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Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors’ combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.

Natural hydrogen exploration is picking up around the world while the geogenic hydrogen system is still a Frontier science. Natural hydrogen seepage can occur in the form of a sub-circular surface feature named by some authors “fairy circles.” Numerous hydrogen seep-alike surface features are visible from the sky in Australia but can be difficult to distinguish from the many salt lakes. In this study, we combined literature review, remote sensing, field and lab measurements (soil gas sampling, X-Ray diffraction, salinity) to uncover a potential hydrogen system and its differences with the salt lakes in the Grass Patch area in Western Australia. The local geology shows a good potential to generate hydrogen. Study of the surface geology and Digital Elevation Model showed that salt lakes are static old features influenced by the soil composition and long-term climatic trend whereas potential hydrogen seeps have recently appeared. This study soil-gas sampling method includes a monitoring procedure compatible with time series measurements via a portable gas analyser, getting rid of artificially produced hydrogen. Low hydrogen values (

Instructors’ interactions can foster knowledge sharing around teaching and the use of research-based instructional strategies (RBIS). Coordinated teaching presents an impetus for instructors’ interactions and creates opportunities for instructional improvement but also potentially limits an instructor’s autonomy. In this study, we sought to characterize the extent of coordination present in introductory undergraduate courses and to understand how departments and instructors implement and experience course coordination. We examined survey data from 3,641 chemistry, mathematics, and physics instructors at three institution types and conducted follow-up interviews with a subset of 24 survey respondents to determine what types of coordination existed, what factors led to coordination, how coordination constrained instruction, and how instructors maintained autonomy within coordinated contexts. We classified three approaches to coordination at both the overall course and course component levels: independent (i.e., not coordinated), collaborative (decision-making by instructor and others), controlled (decision-making by others, not instructor). Two course components, content coverage and textbooks, were highly coordinated. These curricular components were often decided through formal or informal committees, but these decisions were seldom revisited. This limited the ability for instructors to participate in the decision-making process, the level of interactions between instructors, and the pedagogical growth that could have occurred through these conversations. Decision-making around the other two course components, instructional methods and exams, was more likely to be independently determined by the instructors, who valued this autonomy. Participants in the study identified various ways in which collaborative coordination of courses can promote but also inhibit pedagogical growth. Our findings indicate that the benefits of collaborative course coordination can be realized when departments develop coordinated approaches that value each instructor’s autonomy, incorporate shared and ongoing decision-making, and facilitate collaborative interactions and knowledge sharing among instructors.

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments is one of the major challenges of this disease. The DNA helicase BLM, whose depletion or mutation causes the cancer-prone Bloom’s syndrome (BS), is a central factor of DNA damage repair by homologous recombination (HR) and genomic stability maintenance. Using independent cohorts of MM patients, we identified that high expression of BLM is associated with a poor outcome with a significant enrichment in replication stress signature. We provide evidence that chemical inhibition of BLM by the small molecule ML216 in HMCLs (human myeloma cell lines) leads to cell cycle arrest and increases apoptosis, likely by accumulation of DNA damage. BLM inhibition synergizes with the alkylating agent melphalan to efficiently inhibit growth and promote cell death in HMCLs. Moreover, ML216 treatment re-sensitizes melphalan-resistant cell lines to this conventional therapeutic agent. Altogether, these data suggest that inhibition of BLM in combination with DNA damaging agents could be of therapeutic interest in the treatment of MM, especially in those patients with high BLM expression and/or resistance to melphalan.

Active learning pedagogies are shown to enhance the outcomes of students, particularly in disciplines known for high attrition rates. Despite the demonstrated benefits of active learning, didactic lecture continues to predominate in science, technology, engineering, and mathematics (STEM) courses. Change agents and professional development programs have historically placed emphasis on develop–disseminate efforts for the adoption of research-based instructional strategies (RBIS). With numerous reported barriers and motivators for trying out and adopting active learning, it is unclear to what extent these factors are associated with adoption of RBIS and the effectiveness of change strategies. We present the results of a large-scale, survey-based study of introductory chemistry, mathematics, and physics instructors and their courses in the United States. Herein, we evaluate the association of 17 malleable factors with the tryout and adoption of RBIS. Multilevel logistic regression analyses suggest that several contextual, personal, and teacher thinking factors are associated with different stages of RBIS adoption. These results are also compared with analogous results evaluating the association of these factors with instructors’ time spent lecturing. We offer actionable implications for change agents to provide targeted professional development programming and for institutional leaders to influence the adoption of active learning pedagogies in introductory STEM courses.

The purpose of this study was to expand the mutation spectrum by searching the causative mutations in nine Lebanese families with Usher syndrome (USH) using whole-exome sequencing. The pathogenicity of candidate mutations was first evaluated according to their frequency, conservation, and in silico prediction tools. Then, it was confirmed via Sanger sequencing, followed by segregation analysis. Finally, a meta-analysis was conducted to calculate the prevalence of USH genes in the Lebanese population. Three missense mutations, two splice site mutations, and one insertion/deletion were detected in eight of the families. Four of these variants were novel: c.5535C > A; p.(Asn1845Lys) in exon 41 of CDH23, c.7130G > A; p.(Arg2377Gln) in exon 32 of ADGRV1, c.11390-1G > A in USH2A, and c.3999–6A > G in PCDH15. All the identified mutations were shown to be likely disease-causing through our bioinformatics analysis and co-segregated with the USH phenotype. The mutations were classified according to the ACMG standards. Finally, our meta-analysis showed that the mutations in ADGRV1, USH2A, and CLRN1 are the most prevalent and responsible for approximately 75% of USH cases in Lebanon. Of note, the frequency USH type 3 showed a relatively high incidence (23%) compared to the worldwide prevalence, which is around 2–4%. In conclusion, our study has broadened the mutational spectrum of USH and showed a high heterogeneity of this disease in the Lebanese population.

The pathways from trauma—via dissociation—to psychosis have been thoroughly tested and evidenced, but what has received less attention has been the social pathways—via dissociation—to psychosis. Often social factors are more commonly linked to other influences, e.g., to appraisals and the creation of negative schema in cognitive models, or to unsupportive caregiving experiences where there is high “expressed emotion.” However, evidence is now emerging that negative social rank experiences, such as being excluded or shamed, may themselves have dissociative properties, which poses intriguing questions as to how trauma pathways and social pathways might interact. This article reviews the state of knowledge in trauma and social pathways to psychosis and then considers the potential mechanisms and the relationships between them, specifically (i) dissociation, (ii) attachment, and (iii) social rank. Recommendations are suggested for future modeling and testing of three-way interactions (dissociation × attachment × social rank) in the pathway from trauma to psychosis.

Cytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (α-IL-6R mAbs). We present data showing that direct neutralization of IL-6 with an α-IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 h of challenge and repeated every 72 h. A similar effect was seen in mice treated with the same dose of α-IL-6R mAb when the treatment was delayed 48 h post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.

This paper presents an outline of voice-hearing phenomenology in the context of evolutionary mechanisms for self- and social- monitoring. Special attention is given to evolved systems for monitoring dominant-subordinate social roles and relationships. These provide information relating to the interpersonal motivation of others, such as neutral, friendly or hostile, and thus the interpersonal threat, versus safe, social location. Individuals who perceive themselves as subordinate and dominants as hostile are highly vigilant to down-rank threat and use submissive displays and social spacing as basic defenses. We suggest these defense mechanisms are especially attuned in some individuals with voices, in which this fearful-subordinate – hostile-dominant relationship is played out. Given the evolved motivational system in which voice-hearers can be trapped, one therapeutic solution is to help them switch into different motivational systems, particularly those linked to social caring and support, rather than hostile competition. Compassion focused therapy (CFT) seeks to produce such motivational shifts. Compassion focused therapy aims to help voice-hearers, (i) notice their threat-based (dominant-subordinate) motivational systems when they arise, (ii) understand their function in the context of their lives, and (iii) shift into different motivational patterns that are orientated around safeness and compassion. Voice-hearers are supported to engage with biopsychosocial components of compassionate mind training, which are briefly summarized, and to cultivate an embodied sense of a compassionate self-identity. They are invited to consider, and practice, how they might wish to relate to themselves, their voices, and other people, from the position of their compassionate self. This paper proposes, in line with the broader science of compassion and CFT, that repeated practice of creating internal patterns of safeness and compassion can provide an optimum biopsychosocial environment for affect-regulation, emotional conflict-resolution, and therapeutic change. Examples of specific therapeutic techniques, such as chair-work and talking with voices, are described to illustrate how these might be incorporated in one-to-one sessions of CFT.

Background: Peer-led interventions have been applied to prevent various health behavior problems and may be an important complement to individual-level suicide prevention approaches. Sources of Strength trains student “peer leaders” in secondary schools to conduct prevention activities that encourage other students to build healthy social bonds and strengthen help-seeking norms. Prior work examining diffusion of peer-led programs has focused on youths' closeness to peer leaders but minimally on other factors such as connections to adults and suicidal behavior.Methods: We examined implementation and dissemination of Sources of Strength in 20 schools. Over 1 year 533 students were trained as peer leaders and 3,730 9th−12th graders completed baseline surveys assessing friendships and adults at school, and suicidal thoughts/behaviors; and end-of-year surveys reporting intervention exposure: viewed poster/video, attended presentation, direct peer communication, and activity participation. Chi-square tests compared exposure rates by student and network characteristics. Multi-level logistic regression models tested predictors of exposure across individual and school-level characteristics.Results: Exposure to the intervention varied greatly by school and by individual student characteristics and network position. Training more peer leaders increased school-wide exposure for all modalities except presentation (Bs 0.06–0.10, p's < 0.05). In multivariate models, exposure was consistently higher for students closer to peer leaders in the friendship network (ORs 1.13–1.54, p's < 0.05) and students who named more trusted adults (ORs 1.08–1.16, p's < 0.001); and lower for males (ORs 0.56–0.83, p's < 0.05). In multivariate models, training more students as peer leaders predicted exposure to poster-video and direct peer communication in larger schools (OR = 3.34 and 2.87, respectively). Network characteristics influenced exposure similarly for students with suicidal thoughts and behaviors.Discussion: Our findings confirm prior work showing the importance of personal affiliations to peer leaders and natural networks as a medium for diffusion of peer-led prevention efforts. We build on that work by showing independent effects of closeness to adults at school and number of peer leaders trained. There is a need to strategically select peer leaders to maximize closeness to students school-wide, particularly in larger schools. Additional work is required for Sources of Strength to devise messaging strategies to engage males and students isolated from adults at school.