Search

The \emph{MIDNA} application specific integrated circuit (ASIC) is a skipper-CCD readout chip fabricated in a 65 nm LP-CMOS process that is capable of working at cryogenic temperatures. The chip integrates four front-end channels that process the skipper-CCD signal and performs differential averaging using a dual slope integration (DSI) circuit. Each readout channel contains a pre-amplifier, a DC restorer, and a dual-slope integrator with chopping capability. The integrator chopping is a key system design element in order to mitigate the effect of low-frequency noise produced by the integrator itself, and it is not often required with standard CCDs. Each channel consumes 4.5 mW of power, occupies 0.156 mm${^2}$ area and has an input referred noise of 2.7${\mu\nu}_{rms}$. It is demonstrated experimentally to achieve sub-electron noise when coupled with a skipper-CCD by means of averaging samples of each pixel. Sub-electron noise is shown in three different acquisition approaches. The signal range is 6000 electrons. The readout system achieves 0.2${e^{-}}$ RMS by averaging 1000 samples with MIDNA both at room temperature and at 180 Kelvin.

Acculturative stress has demonstrated significant negative relationships with Latinx students' academic outcomes. Framed through interpersonal contact theory, we examined the moderating roles of school ethnic representation (proportion of same-ethnic peers) and school ethnic diversity (proportion of different ethnic groups in student body) in the relationship between acculturative stress and both academic self-efficacy and school belonging. A sample of 190 Latinx youth (14-18 years old) completed measures of acculturative stress and school functioning, and they provided the name and location of their high school to facilitate calculation of school ethnic composition. Both ethnic representation and ethnic diversity moderated relationships between English Competency Pressure (ECP), a specific form of acculturative stress, and academic-self efficacy. School ethnic diversity also interacted with ECP to predict school belonging. Negative relationships between ECP and academic self-efficacy or school belonging only emerged for students in schools with very low ethnic diversity. In contrast, ECP was significantly negatively related to academic self-efficacy only for students in schools with the highest ethnic representation. These findings add complexity to the discussion of how school context matters for Latinx students' academic performance.

A mechanical stimulus to skeletal muscle during exercise activates the sympathetic nervous system via the skeletal muscle mechanoreflex. However, to date, the receptor mechanisms responsible for mechanotransduction in skeletal muscle afferents have not been fully identified. Transient receptor potential vanilloid 4 (TRPV4), a multimodally activated, nonselective cation channel, is sensitive to mechanical stimuli such as shear stress, osmotic pressure and stretch in various organs. Therefore, it is hypothesized that TRPV4 contributes to mechanotransduction in thin-fiber primary afferents innervating skeletal muscle. Purpose: The aim of this investigation was to determine 1) the extent to which TRPV4 and the afferent marker peripherin are co-localized in dorsal root ganglion (DRG) neurons subserving thin-fiber skeletal muscle afferents using a retrograde tracing technique, and 2) the impact of a selective TRPV4 antagonist, HC067047 on mechanotransduction in small DRG neurons. Methods: To label muscle afferent DRG neurons, dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate, (Dil, 60 mg/mL, 3 μL total) was injected into the white portion of the gastrocnemius muscle. Five days after the injection, L4-L6 DRGs were harvested from rats (Sprague-Dawley (SD), n = 3, body weight: 318.0 ± 8.7 g). The number of positively stained small-diameter DRG neurons (i.e. less than 30 μm in diameter) were counted and the percentage of peripherin- or DiI-positive neurons in TRPV4-positive neurons was calculated. In vitro whole-cell patch clamp recordings from cultured rat DRG neurons (SD, n = 10, body weight: 352.1 ± 52.4 g), mechanically-activated (MA) current amplitude and mechanical threshold were measured before and 5 min after the application of either HEPES-buffered solution as a control or 1 μM HC067047 solution. Results: Fluorescence immunostaining demonstrated that 20.1 ± 10.1% of TRPV4 positive neurons were expressed with Dil-labeled small DRG neurons. Of these, 9.5 ± 6.1% and 10.6 ± 7.2% were peripherin-positive and -negative neurons, respectively. In in vitro whole-cell patch clamp recordings, MA current amplitude was significantly decreased 5 min after the application of HC067047 ( P < 0.01), while mechanical threshold did not change. Conclusion: The data demonstrates that 1) TRPV4 is expressed in DRGs innervating group IV muscle afferent C-fibers, and 2) HC067047 suppresses the response to mechanical stimulation in DRG neurons. These findings suggest that TRPV4 channels play an important role as mechanoreceptors contributing to mechanotransduction in thin muscle afferents. Supported by NIH HL-151632, JSPS 21J20070 & 22KK0154, and UMF 202131013 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Type 2 diabetes mellitus (T2D) leads to alterations in insulin signaling and autonomic function, including abnormal cardiovascular response to exercise. Cardiovascular control during exercise is in part mediated by the exercise pressor reflex (EPR). The EPR transmits information from primary sensory neurons in working skeletal muscle to cardiovascular control centers in the brain, resulting in reflexively increased blood pressure (BP). Insulin receptors are expressed on neurons in these cardiovascular control centers. Thus, it is logical to suggest that insulin signaling could be disrupted in these neurons in T2D. We hypothesized that the augmented cardiovascular and sympathetic responses to exercise in T2D may be attenuated by administration of insulin into the brain. Purpose: This study was conducted to demonstrate that insulin administration into the central nervous system of rats acutely attenuates the augmented BP and sympathetic responses to muscle contraction in rats with T2D. Methods: T2D and control rats were generated by feeding Sprague-Dawley rats either a high fat diet (T2D, n=10) or normal diet (control, n=7) for 12-16 wks. Before beginning the diet, either two low doses of i.p. streptozotocin (T2D, 35mg/kg week 1, 25mg/kg week 2) or two i.p. saline injections (control) were administered. A precollicular decerebration was performed, and the left L4 and L5 ventral roots were electrically stimulated to evoke hindlimb skeletal muscle contractions. Renal sympathetic nerve activity (RSNA) and BP responses to activation of the EPR were assessed before, and post 1 and 2hr intracerebroventricular (ICV) insulin injection (500mU, 50nL). Fasting blood glucose was measured before experiments. Data were evaluated by Two-way Repeated Measures ANOVA or Student’s t-test. Results: Fasting blood glucose was significantly higher in T2D as compared to control rats (T2D 150±55 mg/dL vs 100±16 mg/dL, P=0.0353). In the T2D group, the BP and RSNA responses to contraction were significantly attenuated at 1hr post-ICV insulin (ΔMAP Pre [36±14 mmHg] vs 1hr post [21±14 mmHg], P=0.0002; ΔRSNA Pre [107.5±40%], vs 1hr post [75.4±46%], P=0.0043), and then further attenuated at 2hr post (ΔMAP 1hr [21±14 mmHg] vs 2hr [11±6 mmHg], P= 0.0155; ΔRSNA 1hr [75.4±46%] vs 2hr [51±35%], P=0.0363). There were no differences in pressor or sympathetic responses observed in the control group post-ICV insulin. Conclusion: The data demonstrate that brain insulin normalizes the potentiated BP and RSNA responses to muscle contraction in T2D rats. Thus, impaired insulin signaling within cardiovascular control centers of the brain may underlie the augmented EPR in T2D rats. Central insulin treatment may potentially restore normal autonomic function in part by decreasing neuronal excitability in T2D. Supported by NIH-NHLBI, Lawson & Rogers Lacy Research Fund This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Bispecific T-cell engager (BiTE) molecules have great potential to treat cancer. Nevertheless, dependent on the targeted tumor antigen, the mechanism of action that drives efficacy may also contribute to on-target/off-tumor toxicities. In this study, we characterize an anti-CD70 half-life extended BiTE molecule (termed N6P) which targets CD70, a TNF family protein detected in several cancers. First, the therapeutic potential of N6P was demonstrated using in vitro cytotoxicity assays and an orthotopic xenograft mouse study resulting in potent killing of CD70+ cancer cells. Next, in vitro characterization demonstrated specificity for CD70 and equipotent activity against human and cynomolgus monkey CD70+ cells. To understand the potential for on-target toxicity, a tissue expression analysis was performed and indicated CD70 is primarily restricted to lymphocytes in normal healthy tissues and cells. Therefore, no on-target toxicity was expected to be associated with N6P. However, in a repeat-dose toxicology study using cynomolgus monkeys, adverse N6P-mediated inflammation was identified in multiple tissues frequently involving the mesothelium and epithelium. Follow-up immunohistochemistry analysis revealed CD70 expression in mesothelial and epithelial cells in some tissues with N6P-mediated injury, but not in control tissues or those without injury. Collectively, the data indicate that for some target antigens such as CD70, BiTE molecules may exhibit activity in tissues with very low antigen expression or the antigen may be upregulated under stress enabling molecule activity. This work illustrates how a thorough understanding of expression and upregulation is needed to fully address putative liabilities associated with on-target/off-tumor activity of CD3 bispecific molecules.

Skeletal muscle reflexes play a crucial role in determining the magnitude of the cardiovascular response to exercise. However, evidence supporting an association between the magnitude of the pressor response and velocity of muscle deformation has remained to be elucidated. Thus, we investigated the impact of different muscle deformation rates on the neural discharge of muscle afferents as well as pressor and sympathetic responses in Sprague-Dawley rats. In an ex vivo muscle-nerve preparation, action potentials elicited by sinusoidal mechanical stimuli (137 mN) at different frequencies (0.01, 0.05, 0.1, 0.2, and 0.25 Hz) were recorded in mechanosensitive group III and IV fibers. The afferent response magnitude to sine-wave stimulation significantly varied at different frequencies (ANOVA, P=0.025). Specifically, as compared to 0.01 Hz (0.83±0.96 spikes/s), the response magnitudes were significantly greater at 0.20 Hz (4.07±5.04 spikes/s, P=0.031) and 0.25 Hz (4.91±5.30 spikes/s, P=0.014). In an in vivo decerebrated rat preparation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch (1kg) of hindlimb skeletal muscle at different velocities of loading (slow, medium, fast) was measured. Pressor responses to passive stretch were significantly associated with velocity of muscle deformation (ANOVA, P

Tissue expression datasets

Supplementary Figure 3 from Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody

AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings. Mol Cancer Ther; 9(10); 2641–51. ©2010 AACR.

File contains Supplementary Methods

Supplementary Figure 3 Evaluation of DLL3 expression in tumor types other than SCLC.

Supplementary Figure 6 A, Expression of human CD25, CD69, PD-1, and 4-1BB on human CD4+ T cells isolated from mouse lungs harboring SHP-77 tumors 168 hours after treatment with AMG 757 or a control HLE BiTE® molecule. B, Expression of human CD25, CD69, PD-1, and 4-1BB on human CD8+ T cells isolated from mouse lungs harboring SHP-77 tumors 168 hours after treatment with either AMG 757 or a control HLE BiTE® molecule. *P < 0.05; **P < 0.01; *** P< 0.001

Purpose:Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression.Experimental Design:AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs).Results:AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (Conclusions:AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

This file contains Supplementary Tables 1-5

Supplementary Methods, Figure Legends, and References from Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody

Supplementary Figure 1 from Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody

Supplementary Figure 1 DLL3 is differentially expressed in SCLC tumors and cell lines compared with normal tissues.

Supplementary Figure 2 Representative photomicrographs of DLL3 immunostaining (brown color) in normal human tissues using immunohistochemistry.

Supplementary Figure 5 A, DLL3 RNA expression levels in a panel of SCLC patient-derived xenograft (PDX) models compared with positive (NCI-H82) and negative (NCI-H460) control SCLC cell lines. Data are reported as relative quantification normalized to NCI-H460 cell line expression. B, DLL3 protein expression levels in a panel of SCLC PDX models compared with positive (NCI-H82) and negative (NCI-H460) control SCLC cell lines. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

Supplementary Figure 2 from Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody

Supplementary Figure 4 from Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody

Supplementary FIgure 4 AMG 757 demonstrated antitumor activity in the WM266-4 melanoma xenograft model.

El nitrógeno es el nutriente más importante en cultivos forrajeros, debido a su participación en diversas reacciones bioquímicas en las diferentes etapas fenológicas de la planta. El objetivo del presente estudio fue desarrollar un modelo de regresión lineal múltiple para estimar el nitrógeno total (Nt) en planta de maíz a partir de imágenes satelitales. El porcentaje de Nt se determinó mediante tres muestreos de planta en cuatro parcelas experimentales. El modelo de estimación se obtuvo al procesar las imágenes satelitales Sentinel-2 de acuerdo a las fechas de muestreo, se calcularon 13 índices espectrales y se analizó la asociación entre los valores del contenido de nitrógeno y la reflectancia a través de: análisis de componentes principales (ACP), matriz de correlación y dendrograma. Los índices con mayor relación fueron MCARI/OSAVI, TCARI/OSAVI, MCARI/OSAVI RE y TCARI/OSAVI RE, esto permitió explicar más de 50% de la variabilidad del modelo propuesto y un EMC de 0.12. El presente estudio indicó que el cálculo de índices espectrales derivados de Sentinel-2 tiene gran potencial para conocer el estado nitrogenado del cultivo de maíz, sin embargo, para futuras investigaciones se sugiere obtener modelos de estimación de Nt por etapa fenológica del cultivo.

Background: Telestroke has been increasingly adopted by hospitals with limited access to neurological expertise and is often followed by transfer for a higher level of care. We sought to characterize factors independently associated with patient transfers after telestroke consultation in our regional telestroke network. Methods: We studied all telestroke consults from our urban comprehensive stroke center from 1/1/2005 to 06/30/2022 using the records in our telehealth portal. We examined the annual proportion of transfers among all consults overall and stratified by 6 levels of NIHSS severity and 4 levels of spoke hospital rurality. We used generalized linear mixed models to evaluate the association between transfer and patient demographics, hospital characteristics, use of video and care quality metrics (timeliness and tPA use), accounting for clustering by spoke hospital. Results: We identified 20,618 consecutive telestroke consults, of which 5,276 (25.6%) were transferred (602 cases excluded with unknown transfer status). The proportion of transfers decreased significantly over the study period (Figure). Decreases were observed for all rurality strata and all but the most severe strokes. After adjusting for temporal trends, factors independently associated with transfer included younger age, male gender, more severe stroke, and tPA use (Table). Conclusion: In our regional telestroke network, the proportion of transfers decreased substantially from 2005 to 2022 overall and across almost all patient and hospital groups. Telestroke may facilitate capacity management and retaining care in lower cost community settings, which may increase healthcare value.

Un garañón, raza Costarricense de Paso, de 5 años, presentó un trauma de pene durante el coito. desarrolló parafimosis complicada con: edema, hematoma, infección local y ulceraciones cutáneas. Se efectúa una revisión de la literatura relacionada con aspectos importantes del tema, incluyendo la perspectiva de bienestar animal en reproducción caballar. Si se considera que el trauma de pene es un problema relativamente frecuente en equinos, es importante publicar esta información, para beneficio del profesional veterinario que trabaja en condiciones de campo sin el adecuado soporte de un hospital equino, como sucede en algunos países. Se describe cómo fabricar, caseramente, y aplicar un suspensorio genital para el manejo conservador exitoso del problema. Se exponen instrucciones generales para prevenir accidentes relacionados con el coito equino. Este tema se considera materia importante para evitar maltrato animal.

Este manuscrito proporciona una visión general sobre la vulnerabilidad de México, como región geográfica, a los impactos del cambio climático. Es en el dinamismo del sector primario donde los cambios climáticos globales climáticos globales tienen mayor influencia. Para reescalar las observaciones globales a escala local, regional y nacional, el INIFAP como centro público de investigación, aporta soluciones tecnológicas al alcance de los usuarios, tomadores de decisiones, investigadores, académicos y consultores. Desde su creación, el instituto mantiene líneas de investigación para estudiar los impactos del cambio climático en lo agrícola, pecuario y forestal. Esta la lleva a cabo a través de la organización de encuentros nacionales e internacionales de intercambio técnico-científico y la ejecución de proyectos de investigación y de servicios. A través de la integración y análisis de bases de datos, de la implementación de técnicas de máquinas de aprendizaje en arquitecturas de cómputo, series de tiempo de imágenes satelitales y datos de procesos de intercambio entre la cubierta del suelo y la atmósfera, el Laboratorio Nacional de Modelaje y Sensores Remotos oferta al usuario productos y servicios basados en TICs. Pronósticos numéricos de lluvia y sequía, conforman la oferta institucional para proveer de información útil para la mitigar los efectos del cambio climático en el sector primario. A través de estos productos y servicios se promueve un cambio de paradigma para el estudio de los impactos del cambio climático en México.

BackgroundCheckpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) have demonstrated clinical efficacy in advanced melanoma, but only a subset of patients with inflamed tumors are responsive. Talimogene laherparepvec (T-VEC), a modified herpes simplex virus type 1 (HSV-1) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), is a first-in-class oncolytic immunotherapy approved for the treatment of melanoma and has been shown to inflame the tumor microenvironment. To evaluate the potential and mechanisms of T-VEC to elicit systemic antitumor immunity and overcome resistance to checkpoint inhibitors in murine tumor models, OncoVEXmGM-CSFwas developed similarly to T-VEC, except the human GM-CSF transgene was replaced with murine GM-CSF. Previous work had demonstrated that OncoVEXmGM-CSFgenerated systemic antitumor immunity dependent on CD8+ T cells in an immune checkpoint-sensitive tumor cell model.MethodsA novel B16F10 syngeneic tumor model with both HSV-1−permissive subcutaneous tumors and HSV-1−refractory experimental lung metastasis was used to study the local and systemic effects of OncoVEXmGM-CSFtreatment alone or in combination with checkpoint inhibitors.ResultsIntratumoral injection of OncoVEXmGM-CSFin combination with an anti-CTLA-4 or anti-PD-1 blocking antibody led to increased tumor growth inhibition, a reduction in the number of lung metastases, and prolonged animal survival. OncoVEXmGM-CSFinduced both neoantigen-specific and tumor antigen-specific T-cell responses. Furthermore, cured mice from the combination treatment of OncoVEXmGM-CSFand anti-CTLA-4 antibody rejected tumor rechallenges.ConclusionsThese data support the concept that T-VEC and checkpoint inhibition may be an effective combination to treat patients with advanced melanoma.

Background and Purpose: Patient care-seeking has likely changed during the coronavirus disease 2019 (COVID-19) pandemic. In stroke, delayed or avoided care may translate to substantial morbidity. We sought to determine the effect of the pandemic on patterns of stroke patient presentation and quality of care. Methods: We analyzed data from 25 New England hospitals: one urban, academic comprehensive stroke center and telestroke hub, and 24 spoke hospitals in the telestroke network. We included all telestroke consultations from the 24 spokes, and all stroke admissions to the comprehensive stroke center hub from November 1, 2019 through April 30, 2020. We compared rates of presentation, timeliness presentation, and quality of care pre- versus post-March 1, 2020. We examined trends in patient demographics, stroke severity, timeliness, diagnoses including large vessel occlusion, alteplase use, and endovascular thrombectomy among eligible subjects. We compared proportions and bivariate comparisons to examine for changes pre- versus post-March 1, 2020 and used linear regression to examine trends over time. Results: Among 1248 patient presentations (844 telestroke consultations, 404 comprehensive stroke center admissions), telestroke consultations and ischemic stroke patient admissions decreased among the spokes and hub. Age and stroke severity were unchanged over the study period. We found no change in alteplase administration at telestroke spoke hospitals but did note a decrease in both alteplase use and thrombectomy at our comprehensive stroke center. Time metrics for patient presentation and care delivery were unchanged; however, rates of adherence for the quality measures dysphagia screening, early antithrombotic initiation, and early venous thromboembolism prophylaxis were reduced during the pandemic. Conclusions: In this regional analysis, we found decreasing telestroke consultations and ischemic stroke admissions, and reduced performance on stroke quality of care measures during the COVID-19 pandemic. Contrary to prior reports, we did not find an increase in thrombectomy nor decrease in clinical severity that might be expected if patients with milder symptoms avoided hospitalization.

Purpose: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression. Experimental Design: AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs). Results: AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression ( Conclusions: AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

ObjectiveTo determine whether providing teleneurology (TN) consultations aiding in determination of death by neurologic criteria (DNC) to a bedside intensivist is feasible and whether timely access and expert input increase the quality of the DNC examination and identification of potential organ donors, we reviewed retrospective data related to outcomes of such consultations.MethodsBetween November 2017 and March 2019, TN consults were requested for sequential comatose patients in the intensive care unit (ICU). We recorded patients' demographic information, causes leading to coma or suspected DNC, and the results of TN consultations. We obtained data on the number of referrals to the organ bank and number of organ donors.ResultsNinety-nine consults were performed with a median time from request to start of the consult of 20.2 minutes (interquartile range 5.4–65.3 minutes). Eighty consults were requested for determination of prognosis, whereas 19 consults were requested for supervision of the DNC examination. In 1 of 80 (1.2%) prognostication consults, the patient was determined by the neurologist to require assessment of DNC and was found to meet DNC criteria; determination of DNC occurred in 11 of the 19 (57.9%) consultations for a supervised DNC examination. In a comparison of the pre-TN (94 months) and post-TN (17 months) periods, there was 2.56-fold increase in the proportion of patients meeting DNC criteria who were medically suitable for donation (pre-TN 8.9% vs post-TN 21.1%, p = 0.02) and a 2.12-fold increase in the proportion of donors (pre-TN 6.14% vs post-TN 13.1%, p = 0.14).ConclusionsIt is feasible to perform TN consultations for patients with severe neurologic damage and to allow expert supervision for DNC examination. Having a teleneurologist as part of the ICU assessment team helped differentiate severe neurologic deficits from DNC and was associated with increase in organ donation.

This paper presents the implementation of a multiplexed analog readout electronics system that can achieve single-electron counting using Skipper-CCDs with non-destructive readout. The proposed system allows the best performance of the sensors to be maintained, with sub-electron noise-level operation, while maintaining low-bandwidth data transfer, a minimum number of analog-to-digital converters (ADC) and low disk storage requirement with zero added multiplexing time, even for the simultaneous operation of thousands of channels. These features are possible with a combination of analog charge pile-up, sample and hold circuits and analog multiplexing. The implementation also aims to use the minimum number of components in circuits to keep compatibility with high-channel-density experiments using Skipper-CCDs for low-threshold particle detection applications. Performance details and experimental results using a sensor with 16 output stages are presented along with a review of the circuit design considerations.

This article proposes a new technique to reduce the readout noise in charge-coupled devices (CCDs). The objective is to minimize the common noise between the channels. This noise is either induced by the readout electronics or by the environment, and it could be present in small (single CCD and a few channels) or large systems (dozens of CCDs and hundreds of channels). By interleaving the video signals, we show that it is possible to reduce the readout noise by around 50% without sacrificing output channels at the expense of a moderate increase of the readout time, which is less compared with other techniques. Up until now, similar approaches have used half of the output stages only for noise measurement doubling the total readout time of the sensor. Simulations and experimental results are presented to validate the proposed approach. Moreover, the technique is measured using a Skipper CCD, and its operation is validated together with the ability of the Skipper sensor for nondestructively reading, several times, the same pixel charge. With the combination of both techniques, we achieve deep subelectron readout noise levels (0.1 e−).

We present a simulated cosmology analysis using the second and third moments of the weak lensing mass (convergence) maps. The second moment, or variances, of the convergence as a function of smoothing scale contains information similar to standard shear two-point statistics. The third moment, or the skewness, contains additional non-Gaussian information. The analysis is geared towards the third year (Y3) data from the Dark Energy Survey (DES), but the methodology can be applied to other weak lensing data sets. We present the formalism for obtaining the convergence maps from the measured shear and for obtaining the second and third moments of these maps given partial sky coverage. We estimate the covariance matrix from a large suite of numerical simulations. We test our pipeline through a simulated likelihood analyses varying 5 cosmological parameters and 10 nuisance parameters and identify the scales where systematic or modelling uncertainties are not expected to affect the cosmological analysis. Our simulated likelihood analysis shows that the combination of second and third moments provides a 1.5 per cent constraint on S8 σ8(ωm/0.3)0.5 for DES Year 3 data. This is 20 per cent better than an analysis using a simulated DES Y3 shear two-point statistics, owing to the non-Gaussian information captured by the inclusion of higher order statistics. This paper validates our methodology for constraining cosmology with DES Year 3 data, which will be presented in a subsequent paper., Funding for the DES Projects has been provided by the U.S. Department of Energy, the U.S. National Science Foundation, the Ministry of Science and Education of Spain, the Science and Technology Facilities Council of the United Kingdom, the Higher Education Funding Council for England, the National Center for Supercomputing Applications at the University of Illinois at Urbana-Champaign, the Kavli Institute of Cosmological Physics at the University of Chicago, the Center for Cosmology and Astro-Particle Physics at the Ohio State University, the Mitchell Institute for Fundamental Physics and Astronomy at Texas A&M University, Financiadora de Estudos e Projetos, Fundac¸ao Carlos Chagas Filho de Amparo ˜ a Pesquisa do ` Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Cient´ıfico e Tecnologico and the Minist ´ erio da Ci ´ encia, Tecnologia ˆ e Inovac¸ao, the Deutsche Forschungsgemeinschaft and the Collabo- ˜ rating Institutions in the Dark Energy Survey. The Collaborating Institutions are Argonne National Laboratory, the University of California, Santa Cruz, the University of Cambridge, Centro de Investigaciones Energeticas, Medioambientales y ´ Tecnologicas-Madrid, the University of Chicago, University College ´ London, the DES-Brazil Consortium, the University of Edinburgh, the Eidgenossische Technische Hochschule (ETH) Z ¨ urich, Fermi ¨ National Accelerator Laboratory, the University of Illinois at UrbanaChampaign, the Institut de Ciencies de l’Espai (IEEC/CSIC), the ` Institut de F´ısica d’Altes Energies, Lawrence Berkeley National Laboratory, the Ludwig-Maximilians Universitat M¨ unchen, and the ¨ associated Excellence Cluster Universe, the University of Michigan, the National Optical Astronomy Observatory, the University of Nottingham, the Ohio State University, the University of Pennsylvania, the University of Portsmouth, SLAC National Accelerator Laboratory, Stanford University, the University of Sussex, Texas A&M University, and the OzDES Membership Consortium. Based in part on observations at Cerro Tololo Inter-American Observatory, National Optical Astronomy Observatory, which is operated by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. The DES data management system is supported by the National Science Foundation under Grant Numbers AST-1138766 and AST-1536171. The DES participants from Spanish institutions are partially supported by MINECO under grants AYA2015- 71825, ESP2015-66861, FPA2015-68048, SEV-2016-0588, SEV2016-0597, and MDM-2015-0509, some of which include ERDF funds from the European Union. IFAE is partially funded by the CERCA program of the Generalitat de Catalunya. Research leading to these results has received funding from the European Research Council under the European Union 7th Framework Program (FP7/2007-2013) including ERC grant agreements 240672, 291329, and 306478. We acknowledge support from the Brazilian Instituto Nacional de Ciencia e Tecnologia (INCT) e-Universe (CNPq grant ˆ 465376/2014-2). This manuscript has been authored by Fermi Research Alliance, LLC under Contract No. DE-AC02-07CH11359 with the U.S. Department of Energy, Office of Science, Office of High Energy Physics.

The extreme hydroclimatic events in the Conchos River Basin, are strongly associated with ocean–atmospheric phenomena such as the El Nino Southern Oscillation, Pacific Decadal Oscillation, and Atlantic Multidecadal Oscillation, the streamflow reconstruction showed the occurrence of up to 10-year droughts. Dendrochronology is a modern science used to study hydroclimatic events through the measurement and standardization of tree-rings. Long-term dendrochronological series contribute to the improvement of our knowledge of past climatic events and provide information for wise management of water resources. The objective of this study was to generate an actualized streamflow volume reconstruction with a regional chronology and identify extreme hydroclimatic events in the Conchos River Basin. We analyzed the hydroclimatic behavior of the streamflow volume through a dendrochronological network in the Basin. The regional earlywood chronology was analyzed by single correlation and principal component analysis, which allowed obtaining the transfer model to determine extreme hydroclimatic events and defined the influence of large-scale ocean–atmospheric phenomena. Nine earlywood series showed a common variance and responded significantly (r = 0.68, n = 67, p

Dendrochronological series are reliable sources of information to analyze past hydrological and climatological variation that provides useful information for the management of water resources within basins. We analyzed dendrochronological series obtained from the upper Mayo River Basin using principal components analysis to determine a common climatic signal. Although the complete series extended for over 350 years, the representative period common to all series was from 1750 to 2014 (265 years) with an expressed population signal of over 0.85. Climate data (precipitation and temperature) were collected from the North American Land Data Assimilation System 2 model of the Land Data Assimilation System and hydrometrics records were obtained from the National Commission of Water in Mexico. The results of the response function showed an association of mean monthly temperature with the ring width series for the months of December of the previous year, May and October of the year of growth, and seasonally from January to July (r = -0.75, n = 36, p < 0.05). A significant response to rainfall of earlywood growth was observed for June, November, and December of the previous year, January and February of the growth year, and seasonally, from October of previous year to May of the current growth year (r = 0.70, n = 35, p < 0.05). Significant association also was found between earlywood and the accumulated runoff from October of the previous year to May of the growth year, which was used for reconstruction of the runoff flow between 1750 and 2014, which showed evidence of decadal drought. Significant correlation was found between the reconstructed runoff series, and the Southern Oscillation index (r = -0.42, n = 228, p < 0.05), but not significant with the Pacific Decadal Oscillation index (r = 0.16, n = 115, p < 0.05). We also observed significant (p < 0.05) associations with the drought indices Palmer Drought Severity Index and Standardized Precipitation Evapotranspiration Index (r = 0.56, r = 0.41, respectively). Our study demonstrated the potential of assimilated data for dendroclimatic reconstructions and the feasibility of generating hydroclimatic information of extreme events that have not been recorded in the available climatic and hydrological instrumental records.

This article provides a practical design methodology to calculate an optimal filter for noise reduction in the readout of charge‐coupled devices (CCDs) taking into account the charge transfer and feedthroughs due to capacitive coupling in the CCD. A detailed analysis of the dynamics of the video signal and charge transfer is presented, including the circuital modeling of the output stage of the CCD and the dynamics of the electronics in the video chain before the analog‐to‐digital (AD) converter. This model is used to compute an optimal filter that minimizes the variance of the pixel noise and uses the samples of the charge transfer, before the charge is fully settled. This is necessary to enhance the performance of previous results that also use optimal filters but do not use the transition samples, while also reducing the pixel readout time, resulting in faster readouts. As a proof of concept for the optimal filter, we present novel experimental results using a Skipper CCD, which has a floating sense node that allows to measure the charge packet an arbitrary number of times. However, this technique can be applied to any CCD that has a readout system that digitally samples the video signal. Fil: Chierchie, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina Fil: Fernández Moroni, Guillermo. Fermi National Accelerator Laboratory; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina Fil: Querejeta Simbeni, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina Fil: Stefanazzi, Leandro. Fermi National Accelerator Laboratory; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina Fil: Paolini, Eduardo Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina Fil: Sofo Haro, Miguel Francisco. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Fermi National Accelerator Laboratory; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cancelo, Gustavo Indalecio. Fermi National Accelerator Laboratory; Estados Unidos Fil: Estrada, Juan. Fermi National Accelerator Laboratory; Estados Unidos

The diagnosis of brain death and the determination of neurologic prognosis following cardiac arrest are important reasons for neurology consultation in the intensive care unit. In hospitals without access to neurology consultation, it may be challenging to address these important questions with high reliability in a timely manner. The American Academy of Neurology has established consensus criteria for diagnosis of brain death, which include (i) comatose state; (ii) presence of apnea; and (iii) absence of brainstem reflexes in the setting of a diagnosis of underlying brain injury compatible with brain death. It has recently been shown that virtual assessment of coma using standardized scales is feasible with good inter-rater reliability. The supervision of apnea testing and the neurologic examination of the brainstem by a remote neurologist are possible if conducted in conjunction with a well-trained and experienced bedside team. In this communication, we explore the essential clinical and legal framework that can support using virtual teleconsultations to address this complex topic.

Baldcypress, a long-lived species of riparian habitats, is sensitive to interannual climate variability. The annual radial growth is associated with the Standardized Precipitation Evaporation Index (SPEI) and Palmer Drought Severity Index (PDSI), both depending on a water balance. The baldcypress (Taxodium mucronatum Ten.) is a long-lived species and Mexico’s national tree. The objective of this study was to analyze the dendroclimatic response of baldcypress at sites located on the transitional zone between the semiarid and subtropical regions of Mexico, known as the Middle Zone of the state of San Luis Potosi, Mexico. The first site, Los Peroles (LPO), is a wetland where the oldest known baldcypress specimens in Mexico are found. The second site, Rio Verde (RVDE), is a riparian site located along a tributary of the Moctezuma River that drains into the Gulf of Mexico. Two ring-width chronologies were analyzed. The first one from LPO with a length of 633 years and the second one from RVDE with a length of 423 years. The species responded positively to the seasonal January–July precipitation (r = 0.52, p = 0.001) and negatively to the maximum monthly temperature of January, May, and June (r = − 0.42, −0.46, and −0.34; respectively). The average chronology was significantly associated with the mean January–August Standardized Precipitation Evaporation Index (SPEI) (r = 0.62, p = 0.000). An SPEI reconstruction was developed for the period 1575–1996 where the most prolonged and severe droughts were found at 70-year peaks in the El Nino Southern Oscillation frequency band. The annual radial growth of the species is a suitable indicator of the January–August water availability, and is important information that can be used to establish water management strategies for this semiarid environment and to preserve millennial baldcypress specimens.

Los sistemas de información geográfica (SIG) y de percepción remota (PR) ayudan en el manejo y análisis de la información en los distritos de riego (DR). Por tal motivo, el objetivo del presente estudio fue generar un SIG y dar seguimiento al avance de riego superficial de un módulo del distrito de riego 017 Región Lagunera, México. Para esto, se integró un SIG a partir de topografía de precisión, y se utilizaron diez imágenes del satélite Landsat 8. Los resultados indican que la red principal tiene 19.5 por ciento de menor longitud en el canal lateral derecho (CLD) 57+839, de acuerdo con las cifras oficiales. Los principales cultivos sembrados fueron algodón (35.7%) y nogal (34.3%); asimismo, se identificó 24.2 por ciento de superficie excedente. Los SIG y PR facilitan el seguimiento del avance de riego en el módulo, lo cual contribuye a realizar un uso eficiente del agua.

In this work, we study the potential of using a Skipper-CCD detector in a twin-beam source for preserving spatial correlations. An improvement in the noise reduction factor is predicted and preliminary experimental results are presented.

Image sensors with nondestructive charge readout provide single-photon or single-electron sensitivity, but at the cost of long readout times. We present a smart readout technique to allow the use of these sensors in visible light and other applications that require faster readout times. The method optimizes the readout noise and time by changing the number of times pixels are read out either statically, by defining an arbitrary number of regions of interest in the array, or dynamically, depending on the charge or energy of interest in the pixel. This technique is tested in a Skipper CCD showing that it is possible to obtain deep subelectron noise, and therefore, high resolution of quantized charge, while dynamically changing the readout noise of the sensor. These faster, low noise readout techniques show that the skipper CCD is a competitive technology even where other technologies such as electron multiplier charge coupled devices, silicon photo multipliers, etc. are currently used. This technique could allow skipper CCDs to benefit new astronomical instruments, quantum imaging, exoplanet search and study, and quantum metrology. Fil: Chierchie, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina Fil: Fernández Moroni, Guillermo. Fermi National Accelerator Laboratory; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina Fil: Stefanazzi, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina. Fermi National Accelerator Laboratory; Estados Unidos Fil: Paolini, Eduardo Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; Argentina Fil: Tiffenberg, Javier Sebastian. Fermi National Accelerator Laboratory; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Estrada, Juan. Fermi National Accelerator Laboratory; Estados Unidos Fil: Cancelo, Gustavo Indalecio. Fermi National Accelerator Laboratory; Estados Unidos Fil: Uemura, Sho. Universitat Tel Aviv; Israel