Analysing Inter-Relationships among Water, Governance, and Human Development Variables in Developing Countries - Preliminary Results on Africa for 2004

The experience of the last 50 years of international cooperation indicates that improving the understanding of the inter-relations among different variables linked with economic and human development can be an essential baseline in the design of development cooperation policies and strategies at national, regional and continental levels. In this way, understanding the Water sector in developing countries relies on complex interactions between different environmental, socio-economic, governance and other human development factors. In this preliminary phase, this research focuses geographically on Africa. Data have been processed using the EM algorithm, hot deck imputation methods, logarithmic or square roots normalization to get a coherent dataset, baseline for performing statistical analyses. Through this first analysis, this approach and methods showed their interest and capacity to quickly bringing to results. In fact, using Principal Component Analysis and linear regression analysis, we have explained a major part of behaviour of two variables: water services access level at 70% and sanitation services access level at 53%. Main outputs are the ranking and weighting of variables according to their influence on the targeted variable. For water supply access level, the key elements are the governance aspects, in particular, the capacity of being effective in delivering services, the capacity of regulation through police, courts, property right respect¿.. and, finally, the control of the corruption in the country. For sanitation access level, the key elements are respectively education of girls far ahead the governance aspects. Concerning the latter, special attention should be taken first to the control of the corruption, then to reinforcement of governance effectiveness in delivering services and finally, the capacity of regulation of the country through police, courts, property right respect. This study allows us to move forward to more complex and detailed analysis having shown that data are enough coherent and reliable.JRC.DDG.H.3-Global environement monitorin

Dexamethasone Attenuates Hyperexcitability Provoked by Experimental Febrile Status Epilepticus.

The role of neuroinflammation in the mechanisms of epilepsy development is important because inflammatory mediators provide tractable targets for intervention. Inflammation is intrinsically involved in the generation of childhood febrile seizures (FSs), and prolonged FS [febrile status epilepticus (FSE)] precedes a large proportion of adult cases of temporal lobe epilepsy (TLE). As TLE is often refractory to therapy and is associated with serious cognitive and emotional problems, we investigated whether its development can be prevented using anti-inflammatory strategies. Using an immature rat model of FSE [experimental FSE (eFSE)], we administered dexamethasone (DEX), a broad anti-inflammatory agent, over 3 d following eFSE. We assessed eFSE-provoked hippocampal network hyperexcitability by quantifying the presence, frequency, and duration of hippocampal spike series, as these precede and herald the development of TLE-like epilepsy. We tested whether eFSE provoked hippocampal microgliosis, astrocytosis, and proinflammatory cytokine production in male and female rats and investigated blood-brain barrier (BBB) breaches as a potential contributor. We then evaluated whether DEX attenuated these eFSE sequelae. Spike series were not observed in control rats given vehicle or DEX, but occurred in 41.6% of eFSE-vehicle rats, associated with BBB leakage and elevated hippocampal cytokines. eFSE did not induce astrocytosis or microgliosis but provoked BBB disruption in 60% of animals. DEX significantly reduced spike series prevalence (to 7.6%) and frequency, and abrogated eFSE-induced cytokine production and BBB leakage (to 20%). These findings suggest that a short, postinsult intervention with a clinically available anti-inflammatory agent potently attenuates epilepsy-predicting hippocampal hyperexcitability, potentially by minimizing BBB disruption and related neuroinflammation

Mixture of Soft Prompts for Controllable Data Generation

Large language models (LLMs) effectively generate fluent text when the target output follows natural language patterns. However, structured prediction tasks confine the output format to a limited ontology, causing even very large models to struggle since they were never trained with such restrictions in mind. The difficulty of using LLMs for direct prediction is exacerbated in few-shot learning scenarios, which commonly arise due to domain shift and resource limitations. We flip the problem on its head by leveraging the LLM as a tool for data augmentation rather than direct prediction. Our proposed Mixture of Soft Prompts (MSP) serves as a parameter-efficient procedure for generating data in a controlled manner. Denoising mechanisms are further applied to improve the quality of synthesized data. Automatic metrics show our method is capable of producing diverse and natural text, while preserving label semantics. Moreover, MSP achieves state-of-the-art results on three benchmarks when compared against strong baselines. Our method offers an alternate data-centric approach for applying LLMs to complex prediction tasks.Comment: 19 pages, 13 Tables, 2 Figures. Accepted at EMNLP 202

Transcriptional outcomes (fates) in response to DNA damage

Various types of DNA damage interfere with key vital processes which use DNA as a template, like replication and transcription. Upon large amount of genotoxic impacts, transcription is over-activated and probably results in the activation of several DNA damage recognition processes. During transcrip-tion, numerous components of the transcription machinery may act as a platform to recruit repair proteins at break sites. In contrast to that, when DNA damage occurs at a transcribing unit, it leads to transcriptional block. This multistep process in-volves several kinases and the ubiquitin ligases like NEDD4 and CUL3 leading to proteasome dependent degradation of RNA polymerase II (RNAPII) which happens at the site of the damage. Finally, at the break site ddRNA (a new class of noncoding RNA) production could be observed by controlling the DDR activation at sites of DNA damage. Taken together these results support an uncharacterized function of RNAPII complexes which allow the rec-ognition of DNA damages and like this enhance cell survival following DNA damage. This work was supported by OTKA-PD [112118], and the János Bolyai Research Scholarship of the Hungarian Acad-emy of Sciences

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses.Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved.Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10 μM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone.Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses.Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved.Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10 μM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone.Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management

Mechanistic insights into the transcriptional arrest in the presence of Double Strand Breaks

Double-strand breaks (DSBs) occur frequently in the genome during genome replication or by DNA damaging agents. DNA lesions affect fundamental DNA-dependent nuclear processes, such as replication and transcription. We have developed an experimental system where DSBs are induced at coding regions of RNA polymerase II transcribing genes. We have started to study the kinetics of RNA polymerase II transcription inhibition in the presence of DNA breaks. We observed that induction of the break led to transcription inhibition and the restoration of transcription closely followed the dynamics of the repair of breaks. We confirmed by chromatinimmunoprecipitation that the break induction led to displacement of RNA polymerase II affecting both the elongation and the initiation of transcription. Our results show that this is dependent on one of the major kinase in DNA damage repair called DNAPKcs. We also investigated the downstream steps of RNA polymerase II removal and we claimed that it was a multistep process involving additional kinases and ubiquitin ligases NEDD4 and CUL3. At the last step of break dependent transcriptional silencing the RNA polymerase II is targeted for proteasome dependent degradation. These data demonstrate that the DNA damage repair complexes and proteasomal system have a synergistic and active role in transcriptional silencing during the DSB repair by removing the RNA pol II from the transcribing region. We show here that DNA lesions occurring at transcribed regions cause a transient repression until the lesion is repaired. This is probably a cell defense mechanism to avoid production of truncated or mutated transcripts in essential genes whose alterations in their gene expression would endanger cell viability. Understudying the role of DNAPKcs, in preventing RNA pol II bypassing a DSB might be a key in avoiding the production of mutated transcripts that could lead to cancerous phenotypes

The effects of graded levels of calorie restriction : VIII. impact of short term calorie and protein restriction on basal metabolic rate in the C57BL/6 mouse

We are grateful to the animal house staff for looking after the animals. The work was supported by the UK Biotechnology and Biological Sciences Research Council BBSRC (grants BB/G009953/1 and BB/J020028/1) to JRS and SEM. DD was supported by a studentship from the Centre for Genome Enabled Biology and Medicine, Aberdeen, UK, and CG was supported by a BBSRC EastBio studentship. Joint meetings were funded by a BBSRC China partnering award (BB/JO20028/1).Peer reviewedPublisher PD

Transcriptional Pathways Associated with Skeletal Muscle Changes after Spinal Cord Injury and Treadmill Locomotor Training.

The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and corrected with treadmill training. The BMP pathway was differentially activated with early treadmill training as shown by Ingenuity Pathway Analysis. The expression of several muscle mass regulators was modulated by treadmill training, including Fst, Jun, Bmpr2, Actr2b, and Smad3. In addition, key players in fatty acids metabolism (Lpl and Fabp3) responded to both SCI induced inactivity and reloading with training. The decrease in Smad3 and Fst early after the initiation of treadmill training was confirmed by RT-PCR. Our data suggest that TGFβ/Smad3 signaling may be mainly involved in the decrease in muscle mass observed with SCI, while the BMP pathway was activated with treadmill training

Transcriptional Pathways Associated with Skeletal Muscle Changes after Spinal Cord Injury and Treadmill Locomotor Training.

The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and corrected with treadmill training. The BMP pathway was differentially activated with early treadmill training as shown by Ingenuity Pathway Analysis. The expression of several muscle mass regulators was modulated by treadmill training, including Fst, Jun, Bmpr2, Actr2b, and Smad3. In addition, key players in fatty acids metabolism (Lpl and Fabp3) responded to both SCI induced inactivity and reloading with training. The decrease in Smad3 and Fst early after the initiation of treadmill training was confirmed by RT-PCR. Our data suggest that TGFβ/Smad3 signaling may be mainly involved in the decrease in muscle mass observed with SCI, while the BMP pathway was activated with treadmill training