scholarly journals How “is” shapes “ought” for folk-biological concepts

2021 ◽  
Author(s):  
Emily Foster-Hanson ◽  
Tania Lombrozo
Keyword(s):  
Natural World ◽  
Normative Evaluation ◽  
Causal Assumptions ◽  
Biological Concepts ◽  
Functional Features ◽  
Functional Explanations ◽  
And Function ◽  
Shed Light ◽  
Feature Frequency ◽  
Normative Judgments

Knowing which features are frequent among a biological kind (e.g., that most zebras have stripes) shapes people’s representations of what category members are like (e.g., that typical zebras have stripes) and normative judgments about what they ought to be like (e.g., that zebras should have stripes). In the current work, we ask if people’s inclination to explain why features are frequent is a key mechanism through which what “is” shapes beliefs about what “ought” to be. Across four studies (N = 591), we find that frequent features are often explained by appeal to feature function (e.g., that stripes are for camouflage), that functional explanations in turn shape judgments of typicality, and that functional explanations and typicality both predict normative judgments that category members ought to have functional features. We also identify the causal assumptions that license inferences from feature frequency and function, as well as the nature of the normative inferences that are drawn: by specifying an instrumental goal (e.g., camouflage), functional explanations establish a basis for normative evaluation. These findings shed light on how and why our representations of how the natural world is shape our judgments of how it ought to be.

Varieties of Understanding

2019 ◽  
Keyword(s):  
Natural World ◽  
Cognitive Resources ◽  
The World ◽  
Historical Tradition ◽  
Normative Considerations ◽  
Shed Light

According to a long historical tradition, understanding comes in different varieties. In particular, it is said that understanding people has a different epistemic profile than understanding the natural world—it calls on different cognitive resources, for instance, and brings to bear distinctive normative considerations. Thus in order to understand people we might need to appreciate, or in some way sympathetically reconstruct, the reasons that led a person to act in a certain way. By comparison, when it comes to understanding natural events, like earthquakes or eclipses, no appreciation of reasons or acts of sympathetic reconstruction is arguably needed—mainly because there are no reasons on the scene to even be appreciated, and no perspectives to be sympathetically pieced together. In this volume some of the world’s leading philosophers, psychologists, and theologians shed light on the various ways in which we understand the world, pushing debates on this issue to new levels of sophistication and insight.

scholarly journals Intrinsic disorder in protein domains contributes to both organism complexity and clade-specific functions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chao Gao ◽  
Chong Ma ◽  
Huqiang Wang ◽  
Haolin Zhong ◽  
Jiayin Zang ◽  
...  
Keyword(s):  
Biological Significance ◽  
Protein Domains ◽  
Functional Requirements ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Genome Wide ◽  
Complex Functions ◽  
Disorder Degree ◽  
Functional Features ◽  
And Function

AbstractInterestingly, some protein domains are intrinsically disordered (abbreviated as IDD), and the disorder degree of same domains may differ in different contexts. However, the evolutionary causes and biological significance of these phenomena are unclear. Here, we address these issues by genome-wide analyses of the evolutionary and functional features of IDDs in 1,870 species across the three superkingdoms. As the result, there is a significant positive correlation between the proportion of IDDs and organism complexity with some interesting exceptions. These phenomena may be due to the high disorder of clade-specific domains and the different disorder degrees of the domains shared in different clades. The functions of IDDs are clade-specific and the higher proportion of post-translational modification sites may contribute to their complex functions. Compared with metazoans, fungi have more IDDs with a consecutive disorder region but a low disorder ratio, which reflects their different functional requirements. As for disorder variation, it’s greater for domains among different proteins than those within the same proteins. Some clade-specific ‘no-variation’ or ‘high-variation’ domains are involved in clade-specific functions. In sum, intrinsic domain disorder is related to both the organism complexity and clade-specific functions. These results deepen the understanding of the evolution and function of IDDs.

scholarly journals Emerging strategies to target RAS signaling in human cancer therapy

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kun Chen ◽  
Yalei Zhang ◽  
Ling Qian ◽  
Peng Wang
Keyword(s):  
Human Cancer ◽  
Ras Signaling ◽  
Targeting Therapy ◽  
Ras Protein ◽  
Patients With Cancer ◽  
Mutational Status ◽  
Poor Differentiation ◽  
And Function ◽  
Nsclc Patients ◽  
Shed Light

AbstractRAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.

P53/miR-34a/SIRT1 Positive Feedback Loop regulates cell proliferation and promotes cell apoptosis in the termination stage of liver regeneration.

2021 ◽  
Author(s):  
Junhua Gong ◽  
Minghua Cong ◽  
Hao Wu ◽  
Menghao Wang ◽  
He Bai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Regeneration ◽  
Positive Feedback ◽  
Cell Apoptosis ◽  
Feedback Loop ◽  
Late Phase ◽  
Liver Weight ◽  
Positive Feedback Loop ◽  
And Function ◽  
Shed Light

Abstract Background The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury or cancer resection. In our study, we found that the P53/miR-34a/SIRT1 positive feedback loop has a remarkable negative regulatory effect, which is related to the termination of liver regeneration. Here, we described how P53/miR-34a/SIRT1 positive feedback loop controls liver regeneration and its possible relationship with liver cancer.Method We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) knock-downing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. Mice from the Ade-P53 group showed smaller livers and higher levels of serum ALT and AST than control mice. While knock-down of miR-34a abolished P53/miR-34a/SIRT1 positive feedback loop during LR. Mice from anti-miR-34a group showed larger livers and lower levels of PCNA-positive cells than control mice. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. Conclusion The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings shed light on the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.

Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5495-5504 ◽  
Author(s):  
D.M. Supp ◽  
M. Brueckner ◽  
M.R. Kuehn ◽  
D.P. Witte ◽  
L.A. Lowe ◽  
...  
Keyword(s):  
Motor Function ◽  
Single Amino Acid ◽  
Atp Binding ◽  
Amino Acid Difference ◽  
Sequence Classification ◽  
Ciliated Cells ◽  
Targeted Deletion ◽  
Targeted Mutation ◽  
And Function ◽  
Shed Light

Vertebrates develop distinct asymmetries along the left-right axis, which are consistently aligned with the anteroposterior and dorsoventral axes. The mechanisms that direct this handed development of left-right asymmetries have been elusive, but recent studies of mutations that affect left-right development have shed light on the molecules involved. One molecule implicated in left-right specification is left-right dynein (LRD), a microtubule-based motor protein. In the LRD protein of the inversus viscerum (iv) mouse, there is a single amino acid difference at a conserved position, and the lrd gene is one of many genes deleted in the legless (lgl) mutation. Both iv and lgl mice display randomized left-right development. Here we extend the analysis of the lrd gene at the levels of sequence, expression and function. The complete coding sequence of the lrd gene confirms its classification as an axonemal, or ciliary, dynein. Expression of lrd in the node at embryonic day 7.5 is shown to be symmetric. At embryonic day 8.0, however, a striking asymmetric expression pattern is observed in all three germ layers of the developing headfold, suggesting roles in both the establishment and maintenance of left-right asymmetries. At later times, expression of lrd is also observed in the developing floorplate, gut and limbs. These results suggest function for LRD protein in both ciliated and non-ciliated cells, despite its sequence classification as axonemal. In addition, a targeted mutation of lrd was generated that deletes the part of the protein required for ATP binding, and hence motor function. The resulting left-right phenotype, randomization of laterality, is identical to that of iv and lgl mutants. Gross defects in ciliary structure were not observed in lrd/lrd mutants. Strikingly, however, the monocilia on mutant embryonic node cells were immotile. These results prove the identity of the iv and lrd genes. Further, they argue that LRD motor function, and resulting nodal monocilia movement, are required for normal left-right development.

scholarly journals hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

2022 ◽  
Author(s):  
Homa Majd ◽  
Ryan M Samuel ◽  
Jonathan T Ramirez ◽  
Ali Kalantari ◽  
Kevin Barber ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Xenograft Model ◽  
Developmental Relationships ◽  
Drug Candidates ◽  
Effective Strategies ◽  
Wide Range ◽  
Functional Features ◽  
And Function

The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.  

scholarly journals Reverse evolution leads to genotypic incompatibility despite functional and active site convergence

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Miriam Kaltenbach ◽  
Colin J Jackson ◽  
Eleanor C Campbell ◽  
Florian Hollfelder ◽  
Nobuhiko Tokuriki
Keyword(s):  
Active Site ◽  
Adaptive Landscape ◽  
Sequence Structure ◽  
Activity Increase ◽  
Enzyme Active Site ◽  
Fundamental Relationship ◽  
And Function ◽  
Alternative Set ◽  
Shed Light ◽  
New Mutations

Understanding the extent to which enzyme evolution is reversible can shed light on the fundamental relationship between protein sequence, structure, and function. Here, we perform an experimental test of evolutionary reversibility using directed evolution from a phosphotriesterase to an arylesterase, and back, and examine the underlying molecular basis. We find that wild-type phosphotriesterase function could be restored (>104-fold activity increase), but via an alternative set of mutations. The enzyme active site converged towards its original state, indicating evolutionary constraints imposed by catalytic requirements. We reveal that extensive epistasis prevents reversions and necessitates fixation of new mutations, leading to a functionally identical sequence. Many amino acid exchanges between the new and original enzyme are not tolerated, implying sequence incompatibility. Therefore, the evolution was phenotypically reversible but genotypically irreversible. Our study illustrates that the enzyme's adaptive landscape is highly rugged, and different functional sequences may constitute separate fitness peaks.

scholarly journals Unexpected cryptic species among streptophyte algae most distant to land plants

2021 ◽  
Vol 288 (1963) ◽  
Author(s):  
Iker Irisarri ◽  
Tatyana Darienko ◽  
Thomas Pröschold ◽  
Janine M. R. Fürst-Jansen ◽  
Mahwash Jamy ◽  
...  
Keyword(s):  
Land Plants ◽  
Comparative Genomic ◽  
Future Studies ◽  
Form And Function ◽  
Genomic Studies ◽  
Plant Form ◽  
Phylogenomic Analyses ◽  
And Function ◽  
Shed Light ◽  
Green Lineage

Streptophytes are one of the major groups of the green lineage (Chloroplastida or Viridiplantae). During one billion years of evolution, streptophytes have radiated into an astounding diversity of uni- and multicellular green algae as well as land plants. Most divergent from land plants is a clade formed by Mesostigmatophyceae, Spirotaenia spp. and Chlorokybophyceae. All three lineages are species-poor and the Chlorokybophyceae consist of a single described species, Chlorokybus atmophyticus. In this study, we used phylogenomic analyses to shed light into the diversity within Chlorokybus using a sampling of isolates across its known distribution. We uncovered a consistent deep genetic structure within the Chlorokybus isolates, which prompted us to formally extend the Chlorokybophyceae by describing four new species. Gene expression differences among Chlorokybus species suggest certain constitutive variability that might influence their response to environmental factors. Failure to account for this diversity can hamper comparative genomic studies aiming to understand the evolution of stress response across streptophytes. Our data highlight that future studies on the evolution of plant form and function can tap into an unknown diversity at key deep branches of the streptophytes.

scholarly journals Immune Checkpoints Expression in Chronic Lung Allograft Rejection

2021 ◽  
Vol 12 ◽  
Author(s):  
Ilaria Righi ◽  
Valentina Vaira ◽  
Letizia Corinna Morlacchi ◽  
Giorgio Alberto Croci ◽  
Valeria Rossetti ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Bronchiolitis Obliterans Syndrome ◽  
Immune Checkpoints ◽  
Hla Antibodies ◽  
Restrictive Allograft Syndrome ◽  
And Function ◽  
Shed Light

Chronic lung allograft dysfunction (CLAD) is the main cause of poor survival and low quality of life of lung transplanted patients. Several studies have addressed the role of dendritic cells, macrophages, T cells, donor specific as well as anti-HLA antibodies, and interleukins in CLAD, but the expression and function of immune checkpoint molecules has not yet been analyzed, especially in the two CLAD subtypes: BOS (bronchiolitis obliterans syndrome) and RAS (restrictive allograft syndrome). To shed light on this topic, we conducted an observational study on eight consecutive grafts explanted from patients who received lung re-transplantation for CLAD. The expression of a panel of immune molecules (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein) was analyzed by immunohistochemistry in these grafts and in six control lungs. Results showed that RAS compared to BOS grafts were characterized by 1) the inversion of the CD4/CD8 ratio; 2) a higher percentage of T lymphocytes expressing the PD-1, PD-L1, and CTLA4 checkpoint molecules; and 3) a significant reduction of exhausted PD-1-expressing T lymphocytes (PD-1pos/TOXpos) and of exhausted Treg (PD-1pos/FOXP3pos) T lymphocytes. Results herein, although being based on a limited number of cases, suggest a role for checkpoint molecules in the development of graft rejection and offer a possible immunological explanation for the worst prognosis of RAS. Our data, which will need to be validated in ampler cohorts of patients, raise the possibility that the evaluation of immune checkpoints during follow-up offers a prognostic advantage in monitoring the onset of rejection, and suggest that the use of compounds that modulate the function of checkpoint molecules could be evaluated in the management of chronic rejection in LTx patients.

Sarajevo and the Sarajevo Sephardim

2018 ◽  
Vol 46 (5) ◽  
pp. 892-910
Author(s):  
Jonna Rock
Keyword(s):  
Identity Formation ◽  
Fifteenth Century ◽  
Status Quo ◽  
Structured Interviews ◽  
Jewish Identification ◽  
The Status ◽  
Late Fifteenth ◽  
And Function ◽  
Role And Function ◽  
Shed Light

This article highlights issues pertaining to the Sephardim ([-im] is the masculine plural Hebrew ending and Sepharad is the Hebrew name for Spain. Sephardim thus literally means the Jews of Spain) in Sarajevo from the time of their arrival in the Ottoman Empire in the late fifteenth century until the present day. I describe the status quo for the Sephardi minority in post-Ottoman Sarajevo, in the first and second Yugoslavia, and in today's post-Communist Sarajevo, the capital of Bosnia and Herzegovina. The objective is to shed light on how historic preconditions have influenced identity formation as it expresses itself from a Sephardic perspective. The aim is moreover to generate knowledge of the circumstances that affected how Sephardim came to understand themselves in terms of their Jewish identification. I present empirical findings from my semi-structured interviews with Sarajevo Sephardim of different generations (2015 and 2016). I argue that while none of the interlocutors conceive of Jewish identification as divergent from halachic interpretations of matrilineal descent, they moreover propose other conceptions of what it means to be Jewish, such as celebrating Shabbat and other Jewish holidays, and other patterns of socialization. At the same time, these individuals also assert alternative forms of being Bosnian, one that includes multiple ethnicities, and multiple religious ascriptions. This study elucidates a little-explored history and sheds light on the ways in which historical conditions have shaped contemporary, layered framings of identification among Sarajevo's current Jewish population. This article is relevant for those interested in contemporary Sephardic Bosnian culture and in the role and function of ideology in creating conditions for identity formation and transformation.

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