Review
Oncology
Kristopher A. Sarosiek, Kris C. Wood
Summary: The BCL-2 family of proteins controls the intrinsic apoptosis pathway, which can be targeted therapeutically to exploit apoptotic vulnerabilities in cancer. These vulnerabilities can be driven by various factors, including genetics, signaling, metabolism, structure, lineage, and exposure to anticancer agents. BH3 mimetics that inhibit prosurvival BCL-2 family proteins have shown promising clinical success in targeting these vulnerabilities. This review highlights the key concepts necessary for understanding and exploiting apoptotic vulnerabilities in cancer for improved patient outcomes.
Article
Plant Sciences
Jie Yu, Jingling Li, Youwei Zuo, Qiulin Qin, Siyuan Zeng, Heinz Rennenberg, Hongping Deng
Summary: This study assembled and annotated 35 plastomes of the Cereoideae subfamily, revealing their high diversity and complexity, and providing insights into their evolutionary history and relationships.
Article
Cell Biology
Hanover Matz, Richard S. Taylor, Anthony K. Redmond, Thomas M. Hill, Rose Ruiz Daniels, Mariana Beltran, Neil C. Henderson, Daniel J. Macqueen, Helen Dooley
Summary: By studying the spleens of nurse sharks, we found that sharks are capable of producing robust antigen-specific responses and affinity maturation of B cells, despite the absence of germinal centers (GCs) observed in other animals. We also identified immune-related marker gene expression in the spleen cells of sharks and tracked their localization in the splenic follicles. These findings provide insights into the evolutionary foundation of GCs.
Article
Biochemistry & Molecular Biology
Neel Prabh, Christian Roedelsperger
Summary: The birth of new genes is a major driving force behind phenotypic diversity in all life forms. Previous studies have focused on the duplication of existing protein-coding material as the main process of new gene formation, but recent research has found that transcriptionally active sequences can also be a rich source of new genes. However, the high birth rates of these new genes have to be balanced with the loss rates in order to explain the dominance of ancient gene families in individual genomes. In this study, the researchers tested the hypothesis of rapid turnover in the nematode model organism Pristionchus pacificus. By sequencing the genomes of six divergent P. pacificus strains, they studied the evolutionary dynamics of different age classes and categories of origin at a population level. They found that de novo candidates, new genes that are not derived from duplication and divergence of known genes, are typically shorter, show less expression, and are overrepresented on the sex chromosome. In addition, the researchers discovered that de novo candidates have higher attrition rates compared to known genes within the same age class. These findings provide empirical evidence for the rapid turnover hypothesis and emphasize the importance of considering the evolutionary timescale when studying new gene formation.
Article
Biochemistry & Molecular Biology
Qing Zhang, Pengpeng Guan, Lun Zhao, Meng Ma, Liang Xie, Yue Li, Ruiqin Zheng, Weizhi Ouyang, Shunyao Wang, Hongmeijuan Li, Ying Zhang, Yong Peng, Zhilin Cao, Wei Zhang, Qin Xiao, Yuanling Xiao, Tingdong Fu, Guoliang Li, Xingwang Li, Jinxiong Shen
Summary: The study conducted a comprehensive analysis of the epigenome in two Brassica napus lines, revealing significant differences between the An and Cn subgenomes and distinct patterns of histone modification and DNA methylation in duplicated genes. The findings provide valuable insights into epigenetic regulation in allopolyploid plants.
Article
Biochemistry & Molecular Biology
Shuo Lu, Miranda Montoya, Liya Hu, Neetu Neetu, Banumathi Sankaran, B. V. Venkataram Prasad, Timothy Palzkill
Summary: CTX-M beta-lactamases are widespread in Gram-negative bacteria and play a significant role in resistance to beta-lactam antibiotics. This study investigates the preference of CTX-M enzymes for cephalosporins through alanine mutagenesis, revealing key active site residues that contribute to catalysis and specificity. The impact of substitutions on the structure of the active site is also examined.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biology
Pooja Suresh, Vahe Galstyan, Rob Phillips, Sophie Dumont
Summary: This study reveals how spatially regulated anchorage gives rise to spatially distinct mechanics in the mammalian spindle.
Article
Biochemistry & Molecular Biology
Arjun K. Aditham, Craig J. Markin, Daniel A. Mokhtari, Nicole DelRosso, Polly M. Fordyce
Summary: This study utilized a high-throughput microfluidic platform to quantitatively characterize hundreds of TF variants, revealing that many mutations, while altering binding, preserved physiological binding. Additionally, biochemical double-mutant cycles across the TF-DNA interface elucidated molecular mechanisms driving recognition.
Article
Biochemistry & Molecular Biology
Tristram O. Dodge, Katherine A. Farquharson, Claire Ford, Lisa Cavanagh, Kristen Schubert, Molly Schumer, Katherine Belov, Carolyn J. Hogg
Summary: Genomics can provide valuable insights into biodiversity conservation, particularly for species on the brink of extinction and reintroduction efforts. In this study, researchers generated reference genomes for the Christmas Island blue-tailed skink and Lister's gecko using advanced sequencing technologies. They found differences in genetic diversity and inbreeding patterns between the two species, suggesting distinct histories and management implications. These reference genomes offer valuable resources for future research on reptile populations and comparative genomics.
MOLECULAR ECOLOGY RESOURCES
(2023)
Article
Cell Biology
Marie-Claire Fitzgerald, Philip J. O'Halloran, Sean A. Kerrane, Triona Ni Chonghaile, Niamh M. C. Connolly, Brona M. Murphy
Summary: Systems-level analysis of apoptosis protein expression and signaling interactions can differentiate between medulloblastoma cell lines with different responses to chemotherapy. BCL-XL and MCL-1 were identified as key anti-apoptotic proteins in medulloblastoma, with distinct protective roles. We provide rationale for further evaluation of BCL-XL and MCL-1 inhibitors in medulloblastoma treatment.
CELL DEATH & DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Shoshanna C. Kahne, K. Heran Darwin
Summary: Bacteria use proteolytic machines for protein quality control and response to environmental conditions, with ClpP proteases and bacterial proteasomes being common mechanisms, where activators play a key role. Understanding these mechanisms can lead to new approaches in designing targeted therapeutics.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
W. Douglas Fairlie, Erinna F. Lee
Summary: The deregulation of apoptosis plays a crucial role in tumorigenesis, and drugs targeting the prosurvival members of the BCL-2 protein family called BH3-mimetics have shown success in treating hematological malignancies. However, their potential in solid cancer therapy has not been fully realized due to the lack of effective combination strategies to target multiple pro-survival proteins. Exciting new developments in the field have the potential to unleash the full power of BH3-mimetic therapy in treating currently difficult-to-treat solid malignancies.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2021)
Article
Multidisciplinary Sciences
Marie Cariou, Lea Picard, Laurent Gueguen, Stephanie Jacquet, Andrea Cimarelli, Oliver Fregoso, Antoine Molaro, Vincent Navratil, Lucie Etienne
Summary: By analyzing the genomes of bats and primates, we have identified adaptive changes in response to SARS-CoV-2 infection, providing insights into the genetic determinants of virus susceptibility and severity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Toxicology
David Filipovic, Wenjie Qi, Omar Kana, Daniel Marri, Edward L. LeCluyse, Melvin E. Andersen, Suresh Cuddapah, Sudin Bhattacharya
Summary: The aryl hydrocarbon receptor (AhR) is a receptor that binds to environmental contaminants and its binding is tissue-specific and influenced by DNA sequences and chromatin context.
TOXICOLOGICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Zhi Chai, Yafei Lyu, Qiuyan Chen, Cheng-Hsin Wei, Lindsay M. Snyder, Veronika Weaver, Aswathy Sebastian, Istvan Albert, Qunhua Li, Margherita T. Cantorna, A. Catharine Ross
Summary: This study investigated the impact of preexisting vitamin A deficiency on gene expression patterns in the intestines using a mouse model, and identified novel target genes in vitamin A-related biological pathways. The results revealed significant effects of vitamin A deficiency on gene expression patterns in the small intestine, suggesting potential new candidate genes, while in the colon, cell division was the only enriched category negatively associated with vitamin A.
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
(2021)
Article
Microbiology
Guntur Fibriansah, Elisa X. Y. Lim, Jan K. Marzinek, Thiam-Seng Ng, Joanne L. Tan, Roland G. Huber, Xin-Ni Lim, Valerie S. Y. Chew, Victor A. Kostyuchenko, Jian Shi, Ganesh S. Anand, Peter J. Bond, James E. Crowe, Shee-Mei Lok
Summary: Dengue virus has four serotypes (DENV1-4) with different strains within each serotype. The virus can exhibit smooth or bumpy surface morphologies at 37 degrees C, depending on the strain. High-affinity therapeutic antibodies are able to neutralize diverse morphologies of dengue virus.
Review
Cell Biology
Louis De Falco, Nelly M. Silva, Nuno C. Santos, Roland G. Huber, Ivo C. Martins
Summary: The circularization of viral genomes plays vital roles in the viral life cycle, with genomic structures and associated host factors being crucial for this process in flaviviruses. Sequence motifs and RNA structures are key elements involved in circularization, contributing to viral proliferation and replication.
Article
Biochemistry & Molecular Biology
Lorena Zuzic, Firdaus Samsudin, Aishwary T. Shivgan, Palur V. Raghuvamsi, Jan K. Marzinek, Alister Boags, Conrado Pedebos, Nikhil K. Tulsian, Jim Warwicker, Paul MacAry, Max Crispin, Syma Khalid, Ganesh S. Anand, Peter J. Bond
Summary: The COVID-19 pandemic has accelerated the development of vaccines and drugs. Researchers have used simulations and experiments to identify a potential druggable pocket in the SARS-CoV-2 spike glycoprotein and emphasized the importance of pocket dynamics. This pocket is associated with mutations found in concerning SARS-CoV-2 variants.
Article
Biochemistry & Molecular Biology
Manoj Puthia, Jan K. Marzinek, Ganna Petruk, Gizem Erturk Bergdahl, Peter J. Bond, Jitka Petrlova
Summary: This study demonstrates that APOE has anti-bacterial activity against several Gram-negative bacterial strains and exhibits significant binding affinity for lipopolysaccharide and heparin. Molecular dynamics simulations reveal the binding region in helix 4 of APOE as a primary site for interaction with these molecules through electrostatic interactions.
Review
Virology
Siwy Ling Yang, Riccardo Delli Ponti, Yue Wan, Roland G. Huber
Summary: This review article summarizes the importance of RNA viruses and their impact on society and the economy. It presents the significance of studying genome folding and the use of computational and high-throughput RNA structure-mapping approaches. The focus is on the genome structures of dengue, Zika, and SARS-CoV-2 viruses.
Article
Clinical Neurology
Roland G. Huber, Swapnil Pandey, Deepak Chhangani, Diego E. Rincon-Limas, Nathan P. Staff, Crystal Jing Jing Yeo
Summary: This study used proteomics data from induced pluripotent stem cell-derived motor neurons of amyotrophic lateral sclerosis (ALS) patients to identify potential diagnostic and prognostic biomarkers. Through stratification and analysis, differentially expressed proteins indicative of disease severity and progression rate were identified as candidate ALS-related and prognostic biomarkers. The study also utilized RNAi screening and machine learning algorithms to validate and predict novel mechanisms and diagnostic biomarkers in ALS.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Article
Chemistry, Physical
Emmanuella Li, Michelle Y. Yaochai, Joanna M. Ng, Roland G. Huber, Peter J. Bond, Alexander Krah
Summary: Biological macromolecules exhibit biochemical activity near their glass transition temperature, which is likely influenced by their interaction with water molecules. Experimental evidence has shown that the presence of bioprotective compounds, such as sucrose and trehalose, can raise the transition temperature of a protein. In this study, molecular dynamics simulations were used to investigate the transition temperatures of lysozyme in different chemical environments, including water, a sucrose/water mixture, and a trehalose/water mixture. Through this approach, multiple temperature-dependent transitions were identified, suggesting that water-induced transitions occur at various temperatures rather than a single temperature. These findings have implications for selecting stabilizing additives in industries like biotechnology, pharmaceuticals, and food production.
JOURNAL OF MOLECULAR LIQUIDS
(2023)
Article
Medicine, Research & Experimental
Sean Ruane, Zongyi Li, Peter Hollowell, Arwel Hughes, Jim Warwicker, John R. P. Webster, Christopher F. van der Walle, Cavan Kalonia, Jian R. Lu
Summary: Interfacial adsorption is a molecular process that affects the structural stability and bioactivities of antibodies. Neutron reflection was used to study the conformational orientations of COE-3 monoclonal antibody and its fragments at different interfaces. Rigid body rotation modeling was suitable for the fragments, but not for the flexible COE-3. The Fab and Fc fragments adopted different orientations at the air/water and oil/water interfaces, while COE-3 adsorbed in tilted orientations at both interfaces.
MOLECULAR PHARMACEUTICS
(2023)
Article
Medicine, Research & Experimental
Alina Kulakova, Dillen Augustijn, Inas El Bialy, Lorenzo Gentiluomo, Maria Laura Greco, Stefan Hervo-Hansen, Sowmya Indrakumar, Sujata Mahapatra, Marcello Martinez Morales, Christin Pohl, Marco Polimeni, Aisling Roche, Hristo L. Svilenov, Andreas Tosstorff, Matja Zalar, Robin Curtis, Jeremy P. Derrick, Wolfgang Friess, Alexander P. Golovanov, Mikael Lund, Allan Norgaard, Tarik A. Khan, Gunther H. J. Peters, Alain Pluen, Dierk Roessner, Werner W. Streicher, Christopher F. van der Walle, Jim Warwicker, Shahid Uddin, Gerhard Winter, Jens Thostrup Bukrinski, Asmund Rinnan, Pernille Harris
Summary: Therapeutic proteins are difficult to develop due to their complexity and the need for an acceptable formulation. A universal formulation strategy is currently lacking. This study used high-throughput characterization to analyze 14 different proteins formulated under various conditions. pH and ionic strength were identified as the most important factors affecting protein stability. Prediction methods were also developed for real-time and accelerated stress stability.
MOLECULAR PHARMACEUTICS
(2023)
Article
Biochemistry & Molecular Biology
Priscilla L. S. Boon, Ana S. Martins, Xin Ni Lim, Francisco J. Enguita, Nuno C. Santos, Peter J. Bond, Yue Wan, Ivo C. Martins, Roland G. Huber
Summary: Dengue virus is a significant health risk in tropical and subtropical regions. The structure of the packaged genome in complex with C proteins remains elusive. This study investigates the interactions of C proteins with viral RNA and shows their role in coordinating key interactions for proper packaging of viral RNA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Kathleen Elverson, Sally Freeman, Forbes Manson, Jim Warwicker
Summary: Many transmembrane proteins are modulated by intracellular or extracellular pH. Mutagenesis guided by amino-acid conservation and structure can be used to investigate pH dependence, but prediction of pKas can streamline this process. The hypothesis of modulation of calcium/proton coupling and pH-dependent activity through the extent of structural relaxation applies to various proteins, including bestrophin 1, TMEM16A, calmodulin, and calbindin D9k. Predicting altered pH dependence for mutations in ion channel disorders can support experimental studies and clinical intervention.
Article
Chemistry, Physical
Hafiz Saqib Ali, Jim Warwicker, Sam P. de Visser
Summary: The enzyme NapI performs the desaturation of l-arginine in a selective manner, making it a potentially valuable tool in biotechnology for the synthesis of drugs and fragrances. Its enzymatic biosynthesis offers a greener alternative to traditional chemical methods that require heavy metals and solvents.
Article
Immunology
Sunita Awate, Salma Mubarka, Roland G. Huber
Summary: Lates calcarifer, also known as Barramundi or Asian seabass, is a highly productive fish species suitable for large-scale aquaculture. However, the dense populations in aquaculture settings increase the risk of infectious diseases, which negatively impact yield. Immunization of juveniles and development of new immunization agents are crucial for improving aquaculture efficiency and food security.
Article
Multidisciplinary Sciences
Jakob Fleischmann, Selina Schwaighofer, Louis De Falco, Florian Enzler, Andreas Feichtner, Valentina Kugler, Philipp Tschaikner, Roland G. Huber, Eduard Stefan
Summary: Selective targeting of mutated kinases in cancer therapies has the potential to improve therapeutic success and patient survival. Using the KinCon technology, we studied the activated kinase states in melanoma patients and developed personalized treatment strategies. The combination inhibition of BRAF and MEK displayed synergistic effects and induced more pronounced structural changes, as validated by the KinCon biosensor.