Substituent Effects on Torsional Strain in Cyclopentene Derivatives: A Computational Study.

Density functional theory calculations were used to create a library of ring strain energies (RSEs) for 73 cyclopentene derivatives with potential use as monomers for ring-opening metathesis polymerization (ROMP). An overarching goal was to probe how substituent choice may influence torsional strain, which is the driving force for ROMP and one of the most understudied types of RSEs. Potential trends investigated include substituent location, size, electronegativity, hybridization, and steric bulk. Using traditional and recently developed homodesmotic equations, our results show that the size and substitution (bulk) of the atom directly bonded to the ring have the greatest influence on torsional RSE. A complex interplay between bond length, bond angle, and dihedral angle dictates the relative eclipsed conformations between the substituent and its neighboring hydrogens and was found to be responsible for the notable differences in RSEs. Furthermore, substituents placed on the homoallylic position resulted in higher RSEs than the same substituent placed on the allylic position due to increased eclipsing interactions. Different levels of theory were also assessed, and it was determined that consideration of electron correlation in calculations increased RSEs by ∼2-5 kcal mol-1. Further increasing the level of theory did not significantly change RSEs, indicating that the increased computational cost and time may not be necessary for improved accuracy.

Unification of Road Scene Segmentation Strategies Using Multistream Data and Latent Space Attention.

Road scene understanding, as a field of research, has attracted increasing attention in recent years. The development of road scene understanding capabilities that are applicable to real-world road scenarios has seen numerous complications. This has largely been due to the cost and complexity of achieving human-level scene understanding, at which successful segmentation of road scene elements can be achieved with a mean intersection over union score close to 1.0. There is a need for more of a unified approach to road scene segmentation for use in self-driving systems. Previous works have demonstrated how deep learning methods can be combined to improve the segmentation and perception performance of road scene understanding systems. This paper proposes a novel segmentation system that uses fully connected networks, attention mechanisms, and multiple-input data stream fusion to improve segmentation performance. Results show comparable performance compared to previous works, with a mean intersection over union of 87.4% on the Cityscapes dataset.

Expanded [23]-Helicene with Exceptional Chiroptical Properties via an Iterative Ring-Fusion Strategy.

Expanded helicenes are an emerging class of helical nanocarbons composed of alternating linear and angularly fused rings, which give rise to an internal cavity and a large diameter. The latter is expected to impart exceptional chiroptical properties, but low enantiomerization free energy barriers (ΔG‡e) have largely precluded experimental interrogation of this prediction. Here, we report the syntheses of expanded helicenes containing 15, 19, and 23 rings on the inner helical circuit, using two iterations of an Ir-catalyzed, site-selective [2 + 2 + 2] reaction. This series of compounds displays a linear relationship between the number of rings and ΔG‡e. The expanded [23]-helicene, which is 7 rings longer than any known single carbohelicene and among the longest known all-carbon ladder oligomers, exhibits a ΔG‡e that is high enough (29.2 ± 0.1 kcal/mol at 100 °C in o-DCB) to halt enantiomerization at ambient temperature. This enabled the isolation of enantiopure samples displaying circular dichroism dissymmetry factors of ±0.056 at 428 nm, which are ≥1.7× larger than values for previously reported classical and expanded helicenes. Computational investigations suggest that this improved performance is the result of both the increased diameter and length of the [23]-helicene, providing guiding design principles for high dissymmetry molecular materials.

Zwitterions Raise the Dielectric Constant of Soft Materials.

Materials exhibiting high dielectric constants (ϵ_{s}) are critical for energy storage and actuators. A successful approach to increase ϵ_{s} is to incorporate polar additives (with high ϵ_{s}) but controlling the resulting dispersion state is difficult. Here, we show that significant ϵ_{s} increases are realized by adding zwitterions, which are small molecules with a cation and an anion separated by covalent bonds. The increase in ϵ_{s} with zwitterion addition is attributed to the large molecular dipole of zwitterions, ranging from 35 to 41 D, as experimentally quantified and confirmed using density functional theory. At elevated zwitterion concentration in an ethylene glycol medium, there is a nonlinear increase of ϵ_{s} that eventually saturates due to the strong Coulombic interactions between zwitterions. The presented work provides a fundamental molecular understanding of why zwitterions are effective additives in boosting ϵ_{s} in soft materials.

Operationalising the "One Health" approach in India: facilitators of and barriers to effective cross-sector convergence for zoonoses prevention and control.

BACKGROUND: There is a strong policy impetus for the One Health cross-sectoral approach to address the complex challenge of zoonotic diseases, particularly in low/lower middle income countries (LMICs). Yet the implementation of this approach in LMIC contexts such as India has proven challenging, due partly to the relatively limited practical guidance and understanding on how to foster and sustain cross-sector collaborations. This study addresses this gap by exploring the facilitators of and barriers to successful convergence between the human, animal and environmental health sectors in India. METHODS: A mixed methods study was conducted using a detailed content review of national policy documents and in-depth semi-structured interview data on zoonotic disease management in India. In total, 29 policy documents were reviewed and 15 key informant interviews were undertaken with national and state level policymakers, disease managers and experts operating within the human-animal-environment interface of zoonotic disease control. RESULTS: Our findings suggest that there is limited policy visibility of zoonotic diseases, although global zoonoses, especially those identified to be of pandemic potential by international organisations (e.g. CDC, WHO and OIE) rather than local, high burden endemic diseases, have high recognition in the existing policy agenda setting. Despite the widespread acknowledgement of the importance of cross-sectoral collaboration, a myriad of factors operated to either constrain or facilitate the success of cross-sectoral convergence at different stages (i.e. information-sharing, undertaking common activities and merging resources and infrastructure) of cross-sectoral action. Importantly, participants identified the lack of supportive policies, conflicting departmental priorities and limited institutional capacities as major barriers that hamper effective cross-sectoral collaboration on zoonotic disease control. Building on existing informal inter-personal relationships and collaboration platforms were suggested by participants as the way forward. CONCLUSION: Our findings point to the importance of strengthening existing national policy frameworks as a first step for leveraging cross-sectoral capacity for improved disease surveillance and interventions. This requires the contextual adaptation of the One Health approach in a manner that is sensitive to the underlying socio-political, institutional and cultural context that determines and shapes outcomes of cross-sector collaborative arrangements.

A 62-year-old man with new-onset bullae.

Cutaneous blisters and/or bullae can occur in autoimmune disorders, infections, genetic diseases, and drug hypersensitivity. We present the case of a 62-year-old man with two autoimmune conditions who was admitted for antibiotic treatment of a lower extremity infection and suddenly developed a bullous rash. His physical examination was significant for tense, bullous lesions that involved his chin, palms, and inner thighs. Narrowing the differential diagnosis for patients with blistering skin lesions is imperative for timely and appropriate management.

ReCorDE: a framework for identifying drug classes targeting shared vulnerabilities with applications to synergistic drug discovery.

Cancer is typically treated with combinatorial therapy, and such combinations may be synergistic. However, discovery of these combinations has proven difficult as brute force combinatorial screening approaches are both logistically complex and resource-intensive. Therefore, computational approaches to augment synergistic drug discovery are of interest, but current approaches are limited by their dependencies on combinatorial drug screening training data or molecular profiling data. These dataset dependencies can limit the number and diversity of drugs for which these approaches can make inferences. Herein, we describe a novel computational framework, ReCorDE (Recurrent Correlation of Drugs with Enrichment), that uses publicly-available cell line-derived monotherapy cytotoxicity datasets to identify drug classes targeting shared vulnerabilities across multiple cancer lineages; and we show how these inferences can be used to augment synergistic drug combination discovery. Additionally, we demonstrate in preclinical models that a drug class combination predicted by ReCorDE to target shared vulnerabilities (PARP inhibitors and Aurora kinase inhibitors) exhibits class-class synergy across lineages. ReCorDE functions independently of combinatorial drug screening and molecular profiling data, using only extensive monotherapy cytotoxicity datasets as its input. This allows ReCorDE to make robust inferences for a large, diverse array of drugs. In conclusion, we have described a novel framework for the identification of drug classes targeting shared vulnerabilities using monotherapy cytotoxicity datasets, and we showed how these inferences can be used to aid discovery of novel synergistic drug combinations.

Sequence-Directed Covalent Protein-RNA Linkages in a Single Step Using Engineered HUH-Tags.

Replication-initiating HUH-endonucleases (Reps) are enzymes that form covalent bonds with single-stranded DNA (ssDNA) in a sequence specific manner to initiate rolling circle replication. These nucleases have been co-opted for use in biotechnology as sequence specific protein-ssDNA bioconjugation fusion partners dubbed 'HUH-tags'. Here, we describe the engineering and in vitro characterization of a series of laboratory evolved HUH-tags capable of forming robust sequence-directed covalent bonds with unmodified RNA substrates. We show that promiscuous Rep-RNA interaction can be enhanced through directed evolution from nearly undetectable levels in wildtype enzymes to robust reactivity in final engineered iterations. Taken together, these engineered HUH-tags represent a promising platform for enabling site-specific protein-RNA covalent bioconjugation in vitro, potentially mediating a host of new applications and offering a valuable addition to the HUH-tag repertoire.

Hydrogen Sulfide Delivery to Enhance Bone Tissue Engineering Cell Survival.

Though crucial for natural bone healing, local calcium ion (Ca2+) and phosphate ion (Pi) concentrations can exceed the cytotoxic limit leading to mitochondrial overload, oxidative stress, and cell death. For bone tissue engineering applications, H2S can be employed as a cytoprotective molecule to enhance mesenchymal stem cell (MSC) tolerance to cytotoxic Ca2+/Pi concentrations. Varied concentrations of sodium hydrogen sulfide (NaSH), a fast-releasing H2S donor, were applied to assess the influence of H2S on MSC proliferation. The results suggested a toxicity limit of 4 mM for NaSH and that 1 mM of NaSH could improve cell proliferation and differentiation in the presence of cytotoxic levels of Ca2+ (32 mM) and/or Pi (16 mM). To controllably deliver H2S over time, a novel donor molecule (thioglutamic acid-GluSH) was synthesized and evaluated for its H2S release profile. Excitingly, GluSH successfully maintained cytoprotective level of H2S over 7 days. Furthermore, MSCs exposed to cytotoxic Ca2+/Pi concentrations in the presence of GluSH were able to thrive and differentiate into osteoblasts. These findings suggest that the incorporation of a sustained H2S donor such as GluSH into CaP-based bone graft substitutes can facilitate considerable cytoprotection, making it an attractive option for complex bone regenerative engineering applications.

Lestaurtinib's antineoplastic activity converges on JAK/STAT signaling to inhibit advanced forms of therapy resistant ovarian cancer.

Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited JNK and ERK activity, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer. Statement of significance: Lestaurtinib is a novel inhibitor of ovarian cancer, including chemotherapy- and PARPi-resistant models, that acts through robust inhibition of the JAK/STAT pathway and synergizes with standard-of-care agents at clinically relevant concentrations.

West Nile virus T-cell ligand sequences shared with other flaviviruses: a multitude of variant sequences as potential altered peptide ligands.

Phylogenetic relatedness and cocirculation of several major human pathogen flaviviruses are recognized as a possible cause of deleterious immune responses to mixed infection or immunization and call for a greater understanding of the inter-Flavivirus protein homologies. This study focused on the identification of human leukocyte antigen (HLA)-restricted West Nile virus (WNV) T-cell ligands and characterization of their distribution in reported sequence data of WNV and other flaviviruses. H-2-deficient mice transgenic for either A2, A24, B7, DR2, DR3, or DR4 HLA alleles were immunized with overlapping peptides of the WNV proteome, and peptide-specific T-cell activation was measured by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays. Approximately 30% (137) of the WNV proteome peptides were identified as HLA-restricted T-cell ligands. The majority of these ligands were conserved in ∼≥88% of analyzed WNV sequences. Notably, only 51 were WNV specific, and the remaining 86, chiefly of E, NS3, and NS5, shared an identity of nine or more consecutive amino acids with sequences of 64 other flaviviruses, including several major human pathogens. Many of the shared ligands had an incidence of >50% in the analyzed sequences of one or more of six major flaviviruses. The multitude of WNV sequences shared with other flaviviruses as interspecies variants highlights the possible hazard of defective T-cell activation by altered peptide ligands in the event of dual exposure to WNV and other flaviviruses, by either infection or immunization. The data suggest the possible preferred use of sequences that are pathogen specific with minimum interspecies sequence homology for the design of Flavivirus vaccines.

Watson-Crick Base-Pairing Requirements for ssDNA Recognition and Processing in Replication-Initiating HUH Endonucleases.

Replication-initiating HUH endonucleases (Reps) are sequence-specific nucleases that cleave and rejoin single-stranded DNA (ssDNA) during rolling-circle replication. These functions are mediated by covalent linkage of the Rep to its substrate post cleavage. Here, we describe the structures of the endonuclease domain from the Muscovy duck circovirus Rep in complex with its cognate ssDNA 10-mer with and without manganese in the active site. Structural and functional analyses demonstrate that divalent cations play both catalytic and structural roles in Reps by polarizing and positioning their substrate. Further structural comparisons highlight the importance of an intramolecular substrate Watson-Crick (WC) base pairing between the -4 and +1 positions. Subsequent kinetic and functional analyses demonstrate a functional dependency on WC base pairing between these positions regardless of the pair's identity (i.e., A·T, T·A, G·C, or C·G), highlighting a structural specificity for substrate interaction. Finally, considering how well WC swaps were tolerated in vitro, we sought to determine to what extent the canonical -4T·+1A pairing is conserved in circular Rep-encoding single-stranded DNA viruses and found evidence of noncanonical pairings in a minority of these genomes. Altogether, our data suggest that substrate intramolecular WC base pairing is a universal requirement for separation and reunion of ssDNA in Reps. IMPORTANCE Circular Rep-encoding single-stranded DNA (CRESS-DNA) viruses are a ubiquitous group of viruses that infect organisms across all domains of life. These viruses negatively impact both agriculture and human health. All members of this viral family employ a multifunctional nuclease (Rep) to initiate replication. Reps are structurally similar throughout this family, making them targets of interest for viral inhibition strategies. Here, we investigate the functional dependencies of the Rep protein from Muscovy duck circovirus for ssDNA interaction. We demonstrate that this Rep requires an intramolecular Watson-Crick base pairing for origin of replication (Ori) recognition and interaction. We show that noncognate base pair swaps are well tolerated, highlighting a local structural specificity over sequence specificity. Bioinformatic analysis found that the vast majority of CRESS-DNA Oris form base pairs in conserved positions, suggesting this pairing is a universal requirement for replication initiation in the CRESS-DNA virus family.

Enhancement of DNA vaccine efficacy by targeting the xenogeneic human chorionic gonadotropin, survivin and vascular endothelial growth factor receptor 2 combined tumor antigen to the major histocompatibility complex class II pathway.

BACKGROUND: A number of strategies have been used to improve the efficacy of the DNA vaccine for the treatment of tumors. These strategies, ranging from activating CD4+ T cell, manipulating antigen presentation and/or processing to anti-angiogenesis, focus on one certain aspect in the functioning of the vaccine. Therefore, their combination is necessary for rational DNA vaccines design by synergizing different regimens and overcoming the limitations of each strategy. METHODS: A DNA fragment (HSV) encoding the C terminal 37 amino acids of human chorionic gonadotropin ß chain (hCGß), 5 different HLA-restricted cytotoxic T lymphocyte epitopes from human survivin and the third and fourth extracellular domains of vascular endothelial growth factor receptor 2 (VEGFR2) was inserted into the sequence between the luminal and transmembrane domain of human lysosome-associated membrane protein-1 cDNA for the construction of a novel DNA vaccine. RESULTS: This novel vaccine, named p-L/HSV, has a potent antitumor effect on the LL/2 lung carcinoma model in syngeneic C57BL/6 mice. The immunologic mechanism involved in the antitumor effect referred to the activation of both cellular and humoral immune response. In addition, the tumor vasculature was abrogated as observed by immunohistochemistry in p-L/HSV immunized mice. Furthermore, the immunized mice received an additional boost with p-L/HSV 6 months later and showed a strong immune recall response. CONCLUSIONS: The present study indicates that the strategies of combining antitumor with antiangiogenesis and targeting the tumor antigen to the major histocompatibility complex class II pathway cooperate well. Such a study may shed new light on designing vaccine for cancer in the future.

Coexpressed RIG-I agonist enhances humoral immune response to influenza virus DNA vaccine.

Increasing levels of plasmid vector-mediated activation of innate immune signaling pathways is an approach to improve DNA vaccine-induced adaptive immunity for infectious disease and cancer applications. Retinoic acid-inducible gene I (RIG-I) is a critical cytoplasmic double-stranded RNA (dsRNA) pattern receptor required for innate immune activation in response to viral infection. Activation of RIG-I leads to type I interferon (IFN) and inflammatory cytokine production through interferon promoter stimulator 1 (IPS-1)-mediated activation of interferon regulatory factor 3 (IRF3) and NF-κB signaling. DNA vaccines coexpressing antigen and an expressed RNA (eRNA) RIG-I agonist were made, and the effect of RIG-I activation on antigen-specific immune responses to the encoded antigen was determined. Plasmid vector backbones expressing various RIG-I ligands from RNA polymerase III promoters were screened in a cell culture assay for RIG-I agonist activity, and optimized, potent RIG-I ligands were developed. One of these, eRNA41H, combines (i) eRNA11a, an immunostimulatory dsRNA expressed by convergent transcription, with (ii) adenovirus VA RNAI. eRNA41H was integrated into the backbone of DNA vaccine vectors expressing H5N1 influenza virus hemagglutinin (HA). The resultant eRNA vectors potently induced type 1 IFN production in cell culture through RIG-I activation and combined high-level HA antigen expression with RNA-mediated type I IFN activation in a single plasmid vector. The eRNA vectors induced increased HA-specific serum antibody binding avidity after naked DNA intramuscular prime and boost delivery in mice. This demonstrates that DNA vaccine potency may be augmented by the incorporation of RIG-I-activating immunostimulatory RNA into the vector backbone.

Long-term SARS-CoV-2-specific and cross-reactive cellular immune responses correlate with humoral responses, disease severity, and symptomatology.

BACKGROUND: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses. METHODS: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFNγ) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array. RESULTS: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFNγ and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFNγ in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion. CONCLUSION: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses.

Highly conserved influenza A sequences as T cell epitopes-based vaccine targets to address the viral variability.

Vaccines are the only proven effective method for prevention of human infectious diseases. Almost all traditional vaccines require activating immunological memory B cells to secrete neutralizing antibodies against invading pathogens. The complication with influenza viruses is the high viral mutation rate that results in immune escape through modification of the B cell epitopes. Studies of T-cell immunity to influenza infection provide an alternative vaccine strategy based on highly conserved T-cell epitopes. In this review, we discuss the importance of T cell-mediated immunity in influenza infection and the need for a targeted vaccine approach focused on highly conserved T-cell epitopes to mitigate immune escape. We propose 15 highly conserved pan-influenza sequences as possible T cell epitopes-based vaccine targets for broad protection and lasting immunity against variant influenza strains.

The technologically-mediated self: reflections on the container and field of telecommunications.

This paper contains reflections on the use of the imagination in technologically-mediated therapy and analysis. As part of the individuation process the psyche is seen as needing to adapt to new technological ways of communicating. The notion of a technologically-mediated self is posited describing a self which can only be apprehended through, and by, the use of telecommunications. This self is seen as identical to the in-person self, a subset, or superset of it. There is a revisioning of our notions of the container and the field in this work performed through technological-mediation. The need to engage the imagination in approaching this kind of work is emphasized in order to create an imaginal play-space in which the body will be deeply affected. Some thoughts on how the process of individuation might look through such analytic work is presented.

Cet article contient des réflexions sur l'utilisation de l'imagination dans la thérapie et l'analyse pratiquées par la médiation de la technologie. En tant que partie intégrante du processus d'individuation, la psyché est considérée comme devant s'adapter à de nouvelles façons de communiquer, basées sur la technologie. La notion d'un soi atteint par la médiation de la technologie est postulée, un soi qui ne peut être appréhendé que par le biais de l'utilisation des télécommunications. Ce soi est considéré comme étant identique au soi dans la personne; un sous-ensemble, ou un sur-ensemble. L'article présente une révision de nos notions de contenant et de champ quand on travaille avec la médiation de la technologie. Il souligne le besoin de mobiliser l'imagination quand on aborde ce genre de travail afin de créer un espace imaginal de jeu dans lequel le corps sera profondément affecté. Il propose quelques pensées sur comment le processus d'individuation pourrait se présenter au travers d'un tel travail analytique.

El presente trabajo contiene reflexiones sobre el uso de la imaginación en terapia y análisis mediado por la tecnología. Como parte del proceso de individuación, la psique necesita adaptarse a nuevos modos tecnológicos de comunicación. Se propone la noción de un self mediado-tecnológicamente, al describir a un self que solamente puede ser aprehendido a través y por el uso de las telecomunicaciones. Este self es considerado como idéntico al self presencial, una parte o una versión mayor del mismo. Se presenta una revisión de nuestras nociones acerca del campo y del espacio de contención en este trabajo realizado a través de la mediación tecnológica. Se enfatiza la necesidad de comprometer a la imaginación al abordar esta forma de trabajo, para crear un espacio de juego-imaginal, en el cual el cuerpo estará profundamente afectado. Se presentan algunas reflexiones acerca de cómo podría mirarse el proceso de individuación a través de dicho trabajo.

Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia.

Despite the success of the combination of venetoclax with the hypomethylating agents (HMA) decitabine or azacitidine in inducing remission in older, previously untreated patients with acute myeloid leukemia (AML), resistance - primary or secondary - still constitutes a significant roadblock in the quest to prolong the duration of response. Here we review the proposed and proven mechanisms of resistance to venetoclax monotherapy, HMA monotherapy, and the doublet of venetoclax and HMA for the treatment of AML. We approach the mechanisms of resistance to HMAs and venetoclax in the light of the agents' mechanisms of action. We briefly describe potential therapeutic strategies to circumvent resistance to this promising combination, including alternative scheduling or the addition of other agents to the HMA and venetoclax backbone. Understanding the mechanisms of action and evolving resistance in AML remains a priority in order to maximize the benefit from novel drugs and combinations, identify new therapeutic targets, define potential prognostic markers, and avoid treatment failure.

The viral envelope glycoprotein of murine leukemia virus and the pathogenesis of immune complex glomerulonephritis of New Zealand mice.

The use of monospecific antisera for the analysis by radioimmunoassay and immunofluorescence study of two major viral proteins, gp69/71 and p30 of murine leukemia virus, that could be of significance in the pathogenesis of immune complex glomerulonephritis of mice, particularly NZB and B/WF(1) hybrid mice, yielded the following conclusions. A remarkably high concentration of viral envelope glycoprotein, gp69/71, was detected in the spleen and serum of New Zealand mice (NZB, NZW, B/WF(1), and W/BF(1)); the concentration in the spleen was 10-fold greater than that found in AKR mice and 30-fold greater than that present in C57BL/6 mice. The gp69/71 was deposited along with bound immunoglobulins, apparently as an immune complex, in the diseased kidneys of mice, and the glomerular site and extent of deposition of gp69/71 was related to the severity of the glomerulonephritis. This study suggests that the pathogenesis of immune complex glomerulonephritis (and vasculitis) in mice is related to the expression of this specific viral envelope glycoprotein and to the host immune response to this protein.

Internet and game behaviour at a secondary school and a newly developed health promotion programme: a prospective study.

BACKGROUND: This study investigated the Internet and game use of secondary school children, the compulsiveness of their use and the relationship with other health behaviours. It also evaluated the preliminary results of a recently developed school health promotion programme, implemented at a secondary school in the Netherlands in January 2008. This programme is one of the first to combine seven health behaviours in one educational programme and is a pilot project for a case-control study. METHODS: A total of 475 secondary school children completed an extensive questionnaire before and a year after starting the programme. Of these children, 367 were in first, second and third grade; the grades in which the lessons about internet and game behaviour were implemented. Questionnaires contained questions about personal information, Internet and game use (Compulsive Internet Use Scale), and other health behaviours (alcohol use, physical activity, psychosocial wellbeing and body mass index). RESULTS: Heavy Internet use was significantly associated with psychosocial problems, and heavy game use was significantly associated with psychosocial problems and less physical activity. No relationship was found with alcohol use or body mass index. The time spent on Internet (hours/day) and the number of pathological Internet users increased during the study. The number of game users decreased but heavy game use increased. CONCLUSION: The association between heavy Internet use and psychosocial problems and between game use and psychosocial problems and less physical activity emphasizes the need to target different health behaviours in one health education programme. A case-control study is needed to further assess the programme-induced changes in Internet and game behaviour of school children.