulline Herman , Fleming Stephen M. , Stephan Klaas Enno , Manjaly Zina-Mary
Published: January 2023

Numerous disorders are characterised by fatigue as a highly disabling symptom. Fatigue plays a particularly important clinical role in multiple sclerosis (MS) where it exerts a profound impact on quality of life. Recent concepts of fatigue grounded in computational theories of brain-body interactions emphasise the role of interoception and metacognition in the pathogenesis of fatigue. So far, however, for MS, empirical data on interoception and metacognition are scarce.

This study examined interoception and (exteroceptive) metacognition in a sample of 71 persons with a diagnosis of MS. Interoception was assessed by pre-specified subscales of a standard questionnaire (MAIA), while metacognition was investigated with computational models of choice and confidence data from a visual discrimination paradigm. Additionally, autonomic function was examined by several physiological measurements.

Several hypotheses were tested based on a preregistered analysis plan. In brief, we found the predicted association of interoceptive awareness with fatigue (but not with exteroceptive metacognition) and an association of autonomic function with exteroceptive metacognition (but not with fatigue). Furthermore, machine learning (elastic net regression) showed that individual fatigue scores could be predicted out-of- sample from our measurements, with questionnaire-based measures of interoceptive awareness and sleep quality as key predictors.

Our results support theoretical concepts of interoception as an important factor for fatigue and demonstrate the general feasibility of predicting individual levels of fatigue from simple questionnaire- based measures of interoception and sleep.
Influenza transmission dynamics quantified from wastewater
Authors: Nadeau Sarah , Devaux A.J. , Bagutti Claudia , Alt Monica , Hampe Evelyn Ilg , Kraus Melanie , Würfel Eva , Koch Katrin N. , Fuchs Simon , Tschudin-Sutter Sarah , Holschneider Aurélie , Ort Christoph , Chen Chaoran , Huisman Jana S. , Julian Timothy R. , Stadler Tanja
Published: January 2023

Influenza infections are challenging to monitor at the population level due to a high proportion of mild and asymptomatic cases and confounding of symptoms with other common circulating respiratory diseases, including COVID-19. Alternate methods capable of tracking cases outside of clinical reporting infrastructure could improve monitoring of influenza transmission dynamics. Influenza shedding into wastewater represents a promising source of information where quantification is unbiased by testing or treatment-seeking behaviors. We quantified influenza A and B virus loads from influent at Switzerland’s three largest wastewater treatment plants, serving about 12% of the Swiss population. We estimated trends in infection incidence and the effective reproductive number Re in these catchments during a 2021/22 epidemic and compared our estimates to clinical influenza surveillance data. We showed that wastewater-based incidence is better aligned with catchment-level confirmed cases than national ILI, and that only the wastewater data capture a peak in incidence in December 2021. We further estimated Re to have been below 1.05 after introduction of work from home measures in December 2021 and above 0.97 after these measures were relaxed in two out of three catchments based on wastewater data. The third catchment yielded qualitatively the same results, although with wider confidence intervals. The confirmed-case data yielded comparatively less precise estimates that include 1 before and during the period of measures. On the basis of this research we developed an online dashboard for wastewater-based influenza surveillance in Switzerland where we will continue to monitor the onset and dynamics of the 2022/23 flu season.
Delineation of complex gene expression patterns in single cell RNA-seq data with ICARUS v2.0
Authors: Jiang Andrew , You Linya , Snell Russell G , Lehnert Klaus
Published: January 2023

Complex biological traits and disease often involve patterns of gene expression that can be characterised and examined. Here we present ICARUS v2.0, an update to our single cell RNA-seq analysis web server with additional tools to investigate gene networks and understand core patterns of gene regulation in relation to biological traits. ICARUS v2.0 enables gene co-expression analysis with MEGENA, transcription factor regulated network identification with SCENIC, trajectory analysis with Monocle3, and characterisation of cell-cell communication with CellChat. Cell cluster gene expression profiles may be examined against Genome Wide Association Studies with MAGMA to find significant associations with GWAS traits. Additionally, differentially expressed genes may be compared against the Drug-Gene Interaction database (DGIdb 4.0) to facilitate drug discovery. ICARUS v2.0 offers a comprehensive toolbox of the latest single cell RNA-seq analysis methodologies packed into an efficient, user friendly, tutorial style web server application (accessible athttps://launch.icarus-scrnaseq.cloud.edu.au/) that enables single cell RNA-seq analysis tailored to the user’s dataset.
Protocol for mapping of the supplementary motor area using repetitive navigated transcranial magnetic stimulation
Authors: Engelhardt Melina , Kern Giulia , Karhu Jari , Picht Thomas
Published: January 2023

Structured abstract

Background

Damage to the supplementary motor area (SMA) for example during surgery can lead to impairments of motor and language function. A detailed preoperative mapping of functional boarders of the SMA could therefore aid preoperative diagnostics in these patients.

Objective

The aim of this study was the development of a repetitive nTMS protocol for non-invasive functional mapping of the SMA while assuring effects are indeed caused by SMA stimulation rather than activation of M1.

Methods

To this purpose the SMA in the dominant hemisphere of twelve healthy subjects (28.2 ± 7.7 years, 6 females) was mapped using repetitive nTMS at 20 Hz (120% RMT), while subjects performed a finger tapping task. The location of induced errors was marked in each subject’s individual MRI. To further validate the protocol, effects of SMA stimulation were directly compared to effects of M1 stimulation in four different tasks.

Results

Mapping of the SMA was possible for all subjects, yet varying effect sizes were observed. Stimulation of the SMA led to a significant reduction of finger taps compared to baseline (BL: 45 taps, SMA: 35.5 taps; p < 0.01). Line tracing, writing and targeting of circles was less accurate during SMA compared to M1 stimulation.

Conclusion

Mapping of the SMA using repetitive nTMS is feasible. While errors induced in the SMA are not entirely independent of M1 due to the proximity of both regions, disruption of the SMA induces functionally distinct errors. These error maps can aid preoperative diagnostics in patients with SMA related lesions.
Transcriptomic profiling of retinal cells reveals a subpopulation of microglia/macrophages expressing Rbpms and Spp1 markers of retinal ganglion cells (RGCs) that confound identification of RGCs
Authors: Theune William C. , Trakhtenberg Ephraim F.
Published: January 2023

Analysis of retinal ganglion cells (RGCs) by scRNA-seq is emerging as a state-of-the-art method for studying RGC biology and subtypes, as well as for studying the mechanisms of neuroprotection and axon regeneration in the central nervous system (CNS). Rbpms has been established as a pan-RGC marker, and Spp1 has been established as an αRGC type marker. Here, we analyzed by scRNA-seq retinal microglia and macrophages, and found Rbpms+ and Spp1+ subpopulations of retinal microglia/macrophages, which pose a potential pitfall in scRNA-seq studies involving RGCs. We performed comparative analysis of cellular identity of the presumed RGC cells isolated in recent scRNA-seq studies, and found that Rbpms+ and Spp1+ microglia/macrophages confounded identification of RGCs. We also provide solutions for circumventing this potential pitfall in scRNA-seq studies, by including in RGC and αRGC selection criteria other pan-RGC and αRGC markers.
rRNA intermediates coordinate the multilayered nucleolar phase transition inC. elegans
Authors: Xu Demin , Chen Xiangyang , Kuang Yan , Hong Minjie , Xu Ting , Wang Ke , Fu Chuanhai , Ruan Ke , Zhu Chengming , Feng Xuezhu , Guang Shouhong
Published: January 2023

The nucleolus is the most prominent membraneless organelle within the nucleus and plays essential roles in rRNA transcription and processing and ribosome assembly. How the structure of the nucleolus is maintained and regulated is poorly understood. Here, we identified two types of nucleoli inC. elegans. Type I nucleoli are spherical, and rRNA transcription and processing factors are evenly distributed throughout the nucleolus. In type II nucleoli, rRNA transcription and processing factors exclusively accumulate in the periphery rim, which is named the nucleolar ring. The hollow vacuole inside the nucleolar ring contains proteins that usually localize in the nucleoplasm but are capable of exchanging contents across the ring. The high-order structure of the nucleolus is dynamically regulated inC. elegans. Faithful rRNA processing is important to maintain the spherical structure of the nucleoli. The depletion of a class of rRNA processing factors, for example, class I ribosomal proteins of the large subunit (RPL), which are involved in 27SA2rRNA processing, reshaped spherical nucleoli to a ring-shaped nucleolar structure. The inhibition of RNAP I transcription and depletion of two conserved nucleolar factors, nucleolin and fibrillarin, prohibits the formation of the nucleolar ring. We concluded that the integrity of nucleoli is highly dependent on rRNA processing and maturation, which may provide a mechanism to coordinate structure maintenance and gene expression.
Prefrontal cortical protease TACE/ADAM17 is involved in neuroinflammation and stress-related eating alterations
Authors: Sharafeddin Fransua , Ghaly Mina , Simon Timothy B. , Ontiveros-Ángel Perla , Figueroa Johnny D.
Published: January 2023

Childhood traumatic stress profoundly affects prefrontal cortical networks regulating top-down control of eating and body weight. However, the neurobiological mechanisms contributing to trauma-induced aberrant eating behaviors remain largely unknown. Traumatic stress influences brain immune responses, which may, in turn, disrupt prefrontal cortical networks and behaviors. The tumor necrosis factor alpha-converting enzyme / a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and neuroinflammation. This study aimed to determine the role of TACE/ADAM17 on traumatic stress-induced disruption of eating patterns. We demonstrate a novel mechanistic connection between prefrontal cortical TACE/ADAM17 and trauma-induced eating behaviors. Fifty-two (52) adolescent Lewis rats (postnatal day, PND, 15) were injected intracerebrally either with a novel Accell™ SMARTpool ADAM17 siRNA or a corresponding siRNA vehicle. The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Observation cages were used to monitor ethological behaviors in a more naturalistic environment over long periods. We found that traumatic stress blunts startle reactivity and alter eating behaviors (increased intake and disrupted eating patterns). We also found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited decreased eating and increased grooming behaviors compared to controls. These changes were associated with decreased AIF-1 expression (a typical marker of microglia and neuroinflammation). This study demonstrates that prefrontal cortical TACE/ADAM17 is involved in neuroinflammation and may play essential roles in regulating feeding patterns under stress conditions. TACE/ADAM17 represents a promising target to ameliorate inflammation-induced brain and behavior alterations.
Investigating the effect of changes in model parameters on optimal control policies, time to absorption, and mixing times
Authors: Johnson Kathleen , Plaugher Daniel , Murrugarra David
Published: January 2023

Abstract

Many processes in biology and medicine have been modeled using Markov decision processes which provides a rich algorithmic theory for model analysis and optimal control. An optimal control problem for stochastic discrete systems consists of deriving a control policy that dictates how the system will move from one state to another such that the probability of reaching a desired state is maximized. In this paper, we focus on the class of Markov decision processes that is obtained by considering stochastic Boolean networks equipped with control actions. Here, we study the effect of changes in model parameters on optimal control policies. Specifically, we conducted a sensitivity analysis on optimal control policies for a Boolean model of the T-cell large granular lymphocyte (T-LGL). For this model, we quantified how the choice of propensity parameters impacts the effectiveness of the optimal policy and then we provide thresholds at which the effectiveness is guaranteed. We also examined the effect on the optimal control policies of the level of noise that is usually added for simulations. Finally, we studied the effect on changes in the propensity parameters on the time to absorption and the mixing time for a Boolean model of the Repressilator.
Protein semisynthesis underscores role of a conserved lysine in activation and desensitization of acid-sensing ion channels
Authors: Sarkar Debayan , Galleano Iacopo , Heusser Stephanie Andrea , Ou Sofie Yuewei , Refika Uzun Gül , Khoo Keith K. , van der Heden van Noort Gerbrand Jan , Harrison Joseph Scott , Pless Stephan Alexander
Published: January 2023

Acid-sensing ion channels (ASICs) are trimeric ion channels that open a cation-conducting pore in response to proton binding. Excessive ASIC activation during prolonged acidosis in conditions such as inflammation and ischemia is linked to pain and stroke. A conserved lysine in the extracellular domain (Lys211 in mASIC1a) is suggested to play a key role in ASIC function. However, the precise contributions are difficult to dissect with conventional mutagenesis, as replacement of Lys211 with naturally occurring amino acids invariably changes multiple physico-chemical parameters. Here, we study the contribution of Lys211 to mASIC1a function using tandem protein-trans splicing (tPTS) to incorporate non-canonical lysine analogs. We conduct optimization efforts to improve splicing and functionally interrogate semisynthetic mASIC1a. In combination with molecular modeling, we show that Lys211 charge and side chain length are crucial to activation and desensitization, thus emphasizing that tPTS can enable atomic-scale interrogations of membrane proteins in live cells.
Structures of two main components of the virophage and Marseilleviridae virions extend the range of unrelated viruses using fiber head as common receptor binding fold
Authors: Jeudy Sandra , Garcin Elsa , Schmitt Alain , Abergel Chantal
Published: January 2023

The detailed proteomic analysis ofMarseilleviridaeicosahedral capsids revealed that the two most abundant protein components of the virions were the Major Capsid Protein (MCP) and the product of an ORFan gene conserved in allMarseilleviridae. The noumeavirus NMV_189 3D structure revealed a common fold with fiber head proteins used by a variety of viruses to recognize their cellular receptor. However, the trimeric structure of NMV_189 uniquely lacking a tail domain, presented a deep concave site suggesting it could be directly anchored to the pseudo-hexagonal capsomers of the virion. This was confirmed by the unambiguous fit of the structure in the melbournevirus 4.4 Å cryo-EM map. In parallel, our structural genomic study of zamilon vitis virophage capsid proteins revealed that Zav_19 shared the same trimeric fiber head fold, but presented an N-terminal tail with a unique β-prism fold. The fiber head fold thus appears to be conserved in all types of non-enveloped icosahedral virions independently of their genomic contents (dsDNA, ssRNA, dsRNA). This could be a testimony of a common origin or the result of convergent evolution for receptor binding function.

IMPORTANCE

Giant viruses and their associated virophages exhibit a large proportion (≥60%) of orphan genes,i.e. genes without homologs in databases, and thus a vast majority of their proteins are of unknown function. The structural characterization of two ORFans, NMV_189 and Zav_19, both major components of noumeavirus and zamilon virophage capsids, respectively, revealed that despite a total lack of sequence homology, the two proteins share a common trimeric fold typical of viral receptor binding proteins and could be responsible for host receptor recognition. These two structures extend the range of unrelated viruses using fiber head structures as common receptor binding fold.
Metachronal coordination enables omnidirectional swimming via spatially distributed propulsion
Authors: Herrera-Amaya Adrian , Byron Margaret L.
Published: January 2023

Aquatic organisms often employ maneuverable and agile swimming behavior to escape from predators, find prey, or navigate through complex environments. Many of these organisms use metachronally coordinated appendages to execute complex maneuvers. However, though metachrony is used across body sizes ranging from microns to tens of centimeters, it is understudied compared to the swimming of fish, cetaceans, and other groups. In particular, metachronal coordination and control of multiple appendages for three-dimensional maneuvering is not fully understood. To explore the maneuvering capabilities of metachronal swimming, we combine 3D high-speed videography of freely swimming ctenophores (Bolinopsis vitrea) with reduced-order mathematical modeling. Experimental results show that ctenophores can quickly reorient, and perform tight turns while maintaining forward swimming speeds close to 70% of their observed maximum — performance comparable to or exceeding that of many vertebrates with more complex locomotor systems. We use a reduced-order model to investigate turning performance across a range of beat frequencies and appendage control strategies, and reveal that ctenophores are capable of near-omnidirectional turning. Based on both recorded and modeled swimming trajectories, we conclude that the ctenophore body plan enables a high degree of maneuverability and agility, and may be a useful starting point for future bioinspired aquatic vehicles.

Author summary

Metachronal swimming—the sequential, coordinated beating of appendages arranged in a row— exists across a wide range of sizes, from unicellular organisms (micrometers) to marine crustaceans (tens of centimeters). While metachronal swimming is known to be scalable and efficient, the level of maneuverability and agility afforded by this strategy is not well understood. This study explores the remarkable 3D maneuverability of ctenophores (comb jellies), and the appendage control strategies they use to achieve it. Ctenophores have eight rows of appendages (instead of the one or two found in crustaceans and other organisms). This higher number of appendages, their distribution along the body, and the independent frequency control between paired rows enables near-omnidirectional swimming and turning performance, placing ctenophores among the most maneuverable swimmers. We use experiments and mathematical modeling to explore both the real and theoretical performance landscape of the ctenophore body plan, and show that ctenophores are capable of executing tight turns at high speeds in nearly any plane. This omnidirectional swimming capability gives insight into the ecology and behavior of an important taxonomic group, and shows the potential of metachronal swimming as a source of design inspiration for robotic vehicles (particularly those that must navigate complex environments).
Clinical manifestation and laboratory parameters associated with progression to severe dengue in children: a systematic review and meta-analysis
Authors: Sandinirwan Indra , Muslim Bani , Leo Henry , Hasanah Hasanah , Karina Permata Putri
Published: January 2023

Background

The ingenuity to predict the progression to severe dengue is crucial in managing dengue patients. The previous meta-analysis has been performed on adults, and none has been performed specifically on children. We conducted a systematic review and meta-analysis to determine the clinical manifestations and laboratory parameters associated with the progression to severe dengue according to WHO criteria.

Methods

We focused on searching six medical databases for studies published from Jan 1, 2000, to Dec 31, 2020. The meta-analysis used random-effects or fixed-effects models to estimate pooled effect sizes. We also assessed the heterogeneity and publication bias. This study was registered with PROSPERO, CRD42021224439.

Results

We included 49 of papers in the systematic review, and we encased the final selected 39 papers comprising 23 potential predictors in the meta-analyses. Among 23 factors studied, seven clinical manifestations demonstrated association with disease progression in children, including neurological signs, gastrointestinal bleeding, clinical fluid accumulation, hepatomegaly, vomiting, abdominal pain, and petechiae. Six laboratory parameters are associated during the early days of illness, including elevated hematocrit, elevated aspartate aminotransferase [AST], elevated alanine aminotransferase [ALT], low platelet count, low albumin levels, and elevated activated partial thromboplastin time. Dengue virus serotype 2 (DENV-2) and secondary infections were also associated with severe disease progression.

Conclusion

This finding supports the use of the warning signs described in the WHO 2009 guidelines. In addition, monitoring serum albumin, AST/ALT levels, identifying infecting dengue serotypes, and immunological status could improve the risk prediction of disease progression.
Building a genome-based understanding of bacterial pH preferences
Authors: Ramoneda Josep , Stallard-Olivera Elias , Hoffert Michael , Winfrey Claire C. , Stadler Masumi , Niño-García Juan Pablo , Fierer Noah
Published: January 2023

The environmental preferences of many microbes remain undetermined. This is the case for bacterial pH preferences, which can be difficult to predicta prioridespite the importance of pH as a factor structuring bacterial communities in many systems. We compiled data on bacterial distributions from five datasets spanning pH gradients in soil and freshwater systems (1470 samples in total), quantified the pH preferences of bacterial taxa across these datasets, and compiled genomic data from representative bacterial taxa. While taxonomic and phylogenetic information were generally poor predictors of bacterial pH preferences, we identified genes consistently associated with pH preference across environments. We then developed and validated a machine learning model to estimate bacterial pH preferences from genomic information alone, a model which could aid in the selection of microbial inoculants, improve species distribution models, or help design effective cultivation strategies. More generally, we demonstrate the value of combining biogeographic and genomic data to infer and predict the environmental preferences of diverse bacterial taxa.
Distribution and genetic diversity of South FloridaTephrosiashed light on past cultural use
Authors: von Wettberg Eric JB , Sadle Jimi , Ogutcen Ezgi , Possley Jennifer , Lange James , Carrasquila-Garcia Noelia , Chang Peter L.
Published: January 2023

The genusTephrosia(Fabaceae), the hoary peas, contain high levels of rotenone, which has a long history of human use as a fish poison. We examine the distribution ofTephrosia angustissima, in South Florida to clarify patterns of genetic relatedness and shed light on human plant movement before European contact. Several populations ofTephrosia angustissimawith a history of taxonomic uncertainty exist in South Florida and the neighboring Caribbean Islands.

To clarify relationships in this group, and to elucidate the conservation status of populations in Everglades National Park and Big Cypress National Preserve, we used restriction site associated DNA sequencing (RAD-SEQ) on 94 samples from South Florida and three locations in southwest Puerto Rico.

Analysis of variation in SNP markers by the Bayesian STRUCTURE algorithm and principal coordinate analysis both separated the samples into three groups. These three groups were likely separate colonization events of Florida. Genetic diversity is moderate in all of the groups, with only limited evidence of a bottleneck in some of the disjunct South Florida populations.

Overall, the human association of this group is consistent with a history of human use, suggesting conservation efforts for these taxa should consider their pre-Columbian human associations.

Societal impact statement

A great many endangered plant taxa exhibit patterns of edaphic specialization, occurring on particular substrates such as karst or serpentine soils. Human activities, such as the construction of shell middens, can create edaphically unique substrates. In the Americas, post-Columbian land use changes coupled with extensive loss of indigenous cultural knowledge, has created areas where associations of cultivated plants with human-generated habitats may be lost. Here we use population genetic approaches to examine rareTephrosia(hoary pea) taxa from South Florida, a group of plants that produce rotenone that has been used by many indigenous groups as a fish poison. We find evidence of multiple introductions from the broader Caribbean region and an association with anthropogenic habitats such as shell middens. In efforts to conserve rare hoary peas in Florida, an understanding of past use of the landscape by native Americans is essential.
ciRS-7 and miR-7 regulate ischemia induced neuronal death via glutamatergic signaling
Authors: Scoyni Flavia , Sitnikova Valeriia , Giudice Luca , Korhonen Paula , Trevisan Davide M , Hernandez de Sande Ana , Gomez-Budia Mireia , Giniatullina Raisa , Ugidos Irene F , Dhungana Hiramani , Pistono Cristiana , Korvenlaita Nea , Välimäki Nelli-Noora , Kangas Salla M , Hiltunen Anniina E , Gribchenko Emma , Kaikkonen-Määttä Minna U , Koistinaho Jari , Ylä-Herttuala Seppo , Hinttala Reetta , Venø Morten T , Su Junyi , Stoffel Markus , Schaefer Anne , Rajewsky Nikolaus , Kjems Jørgen , LaPierre Mary P , Piwecka Monika , Jolkkonen Jukka , Giniatullin Rashid , Hansen Thomas B , Malm Tarja
Published: January 2023

Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7 and the long non-coding RNA Cyrano. Here we describe ischemia induced alterations in the ncRNA network bothin vitroandin vivoand in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression upon ischemic insults. Mice lacking ciRS-7 show reduced lesion size and motor impairment, whilst the absence of miR-7 alone leads to an increase in the ischemia induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate dendrite morphology and glutamatergic signaling suggesting a potential molecular link to thein vivophenotype. Our data reveal that ciRS-7 and miR-7 contribute to the outcome of ischemic stroke and shed new light into the pathophysiological roles of intracellular networks of non-coding RNAs in the brain.
Human milk variation is shaped by maternal genetics and impacts the infant gut microbiome
Authors: Johnson Kelsey E. , Heisel Timothy , Allert Mattea , Fürst Annalee , Yerabandi Nikhila , Knights Dan , Jacobs Katherine M. , Lock Eric F. , Bode Lars , Fields David A. , Rudolph Michael C. , Gale Cheryl A. , Albert Frank W. , Demerath Ellen W. , Blekhman Ran
Published: January 2023

Human milk is a complex mix of nutritional and bioactive components that provide complete nutrition for the infant. However, we lack a systematic knowledge of the factors shaping milk composition and how milk variation influences infant health. Here, we used multi-omic profiling to characterize interactions between maternal genetics, milk gene expression, milk composition, and the infant fecal microbiome in 242 exclusively breastfeeding mother-infant pairs. We identified 487 genetic loci associated with milk gene expression unique to the lactating mammary gland, including loci that impacted breast cancer risk and human milk oligosaccharide concentration. Integrative analyses uncovered connections between milk gene expression and infant gut microbiome, including an association between the expression of inflammation-related genes with IL-6 concentration in milk and the abundance ofBifidobacteriain the infant gut. Our results show how an improved understanding of the genetics and genomics of human milk connects lactation biology with maternal and infant health.
A new web resource to predict the impact of missense variants at protein interfaces using 3D structural data: Missense3D-PPI
Authors: Pennica Cecilia , Hanna Gordon , Islam Suhail A , Sternberg Michael JE , David Alessia
Published: January 2023

In 2019, we released Missense3D which identifies stereochemical features that are disrupted by a missense variant, such as introducing a buried charge. Missense3D analyses the effect of a missense variant on a single structure and thus may fail to identify as damaging surface variants disrupting a protein interface i.e., a protein-protein interaction (PPI) site. Here we present Missense3D-PPI designed to predict missense variants at PPI interfaces.

Our development dataset comprised of 1,279 missense variants (pathogenic n=733, benign n=546) in 434 proteins and 545 experimental structures of PPI complexes. Benchmarking of Missense3D-PPI was performed after dividing the dataset in training (320 benign and 320 pathogenic variants) and testing (226 benign and 413 pathogenic). Structural features affecting PPI, such as disruption of interchain bonds and introduction of unbalanced charged interface residues, were analysed to assess the impact of the variant at PPI.

Missense3D-PPI’s performance was superior to that of Missense3D: sensitivity 42% versus 8% and accuracy 58% versus 40%, p=4.23×10−16However, the specificity of Missense3D-PPI was slightly lower compared to Missense3D (84% versus 98%). On our dataset, Missense3D-PPI’s accuracy was superior to BeAtMuSiC (p=2.3×10−5), mCSM-PPI2 (p=3.2×10−12) and MutaBind2 (p=0.003).

Missense3D-PPI represents a valuable tool for predicting the structural effect of missense variants on biological protein networks and is available at the Missense3D web portal (http://missense3d.bc.ic.ac.uk/missense3d/indexppi.html).
Competitive interaction between ATP and GTP regulates mitochondrial ATP-sensitive potassium channels
Authors: Palácio Plinio Bezerra , de Freitas Soares Geovanna Carvalho , Bezerra Lima Gabriella Moreira , Oliveira Cunha Pedro Lourenzo , Nunes Varela Anna Lidia , Facundo Heberty Tarso
Published: January 2023

Mitochondrial ATP-sensitive K+channels (mitoKATP) have been recently characterized structurally, and possess a protein through which K+enters mitochondria (MitoKIR), and a regulatory subunit (mitoSUR). The mitoSUR regulatory subunit is an ATP-binding cassette (ABC) protein isoform 8 (ABCB8). Opening of these channels is known to be cardioprotective, but the molecular and physiological mechanisms that activate them are not fully known. Here, to better understand the molecular and physiological mechanisms of activators (GTP) and inhibitors (ATP) on the activity of mitoKATP, we exposed isolated mitochondria to both nucleotides. We also used molecular docking directed to the nucleotide-binding domain of human ABCB8/mitoSUR to test a comparative model of ATP and GTP effects. As expected, we find that ATP dose-dependently inhibits mitoKATP activity (IC50= 21.24 ± 1.4 mM). However, simultaneous exposure of mitochondria to GTP dose-dependently (EC50= 13.19 ± 1.33 mM) reversed ATP inhibition. Pharmacological and computational studies suggest that GTP reverses ATP activity competitively. Docking directed to the site of crystallized ADP reveals that both nucleotides bind to mitoSUR with high affinity, with their phosphates directed to the Mg2+ion and the walker A motif of the protein (SGGGKTT). These effects, when combined, result in GTP binding, ATP displacement, mitochondrial ATP-sensitive K+transport, and lower formation of reactive oxygen species. Overall, our findings demonstrate the basis for ATP and GTP binding in mitoSUR using a combination of biochemical, pharmacological, and computational experiments. Future studies may reveal the extent to which the balance between ATP and GTP actions contribute toward cardioprotection against ischemic events.
Θ-Net: Achieving Enhanced Phase-Modulated Optical Nanoscopyin silicothrough a computational‘string of beads’architecture
Authors: Kaderuppan Shiraz S/O , Wong Eugene Wai Leong , Sharma Anurag , Woo Wai Lok
Published: January 2023

We present herein atripletstring of concatenated O-Net (‘bead’) architectures (formulated as discussed in our previous study) which we term ‘Θ-Net’ as a means of improving the viability of generated super-resolved (SR) imagesin silico. In the present study, we assess the quality of the afore-mentioned SR images with that obtained via other popular frameworks (such as ANNA-PALM, BSRGAN and 3D RCAN). Models developed from our proposed framework result in images which more closely approach the gold standard of the SEM-verified test sample as a means of resolution enhancement for optical microscopical imaging, unlike previous DNNs. In addition,cross-domain (transfer) learningwas also utilized to enhance the capabilities of models trained on DIC datasets, where phasic variations are not as prominently manifested as amplitude/intensity differences in the individual pixels [unlike phase contrast microscopy (PCM)]. The present study thus demonstrates the viability of our current multi-paradigm architecture in attaining ultra-resolved images under poor signal-to-noise ratios, while eliminating the need fora prioriPSF & OTF information. Due to the wide-scale use of optical microscopy for inspection & quality analysis in various industry sectors, the findings of this study would be anticipated to exhibit a far-ranging impact on several engineering fronts.
Lung-mimicking 3-Dimensional hydrogel culture system recapitulates key tuberculosis phenotypes and demonstrates pyrazinamide efficacy
Authors: Gupta Vishal K. , Abhirami P.S. , Vijaya Vaishnavi V. , Jyothsna K.M. , Jeyasankar Sharumathi , Raghunathan Varun , Agarwal Rachit
Published: January 2023

Faithful mimics of tuberculosis (TB) infection are needed to provide mechanistic insights into the complex host-pathogen interactions and accelerate drug discovery. Currentin vitromodels only allow short investigation durations, present divergent transcriptional signatures to human infections, and are unreliable drug discovery platforms. We developed a 3D collagen culture system mimicking the lung microenvironment (collagen fibres, pore size and stiffness), where we incorporatedMycobacterium tuberculosis(Mtb) infected human THP-1 or primary monocytes. Dual RNA-sequencing revealed high mammalian gene expression similarity with patient samples compared to 2D macrophage infections. Similarly, gene expression of bacteria was much more representative toin vivogene expression compared to bacteria in 2D cultures (114 genes in 3D vs 21 genes in 2D). Key phenotypes observed in humans, such as foamy macrophages and mycobacterial cords (never seen in any otherin vitroculture system), were reproduced in our model. Our system overcomes many challenges associated with the traditional platforms, including showing remarkable efficacy with clinically relevant concentrations of first-line anti-TB drug pyrazinamide, not seen in any otherin vitromodel, making it reliable, readily adoptable for tuberculosis studies and drug screening.

Significance statement

Mtb is a slow-growing pathogen which modulates host response over time. The currentin vitroplatforms offer a very short study duration to study, are unreliable as drug discovery platforms, and the phenotypic and genotypic traits of the host and pathogen differ. The collagen-I hydrogel culture system developed in this study addresses these challenges by successfully recapitulating several key phenotypes observed in human infections. Dual RNA sequence also showed excellent gene expression similarities for both the host and the bacteria. Furthermore, remarkable efficacy with the antibiotic Pyrazinamide was demonstrated, a first forin vitrocultures despite over 50 years of clinical use of the drug. We expect our platform to be exploited widely for drug discovery and understanding host-pathogen interactions.
Dominant gingers – discovery and inheritance of a new shell polymorphism in the great pond snailLymnaea stagnalis
Authors: Ledder Matthijs , Nakadera Yumi , Staikou Alexandra , Koene Joris M.
Published: January 2023

Color polymorphism is a classic study system for evolutionary genetics. One of the most color-polymorphic animal taxa is mollusks, but the investigation for the genetic basis of color determination is often hindered by their life history and limited availability of genetic resources. Here we report on the discovery of shell color polymorphism in a much-used model species, the great pond snailLymnaea stagnalis. While their shell is usually beige, some individuals from a Greek population show a distinct red shell color, which we nicknamed Ginger. Moreover, we found that the inheritance fits simple, single-locus Mendelian inheritance with dominance of the Ginger allele. We also compared crucial life history traits between Ginger and wild type individuals, and found no differences between morphs. We conclude that the relative simplicity of this polymorphism will provide new opportunities for a deeper understanding of the genetic basis of shell color polymorphism and its evolutionary origin.
Guide to the construction and use of an adaptive optics two-photon microscope with direct wavefront sensing
Authors: Yao Pantong , Liu Rui , Broginni Thomas , Thunemann Martin , Kleinfeld David
Published: January 2023

Two-photon microscopy, combined with appropriate optical labeling, has enabled the study of structure and function throughout nervous systems. This methodology enables, for example, the measurement and tracking of sub-micrometer structures within brain cells, the spatio-temporal mapping of spikes in individual neurons, and the spatio-temporal mapping of transmitter release in individual synapses. Yet the spatial resolution of two-photon microscopy rapidly degrades as imaging is attempted at depths more than a few scattering lengths into tissue, i.e., below the superficial layers that constitute the top 300 to 400 µm of neocortex. To obviate this limitation, we measure the wavefront at the focus of the excitation beam and utilize adaptive optics that alters the incident wavefront to achieve an improved focal volume. We describe the constructions, calibration, and operation of a two-photon microscopy that incorporates adaptive optics to restore diffraction-limited resolution throughout the nearly 900 µm depth of mouse cortex. Our realization utilizes a guide star formed by excitation of red-shifted dye within the blood serum to directly measure the wavefront. We incorporate predominantly commercial optical, optomechanical, mechanical, and electronic components; computer aided design models of the exceptional custom components are supplied. The design is modular and allows for expanded imaging and optical excitation capabilities. We demonstrate our methodology in mouse neocortex by imaging the morphology of somatostatin-expressing neurons at 700 µm beneath the pia, calcium dynamics of layer 5b projection neurons, and glutamate transmission to L4 neurons.
Three-dimensional morphological analysis revealed the cell patterning bases for the sexual dimorphism development in the liverwortMarchantia polymorpha
Authors: Cui Yihui , Hisanaga Tetsuya , Kajiwara Tomoaki , Yamaoka Shohei , Kohchi Takayuki , Goh Tatsuaki , Nakajima Keiji
Published: January 2023

In land plants, sexual dimorphism can develop in both diploid sporophytes and haploid gametophytes. While developmental processes of sexual dimorphism have been extensively studied in the sporophytic reproductive organs of model flowering plants such as stamens and carpels ofArabidopsis thaliana, those occurring in gametophyte generation are less well characterized due to the lack of amenable model systems. We here performed three-dimensional morphological analyses of gametophytic sexual branch differentiation in the liverwortMarchantia polymorpha, using high-depth confocal imaging and a computational cell segmentation technique. Our analysis revealed that specification of germline precursors initiates in a very early stage of sexual branch development where incipient branch primordia are barely recognizable in the apical notch region. Moreover, spatial distribution patterns of germline precursors differ between males and females from the initial stage of primordium development in a manner dependent on the master sexual differentiation regulator MpFGMYB. In later stages, distribution patterns of germline precursors predict the sex-specific gametangia arrangement and receptacle morphologies seen in mature sexual branches. Taken together, our data suggests a tightly coupled progression of germline segregation and sexual dimorphism development inM. polymorpha.
Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer PDXs
Authors: Perron Umberto , Grassi Elena , Chatzipli Aikaterini , Viviani Marco , Karakoc Emre , Trastulla Lucia , Isella Claudio , Zanella Eugenia R , Klett Hagen , Molineris Ivan , Schueler Julia , Esteller Manel , Medico Enzo , Conte Nathalie , McDermott Ultan , Trusolino Livio , Bertotti Andrea , Iorio Francesco
Published: January 2023

Abstract

Patient-derived xenografts (PDXs) are tumour fragments engrafted into mice for preclinical studies. PDXs offer clear advantages over simplerin vitrocancer models - such as cancer cell lines (CCLs) and organoids - in terms of structural complexity, heterogeneity, and stromal interactions. We characterised 231 colorectal cancer PDXs at the genomic, transcriptomic, and epigenetic level and measured their response to cetuximab, an EGFR inhibitor in clinical use for metastatic colorectal cancer. After assessing PDXs’ quality, stability, and molecular concordance with publicly available patient cohorts, we trained, interpreted, and validated an integrated ensemble classifier (CeSta) which takes in input the PDXs’multi-omiccharacterisation and predicts their sensitivity to cetuximab treatment (AUROC > 0.9). Our study shows that large PDX collections can be used to train accurate, interpretable models of drug sensitivity, which 1) better recapitulate patient-derived therapeutic biomarkers than other models trained on CCL data, 2) can be robustly validated across independent PDX cohorts, and 3) can be used for the development of novel therapeutic biomarkers.