The Behavior of Novae Light Curves Before Eruption

In 1975, E. R. Robinson conducted the hallmark study of the behavior of classical nova light curves before eruption, and this work has now become part of the standard knowledge of novae. He made three points; that 5 out of 11 novae showed pre-eruption rises in the years before eruption, that one nova (V446 Her) showed drastic changes in the variability across eruptions, and that all but one of the novae (excepting BT Mon) have the same quiescent magnitudes before and after the outburst. This work has not been tested since it came out. We have now tested these results by going back to the original archival photographic plates and measuring large numbers of pre-eruption magnitudes for many novae using comparison stars on a modern magnitude scale. We find in particular that four out of five claimed pre-eruption rises are due to simple mistakes in the old literature, that V446 Her has the same amplitude of variations across its 1960 eruption, and that BT Mon has essentially unchanged brightness across its 1939 eruption. Out of 22 nova eruptions, we find two confirmed cases of significant pre-eruption rises (for V533 Her and V1500 Cyg), while T CrB has a deep pre-eruption dip. These events are a challenge to theorists. We find no significant cases of changes in variability across 27 nova eruptions beyond what is expected due to the usual fluctuations seen in novae away from eruptions. For 30 classical novae plus 19 eruptions from 6 recurrent novae, we find that the average change in magnitude from before the eruption to long after the eruption is 0.0 mag. However, we do find five novae (V723 Cas, V1500 Cyg, V1974 Cyg, V4633 Sgr, and RW UMi) that have significantly large changes, in that the post-eruption quiescent brightness level is over ten times brighter than the pre-eruption level.Comment: 91 pages (preprint), AJ accepte

RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK and CD8+ T cell pressure. We identify all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitizes cancer cells to NK and CD8+ T cell killing. This occurs in a tumor necrosis factor (TNF)-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and greatly enhances bystander killing of MHC antigen-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers

Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling

The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells, but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity

Комплексный подход в работе невролога с применением остеопатии для коррекции когнитивных нарушений у лиц с цереброваскулярными заболеваниями

Actuality. In most countries, the proportion of older persons and older persons in society increases with increasing life expectancy. Up to 70% of older people experience memory loss compared to young or middle age. Objective: to improve mnestic functions, cognitive status and health of patients at a later age and prevention, prevention of senile dementia. Materials and methods. The experiment involved a group of people from 58 to 86 years, who have a history of cardiovascular disease (CVD) and Cerebro-vascular disease (CVD). The main subgroups included the study, which for four years engaged in the group on the activation of higher mental functions (HPF) using a variety of techniques for the elderly, senile age on special programs. In the course of the research experiment, osteopathic methods of research and specific testing of functional systems were used: craniosacral, structural (spine, as well as the clavicle, first ribs, thoracic and pelvic diaphragms), as well as osteopathic techniques of correction. Results and conclusion. The application of methods from osteopathic practice in the framework of cognitive Psychoneurology to improve memory processes, in this work the neurologist confirmed its results. The study allows us to recommend the joint work of an osteopath and neurologist in order to improve the results and effectiveness of treatment and reduce the time required to achieve the desired effect. The complex use of neurologist in addition to the methods of cognitive therapy of osteopathic methods of correction has a positive effect on the body of patients, improving their cognitive, mnestic indicators, increasing the productivity of memory, which can be recommended for elderly patients.Актуальность. В большинстве стран с увеличением средней продолжительности жизни растет доля пожилых и стариков в обществе. До 70% пожилых людей отмечают у себя снижение памяти по сравнению с молодым или средним возрастом. Цель: улучшение мнестических функций, когнитивного статуса и здоровья пациентов в позднем возрасте и профилактика, предупреждения старческой деменции. Материалы и методы. В эксперименте участвовала группа людей от 58 до 86 лет, которые имеют в анамнезе сердечно-сосудистые заболевания (ССЗ) и церебро-ва-скулярные заболевания (ЦВЗ). В основные подгруппы вошли исследуемые, которые четыре года занимаются в группе по активизации высших психических функций (ВПФ) с помощью разнообразных методик для лиц пожилого, старческого возраста по специальным программам. В процессе исследовательского эксперимента применялись остеопатические методы исследования и специфическое тестирование функциональных систем: краниосакральной, структуральной (отделы позвоночника, а также ключицы, первые ребра, грудобрюшная и тазовая диафрагмы), а также остеопатические техники коррекции Результаты и заключение. Применение методов из остеопатической практики в рамках когнитивной психоневрологии для улучшения процессов памяти, в данной работе врача невролога подтвердилась ее результатами. Проведенное исследование позволяет рекомендовать совместную работу остеопата и невролога в целях повышения результатов и эффективности лечения и уменьшения сроков, требуемых для достижения нужного эффекта. Комплексное использование в работе врача невролога в дополнение к методам когнитивной терапии остеопатических методов коррекции благоприятно воздействует на организм пациентов, улучшая их когнитивные, мнестические показатели, повышая продуктивность памяти, что может быть рекомендовано для пациентов пожилого и старческого возраста

Комплексный подход в работе невролога с применением остеопатии для коррекции когнитивных нарушений у лиц с цереброваскулярными заболеваниями

Actuality. In most countries, the proportion of older persons and older persons in society increases with increasing life expectancy. Up to 70% of older people experience memory loss compared to young or middle age. Objective: to improve mnestic functions, cognitive status and health of patients at a later age and prevention, prevention of senile dementia. Materials and methods. The experiment involved a group of people from 58 to 86 years, who have a history of cardiovascular disease (CVD) and Cerebro-vascular disease (CVD). The main subgroups included the study, which for four years engaged in the group on the activation of higher mental functions (HPF) using a variety of techniques for the elderly, senile age on special programs. In the course of the research experiment, osteopathic methods of research and specific testing of functional systems were used: craniosacral, structural (spine, as well as the clavicle, first ribs, thoracic and pelvic diaphragms), as well as osteopathic techniques of correction. Results and conclusion. The application of methods from osteopathic practice in the framework of cognitive Psychoneurology to improve memory processes, in this work the neurologist confirmed its results. The study allows us to recommend the joint work of an osteopath and neurologist in order to improve the results and effectiveness of treatment and reduce the time required to achieve the desired effect. The complex use of neurologist in addition to the methods of cognitive therapy of osteopathic methods of correction has a positive effect on the body of patients, improving their cognitive, mnestic indicators, increasing the productivity of memory, which can be recommended for elderly patients.Актуальность. В большинстве стран с увеличением средней продолжительности жизни растет доля пожилых и стариков в обществе. До 70% пожилых людей отмечают у себя снижение памяти по сравнению с молодым или средним возрастом. Цель: улучшение мнестических функций, когнитивного статуса и здоровья пациентов в позднем возрасте и профилактика, предупреждения старческой деменции. Материалы и методы. В эксперименте участвовала группа людей от 58 до 86 лет, которые имеют в анамнезе сердечно-сосудистые заболевания (ССЗ) и церебро-ва-скулярные заболевания (ЦВЗ). В основные подгруппы вошли исследуемые, которые четыре года занимаются в группе по активизации высших психических функций (ВПФ) с помощью разнообразных методик для лиц пожилого, старческого возраста по специальным программам. В процессе исследовательского эксперимента применялись остеопатические методы исследования и специфическое тестирование функциональных систем: краниосакральной, структуральной (отделы позвоночника, а также ключицы, первые ребра, грудобрюшная и тазовая диафрагмы), а также остеопатические техники коррекции Результаты и заключение. Применение методов из остеопатической практики в рамках когнитивной психоневрологии для улучшения процессов памяти, в данной работе врача невролога подтвердилась ее результатами. Проведенное исследование позволяет рекомендовать совместную работу остеопата и невролога в целях повышения результатов и эффективности лечения и уменьшения сроков, требуемых для достижения нужного эффекта. Комплексное использование в работе врача невролога в дополнение к методам когнитивной терапии остеопатических методов коррекции благоприятно воздействует на организм пациентов, улучшая их когнитивные, мнестические показатели, повышая продуктивность памяти, что может быть рекомендовано для пациентов пожилого и старческого возраста

Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold

New opportunities are needed to increase immune checkpoint blockade (ICB) impact for cancer patients. A genome-wide CRISPR/Cas9 screen uncovered several hits in the TNF pathway sensitizing tumor cells to T cell elimination. TNF antitumor activity was generally limited in tumors at baseline and in ICB non-responders, correlating with its low abundance. Selective inactivation of TNF signaling lowered melanoma and lung cancer thresholds to low TNF levels, thereby increasing tumor susceptibility to T cell attack and augmenting benefit from anti-PD-1 treatment

RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells

Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both innate and adaptive immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK and CD8+ T cell pressure. We identify all components, RNF31, RBCK1, and SHARPIN, of the linear ubiquitination chain assembly complex (LUBAC). Genetic and pharmacologic ablation of RNF31, an E3 ubiquitin ligase, strongly sensitizes cancer cells to NK and CD8+ T cell killing. This occurs in a tumor necrosis factor (TNF)-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and greatly enhances bystander killing of MHC antigen-deficient tumor cells. These results merit exploration of RNF31 inhibition as a clinical pharmacological opportunity for immunotherapy-refractory cancers