From "best practice" to "best fit": a framework for designing and analyzing pluralistic agricultural advisory services worldwide

"The paper develops a framework for the design and analysis of pluralistic agricultural advisory services and reviews research methods from different disciplines that can be used when applying the framework. Agricultural advisory services are defined in the paper as the entire set of organizations that support and facilitate people engaged in agricultural production to solve problems and to obtain information, skills and technologies to improve their livelihoods and well-being... To classify pluralistic agricultural advisory services, the paper distinguishes between organizations from the public, the private and the third sector that can be involved in (a) providing and (b) financing of agricultural advisory services. The framework for analyzing pluralistic agricultural advisory services presented in the paper addresses the need for analytical approaches that help policy-makers to identify those reform options that best fit country-specific frame conditions. Thus, the paper supports a shift from a “one-size-fits-all” to a “best fit” approach in the reform of public services... Based on a review of the literature, the paper presents a variety of quantitative and qualitative methodological approaches derived from different disciplines that can be applied when using the framework in empirical research projects. The disciplines include agricultural and institutional economics, communication theory, adult education, and public administration and management. The paper intends to inform researchers as well as practitioners, policy-makers and development partners who are interested in supporting evidence-based reform of agricultural advisory services. from Authors' AbstractAgricultural extension work, Pro-poor growth, Capacity strengthening,

Developing a music-based digital therapeutic to help manage the neuropsychiatric symptoms of dementia

The greying of the world is leading to a rapid acceleration in both the healthcare costs and caregiver burden that are associated with dementia. There is an urgent need to develop new, easily scalable modalities of support. This perspective paper presents the theoretical background, rationale, and development plans for a music-based digital therapeutic to manage the neuropsychiatric symptoms of dementia, particularly agitation and anxiety. We begin by presenting the findings of a survey we conducted with key opinion leaders. The findings highlight the value of a music-based digital therapeutic for treating neuropsychiatric symptoms, particularly agitation and anxiety. We then consider the neural substrates of these neuropsychiatric symptoms before going on to evaluate randomized control trials on the efficacy of music-based interventions in their treatment. Finally, we present our development plans for the adaptation of an existing music-based digital therapeutic that was previously shown to be efficacious in the treatment of adult anxiety symptoms

PRAS40 and PRR5-Like Protein Are New mTOR Interactors that Regulate Apoptosis

TOR (Target of Rapamycin) is a highly conserved protein kinase and a central controller of cell growth. TOR is found in two functionally and structurally distinct multiprotein complexes termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2). In the present study, we developed a two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) based proteomic strategy to identify new mammalian TOR (mTOR) binding proteins. We report the identification of Proline-rich Akt substrate (PRAS40) and the hypothetical protein Q6MZQ0/FLJ14213/CAE45978 as new mTOR binding proteins. PRAS40 binds mTORC1 via Raptor, and is an mTOR phosphorylation substrate. PRAS40 inhibits mTORC1 autophosphorylation and mTORC1 kinase activity toward eIF-4E binding protein (4E-BP) and PRAS40 itself. HeLa cells in which PRAS40 was knocked down were protected against induction of apoptosis by TNFα and cycloheximide. Rapamycin failed to mimic the pro-apoptotic effect of PRAS40, suggesting that PRAS40 mediates apoptosis independently of its inhibitory effect on mTORC1. Q6MZQ0 is structurally similar to proline rich protein 5 (PRR5) and was therefore named PRR5-Like (PRR5L). PRR5L binds specifically to mTORC2, via Rictor and/or SIN1. Unlike other mTORC2 members, PRR5L is not required for mTORC2 integrity or kinase activity, but dissociates from mTORC2 upon knock down of tuberous sclerosis complex 1 (TSC1) and TSC2. Hyperactivation of mTOR by TSC1/2 knock down enhanced apoptosis whereas PRR5L knock down reduced apoptosis. PRR5L knock down reduced apoptosis also in mTORC2 deficient cells. The above suggests that mTORC2-dissociated PRR5L may promote apoptosis when mTOR is hyperactive. Thus, PRAS40 and PRR5L are novel mTOR-associated proteins that control the balance between cell growth and cell death

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Ethnic disparities in the incidence of gynecologic malignancies among Israeli Women of Arab and Jewish Ethnicity: a 10-year study (2010–2019)

Background: Ethnic disparities in healthcare outcomes persist, even when populations share the same environmental factors and healthcare infrastructure. Gynecologic malignancies are a significant health concern, making it essential to explore how these disparities manifest in terms of their incidence among different ethnic groups. Objective: To investigate ethnic disparities in the incidence of gynecologic malignancies incidence among Israeli women of Arab and Jewish ethnicity. Design: Our research employs a longitudinal, population-based retrospective cohort design. Method: Data on gynecologic cancer diagnoses among the Israeli population from 2010 to 2019 was obtained from a National Registry. Disease incidence rates and age standardization were calculated. A comparison between Arab and Jewish patients was performed, with Poisson regression models being used to analyze significant rate changes. Results: Among Jewish women, the age-standardized ratio (ASR) for gynecologic malignancies decreased from 288 to 251 ( p  < 0.001) between 2014 and 2019. However, there was no significant change in the ASR among Arab women during the same period, with rates going from 192 to 186 ( p  = 0.802). During the study period, the incidence of ovarian cancer decreased significantly among Jewish women ( p  = 0.042), while the rate remained stable among Arab women ( p  = 0.102). A similar trend was observed for uterine cancer. The ASR of CIN III (Cervical Intraepithelial Neoplasia Grade 3) in Jewish women notably increased from 2017 to 2019, with an annual growth rate of 43.3% ( p  < 0.001). A similar substantial rise was observed among Arab women, with an annual growth rate of 40.5% ( p  < 0.001). In contrast, the incidence of invasive cervical cancer remained stable from 2010 to 2019 among women of both ethnic backgrounds. Conclusion: Our findings indicate that Arab women in Israel have a lower incidence rate of gynecologic cancers, warranting further investigation into protective factors. Both ethnic groups demonstrate effective utilization of cervical screening

Mismatch string kernels for discriminative protein classification

Motivation: Classification of proteins sequences into functional and structural families based on sequence homology is a central problem in computational biology. Discriminative supervised machine learning approaches provide good performance, but simplicity and computational efficiency of training and prediction are also important concerns. Results: We introduce a class of string kernels, called mismatch kernels, for use with support vector machines (SVMs) in a discriminative approach to the problem of protein classification and remote homology detection. These kernels measure sequence similarity based on shared occurrences of fixed-length patterns in the data, allowing for mutations between patterns.Thus, the kernels provide a biologically wellmotivated way to compare protein sequences without relying on family-based generative models such as hidden Markov models. We compute the kernels efficiently using a mismatch tree data structure, allowing us to calculate the contributions of all patterns occurring in the data in one pass while traversing the tree. When used with an SVM, the kernels enable fast prediction on test sequences. We report experiments on two benchmark SCOP datasets, where we show that the mismatch kernel used with an SVM classifier performs competitively with state-of-the-art methods for homology detection, particularly when very few training examples are available. Examination of the highest-weighted patterns learned by the SVM classifier recovers biologically important motifs in protein families and superfamilies. Availability: SVM software is publicly available a

protein classification

Motivation: Classification of proteins sequences into functional and structural families based on sequence homology is a central problem in computational biology. Discriminative supervised machine learning approaches provide good performance, but simplicity and computational efficiency of training and prediction are also important concerns. Results: We introduce a class of string kernels, called mismatch kernels, for use with support vector machines (SVMs) in a discriminative approach to the problem of protein classification and remote homology detection. These kernels measure sequence similarity based on shared occurrences of fixed-length patterns in the data, allowing for mutations between patterns.Thus, the kernels provide a biologically wellmotivated way to compare protein sequences without relying on family-based generative models such as hidden Markov models. We compute the kernels efficiently using a mismatch tree data structure, allowing us to calculate the contributions of all patterns occurring in the data in one pass while traversing the tree. When used with an SVM, the kernels enable fast prediction on test sequences. We report experiments on two benchmark SCOP datasets, where we show that the mismatch kernel used with an SVM classifier performs competitively with state-of-the-art methods for homology detection, particularly when very few training examples are available. Examination of the highest-weighted patterns learned by the SVM classifier recovers biologically important motifs in protein families and superfamilies. Availability: SVM software is publicly available a

An amino acid shuffle activates mTORC1

The mammalian target of rapamycin complex 1 (mTORC1), which promotes cell growth, is regulated by specific nutrients such as the amino acid leucine. In this issue, Nicklin et al. (2009) describe a mechanism by which glutamine facilitates the uptake of leucine, leading to mTORC1 activation

TOR1 and TOR2 Have Distinct Locations in Live Cells▿ †

TOR is a structurally and functionally conserved Ser/Thr kinase found in two multiprotein complexes that regulate many cellular processes to control cell growth. Although extensively studied, the localization of TOR is still ambiguous, possibly because endogenous TOR in live cells has not been examined. Here, we examined the localization of green fluorescent protein (GFP) tagged, endogenous TOR1 and TOR2 in live S. cerevisiae cells. A DNA cassette encoding three copies of green fluorescent protein (3XGFP) was inserted in the TOR1 gene (at codon D330) or the TOR2 gene (at codon N321). The TORs were tagged internally because TOR1 or TOR2 tagged at the N or C terminus was not functional. The TOR1D330-3XGFP strain was not hypersensitive to rapamycin, was not cold sensitive, and was not resistant to manganese toxicity caused by the loss of Pmr1, all indications that TOR1-3XGFP was expressed and functional. TOR2-3XGFP was functional, as TOR2 is an essential gene and TOR2N321-3XGFP haploid cells were viable. Thus, TOR1 and TOR2 retain function after the insertion of 748 amino acids in a variable region of their noncatalytic domain. The localization patterns of TOR1-3XGFP and TOR2-3XGFP were documented by imaging of live cells. TOR1-3XGFP was diffusely cytoplasmic and concentrated near the vacuolar membrane. The TOR2-3XGFP signal was cytoplasmic but predominately in dots at the plasma membrane. Thus, TOR1 and TOR2 have distinct localization patterns, consistent with the regulation of cellular processes as part of two different complexes