Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors

<p>Abstract</p> <p>Background</p> <p>Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.</p> <p>Results</p> <p>Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca²⁺]_ifollowing exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-<b>[R]</b>) or its inactive enantiomer (CCR2 RA-<b>[S]</b>) by intraperitoneal (i.p.) injection. CCR2 RA-[<b>R</b>] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.</p> <p>Conclusion</p> <p>These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.</p

Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors

Discovery of small-molecule degraders that activate ubiquitin ligase–mediated ubiquitination and degradation of targeted oncoproteins in cancer cells has been an elusive therapeutic strategy. Here, we report a cancer cell–based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007’s binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007’s binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin ligase complex, where SUMO1 was ubiquitinated in several of human cancer cells. HB007 selectively degraded SUMO1 in patient tumor–derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the animals. This cancer cell–based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins

The influence of technology on Higher Education in Morocco, Case study “Ben M’sick faculty of sciences, University Hassan II, Casablanca

This study relies on an experiment with faculty of sciences Ben M'sick Casablanca students from Hassan II University in Morocco, which offers online evaluation on a digital device within the context of university education, with the aim of boosting students' practices using new technological instruments

Virtual Exchange Interactive Technology in the Classroom Casa study, University Hassan II, faculty of sciences, Casablanca, Morocco

This study investigates the efficiency of virtual exchange as a language learning tool in a Master's degree program at the University Hassan II, Faculty of Sciences, Casablanca, Morocco. 27 participants in the study had previously used virtual exchange as a tool for language learning. Pre-test and post-test surveys were used to gather information on the participants' attitudes toward virtual exchange. Ten Likert scale items and two open-ended questions were included in the surveys. In a four-week virtual exchange program with a partner institution, the participants took part in weekly online discussions while utilizing a variety of technological tools. Descriptive statistics were used in the study to analyze the Likert scale items, and thematic analysis was used to analyze the open-ended questions. The findings indicated that participants had a favorable attitude toward the use of virtual exchange as a language learning tool and that their communication and intercultural competence had improved. The participants found that the virtual exchange program was a very efficient way to increase their knowledge of foreign cultures and their language skills. Following a thematic analysis, four overarching themes emerged: "motivation and engagement," "intercultural competence and communication," "collaboration and teamwork," and "technology and online learning." The themes highlight how virtual exchange helps participants develop their motivation, teamwork, and cross-cultural communication skills. Participants expressed a high level of satisfaction with the virtual exchange program's use of interactive technology. This study offers useful information for educators who want to incorporate virtual exchange into their methods of teaching languages. According to the study, virtual exchange can improve language learning and cross-cultural comprehension while also giving students the chance to hone their global competence and intercultural communication skills. The results have implications for pedagogy, curriculum development, and the use of technology in language teaching and learning. The potential of virtual exchange as a useful tool for language learning and cross-cultural communication is highlighted by this study's conclusion. Through meaningful and real-world interactions with native speakers of the target language, virtual exchange programs can help students advance their language skills and intercultural awareness

English medium instruction in Moroccan universities: Case study University Hassan II, Casablanca, Morocco

Morocco is a multi-lingual country with varying degrees of language influence and prominence, so it's unclear what its linguistic policies are. Arabic and Tamazight are the two official languages of the country. Despite the end of French colonial strategy in the twentieth century, French has been utilized as the nation's second language with enormous importance in commerce, diplomacy, and higher education. English and Spanish continue to be foreign languages utilized in a variety of circumstances for a variety of purposes. French is being utilized as a language of instruction at Moroccan Universities. Since English is gradually becoming the language of science and technology, there have been various proposals to replace French. Using a survey questionnaire, this study evaluates the views of doctorate students, Master students and Bachelor students who belong to the faculty of sciences Ben M’sick about the use of English as a medium of instruction. The findings show that students significantly choose English as a medium of education. Some of the reasons for this choice include the requirement to read and cite indexed journal articles in their dissertations, the desire to pursue postgraduate studies overseas, and the desire to have a competitive advantage in the job market

Responses of microbial activity in hyporheic pore water to biogeochemical changes in a drying headwater stream

Microbial heterotrophic activity is a major driver of nutrient and organic matter processing in the hyporheic zone of headwater streams. Additionally, the hyporheic zone might provide refuge for microbes when surface flow ceases during drought events. We investigated chemical (organic and inorganic nutrients) and microbiological parameters (bacterial cell concentration, live-dead ratios, and extracellular enzyme activities) of surface and interstitial pore water in a period of progressive surface‐hyporheic disconnection due to summer drying. The special situation of the chosen study reach, where groundwater mixing is impeded by the bedrock forming a natural channel filled with sediment, allowed as to study the transformation of these parameters along hyporheic flow paths. The chemical composition of the hyporheic pore water reflected the connectivity with the surface water, as expressed in the availability of nitrate and oxygen. Conversely, microbiological parameters in all hyporheic locations were different from the surface waters, suggesting that the microbial activity in the water changes rapidly once the water enters the hyporheic zone. This feature was principally manifested in higher live-dead ratios and lower leucine aminopeptidase (an activity related to nitrogen acquisition) in the hyporheic pore waters. Overall, bacterial cell concentration and extracellular enzyme activities increased along hyporheic flow paths, with a congruent decrease in inorganic nutrients and dissolved organic matter quantity and apparent molecular size. Our findings show two important functions of the hyporheic zone during drought: (1) deeper (−50 cm) water‐saturated layers can act as a refuge for microbial activity; and (2) the hyporheic zone shows high rates of carbon and nitrogen turnover when water residence times are longer during drought. These rates might be even enhanced by an increase in living microbes in the remaining moist locations of the hyporheic zone