Computed structures of core eukaryotic protein complexes Humphreys, Ian R; Pei, Jimin; Baek, Minkyung ...
Science (American Association for the Advancement of Science),
2021-Dec-10, 2021-12-10, 20211210, Letnik:
374, Številka:
6573
Journal Article
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Protein-protein interactions play critical roles in biology, but the structures of many eukaryotic protein complexes are unknown, and there are likely many interactions not yet identified. We take ...advantage of advances in proteome-wide amino acid coevolution analysis and deep-learning–based structure modeling to systematically identify and build accurate models of core eukaryotic protein complexes within the
proteome. We use a combination of RoseTTAFold and AlphaFold to screen through paired multiple sequence alignments for 8.3 million pairs of yeast proteins, identify 1505 likely to interact, and build structure models for 106 previously unidentified assemblies and 806 that have not been structurally characterized. These complexes, which have as many as five subunits, play roles in almost all key processes in eukaryotic cells and provide broad insights into biological function.
Rates of obesity have increased significantly over the last three decades in the United States and globally. In addition to contributing to heart disease and diabetes, obesity is a major unrecognized ...risk factor for cancer. Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities. Research shows that the time after a cancer diagnosis can serve as a teachable moment to motivate individuals to adopt risk-reducing behaviors. For this reason, the oncology care team--the providers with whom a patient has the closest relationships in the critical period after a cancer diagnosis--is in a unique position to help patients lose weight and make other healthy lifestyle changes. The American Society of Clinical Oncology is committed to reducing the impact of obesity on cancer and has established a multipronged initiative to accomplish this goal by 1) increasing education and awareness of the evidence linking obesity and cancer; 2) providing tools and resources to help oncology providers address obesity with their patients; 3) building and fostering a robust research agenda to better understand the pathophysiology of energy balance alterations, evaluate the impact of behavior change on cancer outcomes, and determine the best methods to help cancer survivors make effective and useful changes in lifestyle behaviors; and 4) advocating for policy and systems change to address societal factors contributing to obesity and improve access to weight management services for patients with cancer.
Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of ...therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment.
We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk.
Among 23 601 survivors with a median follow-up of 21 years (IQR 15–25), the 20-year cumulative incidence of at least one grade 3–5 chronic condition decreased significantly from 33·2% (95% CI 32·0–34·3) in those diagnosed 1970–79 to 29·3% (28·4–30·2; p<0·0001) in 1980–89, and 27·5% (26·4–28·6; p=0·012 vs 1980–89) in 1990–99. By comparison, the 20-year cumulative incidence of at least one grade 3–5 condition in 5051 siblings was 4·6% (95% CI 3·9–5·2). The 15-year cumulative incidence of at least one grade 3–5 condition was lower for survivors diagnosed 1990–99 compared with those diagnosed 1970–79 for Hodgkin lymphoma (17·7% 95% CI 15·0–20·5 vs 26·4% 23·8–29·1; p<0·0001), non-Hodgkin lymphoma (16·9% 14·0–19·7 vs 23·8% 19·9–27·7; p=0.0053), astrocytoma (30·5% 27·8–33·2 vs 47·3% 42·9–51·7; p<0·0001), Wilms tumour (11·9% 9·5–14·3 vs 17·6% 14·3–20·8; p=0·034), soft tissue sarcoma (28·3% 23·5–33·1 vs 36·5% 31·5–41·4; p=0·021), and osteosarcoma (65·6% 60·6–70·6 vs 87·5% 84·1–91·0; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3–5 condition was higher (1990–99 vs 1970–79) for medulloblastoma or primitive neuroectodermal tumour (58·9% 54·4–63·3 vs 42·9% 34·9–50·9; p=0·00060), and neuroblastoma (25·0% 21·8–28·2 vs 18·0% 14·5–21·6; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3–5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64–0·92; HR with treatment in the model=0·89, 95% CI 0·72–1·11; pmediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65–0·85; HR with treatment=0·91, 95% CI 0·73–1·12; pmediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970–79 to survivors diagnosed 1990–99 were noted for endocrinopathies (5·9% 5·3–6·4 vs 2·8% 2·5–3·2; p<0·0001), subsequent malignant neoplasms (2·7% 2·3–3·1 vs 1·9% 1·6–2·2; p=0·0033), musculoskeletal conditions (5·8% 5·2–6·4 vs 3·3% 2·9–3·6; p<0·0001), and gastrointestinal conditions (2·3% 2·0–2·7 vs 1·5% 1·3–1·8; p=0·00037), while hearing loss increased (3·0% 2·6–3·5 vs 5·7% 5·2–6·1; p<0·0001).
Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population.
National Cancer Institute and the American Lebanese-Syrian Associated Charities.
We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly ...associated loci (P < 5 × 10
), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10
). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10
) than in HPV-negative (OR = 0.75, P = 0.16) cancers.
Crucial transitions in cancer—including tumor initiation, local expansion, metastasis, and therapeutic resistance—involve complex interactions between cells within the dynamic tumor ecosystem. ...Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.
The Human Tumor Atlas Network outlines their ambitious plan to generate 3D, single-cell, multiparametric, and longitudinal maps of diverse tumor types.
Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical ...substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.
On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in ...Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three “classical” transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small‐group breakout sessions, and large‐group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross‐cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.
Background
Mass casualty incidents (MCIs) create an immediate surge in blood product demand. We hypothesize local inventories in major U.S. cities would not meet this demand.
Study Design and Methods
...A simulated blast in a large crowd estimated casualty numbers. Ideal resuscitation was defined as equal amounts of red blood cells (RBCs), plasma, platelets, and cryoprecipitate. Inventory was prospectively collected from six major U.S. cities at six time points between January and July 2019. City‐wide blood inventories were classified as READY (>1 U/injured survivor), DEFICIENT (<10 U/severely injured survivor), or RISK (between READY and DEFICIENT), before and after resupply from local distribution centers (DC), and features of DEFICIENT cities were identified.
Results
The simulated blast resulted in 2218 injured survivors including 95 with severe injuries. Balanced resuscitation would require between 950 and 2218 units each RBC, plasma, platelets and cryoprecipitate. Inventories in 88 hospitals/health systems and 10 DCs were assessed. Of 36 city‐wide surveys, RISK inventories included RBCs (n = 16; 44%), plasma (n = 24; 67%), platelets (n = 6; 17%), and cryoprecipitate (n = 22; 61%) while DEFICIENT inventories included platelets (n = 30; 83%) and cryoprecipitate (n = 12; 33%). Resupply shifted most RBC and plasma inventories to READY, but some platelet and cryoprecipitate inventories remained at RISK (n = 24; 67% and n = 12; 33%, respectively) or even DEFICIENT (n = 11; 31% and n = 6; 17%, respectively). Cities with DEFICIENT inventories were smaller (p <.001) with fewer blood products per trauma bed (p <.001).
Discussion
In this simulated blast event, blood product demand exceeded local supply in some major U.S. cities. Options for closing this gap should be explored to optimize resuscitation during MCIs.
Disruptive behavior disorders in childhood are increasingly pervasive and associated with numerous, negative long-term outcomes. The current study examined whether adding a brief, home-visitation ...intervention to an existing, multi-component (child and teacher) intervention, would improve social-emotional and behavioral outcomes for young children with challenging behavior in home and school settings who required intensive support. A total of 379 teacher-parent-student triads were screened for elevated levels of behavioral risk in school and home settings and then randomly assigned to school only intervention (i.e., teacher and student components), home only intervention (i.e., parent), both combined, or business-as-usual control conditions. We examined baseline and posttest outcomes across prosocial behavior, problem behavior, and academic domains. The results demonstrated substantial support for the teacher and child-focused condition and combined conditions, and modest support for the parent-focused condition. The study advances the literature by increasing the knowledge base related to these interventions implemented alone and in combination.
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