The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) ...mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Most theories about macromolecular crowding focus on two ideas: the macromolecular nature of the crowder and entropy. For proteins, the volume excluded by the crowder favors compact native states ...over expanded denatured states, enhancing protein stability by decreasing the entropy of unfolding. We tested these ideas with the widely used crowding agent Ficoll-70 and its monomer, sucrose. Contrary to expectations, Ficoll and sucrose have approximately the same stabilizing effect on chymotrypsin inhibitor 2. Furthermore, the stabilization is driven by enthalpy, not entropy. These results point to the need for carefully controlled studies and more sophisticated theories for understanding crowding effects.
Collective intelligence (CI) is the ability of a group to solve a wide range of problems. Synchrony in nonverbal cues is critically important to the development of CI; however, extant findings are ...mostly based on studies conducted face-to-face. Given how much collaboration takes place via the internet, does nonverbal synchrony still matter and can it be achieved when collaborators are physically separated? Here, we hypothesize and test the effect of nonverbal synchrony on CI that develops through visual and audio cues in physically-separated teammates. We show that, contrary to popular belief, the presence of visual cues surprisingly has no effect on CI; furthermore, teams without visual cues are more successful in synchronizing their vocal cues and speaking turns, and when they do so, they have higher CI. Our findings show that nonverbal synchrony is important in distributed collaboration and call into question the necessity of video support.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid ...tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
•Cancer cells of many tissues express an abnormal glycoform of MUC1, Tn-MUC1•Normal human tissue does not express detectable Tn-MUC1 on the cellular surface•CAR T cells are engineered to target Tn-MUC1 lyse tumor cells in vitro and in vivo•Abnormal glycoform epitopes are valid clinical targets for CAR T cells
Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.
Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found ...that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRbNts neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRbNts neurons with local orexin (OX) neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRbNts neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance.
► Neurotensin identifies a circumscribed subpopulation of LepRb neurons (LepRbNts) ► Loss of leptin signaling in LepRbNts neurons of Nts-LepRbKO mice results in obesity ► OX neurons and the mesolimbic DA system are dysregulated in Nts-LepRbKO mice ► Leptin controls OX, mesolimbic DA, and energy balance via LepRbNts neurons
Older adults (age 65+) with T1D are an understudied population. Though many older adults may have long-standing diabetes and the prevalence of multimorbidity accumulates over the lifespan, the ...prevalence of diabetes-related complications and comorbid conditions in older adults with T1D have not been well-characterized, though these factors can affect quality of life. We analyzed electronic health record (EHR) data from older adults with T1D within a large public hospital system (n=560). We used ICD-10 diagnostic codes and calculated the proportion of the sample with different comorbidities and diabetes-related complications, as well as the average number of total complications and the Charlson Comorbidity Index Score (Table). The mean number of T1D-related complications was 3.93 with 29.6% (n=166) having 6+ concurrent T1D complications. The most common T1D complication was retinopathy or other ophthalmic complication with (72%; n=402). The median Charlson Comorbidity index score was 3. Nearly half of the sample (n=282; 50.4%) had cardiovascular disease and more than one third (n=197; 35%) had renal disease. These data underscore a high burden of diabetes complications and comorbidities among older adults with T1D. Understanding the medical complexity of this population can inform future research and intervention.
Disclosure
A.Kahkoska: None. J.M.Weinstein: Research Support; Dexcom, Inc. R.Muthukkumar: None. L.A.Young: Research Support; Novo Nordisk, Rhythm Pharmaceuticals, Inc., Eli Lilly and Company, Jaeb Center for Health Research, Sanofi, Boehringer-Ingelheim.
Funding
National Institutes of Health (KL2TR002490, UL1TR002489)
The smallest flying insects commonly possess wings with long bristles. Little quantitative information is available on the morphology of these bristles, and their functional importance remains a ...mystery. In this study, we (1) collected morphological data on the bristles of 23 species of Mymaridae by analyzing high-resolution photographs and (2) used the immersed boundary method to determine via numerical simulation whether bristled wings reduced the force required to fling the wings apart while still maintaining lift. The effects of Reynolds number, angle of attack, bristle spacing and wing-wing interactions were investigated. In the morphological study, we found that as the body length of Mymaridae decreases, the diameter and gap between bristles decreases and the percentage of the wing area covered by bristles increases. In the numerical study, we found that a bristled wing experiences less force than a solid wing. The decrease in force with increasing gap to diameter ratio is greater at higher angles of attack than at lower angles of attack, suggesting that bristled wings may act more like solid wings at lower angles of attack than they do at higher angles of attack. In wing-wing interactions, bristled wings significantly decrease the drag required to fling two wings apart compared with solid wings, especially at lower Reynolds numbers. These results support the idea that bristles may offer an aerodynamic benefit during clap and fling in tiny insects.
The scaffold is a porous three‐dimensional (3D) material that supports cell growth and tissue regeneration. Such 3D structures should be generated with simple techniques and nontoxic ingredients to ...mimic bio‐environment and facilitate tissue regeneration. In this work, simple but powerful techniques are demonstrated for the fabrication of lamellar and honeycomb‐mimic scaffolds with poly(L‐lactic acid). The honeycomb‐mimic scaffolds with tunable pore size ranging from 70 to 160 µm are fabricated by crystal needle‐guided thermally induced phase separation in a directional freezing apparatus. The compressive modulus of the honeycomb‐mimic scaffold is ≈4 times higher than that of scaffold with randomly oriented pore structure. The fabricated honeycomb‐mimic scaffold exhibits a hierarchical structure from nanofibers to micro‐/macro‐tubular structures. Pre‐osteoblast MC3T3‐E1 cells cultured on the honeycomb‐mimic nanofibrous scaffolds exhibit an enhanced osteoblastic phenotype, with elevated expression levels of osteogenic marker genes, than those on either porous lamellar scaffolds or porous scaffolds with randomly oriented pores. The advanced techniques for the fabrication of the honeycomb‐mimic structure may potentially be used for a wide variety of advanced functional materials.
A novel method for the fabrication of the honeycomb‐mimic PLLA scaffold by crystal needle‐guided directional phase separation is presented. The fabricated honeycomb‐mimic scaffold shows a hierarchical architecture from nano‐ to macro‐scale with nanofibrous walls. The differentiation of MC3T3‐E1 pre‐osteoblastic cells is enhanced on the honeycomb‐mimic PLLA scaffold.
Mechanisms of forest resilience Falk, Donald A; van Mantgem, Philip J; Keeley, Jon E ...
Forest ecology and management,
05/2022, Letnik:
512
Journal Article
Recenzirano
Odprti dostop
•Resilience is an emergent outcome of persistence, recovery, and reorganization processes, reflecting mechanisms specific to each type of response.•Persistence and recovery are most closely ...associated with return to pre-disturbance conditions.•Reorganization is a natural process of ecosystem adaptation to changing conditions.•Projected environmental changes make ecosystem reorganization increasingly likely.•Managers can use understanding of resilience to guide ecosystem transitions.
Ecosystems are dynamic systems with complex responses to environmental variation. In response to pervasive stressors of changing climate and disturbance regimes, many ecosystems are realigning rapidly across spatial scales, in many cases moving outside of their observed historical range of variation into alternative ecological states. In some cases, these new states are transitory and represent successional stages that may ultimately revert to the pre-disturbance condition; in other cases, alternative states are persistent and potentially self-reinforcing, especially under conditions of altered climate, disturbance regimes, and influences of non-native species. These reorganized states may appear novel, but reorganization is a characteristic ecosystem response to environmental variation that has been expressed and documented throughout the paleoecological record. Resilience, the ability of an ecosystem to recover or adapt following disturbance, is an emergent property that results from the expression of multiple mechanisms operating across levels of organism, population, and community. We outline a unifying framework of ecological resilience based on ecological mechanisms that lead to outcomes of persistence, recovery, and reorganization. Persistence is the ability of individuals to tolerate exposure to environmental stress, disturbance, or competitive interactions. As a direct expression of life history evolution and adaptation to environmental variation and stress, persistence is manifested most directly in survivorship and continued growth and reproduction of established individuals. When persistence has been overcome (e.g., following mortality from stress, disturbance, or both), populations must recover by reproduction. Recovery requires the establishment of new individuals from seed or other propagules following dispersal from the parent plant. When recovery fails to re-establish the pre-disturbance community, the ecosystem will assemble into a new state. Reorganization occurs along a gradient of magnitude, from changes in the relative dominance of species present in a community, to individual species replacements within an essentially intact community, to complete species turnover and shift to dominance by plants of different functional types, e.g. transition from forest to shrub or grass dominance. When this latter outcome is persistent and involves reinforcing mechanisms, the resulting state represents a vegetation type conversion (VTC), which in this framework represents an end member of reorganization processes. We explore reorganization in greater detail as this phase is increasingly observed but the least understood of the resilience responses. This resilience framework provides a direct and actionable basis for ecosystem management in a rapidly changing world, by targeting specific components of ecological response and managing for sustainable change.
Background
Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC‐targeted therapies are approved in ...several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX‐0159, an anti‐KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers.
Methods
CDX‐0159‐mediated KIT inhibition was tested in vitro using KIT‐expressing immortalized cells and primary human mast cells. CDX‐0159 safety and pharmacokinetics were evaluated in a 13‐week good laboratory practice (GLP)‐compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double‐blinded placebo‐controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX‐0159.
Results
CDX‐0159 inhibits SCF‐dependent KIT activation in vitro. Fc modifications in CDX‐0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX‐0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX‐0159 led to dose‐dependent, profound suppression of plasma tryptase, a MC‐specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation.
Conclusion
CDX‐0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell‐driven disorders.
This study presents the preclinical characterization, safety, pharmacokinetic and pharmacodynamic activity in a placebo‐controlled phase 1a healthy volunteer study of CDX‐0159, a specific and potent anti‐KIT inhibitory monoclonal antibody. CDX‐0159 inhibits SCF‐dependent KIT and mast cell activation. In a dose‐dependent manner, CDX‐0159 induces suppression of plasma tryptase – a marker of mast cell burden – showing a potential as a therapeutic strategy in mast cell‐driven disorders.Abbreviations: CDX‐0159, anti‐KIT inhibitory monoclonal antibody; FcR, Fc receptor; KIT, KIT proto‐oncogene, receptor tyrosine kinase; MRGPRX2, mas‐related G protein‐coupled receptor‐X2; SCF, stem cell factor
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