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This study explored the perspective of eight education stakeholders on Critical Race Theory (CRT) and the educational attainment opportunities for African American males in the current system of education in the United States of America. A qualitative research approach was employed using a semi-structured interview protocol. The data gathered from this study revealed that there was a general consensus among participants at an African American Male Empowerment Summit around the favorability and usefulness of Critical Race Theory in understanding the current state of African American males in education.

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

We sought to integrate a brief computer and counseling support intervention into the routine practices of HIV clinics and evaluate effects on patients' viral loads. The project targeted HIV patients in care whose viral loads exceeded 1000 copies/ml at the time of recruitment. Three HIV clinics initiated the intervention immediately, and three other HIV clinics delayed onset for 16 months and served as concurrent controls for evaluating outcomes. The intervention components included a brief computer-based intervention (CBI) focused on antiretroviral therapy adherence; health coaching from project counselors for participants whose viral loads did not improve after doing the CBI; and behavioral screening and palm cards with empowering messages available to all patients at intervention clinics regardless of viral load level. The analytic cohort included 982 patients at intervention clinics and 946 patients at control clinics. Viral loads were assessed at 270 days before recruitment, at time of recruitment, and +270 days later. Results indicated that both the control and intervention groups had significant reductions in viral load, ending with approximately the same viral level at +270 days. There was no evidence that the CBI or the targeted health coaching was responsible for the viral reduction in the intervention group. Results may stem partially from statistical regression to the mean in both groups. Also, clinical providers at control and intervention clinics may have taken action (e.g., conversations with patients, referrals to case managers, adherence counselors, mental health, substance use specialists) to help their patients reduce their viral loads. In conclusion, neither a brief computer-based nor targeted health coaching intervention reduced patients' viral loads beyond levels achieved with standard of care services available to patients at well-resourced HIV clinics.

Biofilms are viscoelastic materials that are a prominent public health problem and a cause of most chronic bacterial infections, in large part due to their resistance to clearance by the immune system. Viscoelastic materials combine both solid-like and fluid-like mechanics, and the viscoelastic properties of biofilms are an emergent property of the intercellular cohesion characterizing the biofilm state (planktonic bacteria do not have an equivalent property). However, how the mechanical properties of biofilms are related to the recalcitrant disease that they cause, specifically to their resistance to phagocytic clearance by the immune system, remains almost entirely unstudied. We believe this is an important gap that is ripe for a large range of investigations. Here we present an overview of what is known about biofilm infections and their interactions with the immune system, biofilm mechanics and their potential relationship with phagocytosis, and we give an illustrative example of one important biofilm-pathogen (Pseudomonas aeruginosa) which is the most-studied in this context. We hope to inspire investment and growth in this relatively-untapped field of research, which has the potential to reveal mechanical properties of biofilms as targets for therapeutics meant to enhance the efficacy of the immune system.

Metal alkylidenes, which are key organometallic intermediates in reactions such as olefination or alkene and alkane metathesis, are typically generated from metal dialkyl compounds [M](CH2R)2 that show distinctively deshielded chemical shifts for their α-carbons. Experimental solid-state NMR measurements combined with DFT/ZORA calculations and a chemical shift tensor analysis reveal that this remarkable deshielding originates from an empty metal d-orbital oriented in the M-Cα-Cα' plane, interacting with the Cα p-orbital lying in the same plane. This π-type interaction inscribes some alkylidene character into Cα that favors alkylidene generation via α-H abstraction. The extent of the deshielding and the anisotropy of the alkyl chemical shift tensors distinguishes [M](CH2R)2 compounds that form alkylidenes from those that do not, relating the reactivity to molecular orbitals of the respective molecules. The α-carbon chemical shifts and tensor orientations thus predict the reactivity of metal alkyl compounds towards alkylidene generation.

This case study presents a detailed description of how community-based environmental education can be used to increase environment awareness and knowledge among migrant children and youth. Data was collected primarily from interviews and learning activities with 454 participants aged 11 to 19 years. The results show that children and youth are aware of environmental problems in their local communities. Environmental problems identified include open defecation, pollution, poor waste management and the use of unsustainable fishing methods. They are also capable of recommending solutions to some of these problems. Solutions recommended include planting more trees, providing waste bins in schools and public places, arresting and prosecuting people who practise open defecation, and public education on the need to stop practices that degrade the environment. The most popular tools recommended for educating children and youth on proper environmental practices and behaviour were dramas and plays. Children and youth thus prefer methods of teaching and communication that are audio-visual, encourage interaction and that keep participants actively involved in the process.

Metallacyclobutanes are an important class of organometallic intermediates, due to their role in olefin metathesis. They can have either planar or puckered rings associated with characteristic chemical and physical properties. Metathesis active metallacyclobutanes have short M-Cα/α' and M···Cβ distances, long Cα/α'-Cβ bond length, and isotropic 13C chemical shifts for both early d0 and late d4 transition metal compounds for the α- and β-carbons appearing at ca. 100 and 0 ppm, respectively. Metallacyclobutanes that do not show metathesis activity have 13C chemical shifts of the α- and β-carbons at typically 40 and 30 ppm, respectively, for d0 systems, with upfield shifts to ca. -30 ppm for the α-carbon of metallacycles with higher d n electron counts (n = 2 and 6). Measurements of the chemical shift tensor by solid-state NMR combined with an orbital (natural chemical shift, NCS) analysis of its principal components (δ11 ≥ δ22 ≥ δ33) with two-component calculations show that the specific chemical shift of metathesis active metallacyclobutanes originates from a low-lying empty orbital lying in the plane of the metallacyclobutane with local π*(M-Cα/α') character. Thus, in the metathesis active metallacyclobutanes, the α-carbons retain some residual alkylidene character, while their β-carbon is shielded, especially in the direction perpendicular to the ring. Overall, the chemical shift tensors directly provide information on the predictive value about the ability of metallacyclobutanes to be olefin metathesis intermediates.

The authors provide an interdisciplinary investigation of student videography for assessment in higher education. Video is becoming a dominant communication modality in our world; school students are taught to create and critique it and educators employ it on-line. Yet the opportunity to include appropriate video-based assessments that capture integrated graduate attributes has been largely missed in higher education. The authors reflect on a health professional student case study which illustrates how video enables students to powerfully demonstrate achievement against learning outcomes: they used filmic techniques to display empathy, patient centred collaboration and interprofessional communication. They also reflect on the barriers to video-based assessment raised by academics. Finally, they call upon leaders in higher education to recognise the utility of multi-media approaches to assessment of complex but critical graduate skills such as communication, digital literacy and interdisciplinarity, in addition to demonstrating the application of disciplinary knowledge to relevant and authentic problems.

Chlorambucil-platinum(IV) prodrugs exhibit multi-mechanistic chemotherapeutic activity with promising anticancer potential. The platinum(II) precursors of the prodrugs have been previously found to induce changes in the microtubule cytoskeleton, specifically actin and tubulin of HT29 colon cells, while chlorambucil alkylates the DNA. These prodrugs demonstrate significant anticancer activity in 2D cell and 3D spheroid viability assays. A notable production of reactive oxygen species has been observed in HT29 cells 72 h post treatment with prodrugs of this type, while the mitochondrial membrane potential was substantially reduced. The cellular uptake of the chlorambucil-platinum(IV) prodrugs, assessed by ICP-MS, confirmed that active transport was the primary uptake mechanism, with platinum localisation identified primarily in the cytoskeletal fraction. Apoptosis and necrosis were observed at 72 h of treatment as demonstrated by Annexin V-FITC/PI assay using flow cytometry. Immunofluorescence measured via confocal microscopy showed significant changes in actin and tubulin intensity and in architecture. Western blot analysis of intrinsic and extrinsic pathway apoptotic markers, microtubule cytoskeleton markers, cell proliferation markers, as well as autophagy markers were studied post 72 h of treatment. The proteomic profile was also studied with a total of 1859 HT29 proteins quantified by mass spectroscopy, with several dysregulated proteins. Network analysis revealed dysregulation in transcription, MAPK markers, microtubule-associated proteins and mitochondrial transport dysfunction. This study confirms that chlorambucil-platinum(IV) prodrugs are candidates with promising anticancer potential that act as multi-mechanistic chemotherapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Conventional intravenous platinum(II) chemotherapy medications, including carboplatin, oxaliplatin and cisplatin, have demonstrated remarkable efficacy in treating several forms of cancer. Also, this therapy is frequently accompanied by toxicity and development of resistance. More potent platinum complexes with fewer side effects may be of benefit. This study compares the in vitro anticancer effect of novel platinum(II) complexes and their platinum(IV)-dihydroxy derivatives with cisplatin to understand the influence of different mechanisms of action on potency. The investigation of these complexes is expected to advance our understanding to support further research into their application as cancer therapeutics. Development of resistance to cisplatin, oxaliplatin and carboplatin remains a challenge for their use as chemotherapies, particularly in breast and colorectal cancer. Here, we compare the anticancer effect of novel complexes [Pt(1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtIIPHENSS), [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII5MESS) and [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII56MESS) and their platinum(IV)-dihydroxy derivatives with cisplatin. Complexes are greater than 11-fold more potent than cisplatin in both 2D and 3D cell line cultures with increased selectivity for cancer cells over genetically stable cells. ICP-MS studies showed cellular uptake occurred through an active transport mechanism with considerably altered platinum concentrations found in the cytoskeleton across all complexes after 24 h. Significant reactive oxygen species generation was observed, with reduced mitochondrial membrane potential at 72 h of treatment. Late apoptosis/necrosis was shown by Annexin V-FITC/PI flow cytometry assay, accompanied by increased sub-G0/G1 cells compared with untreated cells. An increase in S and G2+M cells was seen with all complexes. Treatment resulted in significant changes in actin and tubulin staining. Intrinsic and extrinsic apoptosis markers, MAPK/ERK and PI3K/AKT activation markers, together with autophagy markers showed significant activation of these pathways by Western blot. The proteomic profile investigated post-72 h of treatment identified 1597 MDA−MB−231 and 1859 HT29 proteins quantified by mass spectroscopy, with several differentially expressed proteins relative to no treatment. GO enrichment analysis revealed a statistically significant enrichment of RNA/DNA-associated proteins in both the cell lines and specific additional processes for individual drugs. This study shows that these novel agents function as multi-mechanistic chemotherapeutics, offering promising anticancer potential, and thereby supporting further research into their application as cancer therapeutics. [ABSTRACT FROM AUTHOR]

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Titanium silicalite-1 (TS-1) is a zeolitic material with MFI framework structure, in which 1 to 2 per cent of the silicon atoms are substituted for titanium atoms. It is widely used in industry owing to its ability to catalytically epoxidize olefins with hydrogen peroxide (H.sub.2O.sub.2), leaving only water as a byproduct.sup.1,2; around one million tonnes of propylene oxide are produced each year using this process.sup.3. The catalytic properties of TS-1 are generally attributed to the presence of isolated Ti(iv) sites within the zeolite framework.sup.1. However, despite almost 40 years of experimental and computational investigation.sup.4-10, the structure of these active Ti(iv) sites is unconfirmed, owing to the challenges of fully characterizing TS-1. Here, using a combination of spectroscopy and microscopy, we characterize in detail a series of highly active and selective TS-1 propylene epoxidation catalysts with well dispersed titanium atoms. We find that, on contact with H.sub.2.sup.17O.sub.2, all samples exhibit a characteristic solid-state .sup.17O nuclear magnetic resonance signature that is indicative of the formation of bridging peroxo species on dinuclear titanium sites. Further, density functional theory calculations indicate that cooperativity between two titanium atoms enables propylene epoxidation via a low-energy reaction pathway with a key oxygen-transfer transition state similar to that of olefin epoxidation by peracids. We therefore propose that dinuclear titanium sites, rather than isolated titanium atoms in the framework, explain the high efficiency of TS-1 in propylene epoxidation with H.sub.2O.sub.2. This revised view of the active-site structure may enable further optimization of TS-1 and the industrial epoxidation process. A combination of spectroscopy, microscopy and theoretical calculations shows that the reactivity of titanium silicalite-1 as an epoxidation catalyst is due to the presence of dinuclear titanium sites., Author(s): Christopher P. Gordon [sup.1] , Hauke Engler [sup.2] , Amadeus Samuel Tragl [sup.3] , Milivoj Plodinec [sup.3] , Thomas Lunkenbein [sup.3] , Albrecht Berkessel [sup.2] , Joaquim Henrique Teles [...]

Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions, and duplications within a ∼2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ∼1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harboring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS.

Epidemic modeling suggests that a major scale-up in HIV treatment could have a dramatic impact on HIV incidence. This has led both researchers and policymakers to set a goal of an "AIDS-Free Generation." One of the greatest obstacles to achieving this objective is the number of people with undiagnosed HIV infection. Despite recent innovations, new research strategies are needed to identify, engage, and successfully treat people who are unaware of their infection.