Current Issues in Molecular Biology Journal Enters a New Era.

Current Issues in Molecular Biology (CIMB) (https://www [...].

Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. METHODS: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. RESULTS: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-ß proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. CONCLUSIONS: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. LAY SUMMARY: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.

Mantle cell lymphoma - advances in molecular biology, prognostication and treatment approaches.

Mantle cell lymphoma (MCL) is clinically characterised by its heterogenous behaviour with courses ranging from indolent cases that do not require therapy for years to highly aggressive MCL with a very limited prognosis. A better understanding of the complex biology of MCL has already led to the approval of several innovative agents, expanding the landscape of MCL therapies and improving therapeutic options especially for refractory/relapsed (R/R) disease. Nevertheless, to further optimise MCL treatment, early identification of individual risk profile and risk-adapted, patient-tailored choice of therapeutic strategy needs to be prospectively incorporated into clinical patient management. The present review highlights recent advances in deciphering the molecular background of MCL, the definition of prognostically relevant factors and the identification of potential druggable targets and summarises current treatment recommendations for primary and R/R MCL including novel targeted therapies.

The 2021 Nucleic Acids Research database issue and the online molecular biology database collection.

The 2021 Nucleic Acids Research database Issue contains 189 papers spanning a wide range of biological fields and investigation. It includes 89 papers reporting on new databases and 90 covering recent changes to resources previously published in the Issue. A further ten are updates on databases most recently published elsewhere. Seven new databases focus on COVID-19 and SARS-CoV-2 and many others offer resources for studying the virus. Major returning nucleic acid databases include NONCODE, Rfam and RNAcentral. Protein family and domain databases include COG, Pfam, SMART and Panther. Protein structures are covered by RCSB PDB and dispersed proteins by PED and MobiDB. In metabolism and signalling, STRING, KEGG and WikiPathways are featured, along with returning KLIFS and new DKK and KinaseMD, all focused on kinases. IMG/M and IMG/VR update in the microbial and viral genome resources section, while human and model organism genomics resources include Flybase, Ensembl and UCSC Genome Browser. Cancer studies are covered by updates from canSAR and PINA, as well as newcomers CNCdatabase and Oncovar for cancer drivers. Plant comparative genomics is catered for by updates from Gramene and GreenPhylDB. The entire Database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). The NAR online Molecular Biology Database Collection has been substantially updated, revisiting nearly 1000 entries, adding 90 new resources and eliminating 86 obsolete databases, bringing the current total to 1641 databases. It is available at https://www.oxfordjournals.org/nar/database/c/.

[Pathology training in Spain: What is the status quo and how should we improve?] / Residencia de Anatomía Patológica en España: ¿cómo estamos y en qué debemos mejorar?

The unpopularity of Pathology among medical students is of concern worldwide, as is the high drop-out rate during the speciality training programme. Spain is no exception, with an estimated annual drop-out rate greater than 20%. In the present study, we aimed to analyse factors related to motivation, teaching and satisfaction with post-graduate training. Postgraduates in their 3rd and 4th year of speciality training programmes and pathologists during their first three years as specialists were asked to fill in a questionnaire; 155 participants from different parts of Spain took part in the study. Our results revealed a high level of satisfaction among those who had chosen pathology as their specialty and that their satisfaction correlated significantly with two factors: a previous knowledge of the speciality when choosing it and the quality of the training received. We detected certain differences amongst different training centres. The weakest points and thus those that need to be improved were training in molecular techniques, research methods and fine needle aspiration. Improving speciality training is certainly possible and should be the concern of all those who are responsible for postgraduate education in teaching hospitals.

Consequences of PCA graphs, SNP codings, and PCA variants for elucidating population structure.

SNP datasets are high-dimensional, often with thousands to millions of SNPs and hundreds to thousands of samples or individuals. Accordingly, PCA graphs are frequently used to provide a low-dimensional visualization in order to display and discover patterns in SNP data from humans, animals, plants, and microbes-especially to elucidate population structure. PCA is not a single method that is always done the same way, but rather requires three choices which we explore as a three-way factorial: two kinds of PCA graphs by three SNP codings by six PCA variants. Our main three recommendations are simple and easily implemented: Use PCA biplots, SNP coding 1 for the rare allele and 0 for the common allele, and double-centered PCA (or AMMI1 if main effects are also of interest). We also document contemporary practices by a literature survey of 125 representative articles that apply PCA to SNP data, find that virtually none implement our recommendations. The ultimate benefit from informed and optimal choices of PCA graph, SNP coding, and PCA variant, is expected to be discovery of more biology, and thereby acceleration of medical, agricultural, and other vital applications.

Characteristics and evolution of the ecosystem of software tools supporting research in molecular biology.

Daily work in molecular biology presently depends on a large number of computational tools. An in-depth, large-scale study of that 'ecosystem' of Web tools, its characteristics, interconnectivity, patterns of usage/citation, temporal evolution and rate of decay is crucial for understanding the forces that shape it and for informing initiatives aimed at its funding, long-term maintenance and improvement. In particular, the long-term maintenance of these tools is compromised because of their specific development model. Hundreds of published studies become irreproducible de facto, as the software tools used to conduct them become unavailable. In this study, we present a large-scale survey of >5400 publications describing Web servers within the two main bibliographic resources for disseminating new software developments in molecular biology. For all these servers, we studied their citation patterns, the subjects they address, their citation networks and the temporal evolution of these factors. We also analysed how these factors affect the availability of these servers (whether they are alive). Our results show that this ecosystem of tools is highly interconnected and adapts to the 'trendy' subjects in every moment. The servers present characteristic temporal patterns of citation/usage, and there is a worrying rate of server 'death', which is influenced by factors such as the server popularity and the institutions that hosts it. These results can inform initiatives aimed at the long-term maintenance of these resources.

PopSc: Computing Toolkit for Basic Statistics of Molecular Population Genetics Simultaneously Implemented in Web-Based Calculator, Python and R.

Although various computer tools have been elaborately developed to calculate a series of statistics in molecular population genetics for both small- and large-scale DNA data, there is no efficient and easy-to-use toolkit available yet for exclusively focusing on the steps of mathematical calculation. Here, we present PopSc, a bioinformatic toolkit for calculating 45 basic statistics in molecular population genetics, which could be categorized into three classes, including (i) genetic diversity of DNA sequences, (ii) statistical tests for neutral evolution, and (iii) measures of genetic differentiation among populations. In contrast to the existing computer tools, PopSc was designed to directly accept the intermediate metadata, such as allele frequencies, rather than the raw DNA sequences or genotyping results. PopSc is first implemented as the web-based calculator with user-friendly interface, which greatly facilitates the teaching of population genetics in class and also promotes the convenient and straightforward calculation of statistics in research. Additionally, we also provide the Python library and R package of PopSc, which can be flexibly integrated into other advanced bioinformatic packages of population genetics analysis.

[International research trends of pharmacognosy on molecular level --based on analysis of SCI literature].

The techniques and methods of molecular biology have been widely applied in pharmacognosy fields. International development trends of pharmacognosy studies on molecular level were analyzed by bibliometric methods using the SCIE database on Web of Science, the literature distribution, national distribution, agency distribution, periodicals distribution, and hot research topics were described using multivariate statistical analysis and multidimensional scaling analysis method,etc. The number of international pharmacognosy literature on molecular level is increasing year by year. USA, China and Japan have close cooperation, and focus on molecular identification and genetic diversity. Chinese scientists issued high-impact factor journals papers and high citations amount in the international forefront. The international pharmacognosy research on molecular level has developed rapidly. Chinese research has a significant influence.The molecular mechanism of the formation of Dao-di Herbs may become the next hotspot.

The impact of companion diagnostic device measurement performance on clinical validation of personalized medicine.

A key component of personalized medicine is companion diagnostics that measure biomarkers, for example, protein expression, gene amplification or specific mutations. Most of the recent attention concerning molecular cancer diagnostics has been focused on the biomarkers of response to therapy, such as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in metastatic colorectal cancer, epidermal growth factor receptor mutations in metastatic malignant melanoma. The presence or absence of these markers is directly linked to the response rates of particular targeted therapies with small-molecule kinase inhibitors or antibodies. Therefore, testing for these markers has become a critical step in the target therapy of the aforementioned tumors. The core capability of personalized medicine is the companion diagnostic devices' (CDx) ability to accurately and precisely stratify patients by their likelihood of benefit (or harm) from a particular therapy. There is no reference in the literature discussing the impact of device's measurement performance, for example, analytical accuracy and precision on treatment effects, variances, and sample sizes of clinical trial for the personalized medicine. In this paper, using both analytical and estimation method, we assessed the impact of CDx measurement performance as a function of positive and negative predictive values and imprecision (standard deviation) on treatment effects, variances of clinical outcome, and sample sizes for the clinical trials.

NP-Sticky: a web server for optimizing DNA ligation with non-palindromic sticky ends.

High-efficiency DNA ligation is vital for many molecular biology experiments, and it is best achieved using reactants with non-palindromic sticky ends to maximize specificity. However, optimizing such multi-parametric ligation reactions often involves extensive trial and error. We have developed a freely available Web-based ligation calculator, NP-Sticky (http://sarkarlab.umn.edu/npsticky/), that predicts product distribution for given reactant concentrations, thus enabling straightforward computational optimization of these reactions. Built-in schemes include two-piece and three-piece linear ligation, as well as insert-vector circular ligation. The only parameters needed for the underlying thermodynamic model are the free energies of ligation for each sticky end, which can be estimated by the calculator from the overhang sequences or provided by the user from direct experimental measurement. Free energies of sticky-end mismatches are also calculated for determining the extent of byproduct formation. This ligation calculator allows rapid identification of the optimal conditions for maximizing incorporation, efficiency, and/or accuracy, based on specific needs.

Inverse Gillespie for inferring stochastic reaction mechanisms from intermittent samples.

Gillespie stochastic simulation is used extensively to investigate stochastic phenomena in many fields, ranging from chemistry to biology to ecology. The inverse problem, however, has remained largely unsolved: How to reconstruct the underlying reactions de novo from sparse observations. A key challenge is that often only aggregate concentrations, proportional to the population numbers, are observable intermittently. We discovered that under specific assumptions, the set of relative population updates in phase space forms a convex polytope whose vertices are indicative of the dominant underlying reactions. We demonstrate the validity of this simple principle by reconstructing stochastic models (reaction structure plus propensities) from a variety of simulated and experimental systems, where hundreds and even thousands of reactions may be occurring in between observations. In some cases, the inferred models provide mechanistic insight. This principle can lead to the understanding of a broad range of phenomena, from molecular biology to population ecology.

Information recovery in molecular biology: causal modelling of regulated promoter switching experiments.

The recovery of information from indirect measurements takes different forms depending on the sophistication with which the process being researched can be modelled mathematically. The forms range from (1) the historical and classical inverse problems regularization situation where explicit models which guaranteed existence and uniqueness have been formulated, through (2) situations where model formulation is performed implicitly as a calibration-and-prediction ansatz, to (3) the exploratory (biology) situation where the underlying mechanism is unknown and constraining information about its dynamics is being sought through appropriate experimentation. Each represents a different aspect of the solution of inverse problems. It is the nature of the exploratory form that is discussed in this paper. The focus is the causal modelling of regulated promoter switching experiments performed to understand the dynamics of the genetic control of various biological developmental processes such as vernalization in plants; in particular, regulated promoter switching experiments used to examine the relationship between FLC transcription activity and the associated histone H3 lysine 27 trimethylation at a vernalization-responsive gene in plants. Using a causal representation with Kohlrausch function fading memory, it is shown how such modelling can be used to quantitatively assess the closeness of the linking of one biological process with another, and, in particular, to conclude that the dynamics of FLC transcription and associated H3K27me3 activity are closely linked biologically.

Assessment of the scientific-technological production in molecular biology in Brazil (1996-2007): the contribution of genomics programs.

Several genome sequencing programs were launched in Brazil by the end of the nineties and the early 2000s.The most important initiatives were supported by the ONSA program (http://watson.fapesp.br/onsa/Genoma3.htm) and aimed at gaining domain in genomic technology and bringing molecular biology to the state of art. Two main sets of data were collected in the 1996-2007 period to evaluate the results of these genome programs: the scientific production (Scopus and Web of Science databases) and the register of patents (US Patent and Trademark Office), both related to the progress of molecular biology along this period. In regard to the former, Brazil took a great leap in comparison to 17 other developed and developing countries, being only surpassed by China. As to the register of patents in the area of molecular biology, Brazil's performance lags far behind most of the countries focused in the present study, confirming the Brazilian long-standing tendency of poor achievements in technological innovations when compared with scientific production. Possible solutions to surpass this inequality are discussed.

Assessment of the scientific-technological production in molecular biology in Brazil (1996-2007): the contribution of genomics programs

Several genome sequencing programs were launched in Brazil by the end of the nineties and the early 2000s.The most important initiatives were supported by the ONSA program (http://watson.fapesp.br/onsa/Genoma3.htm) and aimed at gaining domain in genomic technology and bringing molecular biology to the state of art. Two mainsets of data were collected in the 1996-2007 period to evaluate the results of these genome programs: the scientific production (Scopus and Web of Science databases) and the register of patents (US Patent and Trademark Office), both related to the progress of molecular biology along this period. In regard to the former, Brazil took a great leap in comparison to 17 other developed and developing countries, being only surpassed by China. As to the register of patents in the area of molecular biology, Brazil's performance lags far behind most of the countries focused in the presentstudy, confirming the Brazilian long-standing tendency of poor achievements in technological innovations when compared with scientific production. Possible solutions to surpass this inequality are discussed.

Vários programas de sequenciamento de genoma foram lançados no Brasil no final da década de noventa e início dadécada de 2000. As mais importantes iniciativas foram sustentadas pelo programa ONSA (http://watson.fapesp.br/onsa/Genoma3.htm) e visavam o domínio da tecnologia genômica e o progresso da biologia molecular para o estado da arte desta disciplina. Dois principais conjuntos de dados foram coletados no período de 1996-2007 para avaliar os resultados destes programas de genômica: a produção científica (bases de dados SCOPUS e o registro de patentes (US Patent and Trademark Office), ambos relacionados com o progresso de biologiamolecular ao longo deste período. Em relação ao primeiro o Brasil de um grande passo em comparação a 17 outros países desenvolvidos e em desenvolvimento, sendo apenas superado pela China. Com relação ao registro de patentes na área de biologia molecular, o desempenho do Brasil fica bem atrás entre os países focados no presente estudo, confirmando a perdurável tendência de pobres conquistas em inovação tecnológica, quando comparado com produção científica. São discutidas as possíveis soluções para superar este desequilíbrio.

Caracterização molecular e fenotípica de amostras bacterianas pertencentes ao complexo Acinetobacter calcoaceticus-Acinetobacter baumannii / Molecular and phenotypic characterization of Acinetobacter calcoaceticus-Acinetobacter baumannii isolates

Nos últimos 30 anos, Acinetobacter tornou-se um dos patógenos de maior preocupação clínica pela falta de terapias eficazes em virtude do fenótipo de multirresistência frequentemente apresentado. Dentre as espécies do gênero Acinetobacter, A. baumannii, A. genoespécie 3 e A. genoespécie 13TU são as mais comumente encontradas a partir de amostras biológicas. Estas espécies ao lado de A. calcoaceticus constituem o complexo A. calcoaceticus-A. baumannii (ACB). Este estudo propõe um esquema composto de duas PCRs para a identificação das espécies de interesse médico que fazem parte do complexo ACB. O método é simples, rápido e, além de identificar as espécies, permite pesquisar a presença de genes de resistência. Foram identificadas 515 amostras do complexo ACB, isoladas de pacientes no período de janeiro de 2005 a dezembro de 2010. A identificação das espécies do complexo ACB foi realizada por esquema composto de duas reações de PCR. Foram avaliados os perfis de sensibilidade por disco difusão e a pesquisa da presença dos genes blaOXA-23-like, blaOXA-24-like, blaOXA-51-like, blaOXA-58-like, blaIMP, blaVIM, blaSIM, blaSPM e blaGIM foi realizada por PCR utilizando-se iniciadores específicos. No grupo de amostras estudas, 82,5% são A. baumannii (425), 11,5% A. genoespécie 13TU (59) e 6,0% A. genoespécie 3 (30), sendo A. baumannii mais isolado em pacientes internados em UTIs (p=0,0407) e A. genoespécie 13TU mais isolado em pacientes de outros ambientes hospitalares (p=0,0204). A. baumannii apresentou menor sensibilidade a todos os antimicrobianos quando comparado com A. genoespécie 13TU e A. genoespécie. 3 (p<0,05). Foi possível observar ao longo do período estudado o aumento significativo da resistência aos carbapenêmicos e da sensibilidade a gentamicina por A. baumannii entre os isolados de pacientes de UTIs (p<0.05). Nenhum dos genes codificadores para metalo-lactamases foi detectado nas amostras estudadas Dentre os cepas resistentes aos carbapenêmico...

The genus Acinetobacter has emerged as one of the most troublesome pathogens for health care institutions globally. Its clinical significance, especially over the last 15 years, has been driven by its remarkable ability to up regulate or acquire resistance determinants, making it one of the organisms threatening the current antibiotic era. A. baumannii, A. 3 and A. 13TU are the most commonly species found from biological samples. These species beside A. calcoaceticus are very closely related and difficult to distinguish from each other by phenotypic properties. Therefore, it has been proposed to refer to these species as the A.calcoaceticus-A. baumannii complex(ACB). In the period from 2005 to 2009, the most frequent bacterial isolates among the nosocomial infection at the HU-USP was ACB (18%). Due to the frequency with which species are involved in ACB outbreaks of infection in the HU-USP and the emergency clinic because of expression of the phenotype of resistance to several classes of antibiotics, this study aimed to identify and characterize the species of complex ACB by molecular methods, to study their mechanisms of resistance and to characterize the different clones from patients admitted to different hospital areas. Furthermore, the ability to characterize biofilm formation, adhesion to different cell lines as well as the mechanisms of cell-cell communication were analyzed. From the ACB complex, 515 samples were identified, isolated from patients from January 2005 to December 2010. The identification of clinical species of the ACB was performed by molecular methods that were developed and validated for identification of Acinetobacter sp. include two reactions of PCR. The profiles of sensibility were evaluated by disc diffusion and the detection of the presence of genes blaOXA-23-like, blaOXA-24-like, blaOXA-51-like, blaOXA-58-like, blaIMP, blaVIM, blaSIM, blaGIM, and blaSPM were performed using specific primers. Molecular typing was performed using...

Origins of Aleuts and the genetic structure of populations of the archipelago: molecular and archaeological perspectives.

We summarize the results of a field and laboratory research program (1999-2006) in the Aleutian Islands on the origins of the inhabitants of the archipelago and the genetic structure of these populations. The Aleuts show closest genetic affinity to the contemporary Siberian Eskimos and Chukchi of Chukotka and differ significantly from the populations of Kamchatka (the terminus of the archipelago) and Alaskan Eskimos. Our findings support the hypothesis that the ancestors of the Aleuts crossed Beringia and expanded westerly into the islands approximately 9,000 years ago. The Monmonier algorithm indicates genetic discontinuity between contemporary Kamchatkan populations and western Aleut populations, suggesting that island hopping from Kamchatka into the western Aleutian Islands was highly unlikely. The primary determinant of the distribution of genes throughout the archipelago is geography. The most intimate relationship exists between the genetics (based on mtDNA sequences and intermatch/mismatch distances) and geographic distances (measured in kilometers). However, the Y-chromosome haplogroup frequencies are not significantly correlated with the geography of the Aleutian Islands. The underlying patterns of precontact genetic structure based on Y-chromosome markers of the Aleut populations is obscured because of the gene flow from Russian male colonizers and Scandinavian and English fishermen. We consider alternative theories about the peopling of the Americas from Siberia. In addition, we attempt a synthesis between archaeological and genetic data for the Aleutian Islands.

Contributions in biochemistry and molecular biology from China and other top-ranking countries: a 10-year survey of the literature.

Over the past decade, research in Biochemistry and Molecular Biology has developed rapidly worldwide. The present study was designed to study the characteristics of publications in Biochemistry and Molecular Biology journals between 1999 and 2008 from the six top-ranking countries - the United States (USA), Japan, Germany, United Kingdom (UK), China and France. We also examined the research output from three different regions - Mainland China (ML), Hong Kong (HK) and Taiwan (TW). The USA contributed 34.1% of the world's total output and ranked first, but its percentage of research articles in this field went down. In total, 26,867 articles were published in journals with an impact factor (IF) <10.000, and 46.5% of these were from the USA. China contributed 4.2% of the total in 268 journals, 0.5% of which were journals with the top 10 IF. Our analysis describes the output from each country and region, and reveals the positive trend in China during the period of 1999-2008. In contrast to other countries, our results suggest that China is behind in conducting high-quality research.