Common genetic variants of mitochondrial DNA (mtDNA) increase the risk of developing several of the major health issues facing the western world, including neurodegenerative diseases. In this Review, ...we consider how these mtDNA variants arose and how they spread from their origin on one single molecule in a single cell to be present at high levels throughout a specific organ and, ultimately, to contribute to the population risk of common age-related disorders. mtDNA persists in all aerobic eukaryotes, despite a high substitution rate, clonal propagation and little evidence of recombination. Recent studies have found that de novo mtDNA mutations are suppressed in the female germ line; despite this, mtDNA heteroplasmy is remarkably common. The demonstration of a mammalian mtDNA genetic bottleneck explains how new germline variants can increase to high levels within a generation, and the ultimate fixation of less-severe mutations that escape germline selection explains how they can contribute to the risk of late-onset disorders.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Antisense therapeutics are a biotechnological form of antibiotic therapy using chemical analogues of short single-stranded nucleic acid sequences modified to form stable oligomers. These molecules ...are termed antisense oligonucleotides (ASOs) because their sequence is complementary, via Watson-Crick specific base pairing, to their target messenger RNA (mRNA). ASOs modify gene expression in this sequence-dependent manner by binding to its complementary mRNA and inhibiting its translation into protein through steric blockage and/or through RNase degradation of the ASO/RNA duplex. The widespread use of conventional antibiotics has led to the increasing emergence of multiple drug-resistant pathogenic bacteria. There is an urgent need to develop alternative therapeutic strategies to reduce the morbidity and mortality associated with bacterial infections, and until recently, the use of ASOs as therapeutic agents has been essentially limited to eukaryotic cells, with ASOs as antibacterials having been largely unexplored primarily due to the poor uptake efficiency of antisense molecules by bacteria. There are conceptual advantages to bacterial antisense antibiotic therapies, including a sequence-dependent approach that allows for a rational design to multiple specific molecular targets. This review summarizes the current knowledge of antisense bacterial biotechnology and highlights the recent progress and the current obstacles in their development for therapeutic applications.
Real-world studies have become increasingly important in providing evidence of treatment effectiveness in clinical practice. While randomized clinical trials (RCTs) are the “gold standard” for ...evaluating the safety and efficacy of new therapeutic agents, necessarily strict inclusion and exclusion criteria mean that trial populations are often not representative of the patient populations encountered in clinical practice. Real-world studies may use information from electronic health and claims databases, which provide large datasets from diverse patient populations, and/or may be observational, collecting prospective or retrospective data over a long period of time. They can therefore provide information on the long-term safety, particularly pertaining to rare events, and effectiveness of drugs in large heterogeneous populations, as well as information on utilization patterns and health and economic outcomes. This review focuses on how evidence from real-world studies can be utilized to complement data from RCTs to gain a more complete picture of the advantages and disadvantages of medications as they are used in practice.
Funding
: Sanofi US, Inc.
The ability to trigger changes to material properties with external stimuli, so‐called “smart” behavior, has enabled novel technologies for a wide range of healthcare applications. Response to small ...changes in temperature is particularly attractive, where material transformations may be triggered by contact with the human body. Thermoreversible gelators are materials where warming triggers reversible phase change from low viscosity polymer solution to a gel state. These systems can be generated by the exploitation of macromolecules with lower critical solution temperatures included in their architectures. The resultant materials are attractive for topical and mucosal drug delivery, as well as for injectables. In addition, the materials are attractive for tissue engineering and 3D printing. The fundamental science underpinning these systems is described, along with progress in each class of material and their applications. Significant opportunities exist in the fundamental understanding of how polymer chemistry and nanoscience describe the performance of these systems and guide the rational design of novel systems. Furthermore, barriers to translating technologies must be addressed, for example, rigorous toxicological evaluation is rarely conducted. As such, applications remain tied to narrow fields, and advancements will be made where the existing knowledge in these areas may be applied to novel problems of science.
Thermoreversible gelators that exhibit a reversible switch from a liquid to gel state upon heating have driven groundbreaking innovations in healthcare. These materials may act as in situ gelators for forming drug depots, scaffolds for cells, or in bioprinting. This review concerns the latest progress in this field, highlighting opportunities for future research.
Considering the development and ongoing influence of Black
thought From 1900 to the present, people of African
descent living in the United States have drawn on homegrown and
diasporic minds to ...create a Black intellectual tradition engaged
with ideas on race, racial oppression, and the world. This volume
presents essays on the diverse thought behind the fight for racial
justice as developed by African American artists and intellectuals;
performers and protest activists; institutions and organizations;
and educators and religious leaders. By including both women's and
men's perspectives from the U.S. and the Diaspora, the essays
explore the full landscape of the Black intellectual tradition.
Throughout, contributors engage with important ideas ranging from
the consideration of gender within the tradition, to intellectual
products generated outside the intelligentsia, to the ongoing
relationship between thought and concrete effort in the quest for
liberation.
Expansive in scope and interdisciplinary in practice, The
Black Intellectual Tradition delves into the ideas that
animated a people's striving for full participation in American
life.
Contributors: Derrick P. Alridge, Keisha N. Blain, Cornelius L.
Bynum, Jeffrey Lamar Coleman, Pero Gaglo Dagbovie, Stephanie Y.
Evans, Aaron David Gresson III, Claudrena N. Harold, Leonard
Harris, Maurice J. Hobson, La TaSha B. Levy, Layli Maparyan,
Zebulon V. Miletsky, R. Baxter Miller, Edward Onaci, Venetria K.
Patton, James B. Stewart, and Nikki M. Taylor
A myriad of specialized and fragmented global regulatory bodies wield ever-increasing power and influence. In making decisions, these mission-oriented authorities tend systematically, due to ...deep-seated structural factors, to give greater regard to the interests and concerns of some actors, especially powerful states and well-organized economic actors, and lesser regard to the often peripheral interests and concerns of more weakly organized and less powerful groups and of vulnerable individuals. The overall pattern of global regulation reflects a similar bias. The most powerful global regulatory regimes promote the objectives of dominant states and economic actors, whereas regimes to protect weaker groups and individuals are often less effective or virtually nonexistent and are thus unable to protect their interests and concerns. As a result of these two types of disregard, the dominant actors in global regulatory governance enjoy disproportionate benefits from international cooperation, while weaker groups and individuals suffer deprivation and often serious harm.
Clostridioides difficile infection occurs when the bacterium produces toxin that causes diarrhea and inflammation of the colon. These guidelines indicate the preferred approach to the management of ...adults with C. difficile infection and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations Assessment, Development, and Evaluation but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not the only, approach to clinical scenarios.
The origins of new genes are among the most fundamental questions in evolutionary biology. Our understanding of the ways that new genetic material appears and how that genetic material shapes ...population variation remains incomplete. De novo genes and duplicate genes are a key source of new genetic material on which selection acts. To better understand the origins of these new gene sequences, we explored the ways that structural variation might alter expression patterns and form novel transcripts. We provide evidence that chromosomal rearrangements are a source of novel genetic variation that facilitates the formation of de novo exons in Drosophila. We identify 51 cases of de novo exon formation created by chromosomal rearrangements in 14 strains of D. yakuba. These new genes inherit transcription start signals and open reading frames when the 5' end of existing genes are combined with previously untranscribed regions. Such new genes would appear with novel peptide sequences, without the necessity for secondary transitions from non-coding RNA to protein. This mechanism of new peptide formations contrasts with canonical theory of de novo gene progression requiring non-coding intermediaries that must acquire new mutations prior to loss via pseudogenization. Hence, these mutations offer a means to de novo gene creation and protein sequence formation in a single mutational step, answering a long standing open question concerning new gene formation. We further identify gene expression changes to 134 existing genes, indicating that these mutations can alter gene regulation. Population variability for chromosomal rearrangements is considerable, with 2368 rearrangements observed across 14 inbred lines. More rearrangements were identified on the X chromosome than any of the autosomes, suggesting the X is more susceptible to chromosome alterations. Together, these results suggest that chromosomal rearrangements are a source of variation in populations that is likely to be important to explain genetic and therefore phenotypic diversity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology ...that can readily detect and discriminate between these two types of events is lacking. Here we establish a computational method, MitoSAlt, for accurate identification, quantification and visualization of mtDNA deletions and duplications from genomic sequencing data. Our method was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Surveillance du glucose en continu Harris, Stewart B.; Bari, Basel; Gilbert, Jeremy
Canadian Medical Association journal (CMAJ),
03/2024, Letnik:
196, Številka:
9
Journal Article
PDF
