Mais uma hipótese da origem da vida: a evolução darwinista começou antes da própria vida!

segunda-feira, fevereiro 22, 2021

Structured sequences emerge from random pool when replicated by templated ligation

Patrick W. Kudella, Alexei V. Tkachenko, Annalena Salditt, Sergei Maslov, and Dieter Braun

PNAS February 23, 2021 118 (8) e2018830118; 

Edited by Eugene V. Koonin, National Institutes of Health, Bethesda, MD, and approved January 20, 2021 (received for review September 7, 2020)


The structure of life emerged from randomness. This is attributed to selection by molecular Darwinian evolution. This study found that random templated ligation led to the simultaneous elongation and sequence selection of oligomers. Product strands showed highly structured sequence motifs which inhibited self-folding and built self-templating reaction networks. By the reduction of the sequence space, the kinetics of duplex formation increased and led to a faster replication through the ligation process. These findings imply that elementary binding properties of nucleotides can lead to an early selection of sequences even before the onset of Darwinian evolution. This suggests that such a simplification of sequence space could result in faster downstream selection for sequence-based function for the origin of life.


The central question in the origin of life is to understand how structure can emerge from randomness. The Eigen theory of replication states, for sequences that are copied one base at a time, that the replication fidelity has to surpass an error threshold to avoid that replicated specific sequences become random because of the incorporated replication errors [M. Eigen, Naturwissenschaften 58 (10), 465–523 (1971)]. Here, we showed that linking short oligomers from a random sequence pool in a templated ligation reaction reduced the sequence space of product strands. We started from 12-mer oligonucleotides with two bases in all possible combinations and triggered enzymatic ligation under temperature cycles. Surprisingly, we found the robust creation of long, highly structured sequences with low entropy. At the ligation site, complementary and alternating sequence patterns developed. However, between the ligation sites, we found either an A-rich or a T-rich sequence within a single oligonucleotide. Our modeling suggests that avoidance of hairpins was the likely cause for these two complementary sequence pools. What emerged was a network of complementary sequences that acted both as templates and substrates of the reaction. This self-selecting ligation reaction could be restarted by only a few majority sequences. The findings showed that replication by random templated ligation from a random sequence input will lead to a highly structured, long, and nonrandom sequence pool. This is a favorable starting point for a subsequent Darwinian evolution searching for higher catalytic functions in an RNA world scenario.

Keywords origin of life DNA replication Darwinian evolution templated ligation sequence entropy


Imagens de alta resolução do DNA surpreendentemente desconcertantes: mero acaso, fortuita necessidade ou design inteligente?

quarta-feira, fevereiro 17, 2021

Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides

Alice L. B. Pyne, Agnes Noy, Kavit H. S. Main, Victor Velasco-Berrelleza, Michael M. Piperakis, Lesley A. Mitchenall, Fiorella M. Cugliandolo, Joseph G. Beton, Clare E. M. Stevenson, Bart W. Hoogenboom, Andrew D. Bates, Anthony Maxwell & Sarah A. Harris 

Nature Communications volume 12, Article number: 1053 (2021)


In the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we overcome these limitations, by a combination of atomic force microscopy (AFM) and atomistic molecular dynamics (MD) simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution. We observe that negative superhelical stress induces local variation in the canonical B-form DNA structure by introducing kinks and defects that affect global minicircle structure and flexibility. We probe how these local and global conformational changes affect DNA interactions through the binding of triplex-forming oligonucleotides to DNA minicircles. We show that the energetics of triplex formation is governed by a delicate balance between electrostatics and bonding interactions. Our results provide mechanistic insight into how DNA supercoiling can affect molecular recognition, that may have broader implications for DNA interactions with other molecular species.

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Michael Behe vindicado, mas não citado em artigo da Nature Heredity apoiando sua hipótese de Involução

The population genomics of adaptive loss of function

J. Grey Monroe, John K. McKay, Detlef Weigel & Pádraic J. Flood 

Heredity (2021)


Discoveries of adaptive gene knockouts and widespread losses of complete genes have in recent years led to a major rethink of the early view that loss-of-function alleles are almost always deleterious. Today, surveys of population genomic diversity are revealing extensive loss-of-function and gene content variation, yet the adaptive significance of much of this variation remains unknown. Here we examine the evolutionary dynamics of adaptive loss of function through the lens of population genomics and consider the challenges and opportunities of studying adaptive loss-of-function alleles using population genetics models. We discuss how the theoretically expected existence of allelic heterogeneity, defined as multiple functionally analogous mutations at the same locus, has proven consistent with empirical evidence and why this impedes both the detection of selection and causal relationships with phenotypes. We then review technical progress towards new functionally explicit population genomic tools and genotype-phenotype methods to overcome these limitations. More broadly, we discuss how the challenges of studying adaptive loss of function highlight the value of classifying genomic variation in a way consistent with the functional concept of an allele from classical population genetics.



Experimental evolution, loss-of-function mutations, and “the first rule of adaptive evolution”

Michael J.   Behe, and Daniel E.   Dykhuizen


Adaptive evolution can cause a species to gain, lose, or modify a function; therefore, it is of basic interest to determine whether any of these modes dominates the evolutionary process under particular circumstances. Because mutation occurs at the molecular level, it is necessary to examine the molecular changes produced by the underlying mutation in order to assess whether a given adaptation is best considered as a gain, loss, or modification of function. Although that was once impossible, the advance of molecular biology in the past half century has made it feasible. In this paper, I review molecular changes underlying some adaptations, with a particular emphasis on evolutionary experiments with microbes conducted over the past four decades. I show that by far the most common adaptive changes seen in those examples are due to the loss or modification of a pre-existing molecular function, and I discuss the possible reasons for the prominence of such mutations.

Forças motrizes nas origens da vida: mero acaso, fortuita necessidade ou design inteligente?

segunda-feira, fevereiro 15, 2021

Driving forces in the origins of life

K. A. Dill and L. Agozzino

Published:03 February 2021


What were the physico-chemical forces that drove the origins of life? We discuss four major prebiotic ‘discoveries’: persistent sampling of chemical reaction space; sequence-encodable foldable catalysts; assembly of functional pathways; and encapsulation and heritability. We describe how a ‘proteins-first’ world gives plausible mechanisms. We note the importance of hydrophobic and polar compositions of matter in these advances.


A evolução de nosso planeta dinâmico: um bilhão de anos em 40 segundos!

sábado, fevereiro 13, 2021

Earth-Science Reviews

Volume 214, March 2021, 103477

Extending full-plate tectonic models into deep time: Linking the Neoproterozoic and the Phanerozoic

Andrew S. Merdith a Simon E. Williams b Alan S. Collins c Michael G. Tetley a Jacob A. Mulder d Morgan L. Blades c Alexander Young e Sheree E. Armistead f John Cannon g Sabin Zahirovic g R. Dietmar Müller


Recent progress in plate tectonic reconstructions has seen models move beyond the classical idea of continental drift by attempting to reconstruct the full evolving configuration of tectonic plates and plate boundaries. A particular problem for the Neoproterozoic and Cambrian is that many existing interpretations of geological and palaeomagnetic data have remained disconnected from younger, better-constrained periods in Earth history. An important test of deep time reconstructions is therefore to demonstrate the continuous kinematic viability of tectonic motions across multiple supercontinent cycles. We present, for the first time, a continuous full-plate model spanning 1 Ga to the present-day, that includes a revised and improved model for the Neoproterozoic–Cambrian (1000–520 Ma) that connects with models of the Phanerozoic, thereby opening up pre-Gondwana times for quantitative analysis and further regional refinements. In this contribution, we first summarise methodological approaches to full-plate modelling and review the existing full-plate models in order to select appropriate models that produce a single continuous model. Our model is presented in a palaeomagnetic reference frame, with a newly-derived apparent polar wander path for Gondwana from 540 to 320 Ma, and a global apparent polar wander path from 320 to 0 Ma. We stress, though while we have used palaeomagnetic data when available, the model is also geologically constrained, based on preserved data from past-plate boundaries. This study is intended as a first step in the direction of a detailed and self-consistent tectonic reconstruction for the last billion years of Earth history, and our model files are released to facilitate community development.

Keywords Palaeogeography Rodinia Gondwana Plate tectonics Neoproterozoic

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Origens da ancestralidade humana moderna: nem o registro genético ou fóssil até agora revelou um tempo e lugar definidos para a origem de nossa espécie.

quinta-feira, fevereiro 11, 2021

Origins of modern human ancestry

Anders Bergström, Chris Stringer, Mateja Hajdinjak, Eleanor M. L. Scerri & Pontus Skoglund

Nature volume 590, pages 229–237(2021)

Modern human origins and diversification in Africa in the past 300 thousand years.


New finds in the palaeoanthropological and genomic records have changed our view of the origins of modern human ancestry. Here we review our current understanding of how the ancestry of modern humans around the globe can be traced into the deep past, and which ancestors it passes through during our journey back in time. We identify three key phases that are surrounded by major questions, and which will be at the frontiers of future research. The most recent phase comprises the worldwide expansion of modern humans between 40 and 60 thousand years ago (ka) and their last known contacts with archaic groups such as Neanderthals and Denisovans. The second phase is associated with a broadly construed African origin of modern human diversity between 60 and 300 ka. The oldest phase comprises the complex separation of modern human ancestors from archaic human groups from 0.3 to 1 million years ago. We argue that no specific point in time can currently be identified at which modern human ancestry was confined to a limited birthplace, and that patterns of the first appearance of anatomical or behavioural traits that are used to define Homo sapiens are consistent with a range of evolutionary histories.

Subscription or Payment needed/Requer assinatura ou pagamento: Nature


Co-author Pontus Skoglund from The Francis Crick Institute said: "Contrary to what many believe, neither the genetic or fossil record have so far revealed a defined time and place for the origin of our species. Such a point in time, when the majority of our ancestry was found in a small geographic region and the traits we associate with our species appeared, may not have existed. For now, it would be useful to move away from the idea of a single time and place of origin."

On the origin of our species - Science Daily


Professores, pesquisadores e alunos de universidades públicas e privadas com acesso ao Portal de Periódicos CAPES-MEC podem ler gratuitamente este artigo da Nature e mais 33.000 periódicos científicos.

O dobramento incomum do DNA aumenta as taxas de mutações: isso pode mudar a forma como pensamos sobre a evolução.

quarta-feira, fevereiro 10, 2021

Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome

Wilfried M. Guiblet, Marzia A Cremona, Robert S Harris, Di Chen, Kristin A Eckert, Francesca Chiaromonte, Yi-Fei Huang, Kateryna D Makova Author Notes

Nucleic Acids Research, gkaa1269,

Published: 15 January 2021

Schematic of different types of non-B DNA structures. (A) G-quadruplex, (B) H-DNA, (C) Z-DNA, (D) cruciform, (E) slipped strands and (F) A-tract bending.


Mutation rates vary across the genome (1,2), and this phenomenon contributes to differences in the levels of intra- and interspecific genetic variation (henceforth called ‘diversity’ and ‘divergence’, respectively). As a result, certain genomic regions may be at a higher (or at a lower) risk of acquiring mutations important for adaptation and/or genetic diseases (1–3). In a broad sense, deciphering the causes of regional variation in mutation rates is essential to understanding both evolution and diseases (1,2).

Numerous genomic features contribute to regional variation in mutation rates, but those identified to date cannot account for all such variation. Some features are directly related to DNA sequence and usually act at the scale of single nucleotides, e.g. guanines and cytosines are more mutable than adenines and thymines (4,5). Neighboring nucleotides also have an effect, e.g. methylated cytosines in CpG dinucleotides are 10 times more mutable than other sites because of their spontaneous deamination (6), and several other contexts leading to guanine holes and increased mutagenesis were previously identified (7). Other genomic features—such as recombination rate (8), replication timing (9), chromatin accessibility (10,11), histone modifications (12,13), and Lamina Associated Domains (14)—contribute to regional variation in mutation rates through the variable activity of different enzymatic processes along the genome. These frequently act at larger scales, from several hundreds of kilobases to several megabases (Mbs). The magnitude of regional variation in mutation rates decreases with the increase in the genomic scale considered; most such regional variation in fact occurs at the single-nucleotide scale (1). At the 1-Mb scale, which is considered the natural long-range variation scale for mammalian genomes (15), most regions have mutation rates deviating by ∼2-fold (1). Notably, at this scale, several analyses indicated that the genomic features listed above explain only ∼50% of the regional variation in mutation rates (12,16,17). The correlation in regional variation in mutation rates between human and great apes (18) suggests that the unexplained portion of this variation is not random, and that additional factors remain to be discovered. Non-B DNA may be one such factor.

Cientistas falam sobre evidências de design inteligente na natureza

Evolução dinâmica dos cromossomos Y do grande símio

Dynamic evolution of great ape Y chromosomes

Monika Cechova, Rahulsimham Vegesna, Marta Tomaszkiewicz, Robert S. Harris, Di Chen, Samarth Rangavittal, Paul Medvedev, and Kateryna D. Makova

PNAS October 20, 2020 117 (42) 26273-26280; first published October 5, 2020;

Edited by Amanda M. Larracuente, University of Rochester, Rochester, NY, and accepted by Editorial Board Member Daniel L. Hartl September 3, 2020 (received for review January 30, 2020)

Evolution of Y chromosome gene content in great apes. 


The male-specific Y chromosome harbors genes important for sperm production. Because Y is repetitive, its DNA sequence was deciphered for only a few species, and its evolution remains elusive. Here we compared the Y chromosomes of great apes (human, chimpanzee, bonobo, gorilla, and orangutan) and found that many of their repetitive sequences and multicopy genes were likely already present in their common ancestor. Y repeats had increased intrachromosomal contacts, which might facilitate preservation of genes and gene regulatory elements. Chimpanzee and bonobo, experiencing high sperm competition, underwent many DNA changes and gene losses on the Y. Our research is significant for understanding the role of the Y chromosome in reproduction of nonhuman great apes, all of which are endangered.


The mammalian male-specific Y chromosome plays a critical role in sex determination and male fertility. However, because of its repetitive and haploid nature, it is frequently absent from genome assemblies and remains enigmatic. The Y chromosomes of great apes represent a particular puzzle: their gene content is more similar between human and gorilla than between human and chimpanzee, even though human and chimpanzee share a more recent common ancestor. To solve this puzzle, here we constructed a dataset including Ys from all extant great ape genera. We generated assemblies of bonobo and orangutan Ys from short and long sequencing reads and aligned them with the publicly available human, chimpanzee, and gorilla Y assemblies. Analyzing this dataset, we found that the genus Pan, which includes chimpanzee and bonobo, experienced accelerated substitution rates. Pan also exhibited elevated gene death rates. These observations are consistent with high levels of sperm competition in Pan. Furthermore, we inferred that the great ape common ancestor already possessed multicopy sequences homologous to most human and chimpanzee palindromes. Nonetheless, each species also acquired distinct ampliconic sequences. We also detected increased chromatin contacts between and within palindromes (from Hi-C data), likely facilitating gene conversion and structural rearrangements. Our results highlight the dynamic mode of Y chromosome evolution and open avenues for studies of male-specific dispersal in endangered great ape species.

sex chromosomespalindromesgene content evolution


Capturando o momento do surgimento do núcleo de cristal da desordem.

terça-feira, fevereiro 02, 2021

Capturing the Moment of Emergence of Crystal Nucleus from Disorder

Takayuki Nakamuro, Masaya Sakakibara, Hiroki Nada, Koji Harano, and Eiichi Nakamura*

Cite this: J. Am. Chem. Soc. 2021, XXXX, XXX, XXX-XXX

Publication Date:January 21, 2021

© 2021 American Chemical Society


Crystallization is the process of atoms or molecules forming an organized solid via nucleation and growth. Being intrinsically stochastic, the research at an atomistic level has been a huge experimental challenge. We report herein in situ detection of a crystal nucleus forming during nucleation/growth of a NaCl nanocrystal, as video recorded in the interior of a vibrating conical carbon nanotube at 20–40 ms frame–1 with localization precision of <0.1 nm. We saw NaCl units assembled to form a cluster fluctuating between featureless and semiordered states, which suddenly formed a crystal. Subsequent crystal growth at 298 K and shrinkage at 473 K took place also in a stochastic manner. Productive contributions of the graphitic surface and its mechanical vibration have been experimentally indicated.


A filogenômica revela discordância da árvore genética primordial na árvore da vida dos anfíbios

Phylogenomics Reveals Ancient Gene Tree Discordance in the Amphibian Tree of Life 

Paul M Hime, Alan R Lemmon, Emily C Moriarty Lemmon, Elizabeth Prendini, Jeremy M Brown, Robert C Thomson, Justin D Kratovil, Brice P Noonan, R Alexander Pyron, Pedro L V Peloso, Michelle L Kortyna, J Scott Keogh, Stephen C Donnellan, Rachel Lockridge Mueller, Christopher J Raxworthy, Krushnamegh Kunte, Santiago R Ron, Sandeep Das, Nikhil Gaitonde, David M Green, Jim Labisko, Jing Che, David W Weisrock

Author Notes

Systematic Biology, Volume 70, Issue 1, January 2021, Pages 49–66,

Published: 30 June 2020


Molecular phylogenies have yielded strong support for many parts of the amphibian Tree of Life, but poor support for the resolution of deeper nodes, including relationships among families and orders. To clarify these relationships, we provide a phylogenomic perspective on amphibian relationships by developing a taxon-specific Anchored Hybrid Enrichment protocol targeting hundreds of conserved exons which are effective across the class. After obtaining data from 220 loci for 286 species (representing 94% of the families and 44% of the genera), we estimate a phylogeny for extant amphibians and identify gene tree–species tree conflict across the deepest branches of the amphibian phylogeny. We perform locus-by-locus genealogical interrogation of alternative topological hypotheses for amphibian monophyly, focusing on interordinal relationships. We find that phylogenetic signal deep in the amphibian phylogeny varies greatly across loci in a manner that is consistent with incomplete lineage sorting in the ancestral lineage of extant amphibians. Our results overwhelmingly support amphibian monophyly and a sister relationship between frogs and salamanders, consistent with the Batrachia hypothesis. Species tree analyses converge on a small set of topological hypotheses for the relationships among extant amphibian families. These results clarify several contentious portions of the amphibian Tree of Life, which in conjunction with a set of vetted fossil calibrations, support a surprisingly younger timescale for crown and ordinal amphibian diversification than previously reported. More broadly, our study provides insight into the sources, magnitudes, and heterogeneity of support across loci in phylogenomic data sets.[AIC; Amphibia; Batrachia; Phylogeny; gene tree–species tree discordance; genomics; information theory.]

Associate Editor: Adam Leaché

FREE PDF GRATIS: Systematic Biology

O osso não precisa permanecer um elefante na sala de datação por radiocarbono!

segunda-feira, fevereiro 01, 2021

Bone need not remain an elephant in the room for radiocarbon dating

Salvador Herrando-Pérez

Published:13 January 2021


Radiocarbon (14C) analysis of skeletal remains by accelerator mass spectrometry is an essential tool in multiple branches of science. However, bone 14C dating results can be inconsistent and not comparable due to disparate laboratory pretreatment protocols that remove contamination. And, pretreatments are rarely discussed or reported by end-users, making it an ‘elephant in the room’ for Quaternary scientists. Through a questionnaire survey, I quantified consensus on the reliability of collagen pretreatments for 14C dating across 132 experts (25 countries). I discovered that while more than 95% of the audience was wary of contamination and would avoid gelatinization alone (minimum pretreatment used by most 14C facilities), 52% asked laboratories to choose the pretreatment method for them, and 58% could not rank the reliability of at least one pretreatment. Ultrafiltration was highly popular, and purification by XAD resins seemed restricted to American researchers. Isolating and dating the amino acid hydroxyproline was perceived as the most reliable pretreatment, but is expensive, time-consuming and not widely available. Solid evidence supports that only molecular-level dating accommodates all known bone contaminants and guarantees complete removal of humic and fulvic acids and conservation substances, with three key areas of progress: (i) innovation and more funded research is required to develop affordable analytical chemistry that can handle low-mass samples of collagen amino acids, (ii) a certification agency overseeing dating-quality control is needed to enhance methodological reproducibility and dating accuracy among laboratories, and (iii) more cross-disciplinary work with better 14C reporting etiquette will promote the integration of 14C dating across disciplines. Those developments could conclude long-standing debates based on low-accuracy data used to build chronologies for animal domestications, human/megafauna extirpations and migrations, archaeology, palaeoecology, palaeontology and palaeoclimate models.

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Os fundamentos das visões de concordância da filogenia numa era discordante

quinta-feira, janeiro 28, 2021

The Foundations of Concordance Views of Phylogeny

Joel D. Velasco, Department of Philosophy, Texas Tech University, 2500 Broadway, Lubbock, Texas 79409, USA



Clade, Concordance Tree, Phylogeny, Plurality Consensus


Volume 11, No. 020, 2019

Received 21 November 2017; Revised 25 November 2018; Accepted 8 March 2019


Despite the enormous importance and widespread use of the term, it is unclear exactly what a phylogeny is and what a phylogenetic tree represents. A natural thought is that a phylogeny should represent the “dominant history” of the flow of genetic information. Here, I will focus on methods in which a tree is determined by input gene trees. I compare various possibilities of how to do this including consensus trees, the R* triplet method, and concordance methods. I make precise the notion of a concordance factor and then compare concordance trees to species trees, which attempt to track population histories through time. I show that even in the most idealized circumstances, it is possible for the primary concordance tree to differ from the species tree. I argue that when these trees differ, there are reasons to think of the primary concordance tree as a better representation of phylogenetic history than the species tree and that when these highly idealized conditions break down, it is especially plausible that we should take concordance trees seriously as an interpretation of phylogeny and as the basis for taxonomic grouping.

Part of the special issue Species in the Age of Discordance, guest-edited by Matthew H. Haber and Daniel J. Molter.


Topoisomerases de DNA - Análise da estrutura-função dos papéis celulares e complexos multiproteicos: mero acaso, fortuita necessidade ou design inteligente?

segunda-feira, janeiro 25, 2021

DNA topoisomerases: Advances in understanding of cellular roles and multi‐protein complexes via structure‐function analysis

Shannon J. McKie Keir C. Neuman Anthony Maxwell

First published: 22 January 2021

DNA topology and DNA topoisomerase mechanisms. 


DNA topoisomerases, capable of manipulating DNA topology, are ubiquitous and indispensable for cellular survival due to the numerous roles they play during DNA metabolism. As we review here, current structural approaches have revealed unprecedented insights into the complex DNA‐topoisomerase interaction and strand passage mechanism, helping to advance our understanding of their activities in vivo. This has been complemented by single‐molecule techniques, which have facilitated the detailed dissection of the various topoisomerase reactions. Recent work has also revealed the importance of topoisomerase interactions with accessory proteins and other DNA‐associated proteins, supporting the idea that they often function as part of multi‐enzyme assemblies in vivo. In addition, novel topoisomerases have been identified and explored, such as topo VIII and Mini‐A. These new findings are advancing our understanding of DNA‐related processes and the vital functions topos fulfil, demonstrating their indispensability in virtually every aspect of DNA metabolism.


Quantas moléculas de água são necessárias para solvatar uma molécula?

quinta-feira, janeiro 21, 2021

How many water molecules are needed to solvate one?† 

Alessandro Rognoni, ORCID logo a Riccardo Conte ORCID logo a and Michele Ceotto *a 

Author affiliations


Many efforts undertaken to study the solvation process have led to general theories that may describe mean properties, but are unable to provide a detailed understanding at the molecular level. Remarkably, the basic question of how many solvent molecules are necessary to solvate one solute molecule is still open. By exploring several water aggregates of increasing complexity, in this contribution we employ semiclassical spectroscopy to determine on quantum dynamical grounds the minimal network of surrounding water molecules to make the central one display the same vibrational features of liquid water. We find out that double-acceptor double-donor tetrahedral coordination constituting the standard picture is necessary but not sufficient, and that particular care must be reserved for the quantum description of the combination band due to the coupling of the central monomer bending mode with network librations. It is actually our ability to investigate the combination band with a quantum-derived approach that allows us to answer the titular question. The minimal structure eventually responsible for proper solvation is made of a total of 21 water molecules and includes two complete solvation shells, of which the whole first one is tetrahedrally coordinated to the central molecule.

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Orientando a formação de proteínas: mero acaso, fortuita necessidade ou design inteligente?

quarta-feira, janeiro 06, 2021

Structural and mechanistic basis of the EMC-dependent biogenesis of distinct transmembrane clients

Lakshmi E Miller-Vedam, Bastian Bräuning, Katerina D Popova, Nicole T Schirle Oakdale, Jessica L Bonnar, Jesuraj R Prabu, Elizabeth A Boydston, Natalia Sevillano, Matthew J Shurtleff, Robert M Stroud, Charles S Craik, Brenda A Schulman Is a corresponding author, Adam Frost Is a corresponding author, Jonathan S Weissman Is a corresponding author s

Molecular, Cellular, and Computational Biophysics Graduate Program, University of California, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, United States; Department of Biology, Whitehead Institute, MIT, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, United States; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Germany; Biomedical Sciences Graduate Program, University of California, San Francisco, United States; Department of Pharmaceutical Chemistry, University of California, San Francisco, United States; Howard Hughes Medical Institute, United States

Three identical snapshots of the structure of human EMC:
Image credit: Lakshmi E Miller-Vedam, Bastian Bräuning and Katerina D Popova, created using UCSF ChimeraX (CC BY 4.0)


Membrane protein biogenesis in the endoplasmic reticulum (ER) is complex and failure-prone. The ER membrane protein complex (EMC), comprising eight conserved subunits, has emerged as a central player in this process. Yet, we have limited understanding of how EMC enables insertion and integrity of diverse clients, from tail-anchored to polytopic transmembrane proteins. Here, yeast and human EMC cryo-EM structures reveal conserved intricate assemblies and human-specific features associated with pathologies. Structure-based functional studies distinguish between two separable EMC activities, as an insertase regulating tail-anchored protein levels and a broader role in polytopic membrane protein biogenesis. These depend on mechanistically coupled yet spatially distinct regions including two lipid-accessible membrane cavities which confer client-specific regulation, and a non-insertase EMC function mediated by the EMC lumenal domain. Our studies illuminate the structural and mechanistic basis of EMC’s multifunctionality and point to its role in differentially regulating the biogenesis of distinct client protein classes.

eLife digest

Cells are surrounded and contained by a plasma membrane consisting of a double layer of fats and proteins. These proteins monitor and facilitate the movement of food, oxygen and messages in and out of the cell, and help neighboring cells communicate. Membrane proteins are manufactured in a cell compartment called the endoplasmic reticulum. Cellular machines called ribosomes visit this compartment’s membrane to manufacture proteins that need to be secreted or embedded into the cell’s membranes. As these proteins are made, they are pulled into the endoplasmic reticulum so they can be folded correctly and inserted in the membrane. A cellular machine in this compartment’s membrane that aids this process is the endoplasmic reticulum membrane protein complex (EMC). Many steps can go wrong during protein assembly, so to control protein quality, the EMC has to accommodate the variety of complex physical features that proteins can have.

To explore the activity of the EMC, Miller-Vedam, Bräuning, Popova et al. studied the normal structure of the EMC in both yeast and human cells grown in the lab. These snapshots of the complex in different species had a lot in common, including how the complex was arranged within and around the membrane.

Next, Miller-Vedam, Bräuning, Popova et al. generated 50 mutant versions of the EMC in human cells to determine how changing different parts of the complex affected the production of three proteins that rely on the EMC to fold correctly. These proteins were an enzyme called squalene synthase, a signaling protein called the beta adrenergic receptor and sigma intracellular receptor 2, a protein involved in the regulation of cholesterol levels.

Mutations in the section of the EMC outside of the endoplasmic reticulum, within the main cellular compartment, negatively impacted the stability of squalene synthase. This section of the EMC provides a platform where proteins can associate before entering the membrane.

The part of EMC that spans the membrane contains both a fat-filled cavity and a cavity with a ‘door’ that is either open or closed. Mutations in this section disrupted the insertion of both squalene synthase and the beta adrenergic receptor into the membrane, a role performed by the cavity with the door. The specific role of the fat-filled cavity is still not fully understood, but a mutation affecting this cavity disrupts the correct production of all three proteins studied.

The largest section of the complex, which sits inside the endoplasmic reticulum, protected proteins as they folded, ensuring they were not destroyed for being folded incorrectly before they were fully formed. Mutations in this part of the EMC negatively impacted the stability of sigma intracellular receptor 2 without negatively affecting the other proteins.

This molecular dissection of the activity of the EMC provides insights into how membrane proteins are manufactured, stabilized, coordinated, and monitored for quality. These findings could contribute towards the development of new treatments for certain congenital diseases. For example, cystic fibrosis, retinitis pigmentosa, and Charcot-Marie-Tooth disease are all thought to be caused by mutations within membrane proteins that require the EMC during their production.


Gilbert 'falou e disse': a teoria da seleção natural de Darwin não funciona e precisa da teoria da recompensa natural!

terça-feira, janeiro 05, 2021

Natural reward drives the advancement of life

Owen M. Gilbert

Comparison of theories of natural selection and natural reward. A The theory of natural selection includes A only. B The theory of natural reward includes A and B, and the connection between them.


Throughout the history of life on earth, rare and complex innovations have periodically increased the efficiency with which abiotic free energy and biotic resources are converted to biomass and organismal diversity. Such macroevolutionary expansions have increased the total amount of abiotic free energy utilized by life and shaped the earth’s ecosystems. Meanwhile, Darwin’s theory of natural selection assumes a historical, worldwide state of effective resource limitation, which could not possibly be true if life evolved from one or a few original ancestors. In this paper, I analyze the self-contradiction in Darwin’s theory that comes from viewing the world and universe as effectively resource limited. I then extend evolutionary theory to include a second deterministic evolutionary force, natural reward. Natural reward operates on complex inventions produced by natural selection and is analogous to the reward for innovation in human economic systems. I hypothesize that natural reward, when combined with climate change and extinction, leads to the increased innovativeness, or what I call the advancement, of life with time. I then discuss applications of the theory of natural reward to the evolution of evolvability, the apparent sudden appearance of new forms in the fossil record, and human economic evolution. I conclude that the theory of natural reward holds promise as an explanation for the historical advancement of life on earth.


invention, entrepreneurship, innovation, success, progress, advancement

FREE PDF GRATIS: Rethinking Ecology

Nem todos os dinossauros morreram no impacto do grande asteroide Chicxulub há 66 milhões de anos!

domingo, janeiro 03, 2021

Over 13,000 elements from a single bonebed help elucidate disarticulation and transport of an Edmontosaurus thanatocoenosis

Keith Snyder, Matthew McLain, Jared Wood, Arthur Chadwick


Over twenty years of work on the Hanson Ranch (HR) Bonebed in the Lance Formation of eastern Wyoming has yielded over 13,000 individual elements primarily of the hadrosaurid dinosaur Edmontosaurus annectens. The fossil bones are found normally-graded within a fine-grained (claystone to siltstone) bed that varies from one to two meters in thickness. Almost all specimens exhibit exquisite preservation (i.e., little to no abrasion, weathering, and breakage), but they are disarticulated which, combined with our sedimentological observations, suggests that the bones were remobilized and buried after a period of initial decay and disarticulation of Edmontosaurus carcasses. Because of the large number of recovered fossil elements, we have been able to gain deeper insight into Edmontosaurus biostratigraphy including disarticulation and transport of skeletal elements. The most common postcranial elements in the bonebed are pubes, ischia, scapulae, ribs, and limb bones. By contrast, vertebrae, ilia, and chevrons are rare. The most common craniomandibular bones include dentaries, nasals, quadrates, and jugals, whereas the premaxillae, predentaries, and braincase bones are underrepresented. Thus, overall, chondrocranial and axial elements, as well as distal elements of the limbs, are distinctly underrepresented. We hypothesize that following decay and disarticulation, hydraulic winnowing removed the articulated sections (e.g., vertebral columns) and the small, distal-most elements before, or at the same time, the remaining bones were swept up in a subaqueous debris flow that generated the deposit. Comparison of the HR Bonebed with other widely dispersed Upper Cretaceous hadrosaurid-dominated bonebeds reveals many shared attributes, which suggests similar processes at work in the formation of these bonebeds across space and time. This in turn reflects similar behavior by populations of these species around the world resulting in similar modes of death, becoming interred in similar depositional settings.



NOTA DESTE BLOGGER: O Dr. Arthur Chadwick é amigo pessoal deste blogger.

Mero acaso, fortuita necessidade ou design inteligente???

terça-feira, dezembro 29, 2020

Click here/Clique aqui: (157) Do You Love Me? - YouTube

Um megatsunami atingiu a costa israelense há 10.000 anos atrás.

segunda-feira, dezembro 28, 2020

A Neolithic mega-tsunami event in the eastern Mediterranean: Prehistoric settlement vulnerability along the Carmel coast, Israel

Gilad Shtienberg ,Assaf Yasur-Landau,Richard D. Norris,Michael Lazar,Tammy M. Rittenour,Anthony Tamberino,Omri Gadol,Katrina Cantu,Ehud Arkin-Shalev,Steven N. Ward,Thomas E. Levy

Published: December 23, 2020


Tsunami events in antiquity had a profound influence on coastal societies. Six thousand years of historical records and geological data show that tsunamis are a common phenomenon affecting the eastern Mediterranean coastline. However, the possible impact of older tsunamis on prehistoric societies has not been investigated. Here we report, based on optically stimulated luminescence chronology, the earliest documented Holocene tsunami event, between 9.91 to 9.29 ka (kilo-annum), from the eastern Mediterranean at Dor, Israel. Tsunami debris from the early Neolithic is composed of marine sand embedded within fresh-brackish wetland deposits. Global and local sea-level curves for the period, 9.91–9.29 ka, as well as surface elevation reconstructions, show that the tsunami had a run-up of at least ~16 m and traveled between 3.5 to 1.5 km inland from the palaeo-coastline. Submerged slump scars on the continental slope, 16 km west of Dor, point to the nearby “Dor-complex” as a likely cause. The near absence of Pre-Pottery Neolithic A-B archaeological sites (11.70–9.80 cal. ka) suggest these sites were removed by the tsunami, whereas younger, late Pre-Pottery Neolithic B-C (9.25–8.35 cal. ka) and later Pottery-Neolithic sites (8.25–7.80 cal. ka) indicate resettlement following the event. The large run-up of this event highlights the disruptive impact of tsunamis on past societies along the Levantine coast.


Nanomáquinas propulsoras: evolução convergente de arquelas, flagelos e cílios ou design inteligente?

terça-feira, dezembro 08, 2020

Propulsive nanomachines: the convergent evolution of archaella, flagella and cilia 

Morgan Beeby, Josie L Ferreira, Patrick Tripp, Sonja-Verena Albers, David R Mitchell 

FEMS Microbiology Reviews, Volume 44, Issue 3, May 2020, Pages 253–304, 

Published: 09 March 2020

Flagellar motor structure - FEMS


Echoing the repeated convergent evolution of flight and vision in large eukaryotes, propulsive swimming motility has evolved independently in microbes in each of the three domains of life. Filamentous appendages – archaella in Archaea, flagella in Bacteria and cilia in Eukaryotes – wave, whip or rotate to propel microbes, overcoming diffusion and enabling colonization of new environments. The implementations of the three propulsive nanomachines are distinct, however: archaella and flagella rotate, while cilia beat or wave; flagella and cilia assemble at their tips, while archaella assemble at their base; archaella and cilia use ATP for motility, while flagella use ion-motive force. These underlying differences reflect the tinkering required to evolve a molecular machine, in which pre-existing machines in the appropriate contexts were iteratively co-opted for new functions and whose origins are reflected in their resultant mechanisms. Contemporary homologies suggest that archaella evolved from a non-rotary pilus, flagella from a non-rotary appendage or secretion system, and cilia from a passive sensory structure. Here, we review the structure, assembly, mechanism and homologies of the three distinct solutions as a foundation to better understand how propulsive nanomachines evolved three times independently and to highlight principles of molecular evolution.

flagella, cilia, archaella, molecular evolution, microbial motility, convergent evolution

FREE PDF GRATIS: FEMS Microbiology Reviews

Será que o cérebro humano se parece com o universo? Mero acaso, fortuita necessidade ou design inteligente?

terça-feira, novembro 17, 2020

Front. Phys., 16 November 2020 |

The Quantitative Comparison Between the Neuronal Network and the Cosmic Web

www.frontiersin.orgF. Vazza1,2,3* and www.frontiersin.orgA. Feletti4,5

1Dipartimento di Fisica e Astronomia, Universitá di Bologna, , Bologna, Italy

2Hamburger Sternwarte, Hamburg, Germany

3Istituto di Radio Astronomia, INAF, Bologna, Italy

4Institute of Neurosurgery, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy

5Azienda Ospedaliera‐Universitaria di Modena, Modena, Italy

1Left: section of cerebellum, with magnification factor 40x, obtained with electron microscopy (Dr. E. Zunarelli, University Hospital of Modena); right: section of a cosmological simulation, with an extension of 300 million light-years on each side (Vazza et al. 2019 A&A). Credit: University of Bologna

We investigate the similarities between two of the most challenging and complex systems in Nature: the network of neuronal cells in the human brain, and the cosmic network of galaxies. We explore the structural, morphological, network properties and the memory capacity of these two fascinating systems, with a quantitative approach. In order to have an homogeneous analysis of both systems, our procedure does not consider the true neural connectivity but an approximation of it, based on simple proximity. The tantalizing degree of similarity that our analysis exposes seems to suggest that the self-organization of both complex systems is likely being shaped by similar principles of network dynamics, despite the radically different scales and processes at play.

FREE PDF GRATIS: Frontiers in Physics

Mais uma hipótese sobre a origem da vida: modelos de precursores potenciais de células resistem às condições simuladas da Terra primitiva

quinta-feira, outubro 29, 2020

Impact of wet-dry cycling on the phase behavior and compartmentalization properties of complex coacervates

Hadi M. Fares, Alexander E. Marras, Jeffrey M. Ting, Matthew V. Tirrell & Christine D. Keating 

Nature Communications volume 11, Article number: 5423 (2020)


Wet-dry cycling on the early Earth is thought to have facilitated production of molecular building blocks of life, but its impact on self-assembly and compartmentalization remains largely unexplored. Here, we investigate dehydration/rehydration of complex coacervates, which are membraneless compartments formed by phase separation of polyelectrolyte solutions. Solution compositions are identified for which tenfold water loss results in maintenance, disappearance, or appearance of coacervate droplets. Systems maintaining coacervates throughout the dehydration process are further evaluated to understand how their compartmentalization properties change with drying. Although added total RNA concentrations increase tenfold, RNA concentration within coacervates remains steady. Exterior RNA concentrations rise, and exchange rates for encapsulated versus free RNAs increase with dehydration. We explain these results in light of the phase diagram, with dehydration-driven ionic strength increase being particularly important in determining coacervate properties. This work shows that wet-dry cycling can alter the phase behavior and protocell-relevant functions of complex coacervates.

Editores de revistas científicas não devem contribuir para politizar a ciência!

segunda-feira, outubro 26, 2020

 Science journal editors shouldn’t contribute to politicizing science


Source/Fonte: Samuel Corum - Getty Images

When the editors of some of the world’s leading science journals agree on something, it is generally safe to assume that they are correct. So when prominent journals like ScienceNature, and the New England Journal of Medicine recently published editorials excoriating President Trump’s deadly bungling of the pandemic response and suppression of scientific activity, the editors accurately spotlighted the troubling deficiencies of the current administration.

But in advocating against or endorsing a presidential candidate, these editors made a grave error. In taking this extraordinary step, they made themselves vulnerable to charges of bias, overstepped their roles as science editors, and succumbed to the politicization of science that they and many other scientists find so alarming.

At first glance, these appear to be similar to run-of-the-mill newspaper endorsements. This analogy, however, is not quite right. At a newspaper, there is a wall between the news operation and the editorial office. It exists to prevent biases of the editorial staff from influencing news reporting. No such wall exists for science journals. The editors who write the editorials are the same ones who evaluate manuscripts and make the final decisions on whether to publish them.

There’s another problem: This political advocacy unnecessarily invites allusions to cronyism, echoing a less savory time when wealthy newspaper owners used their editorial pages to extol the merits of their political chums. Indeed, because of fears surrounding the appearance of undue influence and bias, many newspapers in recent years have abandoned political endorsements.

Read more here: STAT News