Frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity

The segregation of the readily releasable pool of synaptic vesicles (RRP) in sub-pools that are differentially poised for exocytosis shapes short-term plasticity. However, the frequency-dependent mobilization of these sub-pools is poorly understood. Using slice recordings and modeling of synaptic activity at cerebellar granule cell to Purkinje cell synapses of mice, we describe two sub-pools in the RRP that can be differentially recruited upon ultrafast changes in the stimulation frequency. We show that at low frequency stimulations, a first sub-pool is gradually silenced, leading to full blockage of synaptic transmission. Conversely, a second pool of synaptic vesicles that cannot be released by a single stimulus is recruited within milliseconds by high-frequency stimulation and support an ultrafast recovery of neurotransmitter release after low-frequency depression. This frequency-dependent mobilization or silencing of sub-pools in the RRP in terminals of granule cells may play a role in the filtering of sensorimotor information in the cerebellum

Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC

Tensor Regression with Applications in Neuroimaging Data Analysis

Classical regression methods treat covariates as a vector and estimate a corresponding vector of regression coefficients. Modern applications in medical imaging generate covariates of more complex form such as multidimensional arrays (tensors). Traditional statistical and computational methods are proving insufficient for analysis of these high-throughput data due to their ultrahigh dimensionality as well as complex structure. In this article, we propose a new family of tensor regression models that efficiently exploit the special structure of tensor covariates. Under this framework, ultrahigh dimensionality is reduced to a manageable level, resulting in efficient estimation and prediction. A fast and highly scalable estimation algorithm is proposed for maximum likelihood estimation and its associated asymptotic properties are studied. Effectiveness of the new methods is demonstrated on both synthetic and real MRI imaging data.Comment: 27 pages, 4 figure

A triple bottom line construct and reasons for implementing sustainable business practices in companies and their business networks

Purpose – The purpose of this study is to test a Triple Bottom Line (TBL)-construct as well as to describe the TBL-reasons for implementing sustainable business practices in companies and their business networks. This study explores how linking these seemingly disparate pillars of sustainability may be facilitated through a TBL construct. The notion of sustainable business practices has been evolving and is increasingly understood to encompass considerations of economic viability, as well as environmental sustainability and social responsibility. Design/methodology/approach – The research is quantitative in nature, exploring and analysing how companies in different Norwegian industries implement and manage sustainable business practices based on TBL. The survey results are reported here. Findings – The relevance of TBL to different aspects of sustainable business practices is outlined. The study generally supports the view that a heightened propensity for sustainable business practices ensures that organisations are better equipped for meeting the challenge of integrating TBL in companies and their business networks. Research limitations/implications – The study tested a construct of TBL in the context of sustainable business practices. It may be incorporated in further research in relation to other constructs. Suggestions for further research are proposed. Practical implications – Useful for practitioners to get insights into TBL-reasons for implementing business-sustainable practices in companies and their business networks. It may also be valuable to assess the general status of business-sustainable practices in a company and their business networks. Originality/value – Linking two traditionally separate and encapsulated areas of research, namely, the area of business sustainable practices and the area of TBL. The current study has contributed to a TBL-construct in relation to other constructs in measurement and structural models. It has also contributed to provide insights of priority into the main reasons to implement the elements of TBL within companies and their business networks

Características biológicas de cepas de Herpesvirus bovino 1 y 5 utilizando el modelo experimental conejo

Los Herpesvirus bovinos (BoHV) pueden infectar tanto a mustélidos como a conejos y esta última especie ha sido utilizada como modelo de laboratorio para la infección por BoHV-1 y 5. El objetivo de este trabajo fue estudiar la patogenicidad de diferentes cepas argentinas de BoHV-1 y BoHV-5 utilizando el modelo experimental conejo. Se utilizaron conejos de raza neozelandesa que se inocularon por vía intranasal e intravaginal. Los animales inoculados por vía intranasal con cepas de BoHV-5 desarrollaron signos nerviosos en el 83% de los casos, mientras que BoHV-1.1 causó signos nerviosos en el 57% de los animales y BoHV-1.2 no provocó signos clínicos evidentes. El BoHV-5 causó síntomas nerviosos solo en los animales jóvenes mientras que BoHV-1 solo lo hizo ocasionalmente y también en individuos jóvenes. Los conejos inoculados por vía intravaginal no mostraron signos clínicos ni lesiones aparentes en los órganos estudiados; la infección se demostró por seroconversión serológica. El conejo resultó adecuado para estudiar la sintomatología y las lesiones producidas en los distintos órganos, fundamentalmente en el sistema nervioso central. El modelo resultó de utilidad por ser económico, de muy fácil manejo y permitió reconocer diferencias en el comportamiento biológico de las cepas de BoHV-1 y BoHV-5 estudiadas.Bovine Herpesvirus (BoHV) can infect both rabbits and mustelids. Rabbit has been used as a laboratory model for infection with BoHV-1 and 5. The objective of this research was to study the pathogenicity of different Argentinian BoHV-1 and BoHV-5 strains by using the rabbit experimental model. New Zealand rabbits were inoculated by intranasal and intravaginal ways. The animals inoculated intranasally with strains of BoHV-5 developed neurological signs in 83% of the cases. BoHV-1.1 caused neurological signs in 57% of the animals and BoHV-1.2 did not cause clear clinical signs. BoHV-5 caused nervous signs in young animals while BoHV-1 did so occasionally in young rabbits. Animales inoculated intravaginally showed no apparent clinical signs or apparent lesions in the studied organs. The infection was demonstrated by serological seroconversion. The rabbit was appropriate to study the clinical signs and the lesions produced in the different organs, primarily in the central nervous system. The model was useful for being inexpensive and very easy to use, and it enabled to identify differences in the biological behavior of the studied BoHV-1 and BoHV-5 strains

Urinary MicroRNA Profiling in the Nephropathy of Type 1 Diabetes

Background: Patients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease. Methods and Findings: We studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease. Conclusions: Urinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes. © 2013 Argyropoulos et al

Stressors and Coping Mechanisms of the Children of Abra Bahay Pag-asa

This study was designed to determine the profile, the stressors and coping mechanisms of the 18 children of Abra Bahay Pag-asa during this pandemic.  The qualitative method of research was utilized.  An interview schedule was used to elicit the needed data in this study. The interviews were done via the Zoom platform.  The data gathered were presented and treated using thematic analysis through the generation of codes and themes for the final write-up.  The study revealed that almost all the children are teenagers, most of them are enrolled in the Senior High School and College levels and most of their case category is rape. Moreover, the children experienced several stressors particularly about the status of their cases, the situation of their families back home, their modular learning, and their mutual relationships.  Nevertheless, the children employed active and positive coping mechanisms to alleviate their worries.  Specifically, these were performing productive tasks, engaging in recreational activities, seeking social support, and spiritual activities.  As a recommendation, Abra State Institute of Sciences and Technology through the College of Teacher Education may establish a linkage with the Provincial Government of Abra through and Extension Program on juvenile empowerment for the children of Abra Bahay Pag-asa to include literacy and numeracy; arts and music; life skills training; mental health and stress management.  Additionally, other studies may be conducted again among the children to look into other aspects or factors on their personality development and rehabilitation process

Resonance refraction and neutrino oscillations

The refraction index and matter potential depend on neutrino energy and this dependence has a resonance character associated to the production of the mediator in the $s-$channel. For light mediators and light particles of medium (background) the resonance can be realized at energies accessible to laboratory experiments. We study properties of the energy dependence of the potential for different C-asymmetries of background. Interplay of the background potential and the vacuum term leads to (i) bump in the oscillation probability in the resonance region, (ii) dip related to the MSW resonance in the background, (iii) substantial deviation of the effective $\Delta m^2$ above the resonance from the low energy value, etc. We considered generation of mixing in the background. Interactions with background shifts the energy of usual MSW resonance and produces new MSW resonances. Searches of the background effects allow us to put bounds on new interactions of neutrinos and properties of the background. We show that explanation of the MiniBooNE excess, as the bump due to resonance refraction, is excluded.Comment: 36 pages, 6 figure

Joint measurement of the ultra-high-energy neutrino spectrum and cross section

Soon, a new generation of neutrino telescopes, presently under planning, will target the discovery of ultra-high-energy (UHE) neutrinos of cosmic origin, with energies higher than 100 PeV, that promise unique insight into astrophysics and particle physics. Yet, predictions of the UHE neutrino flux and interaction cross section -- whose measurement is co-dependent -- are laden with significant uncertainty that, if unaddressed, could misrepresent the capabilities to measure one or the other. To address this, we advocate for the joint measurement of the UHE neutrino spectrum and neutrino-nucleon cross section, including of their energy dependence, without assuming prior knowledge of either. We illustrate our methods by adopting empirical parametrizations of the neutrino spectrum, in forecasts geared to the planned radio array of the IceCube-Gen2 neutrino telescope. We warn against using simple parametrizations -- a simple power law or one augmented with an exponential cut-off -- that might fail to capture features of the spectrum that are commonplace in the predictions. We argue instead for the use of flexible parametrizations -- a piecewise power law or an interpolating polynomial -- that ensure accuracy. We report loose design targets for the detector energy and angular resolution that are compatible with those under present consideration.Comment: 20 pages, 5 figures, 1 tabl

Comprehensive Measurement Forecasts of the EeV Neutrino-Nucleon Cross Section with Cosmic Neutrinos at IceCube-Gen2

The investigation of neutrino interactions with matter serves as a valuable tool for understanding the fundamental structure of nucleons and potentially uncovering novel physics phenomena. To date, the neutrino-nucleon cross section has been examined across a range of energies spanning from a few hundred MeV to PeV. However, the pursuit of ultra-high-energy (UHE) cosmic neutrinos, surpassing 100 PeV in energy, holds the promise of further advancements. In the next 10-20 years, UHE neutrino telescopes, currently in the planning stage, may ultimately succeed in their detection. This article presents pioneering and comprehensive estimation forecasts for the ultra-high-energy neutrino-nucleon cross section, with a specific focus on the employment of neutrino radio-detection within the IceCube-Gen2 experiment. The study incorporates cutting-edge methodologies in UHE neutrino flux prediction, neutrino propagation within the Earth, radio detection techniques, and the treatment of background data to facilitate accurate cross section measurement projections. Assuming the successful detection of at least a few tens of UHE neutrino-induced events over a 10-year period, IceCube-Gen2 could achieve, for the first time, the measurement of the cross section at center-of-mass energies of approximately $\sqrt{s} \approx 10$--100 TeV. Furthermore, if the number of events exceeds one hundred, the precision of the cross section measurement could be comparable to its corresponding theoretical prediction.Comment: 8 pages, 4 figures, 2 figures. Submitted as a proceeding for ICRC 202