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Abstract Background Brain-computer interfaces (BCIs) can restore communication for movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command click detectors provide a basic yet highly functional capability. Methods We sought to test the performance and long-term stability of click decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis. We trained the participant’s click detector using a small amount of training data (

Abstract Background Theileria haneyi is one of the three known causative agents of equine piroplasmosis. While imidocarb is generally effective in the clearance of the highly pathogenic Theileria equi, it is ineffective in the treatment of T. haneyi. Moreover, co-infection with T. haneyi has been shown to impede the successful treatment of T. equi. Furthermore, tulathromycin and diclazuril have demonstrated inefficacy in eradicating T. haneyi. The absence of an effective therapeutic agent against this parasite represents a significant obstacle in managing equine piroplasmosis. Methods To address this issue, we evaluated the efficacy of buparvaquone in the treatment of T. haneyi in chronically infected horses. Results Our findings showed that treatment of horses with the recommended dose of 2.5 mg/kg of buparvaquone led to a rapid abatement of T. haneyi levels, to a level where the parasites were not detectable by nested PCR. Following treatment, the horses remained PCR negative for a minimum of seven weeks until recrudescence occurred. Subsequent re-administration of buparvaquone at an increased dosage of 6 mg/kg upon recrudescence failed to exert a theilericidal effect on T. haneyi. Throughout the treatment regimen, the hematological parameters of the horses and most components of the chemistry panel remained within the normal range, except for blood urea nitrogen levels, which fell below the normal range in certain instances. conclusions BPQ at 2.5 mg/kg and 6 mg/kg had a robust theilericidal effect but was ineffective in the clearance of the T. haneyi infection in persistently infected animals. Graphical Abstract

BackgroundLimited data are available describing the effects of SARS-CoV-2 breakthrough infections on the plasma proteome.MethodsPCR-positive SARS-CoV-2 patients, enrolled in a natural history study, underwent analysis of the plasma proteome. A prospective cohort of 66 unvaccinated and 24 vaccinated persons with different degrees of infection severity were evaluated acutely (within 40 days of symptom onset), and at three and ten months. Comparisons based on vaccination status alone and unsupervised hierarchical clustering were performed. A second cohort of vaccinated Omicron patients were evaluated acutely and at ten months.ResultsAcutely, unvaccinated patients manifested overexpression of proteins involved in immune and inflammatory responses, while vaccinated patients exhibited adaptive immune responses without significant inflammation. At three and ten months, only unvaccinated patients had diminished but sustained inflammatory (C3b, CCL15, IL17RE) and immune responses (DEFA5,TREM1). Both groups had underexpression of pathways essential for cellular function, signaling, and angiogenesis (AKT1, MAPK14, HSPB1) across phases. Unsupervised clustering, based on protein expression, identified four groups of patients with variable vaccination rates demonstrating that additional clinical factors influence the plasma proteome. The proteome of vaccinated Omicron patients did not differ from vaccinated pre-Omicron patients.ConclusionsVaccination attenuates the inflammatory response to SARS-CoV-2 infection across phases. However, at ten months after symptom onset, changes in the plasma proteome persist in both vaccinated and unvaccinated individuals, which may be relevant to post-acute sequelae of SARS-CoV-2 and other viral infections associated with post-acute infection syndromes.

IntroductionTheileria orientalis, an economically significant tick-borne hemoparasite, infects cattle globally. The T. orientalis Ikeda genotype, transmitted by Haemaphysalis longicornis ticks, is associated with clinical manifestations characterized by anemia, abortions, and mortality, although subclinical infections prevail. Despite the common occurrence of subclinical infections, therapeutic interventions targeting T. orientalis Ikeda in such cases are currently lacking, impeding effective parasite control measures. To address this critical knowledge gap, we assessed the efficacy of buparvaquone (BPQ) in eliminating the T. orientalis Ikeda, US isolate, in sub-clinically infected cattle.MethodsTwelve sub-clinically infected calves, identified by the presence of T. orientalis in peripheral blood alongside the absence of fever and anemia, were enrolled in the study. Six calves received two treatments of the BPQ label dose (2.5 mg/kg) at a 48-h interval, while additional three calves received the drug at a dosage of 6 mg/kg following the same regimen. Three untreated calves served as controls.Results and discussionEndpoint and quantitative PCR analyses revealed that BPQ exerted a transient effect on T. orientalis parasitemia. Parasites remained undetectable in peripheral blood until weeks 4 and 11 post-treatment in animals administered 2.5 mg/kg and 6 mg/kg of BPQ, respectively. Intriguingly, following recrudescence, administering 6 mg/kg to animals previously treated with 2.5 mg/kg did not result in a reduction in parasite load. Pharmacokinetic analysis data suggested that escalating the dosage led to a less than proportional increase in serum concentrations of BPQ. Moreover, a significant yet reversible decrease (p

Abstract Introduction Silica‐sprayed tubes (SSTs) are often used to transport synovial fluid samples in equine practice. They promote the coagulation of the sample. The objective of the study is to evaluate the effect of SST on bacterial culture. Materials and methods The study was divided into two parts: sterile saline (Part A) and synovial fluid (Part B). Four common bacteria associated with equine synovial sepsis were used: Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus and methicillin‐resistant S. aureus (MRSA). Three collection tubes were used: STT, plain (no‐additives) and brain and heart infusion (BHI) broth. Bacteria were cultured in horse blood agar plates for 48 h. Outcome variables were negative culture, positive culture and total number of colony‐forming units (CFUs). Statistical analysis was performed using Mann–Whitney U test, and significance was set at p

Abstract Background Capecitabine is an oral prodrug of the active metabolite 5-fluorouracil, which has been used effectively in human colorectal, head and neck, and mammary carcinomas. Capecitabine has several properties that make it an attractive treatment option for dogs: (i) it is relatively inexpensive, (ii) it has a short half-life in humans, allowing for rapid plasma concentration changes to be achieved with dosage adjustments, (iii) it is effective for treating carcinomas in humans, for which there are no widely-effective oral chemotherapy options in dogs, and (iv) it is thought to preferentially target cancer cells due to different expression of thymidine phosphorylase, thereby decreasing the risk of off-target side effects. However, capecitabine has not been widely explored as a chemotherapy agent for dogs. The goal of this study was to determine the plasma disposition of capecitabine in dogs following a single oral dose and to document any adverse events associated with capecitabine administration over the course of 5 weeks. Results Capecitabine was well tolerated throughout the 5-week study period when administered to 5 dogs with naturally occurring carcinomas at 750 mg/m $$^2$$ 2 by mouth once daily for 14 consecutive days in a 3-week cycle. No dogs withdrew from the study due to adverse events or other causes. The median AUC $$_{\text {0-last}}$$ 0-last was 890 h $$\cdot$$ · ng/ml (range 750-1100 h $$\cdot$$ · ng/ml); however, the maximum blood concentration and time to reach that concentration of capecitabine was highly variable after a single dose. Conclusions Capecitabine appears well-tolerated as an oral chemotherapy agent for dogs with carcinomas, although individualized dosing may be necessary, and further studies are warranted.

Background/Objectives: Bovine babesiosis is a vector-borne disease transmitted by ticks that causes important losses in livestock worldwide. Recent research performed on the drugs currently used to control bovine babesiosis reported several issues including drug resistance, toxicity impact, and residues in edible tissue, suggesting the need for developing novel effective therapies. The endochin-like quinolones ELQ-316 and buparvaquone (BPQ) act as cytochrome bc1 inhibitors and have been proven to be safe and efficacious against related apicomplexans, such as Plasmodium spp. and Babesia microti, without showing toxicity in mammals. The objectives of this study are investigating whether ELQ-316, BPQ, and their combination treatment could be effective against Babesia bovis in an in vitro culture model and comparing with imidocarb (ID), the routinely used drug. Methods: In vitro cultured parasites starting at 2% percentage of parasitemia (PPE) were treated with BPQ, ELQ-316, ID, and the combinations of BPQ + ELQ-316 and ID + ELQ-316 at drug concentrations that ranged from 25 to 1200 nM, during four consecutive days. The IC50% and IC99% were reported. Parasitemia levels were evaluated daily using microscopic examination. Data were compared using the non-parametrical Mann–Whitney and Kruskall–Wallis test. Results: All drugs tested, whether used alone or in combination, significantly decreased the survival (p < 0.05) of B. bovis in in vitro cultures. The combination of BPQ + ELQ-316 had the lowest calculated inhibitory concentration 50% (IC50%) values, 31.21 nM (IC95%: 15.06–68.48); followed by BPQ, 77.06 nM (IC95%: 70.16–86.01); ID + ELQ316, 197 nM (IC95%:129.0–311.2); ID, 635.1 nM (IC95%: 280.9–2119); and ELQ316, 654.9 nM (IC95%: 362.3–1411). Conclusions: The results reinforce the higher efficacy of BPQ at affecting B. bovis survival and the potential synergistic effects of its combination with ELQ-316, providing a promising treatment option against B. bovis.

IntroductionSerum symmetric dimethylarginine (SDMA) and creatinine are commonly used biomarkers of renal function in cats. We hypothesize that the serum analytes creatinine and SDMA are equally effective at detecting impaired renal function caused by meloxicam-induced renal injury in cats. Our primary objective was to compare serum concentrations of SDMA and creatinine in cats before, during, and after induction of renal injury from repeated dosages of meloxicam in the context of a small pilot study.MethodsThis follow-up study results from data collected in a well-controlled study that included 12 healthy female adult purpose-bred cats. Cats in the treatment group received meloxicam 0.3 mg/kg subcutaneously (SC) every 24 h for 31 days. Cats in the control group received saline (0.1 mL SC). Renal injury was defined as the presence of tubular damage, basement membrane damage, and/or interstitial inflammation in histological sections of kidney tissue. Serum creatinine and SDMA concentration were measured every 4 days.ResultsIn the control group, no cats developed renal azotemia. In the treatment group, four out of six cats developed elevated serum creatinine and histopathological evidence of renal injury. Three of these cats developed an elevation in serum SDMA. The time to the development of renal azotemia using serum creatinine or SDMA was not significantly different (p > 0.05).DiscussionIn this pilot study, there was no evidence that serum SDMA was superior to serum creatinine at detecting impaired renal function caused by meloxicam-induced renal injury in cats.

Introduction: Cervical cancer, the second leading cause of cancer-related death for women worldwide, remains a preventable yet persistent disease that disproportionately affects women in low and middle-income countries (LMICs). While existing therapies for treating cervical dysplasia are effective, they are often inaccessible in LMICs. Ethanol ablation is an alternative low-cost, accessible therapy that we previously enhanced into ethyl cellulose (EC)-ethanol gel formulation to improve efficacy.Methods: To evaluate the efficacy of EC-ethanol, in this study, we developed a 3D in vitro model of cervical dysplasia featuring a central lesion of cervical cancer cells surrounded by fibroblasts and keratinocytes. Using a GelMA hydrogel formulation (8.7% w/v), we successfully built a 3D model that captured the architectural complexity of cervical dysplasia. We evaluated changes in cell coverage and cell viability. Then, we compared the viscoelastic properties of the GelMA hydrogels to human cervical tissue and using micro-CT imaging, we assessed EC-ethanol injection deposition in the hydrogel, revealing retention of virtually the entire injected volume near the injection site. Finally, we measured changes in cell viability and cell coverage after the EC-ethanol injection.Results: The developed 3D in vitro model successfully replicated the architectural complexity of cervical dysplasia, demonstrating high cell viability and capturing cell responses effectively. The GelMA hydrogel formulation (8.7% w/v) exhibited viscoelastic properties akin to human cervical tissue. Micro-CT imaging revealed efficient deposition of EC-ethanol within the hydrogel, with retention of the injected volume near the injection site. Furthermore, the EC-ethanol injection significantly reduced cervical cancer cell viability and cell coverage while preserving healthy cells within the model.Conclusion: Our findings indicate that our 3D in vitro model mirrored the architecture of cervical dysplasia and demonstrated the potential of EC-ethanol for localized treatment of cervical dysplasia.

Introduction:B. bovis is an apicomplexan parasite responsible for bovine babesiosis, a tick-borne disease with a worldwide impact. The disease remains inefficiently controlled, and few effective drugs, including imidocarb dipropionate (ID), are currently available in endemic areas. The objective of this study was to evaluate whether buparvaquone (BPQ), a drug currently used to treat cattle infected with the Babesia-related Theileria spp. parasites, could be active against Babesia parasites. Herein, we compared the effect of ID and BPQ on B. bovis growth in vitro erythrocyte culture.Methods:We compared the effect of ID and BPQ on the culture-adapted Texas T2Bo strain of B. bovis. In vitro cultured parasites were incubated with ID and BPQ at two starting parasitemia levels (PPE), 0.2% and 1%. In vitro cultured parasites were treated with ID or BPQ at concentrations ranging from 10 to 300 nM, during 4 consecutive days. Parasitemia levels were daily evaluated using microscopic examination. Data was compared using the independent Student’s t-test.Results and discussion:Both ID and BPQ significantly inhibited (p < 0.05) the growth of B. bovis, regardless of the initial parasitemia used. At 1% parasitemia, BPQ had lower calculated inhibitory concentration 50 (IC50: 50.01) values than ID (IC50: 117.3). No parasites were found in wells with 0.2% starting parasitemia, treated previously with 50 nM of BPQ or ID, after 2 days of culture without drugs. At 1% parasitemia, no parasite survival was detected at 150 nM of BPQ or 300 nM of ID, suggesting that both drugs acted as babesiacidals.Conclusion:Overall, the data suggests that BPQ is effective against B. bovis and shows a residual effect that seems superior to ID, which is currently the first-line drug for treating bovine babesiosis globally.

Background and purpose: Retrospective dose evaluation for organ-at-risk auto-contours has previously used small cohorts due to additional manual effort required for treatment planning on auto-contours. We aimed to do this at large scale, by a) proposing and assessing an automated plan optimization workflow that used existing clinical plan parameters and b) using it for head-and-neck auto-contour dose evaluation. Materials and methods: Our automated workflow emulated our clinic’s treatment planning protocol and reused existing clinical plan optimization parameters. This workflow recreated the original clinical plan (POG) with manual contours (PMC) and evaluated the dose effect (POG-PMC) on 70 photon and 30 proton plans of head-and-neck patients. As a use-case, the same workflow (and parameters) created a plan using auto-contours (PAC) of eight head-and-neck organs-at-risk from a commercial tool and evaluated their dose effect (PMC-PAC). Results: For plan recreation (POG-PMC), our workflow had a median impact of 1.0% and 1.5% across dose metrics of auto-contours, for photon and proton respectively. Computer time of automated planning was 25% (photon) and 42% (proton) of manual planning time. For auto-contour evaluation (PMC-PAC), we noticed an impact of 2.0% and 2.6% for photon and proton radiotherapy. All evaluations had a median ΔNTCP (Normal Tissue Complication Probability) less than 0.3%. Conclusions: The plan replication capability of our automated program provides a blueprint for other clinics to perform auto-contour dose evaluation with large patient cohorts. Finally, despite geometric differences, auto-contours had a minimal median dose impact, hence inspiring confidence in their utility and facilitating their clinical adoption.

The race and the discovery of novel two-dimensional (2D) carbon-based materials have been intensified because many are suitable for energy storage systems, thermoelectric devices, and catalysis applications. Therefore, this study introduces to the scientific community a novel 2D nanosheet named graphenyldiene (GPD), which is formed by arranging cyclobutadiene and bi-phenyl groups to create a monolayer with octadecagonal, hexagonal and tetragonal rings. The cohesive energy of GPD is only 1.37 and 0.65 eV/atom higher than graphene and biphenylene, respectively. Molecular dynamics simulations confirmed its structural and thermal stability. The GPD monolayer remains stable, with no significant deformations at around 1000 K, and the disintegration of the geometry occurs only at a temperature of 1500 K, which is characterized by the formation of an amorphous graphdiyne. The GPD electronic structure shows a direct band gap transition, 1.26 eV, at the Γ point. GPD is a promising alternative to electronic devices due to its carrier mobility of around 103.cm2/V.s. Also, the GPD satisfies the Born-Huang criterion for mechanical stability with elastic constants C11 = 157.62 N/m, C12 = 53.66 N/m and C66 = 51.98 N/m. The Bader's topological analysis indicated that all bonds have strong shared shell characteristics. Finally, the vibrational analysis identified 54 modes, where 21 are Raman active, with A1g and E2g modes dominating the spectrum at 1347, 1685 and 1697 cm−1.

Abstract Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a common feature of many ciliopathies. However, the roles of RPE cilia in vivo remain poorly understood. In this study, we first found that mouse RPE cells only transiently form primary cilia. We then examined the RPE in the mouse model of Bardet-Biedl Syndrome 4 (BBS4), a ciliopathy associated with retinal degeneration in humans, and found that ciliation in BBS4 mutant RPE cells is disrupted early during development. Next, using a laser-induced injury model in vivo, we found that primary cilia in RPE reassemble in response to laser injury during RPE wound healing and then rapidly disassemble after the repair is completed. Finally, we demonstrated that RPE-specific depletion of primary cilia in a conditional mouse model of cilia loss promoted wound healing and enhanced cell proliferation. In summary, our data suggest that RPE cilia contribute to both retinal development and repair and provide insights into potential therapeutic targets for more common RPE degenerative diseases.

OBJECTIVES/GOALS: Incomplete mucosal healingand dysbiosis prevent long-term remission after colitis. IL4 may restore colon homeostasis through its action on immune cells and the microbiome. We will demonstrate this mechanism using genetically modified mice and molecular tools. This may result in target therapies that prolong remission in patients with IBD. METHODS/STUDY POPULATION: Mice were treated with 3% dextran sulfate sodium (DSS) in drinking water for 5 days to induce colitis. Mice were monitored daily for changes in body weight, and to monitor colitis severity. At each endpoint, mice were sacrificed and colon length was measured. For disease severity assessment, mouse colons were prepared in paraffin sections by the 'swiss-rolling' method. For flow cytometry, lamina propria mononuclear cell isolation was performed and cellular populations were stained with fluorophore-conjugated antibodies. IL4-eGFP-expressing (4get) mice were used to analyze the cellular expression of IL4 after colitis. Cell-specific IL4 deletion mice were generated using the cre-lox system. RESULTS/ANTICIPATED RESULTS: IL4-deficient mice had worse colitis compared with wild-type controls. Flow cytometry of lamina propria cells from 4get mice showed that most IL4-producing cells after colitis are eosinophils (CD11b+SiglecF+). Flow cytometry of C57bl6 mice showed an influx of IL4Ra+ monocytes (CD11b+Ly6C+) and macrophages (CD11b+F480+). IL4-stimulated bone marrow-derived macrophages demonstrated an increase in HB-EGF mRNA transcription. Myeloid-specific IL4R deleted mice had no difference in colitis severity compared with controls. Neutrophil-specific IL4R-deleted mice had increased colitis severity and mortality. Co-housing of littermate mice rescued recovery after DSS in IL4 deficient mice. DISCUSSION/SIGNIFICANCE: IL4 appears to play a role in restoring homeostasis after colitis. The mechanism depends on eosinophil-derived IL4, and action through neutrophils. However, the reparative function of IL4 can be shared with deficient mice through the microbiome. I will study the cellular and microbial mechanism by which IL4 restores homeostasis after colitis.

Abstract Solution‐processed networks of semiconducting single‐walled carbon nanotubes (SWCNTs) hold promise as active layers for large‐scale digital circuits, thermoelectric devices, and healthcare applications. Yet, the combined effects of local network properties and (n,m) species composition need to be addressed to improve the performance and reproducibility of state‐of‐the‐art devices. Charge modulation microscopy (CMM) is used to investigate charge transport in field‐effect transistors (FETs) based on monochiral (6,5) SWCNT networks and multichiral networks containing five semiconducting SWCNT species with different band gaps. By mapping the charge‐modulated signal within the FET channel with sub‐micrometer resolution, the spatial distribution of free carriers and its evolution during the switching of the FET are revealed. The CMM maps provide direct evidence that holes and electrons are transported preferentially through the same percolation paths. A moderate positive correlation between the SWCNT density in the monochiral (6,5) network and the charge density in subthreshold regime is demonstrated. In multichiral networks, the charge transport paths are on average less fragmented when involving low band gap species. CMM emerges as a valuable technique to estimate the size of preferential percolation domains associated with the average distance traversed by charge carriers on SWCNTs of the same chirality before tunneling onto other species.

BackgroundAcetaminophen is utilized in human infants for pain management and fever. Neonatal foals might benefit from administration of acetaminophen but effective and safe dosage regimens for neonatal foals remains to be determined.ObjectiveThe objective was to determine the plasma pharmacokinetics of acetaminophen following oral administration of a single dose of 20 mg/kg or 40 mg/kg to neonatal foals. A secondary objective was to evaluate any changes in hematology and biochemistry profiles.Study designRandomized study.MethodsEight clinically healthy 7–9-day old Quarter Horse foals (3 colts and 5 fillies) received a single oral dose of acetaminophen either 20 (n = 4) or 40 (n = 4) mg/kg. Hematology and biochemistry profiles were evaluated before and 7 days after drug administration. Blood samples were collected before and 8 times after acetaminophen administration for 48 h to quantify plasma acetaminophen concentrations. Plasma pharmacokinetic parameters were estimated using non- compartmental analysis.ResultsThe median peak plasma concentrations (and range) occurred at 1.5 (0.5–2) hours, and 1.0 (1–2) hours for the 20 and 40 mg/kg doses. The maximum plasma concentration (and range) was 12 (7.9–17.4) μg/mL for the 20 mg/kg dose and 14 (11–18) μg/mL for 40 mg/kg dose. The median AUC0-∞ ranged from 46 to 100 and 79 to 160 h*-μg/mL for the 20 and 40 mg/kg dose, respectively. Hematology and biochemistry profiles remained within normal limits.ConclusionPlasma disposition of acetaminophen after oral administration of 20 and 40 mg/kg to neonates is comparable to adult horses. However, safety and the optimal dosage regimen of acetaminophen for treating pain and or pyrexia in neonates in this age group remains to be determined.

We present an atlas and follow-up spectroscopic observations of 87 thin stream-like structures detected with the STREAMFINDER algorithm in Gaia DR3, of which 28 are new discoveries. Here, we focus on using these streams to refine mass models of the Galaxy. Fits with a double-power-law halo with the outer power-law slope set to − β _h = −3 yield an inner power-law slope of $-{\gamma }_{h}=-({0.97}_{-0.21}^{+0.17}\,)$ , a scale radius of ${r}_{0,h}={14.7}_{-1.0}^{+4.7}\,\mathrm{kpc}$ , a halo density flattening q _m _, _h = 0.75 ± 0.03, and a local dark matter density of ρ _h _,⊙ = 0.0114 ± 0.0007 M _⊙ pc ^−3 . Freeing β yields $\beta ={2.53}_{-0.16}^{+0.42}$ , but this value is heavily influenced by our chosen virial mass limit. The stellar disks are found to have a combined mass of ${4.20}_{-0.53}^{+0.44}\times {10}^{10}\,{M}_{\odot }$ , with the thick disk contributing 12.4% ± 0.7% to the local stellar surface density. The scale lengths of the thin and thick disks are ${2.17}_{-0.08}^{+0.18}$ and ${1.62}_{-0.13}^{+0.72}\,\mathrm{kpc}$ , respectively, while their scale heights are ${0.347}_{-0.010}^{+0.007}$ and ${0.86}_{-0.02}^{+0.03}\,\mathrm{kpc}$ , respectively. The virial mass of the favored model is ${M}_{200}={1.09}_{-0.14}^{+0.19}\times {10}^{12}\,{M}_{\odot }$ , while the mass inside of 50 kpc is M _R _

The risks of secondary cancers associated with human papillomavirus (HPV) infection are as much as three times higher for survivors of pediatric, adolescent, and young adult cancer (PYAC) compared to the general population. Despite this, HPV vaccination rates among PYAC survivors remain low. Whereas pediatric oncology providers endorse HPV vaccination of PYAC survivors, many lack the resources or opportunities to intervene. The responsibility of HPV vaccination, therefore, falls to primary care providers and practices. This article provides an overview of the challenges with HPV vaccination that are distinct to PYAC survivors and discusses potential strategies to increase HPV vaccine coverage in this population.

Primary cilia are hair-like structures found on nearly all mammalian cell types, including cells in the developing and adult brain. A diverse set of receptors and signaling proteins localize within cilia to regulate many physiological and developmental pathways, including the Hedgehog (Hh) pathway. Defects in cilia structure, protein localization, and function lead to genetic disorders called ciliopathies, which present with various clinical features that include several neurodevelopmental phenotypes and hyperphagia-associated obesity. Despite their dysfunction being implicated in several disease states, understanding their roles in central nervous system (CNS) development and signaling has proven challenging. We hypothesize that dynamic changes to ciliary protein composition contribute to this challenge and may reflect unrecognized diversity of CNS cilia. The proteins ARL13B and ADCY3 are established markers of cilia in the brain. ARL13B is a regulatory GTPase important for regulating cilia structure, protein trafficking, and Hh signaling, and ADCY3 is a ciliary adenylyl cyclase. Here, we examine the ciliary localization of ARL13B and ADCY3 in the perinatal and adult mouse brain. We define changes in the proportion of cilia enriched for ARL13B and ADCY3 depending on brain region and age. Furthermore, we identify distinct lengths of cilia within specific brain regions of male and female mice. ARL13B+ cilia become relatively rare with age in many brain regions, including the hypothalamic feeding centers, while ADCY3 becomes a prominent cilia marker in the mature adult brain. It is important to understand the endogenous localization patterns of these proteins throughout development and under different physiological conditions as these common cilia markers may be more dynamic than initially expected. Understanding regional- and developmental-associated cilia protein composition signatures and physiological condition cilia dynamic changes in the CNS may reveal the molecular mechanisms associated with the features commonly observed in ciliopathy models and ciliopathies, like obesity and diabetes.

We present the demography of the dynamics and gas mass fraction of 33 extremely metal-poor galaxies (EMPGs) with metallicities of 0.015–0.195 Z _⊙ and low stellar masses of 10 ^4 –10 ^8 M _⊙ in the local universe. We conduct deep optical integral field spectroscopy (IFS) for the low-mass EMPGs with the medium-high resolution ( R = 7500) grism of the 8 m Subaru FOCAS IFU instrument by the EMPRESS 3D survey, and investigate the H α emission of the EMPGs. Exploiting the resolution high enough for the low-mass galaxies, we derive gas dynamics with the H α lines by the fitting of three-dimensional disk models. We obtain an average maximum rotation velocity ( v _rot ) of 15 ± 3 km s ^−1 and an average intrinsic velocity dispersion ( σ _0 ) of 27 ± 10 km s ^−1 for 15 spatially resolved EMPGs out of 33 EMPGs, and find that all 15 EMPGs have v _rot / σ _0 < 1 suggesting dispersion-dominated systems. There is a clear decreasing trend of v _rot / σ _0 with the decreasing stellar mass and metallicity. We derive the gas mass fraction ( f _gas ) for all 33 EMPGs, and find no clear dependence on stellar mass and metallicity. These v _rot / σ _0 and f _gas trends should be compared with young high- z galaxies observed by the forthcoming JWST IFS programs to understand the physical origins of the EMPGs in the local universe.

Here, Burk et al. develop an algorithm to diagnose bacterial vaginosis (BV) using the 16S rRNA gene, called molBV, which they use to profile the inflammatory landscape of BV and predict progression of human papillomavirus infection to cervical pre-cancer.

Antecedentes y Objetivos: Se realizó una encuesta transversal que incluyó 38 preguntas sobre demografía, estado clínico, cambio de hábitos de salud, tratamientos médicos a pacientes cardiometabólicos en seguimiento ambulatorio. Un total de 13 países latinoamericanos inscribieron pacientes del 15 de junio al 15 de julio de 2020. Método: Los países se dividieron en 3 regiones geográficas Región 1 (NCCR): Región Norte, Centro y Caribe; Región 2 (AR): Región Andina; Región 3 (SCR): Región Cono Sur. Las medidas de aislamiento se estimaron a partir de informes nacionales y se correlacionaron utilizando el coeficiente R de Spearman. Se analizaron 4.216 pacientes, NCCR (33.82%); AR (32.23%) SCR (33.94%). Resultados: Se encontraron diferencias significativas entre regiones. Este análisis de la medicación habitual mostró que la discontinuación de la medicación fue mayor en RA, llegando a casi el 30% (p < 0.001). El principal hallazgo de este estudio fue el impacto negativo que tienen las medidas restrictivas sobre la adherencia a la medicación y la actividad física, Rs = 0.84 (p = 0.0003) y Rs = 0.61 (p = 0.0032), respectivamente. Se encontraron diferencias significativas entre regiones. AR es la región más vulnerable. Conclusiones: Las medidas restrictivas impuestas por los diferentes países (cuarentena) mostraron una correlación positiva con la interrupción de la medicación y una correlación negativa con la cantidad de actividad física. El impacto de las consecuencias que deja esta pandemia será muy profundo en la mayoría de los países latinoamericanos.

Design representations play a crucial role in facilitating communication between individuals in design. Sketches and physical prototypes are frequently used to communicate design concepts in early-stage design. However, we lack an understanding of the communicative benefits each representation provides and how these benefits relate to the effort and resources required to create each representation. A mixed-methods study was conducted with 44 participants to identify whether sketches and physical prototypes led to different levels of cognitive load perceived by a communicator and listener and the characteristics that shape their cognitive load during communication. Results showed that listeners perceived higher levels of mental and physical demands when understanding ideas as low-fidelity physical prototypes, as compared to sketches. No significant differences were found in the cognitive load levels of communicators between the two conditions. Qualitative analyses of post-task semi-structured interviews identified five themes relating to verbal explanations and visual representations that shape designers’ cognitive load when understanding and communicating ideas through design representations. Results indicate that designers should be aware of the specific objectives they seek to accomplish when selecting the design representation used to communicate. This work contributes to the knowledge base needed for designers to use design representations more effectively as tools for communication.

Abstract Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t 49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = −0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = −0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

Abstract Knee cartilage does not regenerate spontaneously after injury, and a gold standard regenerative treatment algorithm has not been established. This study demonstrates preclinical safety and efficacy of scaffold-free, human juvenile cartilage-derived-chondrocyte (JCC) sheets produced from routine surgical discards using thermo-responsive cultureware. JCCs exhibit stable and high growth potential in vitro over passage 10, supporting possibilities for scale-up to mass production for commercialization. JCC sheets contain highly viable, densely packed cells, show no anchorage-independent cell growth, express mesenchymal surface markers, and lack MHC II expression. In nude rat focal osteochondral defect models, stable neocartilage formation was observed at 4 weeks by JCC sheet transplantation without abnormal tissue growth over 24 weeks in contrast to the nontreatment group showing no spontaneous cartilage repair. Regenerated cartilage was safranin-O positive, contained type II collagen, aggrecan, and human vimentin, and lacked type I collagen, indicating that the hyaline-like neocartilage formed originates from transplanted JCC sheets rather than host-derived cells. This study demonstrates the safety of JCC sheets and stable hyaline cartilage formation with engineered JCC sheets utilizing a sustainable tissue supply. Cost-benefit and scaling issues for sheet fabrication and use support feasibility of this JCC sheet strategy in clinical cartilage repair.

A subset of genetic disorders termed ciliopathies are associated with obesity. The mechanisms behind cilia dysfunction and altered energy homeostasis in these syndromes are complex and likely involve deficits in both development and adult homeostasis. Interestingly, several cilia-associated gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis, including their roles in centrally mediated food intake and peripheral tissues, many questions remain. Here, we briefly discuss syndromic ciliopathies and monogenic cilia signaling mutations associated with obesity. We then focus on potential ways neuronal cilia regulate energy homeostasis. We discuss the literature around cilia and leptin-melanocortin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We also discuss the different brain regions where cilia are implicated in energy homeostasis and the potential for cilia dysfunction in neural development to contribute to obesity. We close with a short discussion on the challenges and opportunities associated with studies looking at neuronal cilia and energy homeostasis. This review highlights how neuronal cilia-mediated signaling is critical for proper energy homeostasis.

Covalent functionalization of single-walled carbon nanotubes with luminescent sp 3-defects generally produces a variety of binding configurations and emission wavelengths. The authors propose a base-mediated nucleophilic functionalization approach to selectively achieve configurations for E11* and E11*- or purely E11*- defect emission.

Background: HIV has been shown to increase the likelihood of oral HPV infection. In this study, we evaluated the risk of oral HPV in HIV infected patients compared with HIV-negative controls. Methods: 101 healthy adult volunteers (HIV-) and 245 adults living with HIV infection (HIV+) were recruited from 5 academic medical centers. Questionnaires and saliva samples were obtained every 3–8 months over a period of 2 years (2015–2017). DNA was isolated from the saliva samples and tested for 18 high- and low-risk genotypes. Results: Oral HPV was detected in 23% of HIV + vs. 10% of HIV- participants (p

Multiple strategies are available that could reduce nitrogen (N) fertilizer use in agricultural systems, ranging from voluntary adoption of new N management practices by farmers to government regulations. However, these strategies have different economic and political costs, and their relative effectiveness in decreasing N leaching has not been evaluated at scale, particularly concerning potential trade-offs in crop yield and profitability. To inform policy efforts in the US Midwest, we quantified the effects of four policy scenarios designed to reduce fertilizer N inputs without sacrificing maize yields below 95%. A simulated dataset for economically optimum N rates and corresponding leaching losses was developed using a process-based crop model across 4,030 fields over 30 years. Policy scenarios were (1) higher N prices, (2) N leaching fee, (3) N balance fee, and (4) voluntary reduction of N use by farmers, each implemented under a range of sub-levels (low to high severity). Aggregated results show that all policies decreased N rates and N leaching, but this was associated with an exponential increase in economic costs. Achieving an N leaching reduction target of 20% has an estimated pollution control cost of 30–37 US$/ha, representing 147 million US$/year when scaled up to the state level, which is in the range of current government payments for existing conservation programs. Notably, such control of N losses would reduce the environmental impact of agriculture on water quality (externalities) by an estimated 524 million US$/year, representing an increase in society welfare of 377 million US$/year. Among the four policies, directly charging a fee on N leaching helped mitigate economic losses while improving the point source reduction effect (i.e., targeting fields that were leaching hotspots) and better internalization effect (i.e., targeting fields with higher environmental impact costs). This study provides actionable data to inform the development of cost-effective N fertilizer regulations by integrating changes in crop productivity and N losses in economic terms at the field level.

Human subject experiments are performed to evaluate the influence of artificial intelligence (AI) process management on human design teams solving a complex engineering problem and compare that to the influence of human process management. Participants are grouped into teams of five individuals and asked to generate a drone fleet and plan routes to deliver parcels to a given customer market. The teams are placed under the guidance of either a human or an AI external process manager. Halfway through the experiment, the customer market is changed unexpectedly, requiring teams to adjust their strategy. During the experiment, participants can create, evaluate, share their drone designs and delivery routes, and communicate with their team through a text chat tool using a collaborative research platform called HyForm. The research platform collects step-by-step logs of the actions made by and communication amongst participants in both the design team's roles and the process managers. This article presents the data sets collected for 171 participants assigned to 31 design teams, 15 teams under the guidance of an AI agent (5 participants), and 16 teams under the guidance of a human manager (6 participants). These data sets can be used for data-driven design, behavioral analyses, sequence-based analyses, and natural language processing.

Abstract Traumatic brain injury (TBI) causes a profound inflammatory response within the central nervous system and peripheral immune system, which contributes to secondary brain injury and further morbidity and mortality. Preclinical investigations have demonstrated that treatments that downregulate microglia activation and polarize them toward a reparative/anti‐inflammatory phenotype have improved outcomes in preclinical models. However, no therapy to date has translated into proven benefits in human patients. Regulatory T cells (Treg) have been shown to downregulate pathologic immune responses of the innate and adaptive immune system across a variety of pathologies. Furthermore, cellular therapy has been shown to augment host Treg responses in preclinical models; yet, studies investigating the use of Treg as a therapeutic for TBI are lacking. In a rodent TBI model, we demonstrate that human umbilical cord blood Treg modulate the central and peripheral immune response after injury in vitro and in vivo.

Abstract Background In humans, gabapentin an analgesic, undergoes non‐proportional pharmacokinetics which can alter efficacy. No information exists on the pharmacokinetics of dosages >20 mg/kg, escalating dosages or dose proportionality of gabapentin in horses. Hypothesis and Objectives Gabapentin exposure in plasma would not increase proportionally relative to the dose in horses receiving dosages ≥20 mg/kg. To assess the plasma pharmacokinetics of gabapentin after nasogastric administration of gabapentin at dosages of 10 to 160 mg/kg in adult horses. Animals Nine clinically healthy adult Arabian and Quarter Horses. Methods In a randomized blinded trial, gabapentin was administered by nasogastric intubation to horses at 10, 20 mg/kg (n = 3) and 60, 80, 120, 160 mg/kg (n = 6). Plasma was collected before and at regular times over 64 hours after administration of gabapentin. Gabapentin was quantified using a validated chromatographic method. Dose proportionality was estimated using a power model. Pharmacokinetic parameters were estimated using compartmental pharmacokinetic analysis. Results Plasma pharmacokinetics parameters of gabapentin were estimated after nasogastric administration at dosages of 10 to 160 mg/kg. Gabapentin plasma concentration increased with dose increments. However, the area under the concentration curve from zero to infinity and maximal plasma concentration did not increase proportionally relative to the dose in horses. Conclusions and Clinical Importance Gabapentin exposure in plasma is not proportional relative to the dose in horses receiving nasogastric dosages of 10 to 160 mg/kg.

Nitrogen (N) fertilizer recommendations for corn (Zea mays L.) in the US Midwest have been a puzzle for several decades, without agreement among stakeholders for which methodology is the best to balance environmental and economic outcomes. Part of the reason is the lack of long-term data of crop responses to N over multiple fields since trial data is often limited in the number of soils and years it can explore. To overcome this limitation, we designed an analytical platform based on crop simulations run over millions of farming scenarios over extensive geographies. The database was calibrated and validated using data from more than four hundred trials in the region. This dataset can have an important role for research and education in N management, machine leaching, and environmental policy analysis. The calibration and validation procedure provides a framework for future gridded crop model studies. We describe dataset characteristics and provide thorough descriptions of the model setup.

For several decades, maize (Zea mays L.) management decisions in smallholder farming in tropical regions have been a puzzle. To best balance alternative management practices' environmental and economic outcomes, an extensive dataset was gathered through CIMMYT's knowledge hub in Chiapas, a state in southern Mexico. In a knowledge hub, farmers, with the support of farm advisors, compare conventional and improved agronomic practices side-by-side and install demonstration fields where they implement improved practices. In all these fields data on on-farm operations and results is collected. The dataset was assembled using field variables (yield, cultivars, fertilization and tillage practice), as well as environment variables from soil mapping (slope, elevation, soil texture, pH and organic matter concentration) and gridded weather datasets (precipitation, temperature, radiation and evapotranspiration). The dataset contains observations from 4585 fields and comprises a period of 7 years between 2012 and 2018. This dataset will facilitate analytical approaches to represent spatial and temporal variability of alternative crop management decisions based on observational data and explain model-generated predictions for maize in Chiapas, Mexico. In addition, this data can serve as an example for similar efforts in Big Data in Agriculture.

We build a statistical framework to infer the global properties of the satellite system of the Andromeda galaxy (M31) from the properties of individual dwarf galaxies located in the Pan-Andromeda Archaelogical Survey (PAndAS) and the previously determined completeness of the survey. Using forward modeling, we infer the slope of the luminosity function of the satellite system, the slope of its spatial density distribution, and the size–luminosity relation followed by the dwarf galaxies. We find that the slope of the luminosity function is β = −1.5 ± 0.1. Combined with the spatial density profile, it implies that, when accounting for survey incompleteness, M31 hosts ${92}_{-26}^{+19}$ dwarf galaxies with M _V < −5.5 and a sky-projected distance from M31 between 30 and 300 kpc. We conclude that many faint or distant dwarf galaxies remain to be discovered around Andromeda, especially outside the PAndAS footprint. Finally, we use our model to test if the higher number of satellites situated in the hemisphere facing the Milky Way could be explained simply by the detection limits of dwarf galaxy searches. We rule this out at >99.9% confidence and conclude that this anisotropy is an intrinsic feature of the M31 satellite system. The statistical framework we present here is a powerful tool to robustly constrain the properties of a satellite system and compare those across hosts, especially considering the upcoming start of the Euclid or Rubin large photometric surveys that are expected to uncover a large number of dwarf galaxies in the Local Volume.

We present kinematics of six local extremely metal-poor galaxies (EMPGs) with low metallicities (0.016–0.098 Z _⊙ ) and low stellar masses (10 ^4.7 –10 ^7.6 M _⊙ ). Taking deep medium/high-resolution ( R ∼ 7500) integral-field spectra with 8.2 m Subaru, we resolve the small inner velocity gradients and dispersions of the EMPGs with H α emission. Carefully masking out substructures originating by inflow and/or outflow, we fit three-dimensional disk models to the observed H α flux, velocity, and velocity dispersion maps. All the EMPGs show rotational velocities ( v _rot ) of 5–23 km s ^−1 smaller than the velocity dispersions ( σ _0 ) of 17–31 km s ^−1 , indicating dispersion-dominated ( v _rot / σ _0 = 0.29–0.80 < 1) systems affected by inflow and/or outflow. Except for two EMPGs with large uncertainties, we find that the EMPGs have very large gas-mass fractions of f _gas ≃ 0.9–1.0. Comparing our results with other H α kinematics studies, we find that v _rot / σ _0 decreases and f _gas increases with decreasing metallicity, decreasing stellar mass, and increasing specific star formation rate. We also find that simulated high- z ( z ∼ 7) forming galaxies have gas fractions and dynamics similar to the observed EMPGs. Our EMPG observations and the simulations suggest that primordial galaxies are gas-rich dispersion-dominated systems, which would be identified by the forthcoming James Webb Space Telescope observations at z ∼ 7.

Abstract Background Mycophenolate mofetil (MMF) is an immunosuppressant used in human and veterinary medicine. Little pharmacokinetic and pharmacodynamic information on MMF is available in cats. Objective To evaluate the plasma disposition of mycophenolic acid (MPA) and assess its effect on total peripheral blood mononuclear cells and CD4+/CD8+ ratios after PO administration of MMF. Animals Healthy cats (n = 10). Methods Mycophenolate mofetil was administered at a dosage of 10 mg/kg q12h (n = 3), 15 mg/kg q12h (n = 3), and 15 mg/kg q8h (n = 4) for 7 days. Concentrations of MPA and derivatives were determined using ultra‐high‐performance liquid chromatography. Flow cytometry was used to assess CD4+/CD8+ T‐cell ratios. Results All cats biotransformed MMF into MPA. Half of the cats (5/10) had adverse effects within 1 week of MMF administration. Area under the curve limit of quantification (AUC0‐LOQh) of MPA ranged from 1.27 to 2.03 hours·μg/mL and from 1.77 to 8.54 hours·μg/mL after the first and last PO dose of 10 mg/kg. The AUC0‐loqh of MPA ranged from 2.18 to 31 hours·μg/mL after the first dose of 15 mg/kg of MMF. Before the first dose of MMF, the average total number of PBMC ranged from 1.2 to 9.3 million/mL. At the last dose of MMF, the average total number of PBMC ranged from 3 to 5 million/mL. Conclusion Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long‐term safety in cats of this dosage regimen is unknown.