bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carbopol-coated mucoadhesive PLGA nanoparticles for the sustained delivery of pilocarpine in the buccal cavity
Authors: Valkanioti Vasiliki , Kapourani Afroditi , Chatzitheodoridou Melina , Anagnostaki Maria-Emmanouela , Gkougkourelas Ioannis , Kontogiannopoulos Konstantinos N , Assimopoulou Andreana N , Barmpalexis Panagiotis 
Published: July 2023

Abstract

Objectives
This study investigates a new nanoparticulate (NP) formulation for local buccal administration of pilocarpine (PIL) to treat xerostomia, aiming to improve patient compliance and reduce side effects.

Methods
PIL-loaded NPs were prepared using poly (d,l-lactic-co-glycolic acid) (PLGA) as a matrix/carrier and carbopol (CRB) as a mucoadhesive agent at various concentrations at ratios of 0.05, 0.10 and 0.15% w/v. The NPs were characterized in terms of size, morphology, drug loading, thermophysical and physicochemical properties, in vitro dissolution performance, and mucoadhesion.

Key findings
Smooth spherical drug-loaded NPs (200–300 nm) were prepared in all cases. CRB coating did not impact particle size or polydispersity index but increased NPs’ negative surface charges. Good storage stability, high production yields (72.0–83.7%), and adequate drug loading efficiencies (9.0–9.7%) were achieved, in all cases. Differential scanning calorimetry and powder X-ray diffraction measurements confirmed the amorphous drug dispersion, while attenuated total reflectance-Fourier transform infrared spectroscopy studies revealed strong molecular interactions between the matrix/carrier and the mucoadhesive agent. In-vitro drug release studies showed sustained release profiles for all NPs, whereas the application of a CRB-coating enhanced mucoadhesion performance through the formation of electrostatic ionic interactions and physical entanglement with mucin.

Conclusions
The preparation of a new PLGA-based NP formulation may present itself as a promising strategy for the buccal administration of PIL, while the use of CRB coating could be considered as a useful approach for enhancing the mucus adhesion of NPs.
Social Triage and Exclusions in Community Services for the Criminalized
Authors: Quirouette Marianne 
Published: July 2023

AbstractThis article examines perspectives and practices related to social triage and the exclusion of criminalized and marginalized individuals in community services such as shelters, mental health, substance use, and court supports. Based on two years of fieldwork and interviews with 105 practitioners, I analyze narratives and practices related to working with people described as having (or being) complex, high-needs, or high-risk. I show that individual factors, such as risk, need, or responsivity, are but one type of factor considered when practitioners make decisions about triage or service eligibility. Building from theory about the governance of “risk” and “risky people,” I examine how organizational and systemic factors shape individualized understandings of and responses to risk. I argue that given current practices in under-resourced community supports, triage and resulting exclusions exacerbate social problems and contribute to punitive exclusions, especially for those who seek services, supports, or housing but have records of sexual offense, fire setting, drug use, violence, self-harm or so-called non-compliance. Examining these dynamics bolsters claims that we should shift the responsibilizing gaze upwards to pressure institutional and state bodies who could transform the landscape for practitioners and their clients.
UNI-RNA: UNIVERSAL PRE-TRAINED MODELS REVOLUTIONIZE RNA RESEARCH
Authors: Wang Xi , Gu Ruichu , Chen Zhiyuan , Li Yongge , Ji Xiaohong , Ke Guolin , Wen Han 
Published: July 2023

AbstractRNA molecules play a crucial role as intermediaries in diverse biological processes. Attaining a profound understanding of their function can substantially enhance our comprehension of life’s activities and facilitate drug development for numerous diseases. The advent of high-throughput sequencing technologies makes vast amounts of RNA sequence data accessible, which contains invaluable information and knowledge. However, deriving insights for further application from such an immense volume of data poses a significant challenge. Fortunately, recent advancements in pre-trained models have surfaced as a revolutionary solution for addressing such challenges owing to their exceptional ability to automatically mine and extract hidden knowledge from massive datasets. Inspired by the past successes, we developed a novel context-aware deep learning model named Uni-RNA that performs pre-training on the largest dataset of RNA sequences at the unprecedented scale to date. During this process, our model autonomously unraveled the obscured evolutionary and structural information embedded within the RNA sequences. As a result, through fine-tuning, our model achieved the state-of-the-art (SOTA) performances in a spectrum of downstream tasks, including both structural and functional predictions. Overall, Uni-RNA established a new research paradigm empowered by the large pre-trained model in the field of RNA, enabling the community to unlock the power of AI at a whole new level to significantly expedite the pace of research and foster groundbreaking discoveries.
Estimates of persistent inward currents in lower limb muscles are not different between inactive, resistance-trained and endurance-trained young individuals
Authors: Goreau Valentin , Hug François , Jannou Anthony , Dernoncourt François , Crouzier Marion , Cattagni Thomas 
Published: July 2023

ABSTRACTPersistent inward currents (PICs) increase the intrinsic excitability of α-motoneurons. The main objective of this study was to determine whether estimates of α-motoneuronal PIC magnitude is influenced by chronic endurance and resistance training. We also aimed to investigate whether there is a relationship in the estimates of α-motoneuronal PIC magnitude between muscles. Estimates of PIC magnitude were obtained in three groups of young individuals: resistance-trained (n=12), endurance-trained (n=12), and inactive (n=13). We recorded high-density surface electromyography (HDsEMG) signals from tibialis anterior, gastrocnemius medialis, soleus, vastus medialis, and vastus lateralis. Then, signals were decomposed with convolutive blind source separation to identify motor units spike trains. Participants performed triangular isometric contractions to a peak of 20% of their maximum voluntary contraction. A paired-motor-unit analysis was used to calculate ΔF, which is assumed to be proportional to PIC magnitude. Despite the substantial differences in physical training experience between groups, we found no differences in ΔF, regardless of the muscle. Significant correlations of estimates of PICs magnitude were found between muscles of the same group (VL-VM, SOL-GM). Only one correlation (out of 8) between muscles of different groups was found (GM and TA). Overall, our findings suggest that estimates of PIC magnitude in the lower limb muscles are not influenced by physical training experience in healthy young individuals. They also suggest muscle-specific and muscle group-specific regulations of the diffuse monoamine inputs.
Geographic population structure and distinct population dynamics of globally abundant freshwater bacteria
Authors: Hoetzinger M. , Hahn M.W. , Andersson L.Y. , Buckley N. , Ramsin C. , Buck M. , Nuy J.K. , Garcia S.L. , Puente-Sánchez F. , Bertilsson S. 
Published: July 2023

AbstractGeographic separation is a principal factor for structuring populations of macroorganisms, with important consequences for evolution, by means of processes such as allopatric speciation. For free-living prokaryotes, implications of geographic separation on their evolution are more unclear. The limited phylogenetic resolution of commonly used markers such as 16S rRNA gene sequences have since long impeded prokaryotic population genetics. However, the vast amount of metagenome sequencing data generated during the last decades from various habitats around the world, now provides an excellent opportunity for such investigations. Here we exploited publicly available and new freshwater metagenomes in combination with genomes of abundant freshwater bacteria to study the impact of geographic separation on population structure. We focused on species that were detected across broad geographic ranges at high enough sequence coverage for meaningful population genomic analyses, i.e. members of the predominant freshwater taxa acI, LD12,PolynucleobacterandCa. Methylopumilus. Population differentiation increased significantly with spatial distance in all species, but notable dispersal barriers (e.g. oceanic) were not apparent. Yet, the different species showed contrasting rates of geographic divergence and strikingly different population dynamics in time series within individual lakes. While certain populations hardly diverged over several years, others displayed high divergence after merely a few months, similar in scale to populations separated by thousands of kilometers. We speculate that populations with higher strain diversity evolve more monotonously, while low strain diversity enables more drastic clonal expansion of genotypes which will be reflected in strong but transient differentiation between temporally or spatially adjacent populations.
Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy
Authors: Unda Santiago R. , Pomeranz Lisa E. , Marongiu Roberta , Yu Xiaofei , Kelly Leah , Hassanzadeh Gholamreza , Molina Henrik , Vaisey George , Wang Putianqi , Dyke Jonathan P. , Fung Edward K. , Grosenick Logan , Zirkel Rick , Antoniazzi Aldana M. , Norman Sofya , Liston Conor M. , Schaffer Chris , Nishimura Nozomi , Stanley Sarah A. , Friedman Jeffrey M. , Kaplitt Michael G. 
Published: July 2023

AbstractHere we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. AAV-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine 2a receptor-cre driver mice resulted in motor freezing when placed in an MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasivelyin-vivousing clinically available devices.TeaserA novel magnetogenetics toolbox to regulate neural circuitsin-vivo.
Genome size and repeat content contribute to a complex architecture of flowering time inAmaranthus tuberculatus
Authors: Kreiner Julia M. , Hnatovska Solomiya , Stinchcombe John R. , Wright Stephen I. 
Published: July 2023

AbstractGenome size variation, largely driven by repeat content, is poorly understood within and among populations, limiting our understanding of its significance for adaptation. Here we characterize intraspecific variation in genome size and repeat content across 186 individuals ofAmaranthus tuberculatus, a ubiquitous native weed that shows flowering time adaptation to climate across its range and in response to agriculture. K-mer based genome size estimates vary by up to 20% across individuals, with transposable elements, unknown repeats, and rDNAs being the primary contributors to this variability. The additive effect of this variation has important phenotypic consequences—individuals with more repeats, and thus larger genomes, show slower flowering times and growth rates. Compared to newly-characterized gene copy number and polygenic nucleotide changes underlying variation in flowering time, we show that genome size remains a modest but significant contributor to the genetic basis of flowering time. Differences in flowering time across sexes and habitats are not mirrored by genome size variation, but rather polygenic variation and a gene copy number variant within the ATP synthesis pathway. Repeat content nonetheless shows non-neutral distributions across the genome, and across latitudinal and environmental gradients, reflecting numerous governing processes that in turn influence quantitative genetic variation for phenotypes key to plant adaptation.Author SummaryThe remarkable and seemingly inconsequential variation in genome size across species has long been an enigma in evolutionary biology. Calling this viewpoint into question, correlations between genome size variation and traits linked to fitness are increasingly uncovered. While this suggests that DNA content itself may be a source of adaptive genetic variation, repeat elements that propagate at the cost of the host are known to largely mediate this variation and may thus limit adaptive potential. Here we look to disentangle these multi-level dynamics, characterizing repeat dynamics across the genome and among individuals across diverse collections of a widespread agricultural weed, linking repeat content to genome size variation, and characterizing the relative importance of its phenotypic consequences. InAmaranthus tuberculatus, we find non-neutral repeat distributions across individuals across the range, and while this repeat variation underlies both variation in genome size and flowering time, we show that it makes a relatively minor contribution to variation in a fitness-related trait across the landscape relative to monogenic and polygenic features. Together, this work broadens our perspective on the complex selective dynamics that govern intraspecific variation in genome size and traits key to fitness in plants.
Interchromosomal contacts between regulatory regions trigger stable transgenerational epigenetic inheritance in Drosophila
Authors: Fitz-James Maximilian H. , Sabarís Gonzalo , Sarkies Peter , Bantignies Frédéric , Cavalli Giacomo 
Published: July 2023

SummaryNon-genetic information can be inherited across generations by the process of Transgenerational Epigenetic Inheritance (TEI). TEI can be established by various triggering events, including transient genetic perturbations. InDrosophila, hemizygosity of theFab-7regulatory element triggers inheritance of the histone mark H3K27me3 at a homologous locus on another chromosome, resulting in heritable epigenetic differences in eye colour. By mutating transcription factor binding sites within theFab-7element, we demonstrate the importance of two proteins in the establishment and maintenance of TEI: GAGA-factor and Pleiohomeotic. We show that these proteins function by recruiting the Polycomb Repressive Complex 2 and by mediating interchromosomal chromatin contacts betweenFab-7and its homologous locus. Finally, using anin vivosynthetic biology system to induce them, we show that chromatin contacts alone can establish TEI, providing a mechanism by which hemizygosity of one locus can establish epigenetic memory at anotherin transthrough long-distance chromatin contacts.
Tuning the double lipidation of salmon calcitonin to introduce a pore-like membrane translocation mechanism
Authors: Lund Philip M. , Kristensen Kasper , Larsen Nanna W. , Knuhtsen Astrid , Hansen Morten B. , Hjørringgaard Claudia U. , Eriksen Anne Z. , Urquhart Andrew J. , Mortensen Kim I. , Simonsen Jens B. , Andresen Thomas L. , Larsen Jannik B. 
Published: July 2023

AbstractA widespread strategy to increase the transport of therapeutic peptides across cellular membranes has been to attach lipid moieties to the peptide backbone (lipidation) to enhance their intrinsic membrane interaction. Effortsin vitroandin vivoinvestigating the correlation between lipidation characteristics and peptide membrane translocation efficiency have traditionally relied on end-point read-out assays and trial-and-error-based optimization strategies. Consequently, the molecular details of how therapeutic peptide lipidation affects it’s membrane permeation and translocation mechanisms remain unresolved. Here we employed salmon calcitonin as a model therapeutic peptide and synthesized nine double lipidated analogs with varying lipid chain lengths. We used single giant unilamellar vesicle (GUV) calcein influx time-lapse fluorescence microscopy to determine how tuning the lipidation length can lead to an All-or-None GUV filling mechanism, indicative of a peptide mediated pore formation. Finally, we used a GUVs-containing-inner-GUVs assay to demonstrate that only peptide analogs capable of inducing pore formation show efficient membrane translocation. Our data provided the first mechanistic details on how therapeutic peptide lipidation affects their membrane perturbation mechanism and demonstrated that fine-tuning lipidation parameters could induce an intrinsic pore-forming capability. These insights and the microscopy based workflow introduced for investigating structure-function relations could be pivotal for optimizing future peptide design strategies.Graphical AbstractHighlights- Lipidating the therapeutic peptide salmon calcitonin alters its biophysical characteristics, including oligomer size, hydrophobicity and membrane activity.- Fluorescent microscopy of single GUVs enables the determination of peptide mediated reporter dye influx behavior as either graded or All-or-None, which is coupled to either smaller membrane perturbations or peptide pore formation.- Modulating the number of hydrocarbons constituting the lipidation moieties determines the membrane permeation mechanism.- By increasing the lipid chain length lipidated of salmon calcitonin goes from displaying smaller membrane perturbations to a peptide pore formation mechanism.- Effective membrane translocation of lipidated salmon calcitonin requires a peptide mediated pore forming mechanism.
A Generalized Framework for the Calcium Control Hypothesis Describes Weight-Dependent Synaptic Plasticity
Authors: Moldwin Toviah , Azran Li Shay , Segev Idan 
Published: July 2023

AbstractThe brain modifies synaptic strengths to store new information via long-term potentiation (LTP) and long-term depression (LTD). Evidence has mounted that long-term plasticity is controlled via concentrations of calcium ([Ca2+]) in postsynaptic spines. Several mathematical models describe this phenomenon, including those of Shouval, Bear, and Cooper (SBC) (Shouval et al., 2002, 2010) and Graupner and Brunel (GB)(Graupner & Brunel, 2012). Here we suggest a generalized version of the SBC and GB models, based on a fixed point – learning rate (FPLR) framework, where the synaptic [Ca2+] specifies a fixed point toward which the synaptic weight approaches asymptotically at a [Ca2+]-dependent rate. The FPLR framework offers a straightforward phenomenological interpretation of calcium-based plasticity:the calcium concentration tells the synaptic weight where it is going and how fast it goes there. The FPLR framework can flexibly incorporate various experimental findings, including the existence of multiple regions of [Ca2+] where no plasticity occurs, or plasticity in cerebellar Purkinje cells, where the directionality of calcium-based synaptic changes is thought to be reversed relative to cortical and hippocampal neurons. We also suggest a modeling approach that captures the dependency of late-phase plasticity stabilization on protein synthesis. We demonstrate that due to the asymptotic, saturating nature of synaptic changes in the FPLR rule, the result of frequency- and spike-timing-dependent plasticity protocols are weight-dependent. Finally, we show how the FPLR framework can explain plateau potential-induced place field formation in hippocampal CA1 neurons, also known as behavioral time scale plasticity (BTSP).
EASYSTIFF®, a portable and innovative device able to separately analyze each skin compartment for the evaluation of mechanical properties
Authors: Runel Gael , Lapart Jean-André , Chlasta Julien 
Published: July 2023

AbstractHuman skin is submitted to various factors leading to either extrinsic or intrinsic aging. In addition to inducing molecular and morphological changes, skin aging is characterized by modifications in skin biomechanical properties modifications. These modifications can be used as biomarkers to both evaluate the degree of advancement in skin aging but also to detect potential pathologies. Hence, it is from critical interest to be able to evaluate skin biomechanical properties to fully detect and monitor these alterations. Here we introduce a portable and innovative®device, EASYSTIFF®, which is thought toin vivomeasure stiffness properties of skin. Based on indentation principle, EASYSTIFF allows to identify both global stiffness of skin (all confounded cutaneous compartment) or compartmentalized stiffness, in which stiffness values of each compartment, i.e., the stratum corneum, the epidermis, the dermis and the hypodermis, are separately analyzed. Thus, EASYSTIFF is a complementary tool to 2D and 3Din/ex vivomodel and an alternative to existing devices that measure skin mechanical properties, for assessing the effectiveness of cosmetic products, monitoring skin stiffness over time and to provide better understanding in the evolution of skin mechanical properties.