bluuebunny/crossref_metadata_2025 huggingface dataset:
Opioid-Associated Emergencies
Authors: Candelario Danielle M. , Dume Roberta , Khan Nimrah
Published: January 2024

Although pain is most effectively treated through a multimodal approach, opioids remain a mainstay of treatment for chronic pain despite their considerable adverse effect profile and associated risks. Through modulation of the μ-opioid receptors, opioids can cause respiratory depression, which may result in death if not treated. When used in conjunction with other sedative substances, the risk of respiratory depression is potentiated. If an opioid emergency is suspected, responders should activate the emergency response system as outlined by the American Heart Association. Prompt and appropriate naloxone administration is vital to appropriate emergency care. As a preventative measure, naloxone should be recommended to individuals who are at higher risk of an opioid overdose. Naloxone is available at most pharmacies, can be billed through an individual's insurance, and is now available over the counter without a prescription.
One-Leg Robotic-Assisted Gait Training Efficiently Improves Gait Independence for Acute Stroke Hemiplegic Patients
Authors: Hishikawa Norikazu , Sawada Koshiro , Maeda Hiroshi , Ikeda Takumi , Ohashi Suzuyo , Mikami Yasuo
Published: January 2024

Welwalk is a one-leg robotic-assisted gait system for stroke hemiplegic patients. This study examined the feasibility and efficacy of gait training using Welwalk (Welwalk training) for hemiplegic patients in the early phase after stroke onset, via cooperation between acute care and rehabilitation hospitals. Seven acute stroke patients (mean number of days from onset = 7.9) with severe lower extremity paralysis participated. Patients underwent Welwalk training for 40 min/d, 5 d/wk in an acute care hospital, then 7 d/wk in a rehabilitation hospital with a seamless transition. Functional Independence Measure scores for walking were assessed weekly. The endpoint was reaching Functional Independence Measure walk score of 5 (supervision level). The primary outcome was improvement efficiency of Functional Independence Measure walk, which was the increase in Functional Independence Measure walk score divided by the number of weeks required. Functional Independence Measure walk score for all patients improved from 1.1 to 5 (P = 0.01, r = 0.96). The mean number of weeks to achieve Functional Independence Measure walk score of 5 was 5 wks, and the improvement efficiency of Functional Independence Measure walk had a mean value of 0.9. No adverse events were reported during Welwalk training. Hemiparetic patients’ gait independence may be safely and rapidly improved by starting Welwalk training in the early phase after stroke onset.
Telehealth and Technology
Authors: Yu James , Petersen Carolyn , Reid Sonya , Rosenbloom S. Trent , Warner Jeremy L.
Published: January 2024

Telehealth is a broad concept that refers to any delivery of health care in real time using technologies to connect people or information that are not in the same physical location. Until fairly recently, telehealth was more aspiration than reality. This situation changed radically due in part to the COVID-19 pandemic, which led to a near-overnight inability for patients to be seen for routine management of chronic health conditions, including those with cancer. The purpose of this brief narrative review is to outline some areas where emerging and future technology may allow for innovations with specific implications for people with a current or past diagnosis of cancer, including underserved and/or historically excluded populations. Specific topics of telehealth are broadly covered in other areas of the special issue.
Digital Health for Oncological Care
Authors: Cohen Adam B. , Schwamm Lee H.
Published: January 2024

Digital health tools extend well beyond telemedicine, holding great potential to advance oncological care. We survey digital health and provide recommendations across the health continuum, tailoring them to oncology, including prevention, detection and diagnosis, and treatment and monitoring. Within the prevention realm, we review wellness technologies, cancer screening, mental health solutions, and digital biomarkers. For detection and diagnosis, we describe existing and emerging solutions for remote patient monitoring and various means to capture digital biomarkers, the “digital exam,” and “digital outcomes.” Treatment and monitoring solutions include telemedicine, chatbots, and digital therapeutics, which are also explored. We also discuss a host of technology enablers that are required for successful implementation and sustainment of digital health–enabled care. Our recommendations pertain to health care systems as well as companies that work with these systems or provide care to patients directly.
Telehealth in Cancer Care
Authors: Lopez Ana Maria
Published: January 2024

Telecommunications technology began to be integrated into health care delivery by the mid-1900s, with the goal of increasing access to care including access to cancer care.

There have been at least 3 significant telehealth expansion periods, with the most recent related to the COVID-19 pandemic. Technology uptake increased in the 1990s as quality improved, costs came down, and usability factors were addressed. As telehealth practice transitioned to use of personal devices, the COVID-19 pandemic arose, and necessity compelled widespread telehealth uptake. Most patients and clinicians entered the pandemic with little if any telehealth experience and often no training on using personal devices to access health care. Teleoncology data reveal cancer care feasibility and acceptability with generally high levels of satisfaction for both patients and clinicians. Sustaining the progress made in telehealth uptake requires ongoing insurance coverage with parity in coverage, licensure facilitation, and ongoing development of technology that is easy to use. In addition, to tele–cancer care appointments, the technology may be used for care coordination, education, and increased access to cancer clinical trials.
Rhinoresistometry as a Cost-Efficient and Time-Saving Alternative to Acoustic Rhinometry for Longitudinal Assessment of Nasal Patency in Orthognathic Surgery
Authors: Giotakis Aris I. , Verius Michael , Steinbichler Teresa B. , Runge Annette , Kolk Andreas , Hupp Linus C.
Published: January 2024

Rhinoresistometry (RRM) is implemented along with active anterior rhinomanometry (AAR) and can evaluate nasal dimensions [hydraulic diameter (HD)]. As acoustic rhinometry (AR) is time-consuming, the authors investigated if RRM can be an efficient alternative to AR in nasal dimension assessment in orthognathic surgery. In patients undergoing maxillary advancement and impaction (cases) and removal of maxillary cysts (controls), the authors evaluated RRM and AR, before and 1 year after surgery. Furthermore, the authors investigated the correlation of HD with Nasal Obstruction Symptom Evaluation score and volume by computed tomography and AAR. Lastly, the authors measured RMM reproducibility by the Bland-Altman agreement method in controls. In 14 cases, AR and RMM revealed a significant increase on both sides (all P < 0.011) and the right side, respectively (P = 0.028). The authors noted no changes in 14 controls. Hydraulic diameter correlated only with AAR (most P < 0.004). Acoustic rhinometry lasted ~4 minutes before or after decongestion. In controls, HD after surgery was as large (1.05 times larger) as before surgery (up to 39% error rates). Rhinoresistometry can reproducibly assess nasal dimension changes in orthognathic surgery in a way that is different from AR and correlates with nasal function. Rhinoresistometry can help clinicians avoid AR and save significant time, as well as financial and human resources.
Update on modifiable risk factors for Alzheimer's disease and related dementias
Authors: Jaisa-aad Methasit , Muñoz-Castro Clara , Serrano-Pozo Alberto
Published: January 2024

Purpose of review

All human beings undergo a lifelong cumulative exposure to potentially preventable adverse factors such as toxins, infections, traumatisms, and cardiovascular risk factors, collectively termed exposome. The interplay between the individual's genetics and exposome is thought to have a large impact in health outcomes such as cancer and cardiovascular disease. Likewise, a growing body of evidence is supporting the idea that preventable factors explain a sizable proportion of Alzheimer's disease and related dementia (ADRD) cases.

Recent findings

Here, we will review the most recent epidemiological, experimental preclinical, and interventional clinical studies examining some of these potentially modifiable risk factors for ADRD. We will focus on new evidence regarding cardiovascular risk factors, air pollution, viral and other infectious agents, traumatic brain injury, and hearing loss.

While greater and higher quality epidemiological and experimental evidence is needed to unequivocally confirm their causal link with ADRD and/or unravel the underlying mechanisms, these modifiable risk factors may represent a window of opportunity to reduce ADRD incidence and prevalence at the population level via health screenings, and education and health policies.
Case report and systematic review of cerebellar vermis alterations in psychosis
Authors: Dusi Nicola , Esposito Cecilia Maria , Delvecchio Giuseppe , Prunas Cecilia , Brambilla Paolo
Published: January 2024

Introduction

Cerebellar alterations, including both volumetric changes in the cerebellar vermis and dysfunctions of the corticocerebellar connections, have been documented in psychotic disorders. Starting from the clinical observation of a bipolar patient with cerebellar hypoplasia, the purpose of this review is to summarize the data in the literature about the association between hypoplasia of the cerebellar vermis and psychotic disorders [schizophrenia (SCZ) and bipolar disorder (BD)].

Methods

A bibliographic search on PubMed has been conducted, and 18 articles were finally included in the review: five used patients with BD, 12 patients with SCZ and one subject at psychotic risk.

Results

For SCZ patients and subjects at psychotic risk, the results of most of the reviewed studies seem to suggest a gray matter volume reduction coupled with an increase in white matter volumes in the cerebellar vermis, compared to healthy controls. Instead, the results of the studies on BD patients are more heterogeneous with evidence showing a reduction, no difference or even an increase in cerebellar vermis volume compared to healthy controls.

Conclusions

From the results of the reviewed studies, a possible correlation emerged between cerebellar vermis hypoplasia and psychotic disorders, especially SCZ, ultimately supporting the hypothesis of psychotic disorders as neurodevelopmental disorders.
Flatworm cocoons in the abyss: same plan under pressure
Authors: Kakui Keiichi , Tsuyuki Aoi
Published: January 2024

While knowledge of early ontogeny in abyssal animals is highly limited in general, it was completely lacking for abyssal, free-living platyhelminths. We discovered flatworm egg capsules (or ‘cocoons') on rocks collected at depths of 6176–6200 m on the abyssal slope of the Kuril–Kamchatka Trench, northwestern Pacific. The egg capsules were black and spherical, around 3 mm in diameter, and contained three to seven individuals (
n
= 4) at the same developmental stage, either the spherical (putative early embryo) or vermiform (putative late embryo) stages. A molecular phylogenetic analysis based on 18S and 28S rRNA sequences revealed that the flatworms belong in suborder Maricola in Tricladida and suggested that they may have colonized from shallow to deep waters. This study provides the deepest record for free-living flatworms and the first information on their early life stages in the abyssal zone, which were very similar to those in shallow-water forms. This similarity in development between the relatively benign shallow-water and the extreme abyssal environments suggests that triclads adapting to the latter faced primarily physiological and/or ecological adaptive challenges rather than developmental ones.
Methylocystis suflitae sp. nov., a novel type II methanotrophic bacterium isolated from landfill cover soil
Authors: Garner Christopher T. , Sankaranarayanan Krithivasan , Abin Christopher A. , Garner Rosa M. , Cai Haiyuan , Lawson Paul A. , Krumholz Lee R.
Published: January 2024

A bacterial strain, designated NLS-7T, was isolated through enrichment of landfill cover soil in methane-oxidizing conditions. Strain NLS-7T is a Gram-stain negative, non-motile rod, approximately 0.8 µm wide by 1.3 µm long. Phylogenetic analysis based on 16S rRNA gene sequencing places it within the genus

Methylocystis

, with its closest relatives being

M. hirsuta

,

M. silviterrae

and

M. rosea

, with 99.9, 99.7 and 99.6 % sequence similarity respectively. However, average nucleotide identity and average amino acid identity values below the 95 % threshold compared to all the close relatives and digital DNA–DNA hybridization values between 20.9 and 54.1 % demonstrate that strain NLS-7T represents a novel species. Genome sequencing generated 4.31 million reads and genome assembly resulted in the generation of 244 contigs with a total assembly length of 3 820 957 bp (N50, 37 735 bp; L50, 34). Genome completeness is 99.5 % with 3.98 % contamination. It is capable of growth on methane and methanol. It grows optimally at 30 °C between pH 6.5 and 7.0. Strain NLS-7T is capable of atmospheric dinitrogen fixation and can use ammonium (as NH4Cl), l-aspartate, l-arginine, yeast extract, nitrate, l-leucine, l-proline, l-methionine, l-lysine and l-alanine as nitrogen sources. The major fatty acids are C18:1 ω8c and C18:1 ω7c. Based upon this polyphasic taxonomic study, strain NLS-7T represents a novel species of the genus

Methylocystis

, for which the name Methylocystis suflitae sp. nov. is proposed. The type strain is NLS-7T (=ATCC TSD-256T=DSM 112294T). The 16S rRNA gene and genome sequences of strain NLS-7T have been deposited in GenBank under accession numbers ON715489 and GCA_024448135.1, respectively.
Impact of Mesotherapy with Sodium Deoxycholate on Liver: Metabolic- and Sex-Specific Insights in Swiss mice
Authors: Gonçalves Leidyanne Ferreira , Rosa Beatriz Rodrigues , Ramos Isabela Terra Tavares , Feder Julia Bueno , Messina Julia Rajczuk Martins , Barreira Raissa Moreira , Torres Vanessa Morales , Simões Vitor Lima , Paes-de-Almeida Elan Cardozo , Fernandes-Santos Caroline
Published: January 2024

Background

Sodium deoxycholate (DC) is often used in mesotherapy for the aesthetic improvement of body contouring. Although it is a minimally invasive procedure, DC use is off-label since, to date, it is approved solely for submental fat reduction, lacking evidence to support its safety to other body regions.

Objective

To investigate the systemic and hepatic effects of the prolonged use of DC in mesotherapy for fat reduction in Swiss mice under fructose consumption.

Methods

Female and male Swiss mice received water or 20% fructose (F) ad libitum for 12 weeks. DC 50 μg sc. was administered into the right inguinal white adipose tissue (riWAT) twice weekly for 4 weeks starting week 8. We assessed body weight (BW), glucose, lipolysis, hepatic enzymes, adipose tissue remodeling, liver histopathology, and protein expression.

Results

Chronic DC did not affect BW, glucose, lipolysis, and hepatic enzymes, except for ALT in males. Although the riWAT weight remained stable, we found foam cells, tissue hemorrhage, and fibrosis. DC induced neither hepatomegaly nor hepatocyte hypertrophy in either sex except for fructose in females, which led to heavier livers and increased hepatocyte nuclei volume. Mild fat deposition was present in fructose-fed female mice, with no influence of DC injections. Finally, FXR and FGF21 protein expression were similar among the groups.

Conclusion

DC had no impact on BW or adipose tissue mass, although there were features of chronic riWAT inflammation. It failed to impair glucose and hepatic metabolism, morphology, and protein expression in both sexes.
DIRT/μ – Automated extraction of root hair traits using combinatorial optimization
Authors: Pietrzyk Peter , Phan-Udom Neen , Chutoe Chartinun , Pingault Lise , Roy Ankita , Libault Marc , Saengwilai Patompong Johns , Bucksch Alexander
Published: January 2024

Similar to any microscopic appendages, such as cilia or antennae, phenotyping of root hairs has been a challenge due to their complex intersecting arrangements in two-dimensional (2D) images and the technical limitations of automated measurements. Digital Imaging of Root Traits at Microscale (DIRT/μ) addresses this issue by computationally resolving intersections and extracting individual root hairs from 2D microscopy images. This solution enables automatic and precise trait measurements of individual root hairs. DIRT/μ rigorously defines a set of rules to resolve intersecting root hairs and minimizes a newly designed cost function to combinatorically identify each root hair in the microscopy image. As a result, DIRT/μ accurately measures traits such as root hair length (RHL) distribution and root hair density (RHD), which are impractical for manual assessment. We tested DIRT/μ on three datasets to validate its performance and showcase potential applications. By measuring root hair traits in a fraction of the time manual methods require, DIRT/μ eliminates subjective biases from manual measurements. Automating individual root hair extraction accelerates phenotyping and quantifies trait variability within and among plants, creating new possibilities to characterize root hair function and their underlying genetics.
Matched three-dimensional organoids and two-dimensional cell lines of melanoma brain metastases mirror response to targeted molecular therapy
Authors: Hicks William H. , Gattie Lauren C. , Traylor Jeffrey I , Davar Diwakar , Najjar Yana G. , Richardson Timothy E. , McBrayer Samuel K. , Abdullah Kalil G.
Published: January 2024

Purpose

Despite significant advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors and are grown without artificial extracellular scaffolding. We aimed to develop the first matched patient-derived SXO and cell line models of MBM to investigate responses to targeted therapy.

Methods

MBM SXOs were created by a novel protocol incorporating techniques for establishing glioma and cutaneous melanoma organoids. A BRAFV600K-mutant and BRAF-wildtype MBM sample were collected directly from the operating room for downstream experiments. Organoids were cultured in an optimized culture medium without an artificial extracellular scaffold. Concurrently, matched patient-derived cell lines were created. Drug screens were conducted to assess treatment response in SXOs and cell lines.

Results

Organoid growth was observed within 3-4 weeks, and MBM SXOs retained histological features of the parent tissue, including pleomorphic epithelioid cells with abundant cytoplasm, large nuclei, focal melanin accumulation, and strong SOX10 positivity. After sufficient growth, organoids could be manually parcellated to increase the number of replicates. Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors.

Conclusion

Here, we describe the creation of a scaffold-free organoid model of MBM. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment.
“Musculoskeletal Pathologies Affecting Shoulder Girdle: A Systematic Review with Anatomical and Radiological Validation”
Authors: Charmode Sundip Hemant , Kushwaha Sudhir , Mishra Abhishek Kumar , Nimavat Nirav , Ratanpara Lalit , Mehra Simmi , Ravi Satish Kumar
Published: January 2024

Introduction

Musculoskeletal pathologies affecting shoulder girdle joints, other than gleno-humeral joint such as acromioclavicular joint arthritis, tendonitis, subacromial bursitis, subdeltoid bursitis, and osteochondritis dissecans, are relatively rare. In Middle East and Asian countries, public health services are generally availed by a large number of patients in primary health centres, rural hospitals, and district hospitals, but the scarcity of specialist orthopaedic surgeons in such hospitals usually leads to misdiagnosis of rare musculoskeletal pathologies, which may result in complications and morbidity. Objectives: To determine the presentation, progression, diagnostic evaluation, and treatment of musculoskeletal pathologies affecting the shoulder girdle and develop an algorithm to screen such pathologies.

Methods

A systematic literature search of four medical databases (PubMed, Scopus, Web of Science and Google Scholar) was conducted, from 1stJanuary 1950 to 31stDecember 2022. Studies (case reports, prospective studies, review articles) reporting pathological conditions affecting shoulder girdles, with a focus on clinical presentation, physical examination tests required for diagnostic evaluation, and management, were included. The relevant data was extracted from the selected studies and tabulated for analysis.

Results and Discussion

Seventeen studies were included in the final analysis. Several case reports, case series and review articles showed that very few musculoskeletal conditions can be correctly diagnosed based on only physical examination tests. Radiological and anatomical basis of each of the cases were discussed.

Conclusion

An algorithm was prepared to help diagnose shoulder girdle pathologies based on clinical presentation and examination findings.

Key message

An algorithm was developed which will facilitate precise diagnosis of musculoskeletal conditions affecting shoulder girdle. The musculoskeletal pathologies of shoulder girdle were categorised based on the modalities that led to their confirmatory diagnosis, and the modes management that resulted in complete functional recovery.
ARYANA-BS: Context-Aware Alignment of Bisulfite-Sequencing Reads
Authors: Nikaein Hassan , Sharifi-Zarchi Ali , Afzal Afsoon , Ezzati Saeedeh , Rasti Farzane , Chitsaz Hamidreza , Kunde-Ramamoorthy Govindarajan
Published: January 2024

Motivation

DNA methylation plays a crucial role in biological processes, including imprinting, development, inflammation, and several disorders, such as cancer. Bisulfite sequencing (BS) is the gold standard for single-base resolution in measuring DNA methylation. This process involves treating genomic DNA with sodium bisulfite, followed by polymerase chain reaction (PCR), converting unmethylated cytosines to thymines (C to T) and guanines to adenines (G to A). However, aligning reads obtained through next-generation sequencing (NGS) of the converted DNA is challenging due to the high number of mismatches caused by these conversions.

Various BS aligners aim to simplify BS read alignment to conventional DNA alignment by modifying the reference genome and/or reads. Methods include three-letter alignment and wild-card alignment, each with its limitations.

This work introduces a novel BS aligner, ARYANA-BS, which departs from conventional DNA aligners by considering base alterations in BS reads within its alignment engine. Leveraging well-established DNA methylation patterns in different genomic contexts, ARYANA-BS generates five indexes from the reference, aligns each read to all indexes, and selects the hit with the minimum penalty. To further enhance alignment accuracy, an optional EM step has been developed, incorporating methylation probability information in the decision-making process for the index with the minimum penalty for each read. The presented approach seeks to improve the accuracy of BS read alignment by accounting for the intricacies of DNA methylation patterns in diverse genomic contexts.

Results

Our experimental results, based on both simulated and real data, demonstrate that ARYANA-BS achieves state-of-the-art accuracy while maintaining competitive speed and memory usage.

Availability

The source code of ARYANA and ARYANA-BS, the read simulator for both normal and bisulfite-treated reads, SAM file analyzer which is used for post processing of the alignment penalties, and test procedures for benchmarking different aligners using simulated and real data, are publicly available inhttps://github.com/hnikaein/aryana.

Contact

sharifi@sharif.edu

Supplementary information

Supplementary data are available atJournal Nameonline.
Physical Effort Pre-Crastination Determines Preference in an Isometric Task
Authors: Healy Chadwick M. , Ahmed Alaa A.
Published: January 2024

How the brain decides when to invest effort is a central question in neuroscience. When asked to walk a mile to a destination, would you choose a path with a hill at the beginning or the end? The traditional view of effort suggests we should be indifferent—all joules are equal so long as it does not interfere with accomplishing the goal. Yet when total joules are equal, the brain’s sensitivity to the temporal profile of effort investment throughout a movement remains poorly understood. Here, we sought to parse out the interaction of time and physical effort by comparing subjective preferences in an isometric arm-pushing task that varied the duration and timing of high and low effort. Subjects were presented with a series of two-alternative forced choices, where they chose the force profile they would rather complete. Subjects preferred to pre-crastinate physical effort but were idiosyncratic about preference for task timing. A model of subjective utility that includes physical effort costs, task costs, and independent temporal sensitivity factors described subject preferences best. Interestingly, deliberation time and response vigor are best described by the same subjective utility model that won for preference, further validating this model of subjective utility. These results suggest physical effort costs are temporally sensitive, with earlier investment of effort preferred to later investment. These findings demonstrate that the representation of effort is based not only on the total energy required but its timing as well, and offer an alternative hypothesis for why animals pre-crastinate in physical tasks.

NEW & NOTEWORTHY

This research utilizes a novel paradigm that differentiates between physical effort costs, task costs, and time, where subjects choose between isometric arm-pushing tasks. Here, subjects prefer high physical effort earlier, independent of task timing. We find that deliberation time and response vigor reflect subjective preferences. This research proposes a generalizable subjective utility model that includes independent time-sensitivity factors on physical effort and task costs and offers an alternative hypothesis for why animals may pre-crastinate.
Genome-wide profiling of genetic variation at tandem repeat from long reads
Authors: Jam Helyaneh Ziaei , Zook Justin M. , Javadzadeh Sara , Park Jonghun , Sehgal Aarushi , Gymrek Melissa
Published: January 2024

Tandem repeats are frequent across the human genome, and variation in repeat length has been linked to a variety of traits. Recent improvements in long read sequencing technologies have the potential to greatly improve TR analysis, especially for long or complex repeats. Here we introduce LongTR, which accurately genotypes tandem repeats from high fidelity long reads available from both PacBio and Oxford Nanopore Technologies. LongTR is freely available athttps://github.com/gymrek-lab/longtr.
Engineering multivalent Fc display for FcγR blockade
Authors: Petrova Ekaterina , Kiriako Georges , Rebetz Johan , Johansson Karl , Wennmalm Stefan , Meijer Niels E.J. , Hällberg B. Martin , André Ingemar , Ambrosetti Elena , Semple John W. , Teixeira Ana I.
Published: January 2024

Autoimmune diseases, driven by Fcγ receptor (FcγR) activation through autoantibody immune complexes (IC), present a complex therapeutic challenge of achieving pharmacological blockade of FcγR without triggering receptor activation. The assembly of ICs into polydisperse, higher-order structures is required for FcγR activation. However, engineered multimeric, monodisperse Fc assemblies have been reported to prevent FcγR activation, suggesting that Fc spatial organization determines FcγR activation. In this study, we engineered a functional single-chain Fc domain protein (scFc) for unidirectional, multivalent presentation by virus-like particles (VLPs), used as a display platform. We found that the multivalent display of scFc on the VLPs elicited distinct cellular responses compared with monovalent scFc, highlighting the importance of the structural context of scFc on its function. scFc-VLPs had minimal impact on the nanoscale spatial organization of FcγR at the cell membrane and caused limited receptor activation and internalization. In contrast, the monovalent scFc acted as an FcγR agonist, inducing receptor clustering, activation, and internalization. Increasing scFc valency in scFc-VLPs was associated with increased binding to monocytes, reaching a plateau at high valencies. Notably, the ability of scFc-VLPs to block IC-mediated phagocytosisin vitroincreased with scFc valency. In a murine model of passive immune thrombocytopenia (ITP), a high valency scFc-VLP variant with a desirable immunogenicity profile induced attenuation of thrombocytopenia. Here we show that multivalent presentation of an engineered scFc on a display platform can be tailored to promote suppression of IC-mediated phagocytosis while preventing FcγR activation. This work introduces a new paradigm that can contribute to the development of therapies for autoimmune diseases.
Black Soldier Fly Bioconversion to Cultivated Meat Media Components Using Blue Catfish Gut Microbiome
Authors: Timoneda Alfonso , Amirvaresi Arian , Ovissipour Reza
Published: January 2024

Developing low-cost media is one of the major challenges in the cellular agriculture domain. Thus, this study aimed to develop low-cost media for cell-cultivated seafood using gut-microbial community-assisted fermentation. Black soldier fly larvae (Hermetia illucens) were used as the substrate and exposed to gut microbial communities isolated from Blue catfish (Ictalurus furcatus). In the first step, BSFL slurry was subjected to enzymatic digestion, using pepsin and trypsin to mimic animal digestive processes. The results showed a 2.8% degree of hydrolysis after digestion with pepsin and an additional 5.9% after digestion with trypsin. In the second step, two fermentation approaches were tested, including the direct addition of gut homogenate to the hydrolysates (fermentation A) and the establishment of microbial cultures from the gut homogenate before fermentation (fermentation B). Both fermentations resulted in similar protein content and degree of hydrolysis. Fermentation led to a decrease in species richness, with the loss of important chitinase and protease-producing genera such asPseudomonasand Clostridiaceae. However, there was an increase inParaclostridiumand members of the Enterobacteriaceae. In addition, the effect of fermented hydrolysates from BSFL on the proliferation of zebrafish embryo fibroblasts was tested in comparison to fetal bovine serum (FBS) in in vitro cell cultivation. Lower concentrations of FBS resulted in decreased cell density and altered cell morphology. The supplementation of hydrolysate B at high peptide concentrations had cytotoxic effects on the cells, while at lower peptide concentrations, it improved cell proliferation only in cultures with 2.5% FBS.
Infralimbic activity during REM sleep facilitates fear extinction memory
Authors: Hong Jiso , Choi Kyuhyun , Fuccillo Marc V. , Chung Shinjae , Weber Franz
Published: January 2024

Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories. Consequently, disruption of REM sleep after a traumatic event may increase the risk for developing PTSD. However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory. Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL activity during REM sleep within a 4-hour window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific inhibition of the IL cortex after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings demonstrate that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability, and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories.
Bioengineering a plant NLR immune receptor with a robust binding interface towards a conserved fungal pathogen effector
Authors: Zdrzałek Rafał , Xi Yuxuan , Langner Thorsten , Bentham Adam R. , Petit-Houdenot Yohann , De la Concepcion Juan Carlos , Harant Adeline , Shimizu Motoki , Were Vincent , Talbot Nicholas J. , Terauchi Ryohei , Kamoun Sophien , Banfield Mark J.
Published: January 2024

Bioengineering of plant immune receptors has emerged as a key strategy for generating novel disease resistance traits to counteract the expanding threat of plant pathogens to global food security. However, current approaches are limited by rapid evolution of plant pathogens in the field and may lack durability when deployed. Here, we show that the rice nucleotide-binding, leucine-rich repeat (NLR) immune receptor Pik-1 can be engineered to respond to a conserved family of effectors from the multihost blast fungus pathogenMagnaporthe oryzae. We switched the effector binding and response profile of the Pik NLR from its cognate rice blast effector AVR-Pik to the host-determining factor Pwl2 by installing a putative host target, OsHIPP43, in place of the native integrated HMA domain (generating Pikm-1OsHIPP43). This chimeric receptor also responded to other PWL alleles from diverse blast isolates. The crystal structure of the Pwl2/OsHIPP43 complex revealed a multifaceted, robust interface that cannot be easily disrupted by mutagenesis, and may therefore provide durable, broad resistance to blast isolates carrying PWL effectors in the field. Our findings highlight how the host targets of pathogen effectors can be used to bioengineer new recognition specificities that have more robust properties compared to naturally evolved disease resistance genes.
Epigenetic reprogramming driving successful and failed repair in acute kidney injury
Authors: Muto Yoshiharu , Dixon Eryn E. , Yoshimura Yasuhiro , Ledru Nicolas , Kirita Yuhei , Wu Haojia , Humphreys Benjamin D.
Published: January 2024

Acute kidney injury (AKI) causes epithelial damage followed by subsequent repair. While successful repair restores kidney function, this process is often incomplete and can lead to chronic kidney disease (CKD) in a process called failed repair. To better understand the epigenetic reprogramming driving this AKI-to-CKD transition we generated a single nucleus multiomic atlas for the full mouse AKI time course, consisting of ∼280,000 single nucleus transcriptomes and epigenomes. We reveal cell-specific dynamic alterations in gene regulatory landscapes reflecting especially activation of proinflammatory pathways. We further generated single nucleus multiomic data from four human AKI samples including validation by genome-wide identification of NF-kB binding sites. A regularized regression analysis identifies key regulators involved in both successful and failed repair cell fate, identifying the transcription factor CREB5 as a regulator of both successful and failed tubular repair that also drives proximal tubule cell proliferation after injury. Our interspecies multiomic approach provides a foundation to comprehensively understand cell states in AKI.
Learned response dynamics reflect stimulus timing and encode temporal expectation violations in superficial layers of mouse V1
Authors: Knudstrup Scott G. , Martinez Catalina , Gavornik Jeffrey P.
Published: January 2024

The ability to recognize ordered event sequences is a fundamental component of sensory cognition and underlies the capacity to generate temporally specific expectations of future events based on previous experience. Various lines of evidence suggest that the primary visual cortex participates in some form of predictive processing, though many details remain ambiguous. Here we use two-photon calcium imaging in layer 2/3 (L2/3) of the mouse primary visual cortex (V1) to study changes in neural activity under a multi-day sequence learning paradigm with respect to prediction error responses, stimulus encoding, and time. We find increased neural activity at the time an expected, but omitted, stimulus would have occurred but no significant prediction error responses following an unexpected stimulus substitution. Sequence representations became sparser and less correlated with training, although these changes had no effect on decoding accuracy of stimulus identity or timing. Additionally, we find that experience modifies the temporal structure of stimulus responses to produce a bias towards predictive stimulus-locked activity. Finally, we observe significant temporal structure during intersequence rest periods that was largely unchanged by training.
Dispersion-free inertial focusing (DIF) for high-yield polydisperse micro-particles filtration and analysis
Authors: Lee Kelvin C. M. , Chung Bob M. F. , Siu Dickson M. D. , Ho Sam C. K. , Ng Daniel K. H. , Tsia Kevin K.
Published: January 2024

Inertial focusing excels at the precise spatial ordering and separation of microparticles by size within fluid flows. However, this advantage, brought by its inherent size-dependent dispersion, could turn into a drawback that challenges applications requiring consistent and uniform positioning of polydisperse particles, such as microfiltration and flow cytometry. To overcome this fundamental challenge, we introduce Dispersion-Free Inertial Focusing (DIF). This new method minimizes particle size-dependent dispersion while maintaining the high throughput and precision of standard inertial focusing, even in a highly polydisperse scenario. We demonstrate a rule-of-thumb principle to reinvent inertial focusing system and achieve an efficient focusing of particles ranging from 6 to 30 µm in diameter onto a single plane with less than 3 µm variance and over 95% focusing efficiency at highly scalable throughput (2.4-30 mL/hr) – a stark contrast to existing technologies that struggle with polydispersity. We demonstrated that DIF could be applied in a broad range of applications, particularly enabling high-yield continuous microparticle filtration and large-scale high-resolution single-cell morphological analysis of heterogeneous cell populations. This new technique is also readily compatible with the existing inertial microfluidic design and thus could unleash more diverse systems and applications.
Automated Cell Lineage Reconstruction using Label-Free 4D Microscopy
Authors: Waliman Matthew , Johnson Ryan L , Natesan Gunalan , Tan Shiqin , Santella Anthony , Hong Ray L , Shah Pavak K
Published: January 2024

Here we describe embGAN, a deep learning pipeline that addresses the challenge of automated cell detection and tracking in label-free 3D time lapse imaging. embGAN requires no manual data annotation for training, learns robust detections that exhibits a high degree of scale invariance and generalizes well to images acquired in multiple labs on multiple instruments.
Transcranial Focused Ultrasound Remotely Modulates Extrastriate Visual Cortex with Subregion Specificity
Authors: Yu Kai , Schmitt Samantha , Ni Yunruo , Crane Emily C. , Smith Matthew A. , He Bin
Published: January 2024

Low-intensity transcranial focused ultrasound (tFUS) has emerged as a powerful neuromodulation tool characterized by its deep penetration and precise spatial targeting to influence neural activity. Our study directed low-intensity tFUS stimulation onto a region of prefrontal cortex (the frontal eye field, or FEF) of a rhesus macaque to examine its impact on a remote site, the extrastriate visual cortex (area V4). This pair of cortical regions form a top-down modulatory circuit that has been studied extensively with electrical microstimulation. To measure the impact of tFUS stimulation, we recorded local field potentials (LFPs) and multi-unit spiking activities from a multi-electrode array implanted in the visual cortex. To deliver tFUS stimulation, we leveraged a customized 128-element random array ultrasound transducer with improved spatial targeting. We observed that tFUS stimulation in FEF produced modulation of V4 neuronal activity, either through enhancement or suppression, dependent on the pulse repetition frequency of the tFUS stimulation. Electronically steering the transcranial ultrasound focus through the targeted FEF cortical region produced changes in the level of modulation, indicating that the tFUS stimulation was spatially targeted within FEF. Modulation of V4 activity was confined to specific frequency bands, and this modulation was dependent on the presence or absence of a visual stimulus during tFUS stimulation. A control study targeting the insula produced no effect, emphasizing the region-specific nature of tFUS neuromodulation. Our findings shed light on the capacity of tFUS to modulate specific neural pathways and provide a comprehensive understanding of its potential applications for neuromodulation within brain networks.
The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner
Authors: Stock Amanda J. , Gonzalez-Paredes Pierina , Previato de Almeida Luciana , Kosanke Stanley D. , Chetlur Srinivaas , Budde Hannah , Wakenight Paul , Zwingman Theresa A. , Rosen Aaron B. , Allenspach Eric , Millen Kathleen J. , Buckner Jane H. , Rawlings David J. , Gorman Jacquelyn A.
Published: January 2024

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that theIFIH1A946Trisk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developedIfih1Rknock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis inIfih1Rcompared to non-riskIfih1(Ifih1NR)mice and a significant acceleration of diabetes onset inIfih1Rfemales.Ifih1Rmice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared toIfih1NR, indicative of increased IFN I signaling.Ifih1Rmice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+T cells. Our results indicate thatIFIH1Rmay contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects ofIfih1Rin NOD mice, which will be important to consider for the development of therapeutics for T1D.
Task-related modulation of event-related potentials does not reflect changes to sensory representations
Authors: Rideaux Reuben
Published: January 2024

Attention supports efficient perception by increasing the neural signals of targets while supressing those of distractors. Decades of work studying the event-related potentials of electroencephalography (EEG) recordings have established our understanding of attention in the human brain, but many aspects of this phenomenon remain unknown. Several recent studies suggest that multivariate analyses may provide new insights into how attention shapes the neural representations of stimuli; however, it is unclear whether the increased multivariate decoding accuracy associated with task relevance represents a change in the stimulus representation or an additional cognitive process. To understand what the change in multivariate information that is associated with task relevance reflects, here we used inverted encoding to characterize how task relevance shapes the neural representation of space and colour. For both spatial and feature-based tasks, we found that the change in the EEG recordings associated with task relevance is not related to the stimulus representation. Rather, our findings indicate that this phenomenon reflects an additional cognitive process, such as target recognition.
Protected area establishment in Southern and Eastern Africa: Consequences for management today
Authors: Schroder Bradley , Van Langevelde Frank , Schroder Nicola-Anne Hawkins , Prins Herbert H. T.
Published: January 2024

To understand the complexities of managing protected areas, it is important to understand the causes for their established. We summarized the motives for establishing protected areas in Southern and Eastern Africa, and the possible consequences for management of these areas today. We scrutinised documents for 48 randomly selected protected areas and investigated, (1) when and why each of the protected areas was established? (2) what the management implications were of the reasons for incorporation for these areas? and (3) how/if the original management still impacts conservation in these areas today? First, we learnt that the establishment of protected areas occurred in three periods, namely,Period 1when area protection was started to protect wild animals from decimation;Period 2during which areas considered marginal for agriculture, prone to disease or sickness and considered uninhabitable for humans were set aside; andPeriod 3when areas were proclaimed protected because of ecological or cultural importance. Second, we showed that the establishment of protected areas has ramifications for management of these areas today, which for Period 1 were remote logistics and tourism, anti-poaching difficulties, large size logistics and human wildlife conflict. Period 2 has consequences for community-land issues and intensive management, with Period 3 having intensive management to meet the objectives of these parks. Our insights have consequences for management of protected areas today, with Period 1 protected areas generally being managed on a laissez-faire approach and Period 2 and 3 protected areas being managed on a more intensive management basis.