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Investigating Protostellar Accretion (IPA) is a JWST Cycle 1 GO program that uses NIRSpec integral field units and MIRI Medium Resolution Spectrograph to obtain 2.9–28 μ m spectral cubes of young, deeply embedded protostars with luminosities of 0.2–10,000 L _⊙ and central masses of 0.15–12 M _⊙ . In this Letter, we report the discovery of a highly collimated atomic jet from the Class 0 protostar IRAS 16253−2429, the lowest-luminosity source ( L _bol = 0.2 L _⊙ ) in the IPA program. The collimated jet is detected in multiple [Fe ii ] lines and [Ne ii ], [Ni ii ], and H i lines but not in molecular emission. The atomic jet has a velocity of about 169 ± 15 km s ^−1 , after correcting for inclination. The width of the jet increases with distance from the central protostar from 23 to 60 au, corresponding to an opening angle of 2.°6 ± 0.°5. By comparing the measured flux ratios of various fine-structure lines to those predicted by simple shock models, we derive a shock speed of 54 km s ^−1 and a preshock density of 2.0 × 10 ^3 cm ^−3 at the base of the jet. From these quantities and using a suite of jet models and extinction laws, we compute a mass-loss rate between 0.4 and 1.1 ×10 ^−10 M _⊙ yr ^−1 . The low mass-loss rate is consistent with simultaneous measurements of low mass accretion rate (2.4 ± 0.8 × 10 ^−9 M _⊙ yr ^−1 ) for IRAS 16253−2429 from JWST observations, indicating that the protostar is in a quiescent accretion phase. Our results demonstrate that very low-mass protostars can drive highly collimated, atomic jets, even during the quiescent phase.

Using the MIRI medium-resolution spectrometer on JWST, we have detected pure rotational, suprathermal OH emissions from the vicinity of the intermediate-mass protostar HOPS 370 (OMC2/FIR3). These emissions are observed from shocked knots in a jet/outflow and originate in states of rotational quantum number as high as 46 that possess excitation energies as large as E _U / k = 4.65 × 10 ^4 K. The relative strengths of the observed OH lines provide a powerful diagnostic of the ultraviolet radiation field in a heavily extinguished region ( A _V ∼ 10–20) where direct UV observations are impossible. To high precision, the OH line strengths are consistent with a picture in which the suprathermal OH states are populated following the photodissociation of water in its $\tilde{B}-X$ band by ultraviolet radiation produced by fast (∼80 km s ^−1 ) shocks along the jet. The observed dominance of emission from symmetric ( $A^{\prime} $ ) OH states over that from antisymmetric ( A ″) states provides a distinctive signature of this particular population mechanism. Moreover, the variation of intensity with rotational quantum number suggests specifically that Ly α radiation is responsible for the photodissociation of water, an alternative model with photodissociation by a 10 ^4 K blackbody being disfavored at a high level of significance. Using measurements of the Br α flux to estimate the Ly α production rate, we find that ∼4% of the Ly α photons are absorbed by water. Combined with direct measurements of water emissions in the ν _2 = 1 − 0 band, the OH observations promise to provide key constraints on future models for the diffusion of Ly α photons in the vicinity of a shock front.

Investigating Protostellar Accretion is a Cycle 1 JWST program using the NIRSpec+MIRI integral field units to obtain 2.9–28 μ m spectral cubes of five young protostars with luminosities of 0.2–10,000 L _⊙ in their primary accretion phase. This paper introduces the NIRSpec 2.9–5.3 μ m data of the inner 840–9000 au with spatial resolutions from 28 to 300 au. The spectra show rising continuum emission; deep ice absorption; emission from H _2 , H i , and [Fe ii ]; and the CO fundamental series in emission and absorption. Maps of the continuum emission show scattered light cavities for all five protostars. In the cavities, collimated jets are detected in [Fe ii ] for the four

We present a combined Stratospheric Observatory for Infrared Astronomy (SOFIA) and two-epoch Hubble Space Telescope (HST) study of the region NGC 2071 IR containing the outflow from the protostar HOPS 361-A (NGC 2071 IRS 1). New [O i ] 63 μ m spectra, taken with the German REciever for Astronomy at Terahertz frequencies (GREAT) instrument aboard SOFIA, trace the outflow, spectrally resolve line profiles, and give radial velocities of the far-IR emission to yield 3D kinematics, shock properties, and feedback properties. Proper motions and extinction values from HST give a more complete quasi-3D picture that we use to model shock speeds and densities. We identify 14 distinct features that show proper motions. Combined with the GREAT data, we estimate that HOPS 361-A has a mass outflow rate of 3.16 × 10 ^−6 M _⊙ yr ^−1 with shock speeds up to 51 km s ^−1 . The outflow force summed over all knots per area is measured to be 1.45 × 10 ^−4 M _⊙ km ^−1 s ^−1 yr ^−1 and a power summed over all knotsper area of 2.37 × 10 ^−2 M _⊙ s ^−3 dissipated assuming constant $\dot{M}$ , with large uncertainties on the feedback values. The total [O i ] luminosity using all SOFIA apertures encompassing the HOPS 361 clump is 0.7 L _⊙ , corresponding to a mass outflow rate of 7 × 10 ^−5 M _⊙ yr ^−1 . This is the second 3D kinematic study of an outflow in NGC 2071 IR in the near- and far-IR regimes following Rubinstein et al. ( 2023 ). The SOFIA [O i ] spectra add unique focus to the entrained gas connecting the recent episode of outflows from HOPS 361-A to the outflow cavity and the surrounding NGC 2071 IR star-forming environment.

We investigate the bright CO fundamental emission in the central regions of five protostars in their primary mass assembly phase using new observations from JWST’s Near-Infrared Spectrograph and Mid-Infrared Instrument. CO line emission images and fluxes are extracted for a forest of ∼150 rovibrational transitions from two vibrational bands, v = 1−0 and v = 2−1. However, ^13 CO is undetected, indicating that ^12 CO emission is optically thin. We use H _2 emission lines to correct fluxes for extinction and then construct rotation diagrams for the CO lines with the highest spectral resolution and sensitivity to estimate rotational temperatures and numbers of CO molecules. Two distinct rotational temperature components are required for v = 1 (∼600 to 1000 K and 2000 to ∼10 ^4 K), while one hotter component is required for v = 2 (≳3500 K). ^13 CO is depleted compared to the abundances found in the interstellar medium, indicating selective UV photodissociation of ^13 CO; therefore, UV radiative pumping may explain the higher rotational temperatures in v = 2. The average vibrational temperature is ∼1000 K for our sources and is similar to the lowest rotational temperature components. Using the measured rotational and vibrational temperatures to infer a total number of CO molecules, we find that the total gas masses range from lower limits of ∼10 ^22 g for the lowest mass protostars to ∼10 ^26 g for the highest mass protostars. Our gas mass lower limits are compatible with those in more evolved systems, which suggest the lowest rotational temperature component comes from the inner disk, scattered into our line of sight, but we also cannot exclude the contribution to the CO emission from disk winds for higher mass targets.

We present a two-epoch Hubble Space Telescope study of NGC 2071 IR highlighting HOPS 361-C, a protostar producing an arced 0.2 parsec-scale jet. The proper motions for the brightest knots decrease from 350 to 100 km s ^−1 with increasing distance from the source. The [Fe ii ] and Pa β emission line intensity ratio gives a velocity jump through each knot of 40–50 km s ^−1 . A new [O i ] 63 μ m spectrum, taken with the German REciever for Astronomy at Terahertz frequencies instrument aboard Stratospheric Observatory for Infrared Astronomy, shows a low line-of-sight velocity indicative of high jet inclination. Proper motions and jump velocities then estimate 3D flow speed for knots. Subsequently, we model knot positions and speeds with a precessing jet that decelerates. The measurements are matched with a precession period of 1000–3000 yr and half opening angle of 15°. The [Fe ii ] 1.26-to-1.64 μ m line intensity ratio determines visual extinction to each knot from 5 to 30 mag. Relative to ∼14 mag of extinction through the cloud from C ^18 O emission maps, the jet is embedded at a 1/5–4/5 fractional cloud depth. Our model suggests the jet is dissipated over a 0.2 pc arc. This short distance may result from the jet sweeping through a wide angle, allowing the cloud time to fill cavities opened by the jet. Precessing jets contrast with nearly unidirectional protostellar jets that puncture host clouds and can propagate significantly farther.

Strong magnetic fields affect radiation dose deposition in MRI-guided radiation therapy systems, particularly at interfaces between tissues of differing densities such as those in the thorax. In this study, we evaluated the impact of a 1.5 T magnetic field on radiation-induced lung damage in C57L/J mice. We irradiated 140 mice to the whole thorax with parallel-opposed Co-60 beams to doses of 0, 9.0, 10.0, 10.5, 11.0, 12.0, or 13.0 Gy (20 mice per dose group). Ten mice per dose group were irradiated while a 1.5 T magnetic field was applied transverse to the radiation beam and ten mice were irradiated with the magnetic field set to 0 T. We compared survival and noninvasive assays of radiation-induced lung damage, namely respiratory rate and metrics derived from thoracic cone-beam CTs, between the two sets of mice. We report two main results. First, the presence of a transverse 1.5 T field during irradiation had no impact on survival of C57L/J mice. Second, there was a small but statistically significant effect on noninvasive assays of radiation-induced lung damage. These results provide critical safety data for the clinical introduction of MRI-guided radiation therapy systems.

Objectives: Dermal and subdermal bacterial infections, caused mainly by Staphylococcus aureus, are currently treated by systemic antibiotics. The aim of the present study was to investigate a new approach to treat deep skin and soft tissue bacterial infections by dermal application of erythromycin in an ethosomal carrier.Methods: A model for deep dermal S. aureus infection in mice was developed. The efficiency of ethosomal erythromycin applied to the skin-infected site was compared with intraperitoneal erythromycin administration and with local application of hydroethanolic erythromycin solution. The parameters evaluated were the development of dermal wound, histological sections and bacterial count of the infected tissue.Results: The in vivo experiments demonstrated a very efficient healing of S. aureus-induced deep dermal infections when the mice were treated with ethosomal erythromycin. Bacterial counts and histological evaluation of the skin treated with ethosomal antibiotic revealed no bacterial growth and normal skin structure. On the contrary, no subdermal healing was observed in infected animals treated with topical hydroethanolic erythromycin solution. In this group, animals developed deep dermal abscesses and the dermal structures were destroyed where S. aureus colonies were present. Bacterial counts of the infected tissues were 1.06 × 107 and 0.27 × 107 cfu/g of tissue, respectively, on days 7 and 10.Conclusions: Therapy with ethosomal erythromycin applied to the skin of S. aureus-infected mice was as effective as systemically administered erythromycin, suggesting a new possibility to treat deep dermal infections by local application of antibiotic in ethosomal carrier. [ABSTRACT FROM AUTHOR]

Objective: Long-term therapy for anthrax might induce antimicrobial resistance in Bacillus anthracis. The aim of the present study was to investigate the potential of 18 different antibiotics to select resistant isolates of B. anthracis, (ST-1 and Sterne strains).Methods: Resistant isolates were selected by serial passages on brain heart infusion agar containing increasing concentrations of antibiotics (from the MIC upwards).Results: The MICs of ciprofloxacin, ofloxacin and levofloxacin increased from 0.125–0.25 to 8 mg/L, that of moxifloxacin increased from 0.03–0.06 to 8 mg/L, in both strains, and the MIC of garenoxacin increased from 0.015 to 0.5 mg/L for the ST-1 strain and from 0.03 to 8 mg/L for the Sterne strain. The MICs of tetracycline and minocycline increased from 0.125 to 2–8 mg/L and 0.06 to 1 mg/L, respectively. The MIC of vancomycin increased from 2.5 to 20 mg/L for the ST-1 strain and from 5 to 20 mg/L for the Sterne strain. Linezolid exhibited an MIC increase from 2 to 4 mg/L for both strains. The MIC of quinupristin/dalfopristin increased from 0.125 to 64–128 mg/L. Erythromycin demonstrated an MIC increase from 1 to 128 mg/L, that of clarithromycin increased from 0.125 to 8–64 mg/L and that of telithromycin increased from 0.06–0.125 to 1–4 mg/L. The clindamycin MIC increased from 0.125–0.25 to 8 mg/L. Penicillin G and amoxicillin MICs increased from <1 mg/L to 128–512 mg/L. Isolates made resistant to one fluoroquinolone exhibited cross-resistance to the other quinolones except the ST-1 mutant strain which remained susceptible to garenoxacin. Cross-resistance to fluoroquinolones did not correlate with resistance to other antibiotics.Conclusion: The ease with which B. anthracis can be made resistant in vitro suggests that close monitoring of patients treated for anthrax is mandatory. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate in vitro the post-antibiotic effect (PAE) of 19 antibacterial agents against two strains of Bacillus anthracis (ST-1 and Sterne strains).Methods: PAE was determined by calculating the time required for the viable counts of antibiotic-exposed bacteria (at concentrations of 10 MIC and exposure for 2 h) at 37C to increase by 1 log10 above the counts observed immediately after antibiotic removal compared with the corresponding time for controls not exposed to antibiotics.Results: The PAEs of the fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and garenoxacin) were 25 h. The macrolide (erythromycin, clarithromycin and telithromycin) PAEs were 14 h, and that of clindamycin was 2 h. The PAEs induced by tetracycline and minocycline were 13 h. The PAEs induced by the -lactams (penicillin G, amoxicillin and ceftriaxone), vancomycin, linezolid and chloramphenicol were 12 h. The PAE induced by rifampicin was 45 h. Quinupristin/dalfopristin had the longest PAE, lasting for 78 h.Conclusions: Our results indicate that the PAE is unrelated to the MIC but may be related to the rapidity of bacterial kill. These observations may bear importance on treatment regimens of human anthrax. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the in vitro acquisition of resistance to antibiotics by Bacillus anthracis. Methods: The in vitro activities of 18 antibacterial agents against two strains of B. anthracis, the Sterne strain and the Russian anthrax vaccine strain ST-1, were tested by determining the MICs and by measuring the rates of antibiotic kill at 5× and 10× MIC. Results: The fluoroquinolones ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin, the β-lactams penicillin G and amoxicillin, the macrolide clarithromycin, the ketolide telithromycin, as well as clindamycin, rifampicin and quinupristin/dalfopristin had MICs in the range of 0.03-0.25 mg/L. Minocycline had an MIC of 0.03 mg/L, as did penicillin, against the ST-1 strain. Ciprofloxacin had an MIC of 0.03 mg/L against both strains. Erythromycin, vancomycin and the oxazolidinone linezolid were less active (MIC 0.5-2.5 mg/L). Ceftriaxone was the least active, having an MIC of 8.0 mg/L. Chloramphenicol was inactive (MIC > 256 mg/L). Quinupristin/dalfopristin, rifampicin and moxifloxacin showed the most rapid bacterial killing, achieving a complete eradication of detectable organisms (2 log10 reduction within 0.5-3 h and 4 log10 reduction within 0.5-4 h for both strains at concentrations of 5× and 10× the MIC). The β-lactams and vancomycin demonstrated a 2-4 log10 reduction within 5-15 h. Ceftriaxone had a similar effect to penicillin and amoxicillin against the ST-1 strain, but a slower effect than these two β-lactams against the Sterne strain. The macrolides, tetracyclines and linezolid demonstrated a lower kill rate, while chloramphenicol did not kill at all. Conclusions: These data expand on the spectrum of agents recommended for the treatment of anthrax (ciprofloxacin, penicillin G and tetracyclines) and add new options, such as other fluoroquinolones, amoxicillin, rifampicin and quinupristin/dalfopristin, as potential therapeutic agents. [ABSTRACT FROM AUTHOR]

The physical processes occurring within the inner few astronomical units of protoplanetary disks surrounding Herbig Ae stars are crucial to setting the environment in which the outer planet-forming disk evolves and put critical constraints on the processes of accretion and planet migration. We present the most complete published sample of high angular resolution H- and K-band observations of the stars HD 163296 and HD 190073, including 30 previously unpublished nights of observations of the former and 45 nights of the latter with the CHARA long-baseline interferometer, in addition to archival VLTI data. We confirm previous observations suggesting that significant near-infrared emission originates within the putative dust evaporation front of HD 163296 and show that this is the case for HD 190073 as well. The H- and K-band sizes are the same within (3 ± 3)% for HD 163296 and within (6 ± 10)% for HD 190073. The radial surface brightness profiles for both disks are remarkably Gaussian-like with little or no sign of the sharp edge expected for a dust evaporation front. Coupled with spectral energy distribution analysis, our direct measurements of the stellar flux component at the H and K bands suggest that HD 190073 is much younger (<400 kyr) and more massive (∼5.6 M⊙) than previously thought, mainly as a consequence of the new Gaia distance (891 pc). [ABSTRACT FROM AUTHOR]

To recommend imaging protocols and establish tolerance levels for microCT image quality assurance (QA) performed on conformal image-guided small animal irradiators. A fully automated QA software SAPA (small animal phantom analyzer) for image analysis of the commercial Shelley micro-CT MCTP 610 phantom was developed, in which quantitative analyses of CT number linearity, signal-to-noise ratio (SNR), uniformity and noise, geometric accuracy, spatial resolution by means of modulation transfer function (MTF), and CT contrast were performed. Phantom microCT scans from eleven institutions acquired with four image-guided small animal irradiator units (including the commercial PXi X-RAD SmART and Xstrahl SARRP systems) with varying parameters used for routine small animal imaging were analyzed. Multi-institutional data sets were compared using SAPA, based on which tolerance levels for each QA test were established and imaging protocols for QA were recommended. By analyzing microCT data from 11 institutions, we established image QA tolerance levels for all image quality tests. CT number linearity set to R2  >  0.990 was acceptable in microCT data acquired at all but three institutions. Acceptable SNR  >  36 and noise levels  <55 HU were obtained at five of the eleven institutions, where failing scans were acquired with current-exposure time of less than 120 mAs. Acceptable spatial resolution (>1.5 lp mm−1 for MTF  =  0.2) was obtained at all but four institutions due to their large image voxel size used (>0.275 mm). Ten of the eleven institutions passed the set QA tolerance for geometric accuracy (<1.5%) and nine of the eleven institutions passed the QA tolerance for contrast (>2000 HU for 30 mgI ml−1). We recommend performing imaging QA with 70 kVp, 1.5 mA, 120 s imaging time, 0.20 mm voxel size, and a frame rate of 5 fps for the PXi X-RAD SmART. For the Xstrahl SARRP, we recommend using 60 kVp, 1.0 mA, 240 s imaging time, 0.20 mm voxel size, and 6 fps. These imaging protocols should result in high quality images that pass the set tolerance levels on all systems. Average SAPA computation time for complete QA analysis for a 0.20 mm voxel, 400 slice Shelley phantom microCT data set was less than 20 s. We present image quality assurance recommendations for image-guided small animal radiotherapy systems that can aid researchers in maintaining high image quality, allowing for spatially precise conformal dose delivery to small animals. [ABSTRACT FROM AUTHOR]

ObjectiveInterprofessional care is integral to end-of-life (EOL) and palliative care (PC) and may be suited for EOL and PC education.We evaluate the impact of an interprofessional EOL care curriculum on participants, during the course, on completion and 4 years laterusing quantitative (questionnaires) and qualitative (open-ended questions and interviews) methods.The course included 14 fifth and sixth-year medical students, 9 social work students and 7 nursing students enrolled in master's degree programmes. Seventeen participants completed questionnaires 4 years later and eight participated in interviews.On postcourse questionnaires, participants attributed high value to interprofessional education (IPE) (4.77/5±0.50 on a Likert scale). Four years later, participants reported that IPE impacted their professional (3.65/5±1.11) and personal lives (3.94/5±1.09) and found PC IPE important (4.88/5±0.33).Conventional content analysis showed that the course enabled discussion of death and dying and provided an opportunity for a personal-emotional journey. It offered an approach to EOL care and an opportunity to experience interprofessional teamwork at the EOL resulting in behavioural change.Interprofessional EOL education resulted in meaningful and lasting self-reported personal and professional behavioural outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Increasing vaccine uptake in communities has been essential, even before COVID-19. The use of "vaccine champions" or "VaxChamps" has shown promise. VaxChamps, who are often community members with specialized training but no special credentials, advocate for vaccination by sharing their experiences and knowledge. Pharmacy technicians' scope of practice, coupled with their frequent interactions with pharmacy patients, make them ideal vaccine champions and a natural fit for the VaxChamp program. This study assessed the implementation and impact of the VaxChamp program in North Dakota (ND) community pharmacies., Objectives: To describe the development and implementation of the VaxChamp program in community pharmacies and evaluate its effect on vaccination rates and vaccine-related tasks within each pharmacy's organizational context., Methods: The VaxChamp program involved training one technician per participating pharmacy to spend five hours per week on vaccine-related tasks. Data collection included pre-post surveys, monthly reports, and semi-structured interviews with VaxChamps and Pharmacists-in-Charge (PICs) from six pharmacies. Quantitative data were analyzed using descriptive statistics, while qualitative data were analyzed using inductive methods to identify key themes., Results: The six participating pharmacies varied in location and staffing. Most had prior vaccine administration experience. VaxChamps' roles ranged from administrative tasks to direct vaccine administration, depending on the pharmacy's staffing and workflow. Vaccination rates for pneumococcal and hepatitis B vaccines increased in several pharmacies, while shingles vaccination rates declined. The presence of Advanced Pharmacy Practice Experience (APPE) students often influenced VaxChamps' responsibilities, underscoring the need for clear role delineation., Conclusion: Integrating pharmacy technicians as VaxChamps in community pharmacies is a promising strategy to increase vaccination rates and enhance public health. Future research should explore ways to better integrate technicians into comprehensive immunization strategies and address the contextual factors that influence program implementation., (Copyright © 2024. Published by Elsevier Inc.)

Tunneling nanotubes (TNTs) are open actin- and membrane-based channels, connecting remote cells and allowing direct transfer of cellular material (e.g. vesicles, mRNAs, protein aggregates) from the cytoplasm to the cytoplasm. Although they are important especially, in pathological conditions (e.g. cancers, neurodegenerative diseases), their precise composition and their regulation were still poorly described. Here, using a biochemical approach allowing to separate TNTs from cell bodies and from extracellular vesicles and particles (EVPs), we obtained the full composition of TNTs compared to EVPs. We then focused on two major components of our proteomic data, the CD9 and CD81 tetraspanins, and further investigated their specific roles in TNT formation and function. We show that these two tetraspanins have distinct non-redundant functions: CD9 participates in stabilizing TNTs, whereas CD81 expression is required to allow the functional transfer of vesicles in the newly formed TNTs, possibly by regulating docking to or fusion with the opposing cell., Competing Interests: RN, TC, ER, EP, MM, CZ, CB No competing interests declared, (© 2024, Notario Manzano et al.)

Background: Gamification of behavioral intervention for tic disorders (TDs) potentially enhances compliance and offers key clinical advantages. By delivering immediate positive feedback upon tic-suppression, games may counteract negative reinforcement, which presumably contribute to tic consolidation by relieving uncomfortable premonitory urges., Objectives: We developed a gamified protocol (XTics), which leverages this potential by combining gamified tic-triggering with immediate feedback, and evaluated its clinical value in enhancing tic suppression., Methods: XTics encompasses two conditions: Immediate and Contingent Reward (ICR), where game progression is contingent upon successful tic suppression, and Delayed Reward (DR), where game events' outcomes are random. Employing a randomized crossover design, 35 participants (aged 7-15 years) underwent daily gaming sessions over a week per condition. Improvements in our primary measures, including the inter-tic interval (ITI) and tic severity assessment by blinded evaluators (Yale Global Tic Severity-Total Tic Score [YGTSS-TTS], Rush), and parents (Parent Tic Questionnaire [PTQ]), were compared between ICR and DR, and assessed across conditions for the 4-week protocol., Results: No participant voluntarily left the study before completing its two-phase protocol. As expected, ITI showed significantly larger improvement (Z = 4.19, P = 2.85 × 10-5) after ICR (1442 ± 2250%) versus DR (242 ± 493%) training, increasing at a higher pace (t(67) = 3.15, P = 0.0025). Similarly, Rush tic severity scores reduced more post-ICR versus DR (t(47) = 3.47, P = 0.002). We observed a clinically significant reduction of 25.69 ± 23.39% in YGTSS-TTS following a f4-week protocol including both conditions. Parent-reported tic severity decreased by 42.99 ± 31.69% from baseline to 3 months post-treatment., Conclusions: The combination of gamified tic-triggering with immediate and contingent rewards demonstrates a promising approach for enhancing treatment efficacy in TDs, boosting traditional therapeutic methods. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Extracellular vesicles such as exosomes are now recognized as key players in intercellular communication. Their role is influenced by the specific repertoires of proteins and lipids, which are enriched when they are generated as intraluminal vesicles (ILVs) in multivesicular endosomes. Here we report that a key component of small extracellular vesicles, the tetraspanin CD63, sorts cholesterol to ILVs, generating a pool that can be mobilized by the NPC1/2 complex, and exported via exosomes to recipient cells. In the absence of CD63, cholesterol is retrieved from the endosomes by actin-dependent vesicular transport, placing CD63 and cholesterol at the centre of a balance between inward and outward budding of endomembranes. These results establish CD63 as a lipid-sorting mechanism within endosomes, and show that ILVs and exosomes are alternative providers of cholesterol., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Mild cognitive impairment (MCI) is common in Parkinson's disease (PD). We aimed to assess the incidence of MCI among patients with PD, carriers of mutations in LRRK2 and GBA1 genes, based on the movement disorder society (MDS) criteria for the diagnosis of MCI in early-stage PD., Methods: Patients with PD were included if they scored ≤2 on the Hoehn and Yahr and ≤6 years since motor symptom onset. A group of age and gender matched healthy adults served as controls. A neuropsychological cognitive battery was used covering five cognitive domains (executive functions, working memory, memory, visuospatial and language). MCI was explored while applying two methods (level I and II). Frequency of MCI was assessed in comparison between groups., Results: 70 patients with idiopathic PD (iPD) (68 % males), 42 patients with LRRK2-PD (61 % males), 83 patients with GBA1-PD (63 % males) and 132 age and gender matched controls (61 % males), participated in this study. PD groups were similar in clinical characteristics. Level I criteria were positive in 57.5 % of iPD, 43 % of LRRK2-PD and 63.4 % of the GBA1-PD (p = 0.071). Level II criteria was met by 39 % of iPD, 14 % LRRK2-PD and 41 % of GBA1-PD (p < 0.001), when using a 2 standard-deviation (SD) threshold. GBA1-PD and iPD showed impairments on multiple domains even in the more conservative 2 SD, reflecting MCI., Conclusions: The majority of our PD cohort was classified as MCI when assessed with strict criteria. GBA1-PD and iPD showed a more widespread pattern of MCI compared with LRRK2-PD., Competing Interests: Declaration of competing interest AT – Receiving research grants from MJFF, honoraria from AbbVie and consulting fees from Capsida. VL – nothing to report. ER – nothing to report. NO – nothing to report. AS – nothing to report. BC – nothing to report. NG – Received research grant support from The Michael J Fox Foundation, The National Parkinson Foundation, The European Union and The Israel Science Foundation, Biogen and Ionis. Receives support from The Sieratzki Family Foundation and The Aufzien Academic Center in Tel-Aviv University. Serves as a consultant to Sionara, NeuroDerm and Pharma2B. JCS – Employee of Biogen and holds company stocks. JMC – Reports having equity positions in VanquaBio and Immunobrain Checkpoint. MGW – nothing to report. OG – nothing to report. AO – Research support from the Michael J Fox Foundation and Biogen. RNA – Received research grant support from the MJFF, the Parkisnon's Foundation and the Silverstein Foundation. Received consultation fees from Sanofi, Takeda, Capsida, and Gain Therapeutics. RNA institution (TLVMC) has received research funds from Biogen. AM – Received research grant support from MJFF, The department of defense (DOD), JPND and the Israeli Ministry of Health. Received honoraria from Abbvie and Biogen., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Pre-treatment (PT) therapies in IVF are known to be used as pre-stimulation modality to improve cycle outcomes. This study aims to assess whether PT in GnRH antagonist cycles triggered with GnRH-agonist impact oocyte maturation response., Methods: Data were retrospectively collected for patients who underwent GnRH antagonist cycle with agonist triggering with and without PT. The patients were allocated to groups according to their PT status. The primary outcome evaluated was suboptimal maturation response. Suboptimal maturation to trigger was defined as no oocyte upon retrieval when adequate response was expected., Results: The study population included 196 patients who underwent GnRH antagonist cycle with agonist triggering. The study group included 69 patients who received PT. The control group included 127 patients with no PT. In univariate analysis, the PT group significantly displayed suboptimal response compared to the controls (p = 0.008). All the patients in the study group with suboptimal response (with or without hCG re-triggering) were treated with GnRH-agonist as PT. Basal and pre-trigger LH values were significantly lower in the study group compared to controls (p < 0.001). Multivariate regression analysis revealed that PT with GnRH agonist was a significant predictor for suboptimal response., Conclusions: Pre-treatment, and particularly the use of GnRH-agonist as PT in antagonist cycles triggered with agonist, increases the risk of suboptimal response to GnRH-agonist trigger. This might be explained by prolonged pituitary suppression, which lasts beyond the PT cessation.

Dupilumab has been approved to treat a variety of atopic disorders and was the first US FDA-approved medication for the treatment of eosinophilic esophagitis (EoE), initially approved in May 2022, with expansion in use to patients as young as 1 year of age weighing at least 15 kg in January 2024. It is a fully human monoclonal antibody that inhibits both IL-4 and IL-13 signaling, suppressing TH2-mediated proinflammatory cytokines, chemokines and IgE implicated in EoE pathogenesis. Phase II and III trials in EoE have demonstrated histologic, endoscopic and symptomatic improvement in disease activity with an overall favorable safety profile. This article will review the available clinical trial data and real-world efficacy of dupilumab in EoE.

Background: Mild behavioral impairment (MBI) and loneliness are associated with cognitive decline and an increased risk of dementia., Objective: Our aim was to examine the validity of the Japanese version of the MBI checklist (MBI-C) and investigate the relationship between loneliness and MBI., Methods: The participants in this cross-sectional study included 5 cognitively normal persons and 75 persons with mild cognitive impairment. MBI-C and the revised University of California at Los Angeles loneliness scale (LS) were used to assess MBI and loneliness, respectively. Diagnostic performance of MBI-C was examined using receiver operating characteristic analysis. The relationship between MBI-C and LS was examined using multiple linear regression in 67 subjects who were assessed with both scales, with MBI-C total or domain score as the dependent variable and LS as the independent variable, adjusted for age, gender, living situation, presence of visual and hearing impairment, and Mini-Mental State Examination score., Results: Per the Youden index, in this mostly MCI sample, the optimal MBI-C cut-off score was 5.5 with sensitivity 0.917 and specificity 0.949. In multiple linear regression analysis, LS score was detected as a significant predictor of MBI-C total scores, and MBI-C decreased motivation, affective dysregulation, and abnormal thought and perception scores., Conclusions: The caregiver-rated Japanese MBI-C has excellent diagnostic performance. Loneliness is associated with a greater MBI burden, especially in the decreased motivation, affective dysregulation, and abnormal thought and perception domains. Interventions for loneliness in older people may have the potential to improve MBI.

Tspan8 is a member of the tetraspanins family of cell surface molecules. The ability of tetraspanins to organize membrane microdomains with other membrane molecules and interfere with their function suggests that they could act as surface integrators of external or internal signals. Among the first identified tetraspanins, Tspan8 promotes tumor progression and metastasis, presumably by stimulating angiogenesis and cell motility. In patients, its expression on digestive tract tumors seems to be associated with a bad prognosis. We showed previously that Tspan8 associates with E-cadherin and EGFR and modulates their effects on cell motility. Using Mass spectrometry and western blot, we found a new partner, the endothelin converting enzyme ECE1, and showed that Tspan8 amplifies its activity of conversion of the endothelin-1 precursor bigET1 to endothelin. This was observed by transduction of the colon carcinoma cell line Isreco1, which does not express Tspan8, and on ileum tissue fragments of tspan8ko mice versus wild type mice. Given these results, Tspan8 appears to be a modulator of the endothelin axis, which could possibly be targeted in case of over-activity of endothelins in biological processes of tissues expressing Tspan8.

The tetraspanins CD9, CD81 and CD63 are major components of extracellular vesicles (EVs). Yet, their impact on EV composition remains under-investigated. In the MCF7 breast cancer cell line CD63 was as expected predominantly intracellular. In contrast CD9 and CD81 strongly colocalized at the plasma membrane, albeit with different ratios at different sites, which may explain a higher enrichment of CD81 in EVs. Absence of these tetraspanins had little impact on the EV protein composition as analysed by quantitative mass spectrometry. We also analysed the effect of concomitant knock-out of CD9 and CD81 because these two tetraspanins play similar roles in several cellular processes and associate directly with two Ig domain proteins, CD9P-1/EWI-F/PTGFRN and EWI-2/IGSF8. These were the sole proteins significantly decreased in the EVs of double CD9- and CD81-deficient cells. In the case of EWI-2, this is primarily a consequence of a decreased cell expression level. In conclusion, this study shows that CD9, CD81 and CD63, commonly used as EV protein markers, play a marginal role in determining the protein composition of EVs released by MCF7 cells and highlights a regulation of the expression level and/or trafficking of CD9P-1 and EWI-2 by CD9 and CD81., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Personal Protective Equipment (PPE) that was intentionally designed and manufactured as reusable, including gowns, goggles, face shields, and elastomeric respirators, took on a heightened role during the pandemic. Healthcare workers who had access to these products and infrastructure for cleaning and sterilizing them had a greater sense of confidence to undertake their jobs due to an increased sense of personal safety. Using multiple data sources, including a literature review, roundtables, interviews, surveys, and Internet-based research, the project team investigated the impact of disposable PPE and role of reusable PPE during the pandemic in Canada. This research supports the claim that adopting and supporting reusable PPE systems throughout the health sector can, if used appropriately on an ongoing basis, provide continuous access to reusable PPE while also contributing many co-benefits, including lower costs, domestic jobs, and improved environmental performance such as reduced waste and greenhouse gas emissions.

Objectives: The objective of this study is to determine demographic and clinical characteristics of infants and toddlers <2 years with eosinophilic esophagitis (EoE) and to assess treatment response in this rarely studied pediatric age group., Methods: Retrospective study of children <2 years diagnosed with EoE at a single center from 2016 to 2018. EoE was defined by ≥15 eosinophils per high power field (eos/hpf) on at least 1 esophageal biopsy. Demographics, symptoms, and endoscopic findings were collected via chart review. EoE treatment [proton pump inhibitor (PPI), swallowed steroids, dietary restriction, or a combination] and treatment responses on all follow-up endoscopies were reviewed, with remission defined as <15 eos/hpf., Results: Forty-two children ages 1.3 ± 0.4 years underwent 3.8 ± 2.3 endoscopies over 3.6 ± 1.7 years of follow-up. Thirty-six children (86%) were male, and comorbidities included atopy (86%), reflux (74%), and a history of cow's milk protein allergy (40%). Common symptoms were feeding difficulties in 67% of patients (with gagging or coughing with feeding in 60% and difficulty with progression to pureed or solid foods in 43%), vomiting (57%), and coughing/wheezing (52%). Of the 37 patients with follow-up endoscopies, 25 (68%) had histologic remission. There was an effect of therapy type on histologic response ( P = 0.004) with the best responses seen on combinations of diet/steroids or diet/PPI and the worst response seen on PPIs alone. All patients showed improvement in ≥1 symptom at the time of first follow-up endoscopy., Conclusions: EoE should be considered in young children with feeding difficulties, vomiting, or respiratory symptoms. All patients improved clinically with standard medical or dietary interventions, however there is dissociation between clinical and histologic response with only 2 of 3 patients achieving histologic remission., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Generating evidence from real-world data requires fit-for-purpose study design and data. In addition to validity, decision makers require transparency in the reasoning that underlies study design and data source decisions. The 2019 Structured Preapproval and Postapproval Comparative Study Design Framework to Generate Valid and Transparent Real-World Evidence (SPACE) and the 2021 Structured Process to Identify Fit-For-Purpose Data (SPIFD)-intended to be used together-provide a step-by-step guide to identify decision grade, fit-for-purpose study design and data. In this update (referred to as "SPIFD2" to encompass both the design and data aspects) we provide an update to these frameworks that combines the templates into one, more explicitly calls for articulation of the hypothetical target trial and sources of bias that may arise in the real-world emulation, and provides explicit references to the Structured Template and Reporting Tool for Real-World Evidence (STaRT-RWE) tables that we suggest using immediately after invoking the SPIFD2 framework. Following the steps recommended in the SPIFD2 process requires due diligence on the part of the researcher to ensure that every aspect of study design and data selection is rationalized and supported by evidence. The resulting stepwise documentation enables reproducibility and clear communication with decision makers, and it increases the likelihood that the evidence generated is valid, fit-for-purpose, and sufficient to support healthcare and regulatory decisions., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Extracellular vesicles (EVs) are thought to mediate intercellular communication by transferring cargoes from donor to acceptor cells. The EV content-delivery process within acceptor cells is still poorly characterized and debated. CD63 and CD9, members of the tetraspanin family, are highly enriched within EV membranes and are respectively enriched within multivesicular bodies/endosomes and at the plasma membrane of the cells. CD63 and CD9 have been suspected to regulate the EV uptake and delivery process. Here we used two independent assays and different cell models (HeLa, MDA-MB-231 and HEK293T cells) to assess the putative role of CD63 and CD9 in the EV delivery process that includes uptake and cargo delivery. Our results suggest that neither CD63, nor CD9 are required for this function., (© 2023. The Author(s).)

Purpose: During the COVID-19 pandemic, many radiation oncology departments worldwide adopted the use of shorter and more intense hypofractionated regimens. Hospital foot traffic was reduced through virtual care. This study's primary objective was to assess the collective environmental effect of these strategic changes by identifying sources of carbon dioxide equivalents (CO 2 e). The rate of radiation-related adverse events from the increased use of hypofractionated treatments was assessed., Methods and Materials: All patients treated with external beam radiation therapy from April 1, 2019, to March 31, 2021, at our single institution were identified (n = 10,175) along with their radiation therapy visits (176,423 fractions) and unplanned visits to the radiation nursing clinic or emergency department. Out-patient hospital and virtual visits (n = 75,853) during this same period were also analyzed. Environmental effect measures, including linear accelerator power usage, patient travel distances, and personal protection equipment consumption were all converted into CO 2 e., Results: The use of curative hypofractionated regimens increased from 17% to 27% during the pandemic year. Carbon footprint was reduced by 39% during the pandemic year (1,332,388 kg CO 2 e) compared with the prepandemic year (2,024,823 kg CO 2 e). Comparing patients in the prepandemic versus pandemic year, there was a significant reduction in the proportion of hypofractionated patients who needed a visit to either the radiation nursing clinic (39% vs 25%; P < .001) or emergency department (6% vs 2%; P < .001) during and within 90 days of radiation therapy., Conclusions: This is the first study to demonstrate the environmental benefits of increased use of hypofractionated regimens and virtual care, while assuring that there was no added acute radiation-related adverse event. Our findings support their continued use as one of many long-term strategies to reduce the environmental footprint of health care delivery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

T cells depend on the phosphatase CD45 to initiate T cell receptor signaling. Although the critical role of CD45 in T cells is established, the mechanisms controlling function and localization in the membrane are not well understood. Moreover, the regulation of specific CD45 isoforms in T cell signaling remains unresolved. By using unbiased mass spectrometry, we identify the tetraspanin CD53 as a partner of CD45 and show that CD53 controls CD45 function and T cell activation. CD53-negative T cells (Cd53 -/- ) exhibit substantial proliferation defects, and Cd53 -/- mice show impaired tumor rejection and reduced IFNγ-producing T cells compared with wild-type mice. Investigation into the mechanism reveals that CD53 is required for CD45RO expression and mobility. In addition, CD53 is shown to stabilize CD45 on the membrane and is required for optimal phosphatase activity and subsequent Lck activation. Together, our findings reveal CD53 as a regulator of CD45 activity required for T cell immunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The objective of the present study is to find a fast and accurate procedure to measure the length and width of asbestos fibers using images acquired by a scanning electron microscope (SEM), a phase-contrast microscope (PCM), and a polarized light microscope (PLM). The accuracy of the procedure was evaluated by comparing fiber length and width measurements to manual measurements. Four different types of images were used in the evaluation: (1) backscattered electron SEM images of fibrous tremolite, (2) secondary electron SEM images of fibrous grunerite, (3) PCM images of fibrous grunerite, and (4) PLM images of fibrous grunerite. Fiber length and width were measured with ImageJ (manual measurement) and Image-Pro software and were compared on an individual fiber basis and over the number-length and number-width distribution of each sample. The results of the comparison showed that the individual length and width measurements with ImageJ and Image-Pro software had a nearly 1:1 relationship except for the width measurement in PLM images (8% of the variance in ImageJ width measurements was not explained by Image-Pro width measurements). Similarly, the number-length distributions were not significantly different ( p  > 0.05) between ImageJ and Image-Pro, but the number-width distributions were significantly different ( p  < 0.05) for PLM and secondary electron SEM images. Although the image analysis procedure for measuring fiber length and width with Image-Pro is not a fully automated procedure and still requires some manual intervention, it can be a more efficient and equally accurate alternative to time-consuming manual fiber length and width measurements for well dispersed fibers with high aspect ratios.

Dupilumab is one of a number of biologics currently under investigation for the treatment of eosinophilic esophagitis (EoE). We report on a group of 7 pediatric and young adult patients with EoE who were treated with dupilumab for a primary indication of asthma or atopic dermatitis, all of whom previously failed swallowed topical corticosteroid therapy dietary for management of their EoE. All 7 patients demonstrated histologic improvement in their EoE while on dupilumab, with a drop in median peak esophageal eosinophil count from 50 eosinophils per high-powered field (eos/hpf) (IQR 48-95 eos/hpf) to 2 eos/hpf (IQR 0-5 eos/hpf) off swallowed topical corticosteroid. Additionally, improvements in EoE symptoms and endoscopic findings were noted. This report highlights the effectiveness of dupilumab in a group of multiply atopic pediatric and young adult patients with difficult-to-treat EoE in real world practice., Competing Interests: The author’s institution is a study site for phase 3 trials entitled “A randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of dupilumab in pediatric patients with active eosinophilic esophagitis” sponsored by Regeneron Pharmaceuticals. While the authors will be listed as sub-investigators in this trial, neither author is receiving financial compensation from this study, nor do they have any other competing financial interests., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Invasive mucormycosis (IM) is a rare and often life-threatening fungal infection, for which clinical and epidemiological understanding is lacking. Electronic health record (EHR) data can be utilized to elucidate large populations of patients with IM to address this unmet need. This study aimed to descriptively assess data on patients with IM using the Optum® EHR dataset., Methods: US patient data from the Optum® deidentified EHR dataset (2007-2019) were analyzed to identify patients with IM. Patients with hematologic malignancies (HM), at high risk of IM, were selected and sorted by IM diagnosis (ICD9 117.7; ICD10 B46). Demographics, comorbidities/other diagnoses, and treatments were analyzed in patients with IM., Results: In total, 1133 patients with HM and IM were identified. Most were between 40 and 64 years of age, Caucasian, and from the Midwest. Essential primary hypertension (50.31%) was the most common comorbidity. Of the 1133 patients, only 33.72% were prescribed an antifungal treatment. The most common antifungal treatments were fluconazole (24.27%) and posaconazole (16.33%), which may have been prophylactic, and any AmB (15.62%)., Conclusions: A large population of patients with IM were identified, highlighting the potential of analyzing EHR data to investigate epidemiology, diagnosis, and the treatment of apparently rare diseases., (© 2022. The Author(s).)

To complement real-world evidence (RWE) guidelines, the 2019 Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) framework elucidated a process for designing valid and transparent real-world studies. As an extension to SPACE, here, we provide a structured framework for conducting feasibility assessments-a step-by-step guide to identify decision grade, fit-for-purpose data, which complements the United States Food and Drug Administration (FDA)'s framework for a RWE program. The process was informed by our collective experience conducting systematic feasibility assessments of existing data sources for pharmacoepidemiology studies to support regulatory decisions. Used with the SPACE framework, the Structured Process to Identify Fit-For-Purpose Data (SPIFD) provides a systematic process for conducting feasibility assessments to determine if a data source is fit for decision making, helping ensure justification and transparency throughout study development, from articulation of a specific and meaningful research question to identification of fit-for-purpose data and study design., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Tetraspanins are a family of transmembrane proteins that form a network of protein-protein interactions within the plasma membrane. Within this network, tetraspanin are thought to control the lateral segregation of their partners at the plasma membrane through mechanisms involving specific lipids. Here, we used a single molecule tracking approach to study the membrane behavior of tetraspanins in mammary epithelial cells and demonstrate that despite a common overall behavior, each tetraspanin (CD9, CD81 and CD82) has a specific signature in terms of dynamics. Furthermore, we demonstrated that tetraspanin dynamics on the cell surface are dependent on gangliosides. More specifically, we found that CD82 expression increases the dynamics of CD81 and alters its localization at the plasma membrane, this has no effect on the behavior of CD9. Our results provide new information on the ability of CD82 and gangliosides to differentially modulate the dynamics and organization of tetraspanins at the plasma membrane and highlight that its lipid and protein composition is involved in the dynamical architecture of the tetraspanin web. We predict that CD82 may act as a regulator of the lateral segregation of specific tetraspanins at the plasma membrane while gangliosides could play a crucial role in establishing tetraspanin-enriched areas.

Despite their roles in intercellular communications, the different populations of extracellular vesicles (EVs) and their secretion mechanisms are not fully characterized: how and to what extent EVs form as intraluminal vesicles of endocytic compartments (exosomes), or at the plasma membrane (PM) (ectosomes) remains unclear. Here we follow intracellular trafficking of the EV markers CD9 and CD63 from the endoplasmic reticulum to their residency compartment, respectively PM and late endosomes. We observe transient co-localization at both places, before they finally segregate. CD9 and a mutant CD63 stabilized at the PM are more abundantly released in EVs than CD63. Thus, in HeLa cells, ectosomes are more prominent than exosomes. By comparative proteomic analysis and differential response to neutralization of endosomal pH, we identify a few surface proteins likely specific of either exosomes (LAMP1) or ectosomes (BSG, SLC3A2). Our work sets the path for molecular and functional discrimination of exosomes and small ectosomes in any cell type., (© 2021. The Author(s).)

Background: Mild behavioral impairment (MBI) is associated with accelerated cognitive decline and greater risk of dementia. However, the neural correlates of MBI have not been completely elucidated., Objective: The study aimed to investigate the correlation between cognitively normal participants and participants with amnestic mild cognitive impairment (aMCI) using resting-state functional magnetic resonance imaging., Methods: The study included 30 cognitively normal participants and 13 participants with aMCI (20 men and 23 women; mean age, 76.9 years). The MBI was assessed using the MBI checklist (MBI-C). Region of interest (ROI)-to-ROI analysis was performed to examine the correlation between MBI-C scores and functional connectivity (FC) of the default mode network, salience network, and frontoparietal control network (FPCN). Age, Mini-Mental State Examination score, sex, and education were used as covariates. A p-value of 0.05, with false discovery rate correction, was considered significant., Results: A negative correlation was observed between the MBI-C total score and FC of the left posterior parietal cortex with the right middle frontal gyrus. A similar result was obtained for the MBI-C affective dysregulation domain score., Conclusion: FPCN dysfunction was detected as a neural correlate of MBI, especially in the affective dysregulation domain. This dysfunction may be associated with cognitive impairment in MBI and conversion of MBI to dementia; however, further longitudinal data are needed to examine this relationship.

A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein essential for embryonic development, and its dysregulation underlies disorders such as cancer, Alzheimer's disease, and inflammation. ADAM10 is a "molecular scissor" that proteolytically cleaves the extracellular region from >100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors, and chemokines. ADAM10 has been recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function critically depends on a TspanC8 partner, and a lack of monoclonal antibodies specific for most TspanC8s has hindered investigation of this question. To address this knowledge gap, here we designed an immunogen to generate the first monoclonal antibodies targeting Tspan15, a model TspanC8. The immunogen was created in an ADAM10-knockout mouse cell line stably overexpressing human Tspan15, because we hypothesized that expression in this cell line would expose epitopes that are normally blocked by ADAM10. Following immunization of mice, this immunogen strategy generated four Tspan15 antibodies. Using these antibodies, we show that endogenous Tspan15 and ADAM10 co-localize on the cell surface, that ADAM10 is the principal Tspan15-interacting protein, that endogenous Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Furthermore, two of the four antibodies impaired ADAM10/Tspan15 activity. These findings suggest that Tspan15 directly interacts with ADAM10 in a functional scissor complex., (© 2020 Koo et al.)

Unopposed estrogenic action in the uterus can lead to the development of endometrial cancer in both humans and rats. Aryl hydrocarbon receptor (AHR) activation gives rise to anti-estrogenic actions and may consequently reduce the development of endometrial cancer. In this study, the anti-estrogenic potential of the AHR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and DELAQ, a metabolite of the pharmaceutical laquinimod, was assessed in in primary human and rat endometrial epithelial cells (EECs) with and without co-exposure to endogenous hormones. In human EECs, estradiol and progesterone did not affect AHR gene expression, but in rat EECs, progesterone decreased Ahre xpression (1.4-fold). In accordance, AHR-mediated induction of Cyp1a1/1b1 expression by DELAQ and TCDD decreased in hormone-treated rat EECs. DELAQ was 22-fold more potent than TCDD in human EECs in inducing CYP1A1/1B1 gene expression, while DELAQ was approximately 16-33-fold less potent than TCDD in rat EECs. In human EECs, 10 nM DELAQ decreased estradiol-induced expression of growth-regulated estrogen receptor binding 1 (GREB1) by 1.8-fold. In rat EECs, both DELAQ and TCDD did not affect the expression of estradiol-induced genes. This study shows that AHR ligand DELAQ, but not TCDD, causes anti-estrogenic effects in primary human EECs. Furthermore, although AHR-mediated CYP1A1/1B1/Cyp1a1/1b1 induction by DELAQ and TCDD was stronger in rat EECs than human EECs, this did not result in apparent anti-estrogenic effects in the rat cells. This study shows that primary human and rat endometrial cells respond differently towards hormones and AHR ligands. This should be considered in human risk assessment based on rodent studies., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Sporozoite forms of the Plasmodium parasite, the causative agent of malaria, are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood. The molecular mechanisms involved during sporozoite invasion of hepatocytes remain poorly understood. Two receptors of the Hepatitis C virus (HCV), the tetraspanin CD81 and the scavenger receptor class B type 1 (SR-B1), play an important role during the entry of Plasmodium sporozoites into hepatocytes. In contrast to HCV entry, which requires both CD81 and SR-B1 together with additional host factors, CD81 and SR-B1 operate independently during malaria liver infection. Sporozoites from human-infecting P. falciparum and P. vivax rely respectively on CD81 or SR-B1. Rodent-infecting P. berghei can use SR-B1 to infect host cells as an alternative pathway to CD81, providing a tractable model to investigate the role of SR-B1 during Plasmodium liver infection. Here we show that mouse SR-B1 is less functional as compared to human SR-B1 during P. berghei infection. We took advantage of this functional difference to investigate the structural determinants of SR-B1 required for infection. Using a structure-guided strategy and chimeric mouse/human SR-B1 constructs, we could map the functional region of human SR-B1 within apical loops, suggesting that this region of the protein may play a crucial role for interaction of sporozoite ligands with host cells and thus the very first step of Plasmodium infection.

CD63, a member of the tetraspanin superfamily, is used as a marker of late endosomes and lysosome-related organelles, as well as a marker of exosomes. Here, we selected rare isotype variants of TS63 by sorting hybridoma cells on the basis of their high expression of surface immunoglobulins of the IgG2a and IgG2b subclass. Pure populations of cells secreting IgG2a and IgG2b variants of TS63 (referred to as TS63a and TS63b) were obtained using two rounds of cell sorting and one limited dilution cloning step. We validate that these new TS63 variants are suitable for co-labeling with mAb of the IgG1 subclass directed to other molecules, using anti mouse subclass antibodies, and for the labeling of exosomes through direct binding to protein A-coated gold particles. These mAbs will be useful to study the intracellular localization of various proteins and facilitate electron microscopy analysis of CD63 localization.

: Standard-of-care treatment for haemophilia A or B is to maintain adequate coagulation factor levels through clotting factor administration. The current study aimed to evaluate annualised bleeding rates (ABR) and treatment adherence for haemophilia A or B patients receiving standard half-life (SHL) vs. extended half-life (EHL) factor replacement products. We analysed data from the Adelphi Disease-Specific Programmes, a health record-based survey of United States and European haematologists. Analysis included 651 males with moderate-to-severe haemophilia A or B (the United States, n = 132; Europe, n = 519). The haemophilia A analysis included 501 patients (SHL, n = 435; EHL, n = 66). In the combined United States/European population, mean (SD) ABR was 1.7 (1.69) for the SHL group and 1.8 (2.00) for the EHL group. A total of 72% of patients receiving SHL factor VIII and 75% of patients receiving EHL factor VIII in the combined population were fully adherent (no doses missed of the last 10 doses), as reported by physicians. The haemophilia B analysis included 150 patients (SHL, n = 114; EHL, n = 36). The mean (SD) ABR in the combined population was 2.1 (2.16) for patients receiving SHL factor IX (FIX) and 1.4 (1.48) for patients receiving EHL FIX. The percentage of fully adherent patients (physician-reported) was similar in both treatment groups (SHL FIX, 68%; EHL FIX, 73%). In this preliminary real-world survey in a relatively small sample of patients, measures of ABR and adherence between SHL and EHL products were evaluated. Additional real-world research on prescribing patterns, SHL vs. EHL effectiveness, and adherence is warranted.

Exosomes, extracellular vesicles (EVs) of endosomal origin, emerge as master regulators of cell-to-cell signaling in physiology and disease. Exosomes are highly enriched in tetraspanins (TSPNs) and syndecans (SDCs), the latter occurring mainly in proteolytically cleaved form, as membrane-spanning C-terminal fragments of the proteins. While both protein families are membrane scaffolds appreciated for their role in exosome formation, composition, and activity, we currently ignore whether these work together to control exosome biology. Here we show that TSPN6, a poorly characterized tetraspanin, acts as a negative regulator of exosome release, supporting the lysosomal degradation of SDC4 and syntenin. We demonstrate that TSPN6 tightly associates with SDC4, the SDC4-TSPN6 association dictating the association of TSPN6 with syntenin and the TSPN6-dependent lysosomal degradation of SDC4-syntenin. TSPN6 also inhibits the shedding of the SDC4 ectodomain, mimicking the effects of matrix metalloproteinase inhibitors. Taken together, our data identify TSPN6 as a regulator of the trafficking and processing of SDC4 and highlight an important physical and functional interconnection between these membrane scaffolds for the production of exosomes. These findings clarify our understanding of the molecular determinants governing EV formation and have potentially broad impact for EV-related biomedicine., Competing Interests: The authors declare no competing interest.

ADAM10 is a transmembrane metalloprotease that is essential for development and tissue homeostasis. It cleaves the ectodomain of many proteins, including amyloid precursor protein, and plays an essential role in Notch signaling. ADAM10 associates with six members of the tetraspanin superfamily referred to as TspanC8 (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33), which regulate its exit from the endoplasmic reticulum and its substrate selectivity. We now show that ADAM10, Tspan5, and Tspan15 influence each other's expression level. Notably, ADAM10 undergoes faster endocytosis in the presence of Tspan5 than in the presence of Tspan15, and Tspan15 stabilizes ADAM10 at the cell surface yielding high expression levels. Reciprocally, ADAM10 stabilizes Tspan15 at the cell surface, indicating that it is the Tspan15/ADAM10 complex that is retained at the plasma membrane. Chimeric molecules indicate that the cytoplasmic domains of these tetraspanins contribute to their opposite action on ADAM10 trafficking and Notch signaling. In contrast, an unusual palmitoylation site at the end of Tspan15 C-terminus is dispensable. Together, these findings uncover a new level of ADAM10 regulation by TspanC8 tetraspanins., (© 2019 Eschenbrenner et al.)