The T cell receptor (TCR) and associated CD3γε, δε, and ζζ signaling dimers allow T cells to discriminate between different antigens and respond accordingly, but our knowledge of how these parts fit and work together is incomplete. In this study, we provide additional evidence that the CD3 heterodimers congregate on one side of the TCR in both the αβ and γδTCR-CD3 complexes. We also report that the other side of the αβTCR mediates homotypic αβTCR interactions and signaling. Specifically, an erythropoietin receptor-based dimerization assay was used to show that, upon complex assembly, the CD3ε chains of two CD3 heterodimers are arranged side-by-side in both the αβ and γδTCR-CD3 complexes. This system was also used to show that αβTCRs can dimerize in the cell membrane and that mutating the unusual outer strands of the Cα domain impairs this dimerization. Finally, we present data showing that, for CD4 T cells, the mutations that impair αβTCR dimerization also alter ligand-induced calcium mobilization, TCR accumulation at the site of pMHC contact, and polarization toward the site of antigen contact. These data reveal a "functional-sidedness" to the αβTCR constant region, with dimerization occurring on the side of the TCR opposite from where the CD3 heterodimers are located.D iscriminating among composite surfaces of peptides and major histocompatibility molecules (pMHCs) is critical for αβT cell fate decisions. The T cell receptor (TCR) α and β chains have clonotypic variable (Vα, Vβ) domains that specifically bind pMHC via low affinity interactions (1, 2), while the constant (Cα, Cβ) domains, connecting peptides, and transmembrane domains interact with the CD3γε, δε, and ζζ signaling subunits (3-7) that relay information to the intracellular signaling machinery via immunoreceptor tyrosine activation motifs (ITAMs) (8).How information transits from the TCR-pMHC interface to the ITAMs is not well understood. Residues that stabilize TCR-CD3 interactions have been implicated in signaling (6,7,9) and subtle conformational changes have been proposed (10). In addition, dimerization of the complex is thought to be important because forcing TCRs into juxtaposition can induce signaling (11, 12); however, the evidence for dimerization has been controversial (13-16), and the structural features that would mediate such interactions have not been identified. A more complete understanding of how the subunits fit together within and between complexes is needed to advance our understanding of how this molecular machinery works.Mutagenesis data indicate that both CD3 heterodimers are clustered on the side of the TCR constant domain that includes the Cα DE and Cβ CC' loops (7), leaving the outer strands of the Cα domain unobstructed. This Cα surface is a prime candidate for participating in TCR dimerization because it is structurally distinct from the analogous domains of antibodies or the γδTCR (2, 17) (Fig. S1) and the evolutionary pressures that drive the divergence of related proteins often produce variable parts of related folds...

Glioblastoma is the most common malignant brain tumor, and it carries an extremely poor prognosis. Attempts to develop targeted therapies have been hindered because the blood-brain barrier prevents many drugs from reaching tumors cells. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. A number of alternative methods of delivery have been developed, one of which is convection-enhanced delivery (CED), the focus of this review. The authors describe CED as a therapeutic measure and review preclinical studies and the most prominent clinical trials of CED in the treatment of glioblastoma. The utilization of this technique for the delivery of a variety of agents is covered, and its shortcomings and challenges are discussed in detail.

aBBreViatiONS ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; GH = growth hormone; GnRH = gonadotropin-releasing hormone; IGF-1= insulin-like growth factor-1; LH = luteinizing hormone; NFA = nonfunctional adenoma; T4 = thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone. SuBmitted October 10, 2014. accepted January 13, 2015. iNclude wheN citiNg Published online August 7, 2015; DOI: 10.3171/2015.1.JNS141543. diSclOSure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. * Mr. Jahangiri and Mr. Wagner contributed equally to this work. OBJectiVe The impact of transsphenoidal surgery for nonfunctional pituitary adenomas (NFAs) on preoperative hypopituitarism relative to the incidence of new postoperative endocrine deficits remains unclear. The authors investigated rates of hypopituitarism resolution and development after transsphenoidal surgery. methOdS Over a 5-year period, 305 transsphenoidal surgeries for NFAs performed at The California Center for Pituitary Disorders were retrospectively reviewed. reSultS Patients with preoperative endocrine deficits (n = 153, 50%) were significantly older (mean age 60 vs 54 years; p = 0.004), more frequently male (65% vs 44%; p = 0.0005), and had larger adenomas (2.4 cm vs 2.1 cm; p = 0.02) than patients without preoperative deficits (n = 152, 50%). Of patients with preoperative endocrine deficits, 53% exhibited symptoms. Preoperative deficit rates were 26% for the thyroid axis; 20% and 16% for the male and female reproductive axes, respectively; 13% for the adrenocorticotropic hormone (ACTH)/cortisol axis, and 19% for the growth hormone (GH)/ insulin-like growth factor-1 (IGF-1) axis. Laboratory normalization rates 6 weeks and 6 months after surgery without hormone replacement were 26% and 36% for male and 13% and 13% for female reproductive axes, respectively; 30% and 49% for the thyroid axis; 3% and 3% for the cortisol axis; and 9% and 22% for the IGF-1 axis (p < 0.05). New postoperative endocrine deficits occurred in 42 patients (13.7%). Rates of new deficits by axes were: male reproductive 3% (n = 9), female reproductive 1% (n = 4), thyroid axis 3% (n = 10), cortisol axis 6% (n = 19), and GH/IGF-1 axis 4% (n = 12). Patients who failed to exhibit any endocrine normalization had lower preoperative gland volumes than those who did not (0.24 cm 3 vs 0.43 cm 3 , respectively; p < 0.05). Multivariate analyses revealed that no variables predicted new postoperative deficits or normalization of the female reproductive, cortisol, and IGF-1 axes. However, increased preoperative gland volume and younger age predicted the chances of a patient with any preoperative deficit experiencing normalization of at least 1 axis. Younger age and less severe preoperative hormonal deficit predicted normalization of the thyroid and male reproductive axes (p < 0.05). cONcluSiONS After NFA resection, endocrine normalization rates in this study varied with the horm...

We present constraints on cosmological parameters from the Pantheon+ analysis of 1701 light curves of 1550 distinct Type Ia supernovae (SNe Ia) ranging in redshift from z = 0.001 to 2.26. This work features an increased sample size, increased redshift span, and improved treatment of systematic uncertainties in comparison to the original Pantheon analysis and results in a factor of 2 improvement in cosmological constraining power. For a FlatΛCDM model, we find Ω M = 0.338 ± 0.018 from SNe Ia alone. For a Flatw 0 CDM model, we measure w 0 = −0.89 ± 0.13 from SNe Ia alone, H 0 = 72.86 +0.94 −1.06 km s −1 Mpc −1 when including the Cepheid host distances and covariance (SH0ES), and w 0 = −0.978 +0.024 −0.031 when combining the SN likelihood with constraints from the cosmic microwave background (CMB) and baryon acoustic oscillations (BAO); both w 0 values are consistent with a cosmological constant. We also present the most precise measurements to date on the evolution of dark energy in a Flatw 0 w a CDM universe, and measure w a = −0.4 +1.0 −1.8 from Pantheon+ alone, H 0 = 73.40 +0.99 −1.22 km s −1 Mpc −1 when including SH0ES, and w a = −0.65 +0.28 −0.32 when combining Pan-theon+ with CMB and BAO data. Finally, we find that systematic uncertainties in the use of SNe Ia along the distance ladder comprise less than one third of the total uncertainty in the measurement of H 0 and cannot explain the present "Hubble tension" between local measurements and early-Universe predictions from the cosmological model.

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Here we present 1701 light curves of spectroscopically confirmed Type Ia supernovae (SNe Ia) that will be used to infer cosmological parameters as part of the Pantheon+ SN analysis and the SH0ES (Supernovae and H 0 for the Equation of State of dark energy) distance-ladder analysis. This effort is one part of a series of works that perform an extensive review of redshifts, peculiar velocities, photometric calibration, and intrinsic-scatter models of SNe Ia. The total number of light curves, which are compiled across 18 different surveys, is a significant increase from the first Pantheon analysis (1048 SNe), particularly at low redshift (z). Furthermore, unlike in the Pantheon analysis, we include light curves for SNe with z < 0.01 such that SN systematic covariance can be included in a joint measurement of the Hubble constant (H 0 ) and the dark energy equation-of-state parameter (w). We use the large sample to compare properties of 170 SNe Ia observed by multiple surveys and 12 pairs/triplets of "SN siblings" -SNe found in the same host galaxy. Distance measurements, application of bias corrections, and inference of cosmological parameters are discussed in the companion paper by Brout et al. (2022b), and the determination of H 0 is discussed by Riess et al. (2022). These analyses will measure w with ∼ 3% precision and H 0 with ∼ 1 km/s/Mpc precision.

Ancylostoma caninum is the most prevalent nematode parasite of dogs. We confirmed multiple-drug resistance (MDR) in several A. caninum isolates to all anthelmintic drug classes approved for the treatment of hookworms in dogs in the USA. Cases of MDR hookworms appear to be highly overrepresented in greyhounds. The aims of this study were to evaluate the drug-resistant phenotypes and genotypes of the A. caninum infecting greyhounds. Fecal samples from greyhounds of the USA were acquired from two greyhound adoption kennels, one active greyhound racing kennel, and three veterinary practices. Fecal egg counts (FECs) were performed on fecal samples from 219 greyhounds, and despite treatment with anthelmintics, the mean FEC was 822.4 eggs per gram (EPG). Resistance to benzimidazoles and macrocyclic lactones were measured using the egg hatch assay (EHA) and the larval development assay (LDA), respectively. We performed 23 EHA and 22 LDA on either individual or pooled feces, representing 54 animals. Mean and median IC 50 and IC 95 values for the EHA were 5.3 μM, 3.6 μM, and 24.5 μM, 23.4 μM, respectively. For the LDA, the median IC 50 value was >1000 nM. These values ranged 62–81 times higher than our susceptible laboratory isolate. Only post-treatment samples were available. For samples collected <10 days post-treatment with albendazole, moxidectin, or a combination of febantel-pyrantel-moxidectin, the mean FEC were 349, 333, and 835 EPG, respectively. We obtained DNA from hookworm eggs isolated from 70 fecal samples, comprised of 60 individual dogs and 10 pools. Deep sequencing of the isotype 1 β-tubulin gene only revealed the presence of the F167Y (TTC>TAC) resistance polymorphism in 99% of these samples. These clinical, in vitro, and genetic data provide strong evidence that greyhound dogs in the USA are infected with MDR A. caninum at very high levels in prevalence and infection intensity.

Transforming growth factor beta 1 (TGF-β1) is implicated in osteoarthritis. We therefore studied the role of TGF-β1 signaling in the development of osteoarthritis in a developmental stage-dependent manner. Three different mouse models were investigated. First, the Tgf-β receptor II (Tgfbr2) was specifically removed from the mature cartilage of joints. Tgfbr2-deficient mice were grown to 12 months of age and were then euthanized for collection of knee and temporomandibular joints. Second, Tgfbr2-deficient mice were subjected to destabilization of the medial meniscus (DMM) surgery. Knee joints were then collected from the mice at 8 and 16 weeks after the surgery. Third, wild-type mice were subjected to DMM at the age of 8 weeks. Immediately after the surgery, these mice were treated with the Tgfbr2 inhibitor losartan for 8 weeks and then euthanized for collection of knee joints. All joints were characterized for evidences of articular cartilage degeneration. Initiation or acceleration of articular cartilage degeneration was not observed by the genetic inactivation of Tgfbr2 in the joints at the age of 12 months. In fact, the removal of Tgfbr2 and treatment with losartan both delayed the progression of articular cartilage degeneration induced by DMM compared with control littermates. Therefore, we conclude that inhibition of Tgf-β1 signaling protects adult knee joints in mice against the development of osteoarthritis.