Not only COVID-19: a systematic review of anti-COVID-19 measures and their effect on healthcare-associated infections.

BACKGROUND: Healthcare-associated infections (HAIs) burden healthcare globally. Amid the SARS-CoV-2 pandemic, intensified infection control measures, such as mask usage and hand hygiene, were implemented. AIM: To assess the efficacy of these measures in preventing HAIs among hospitalized patients. METHODS: Using the PICO framework (Population, Intervention, Comparison, Outcome), the study focused on hospitalized patients and the effectiveness of anti-COVID-19 measures in preventing HAIs. A systematic review of literature published in 2020-2022 was conducted, examining interventions such as mask usage, hand hygiene, and environmental cleaning. FINDINGS: This systematic review analysed 42 studies: two in 2020, 21 in 2021, and 19 in 2022. Most studies were from high-income countries (28). Most studies (30 out of 42) reported a reduction in HAIs after implementing anti-COVID-19 measures. Gastrointestinal infections and respiratory tract infections showed significant reduction, unlike bloodstream infections and urinary tract infections. Some wards, like cardiology and neurology, experienced reduced HAIs, unlike intensive care units and coronary care units. There was an increase in studies reporting no effect of hygiene measures on HAIs in 2022, eventually indicating a shift in effectiveness over time. CONCLUSION: Anti-COVID-19 measures have shown selective efficacy in preventing HAIs. The study emphasizes the need for context-specific strategies and increased focus on regions with limited resources. Continued research is essential to refine infection control practices, especially in high-risk settings.

Diverse and dynamic functions of the Sir silencing complex.

The yeast Sir protein complex has been implicated in transcriptional silencing and suppression of recombination. The Sir complex creates structured chromosomal domains at telomeres, silent mating-type loci and ribosomal DNA to invoke these functional states. Mechanistic insights into the function of Sir proteins implicate a range of activities in yeast, including repair of DNA double-strand breaks, regulation of the mitotic cell cycle, meiosis and ageing. I speculate that the Sir proteins may be capable of enzymatic modification of chromatin and other substrates, which enables them to carry out a broad range of cellular functions.

A therapeutic role for sirtuins in diseases of aging?

The sirtuins are a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Among the many genes that have been shown to affect aging in model organisms, sirtuin genes are unique in that their activity level is positively correlated with lifespan (i.e. they are anti-aging genes). Sirtuins are a druggable class of enzymes (i.e. amenable to intervention by small molecules) that could have beneficial effects on a variety of human diseases. In view of the many functions of Sirtuin 1 (SIRT1) in cells, this review focuses on its role in regulating important aspects of mitochondrial biology. Mitochondria have been linked to aging, and also to diseases of aging. Thus, sirtuins might provide a key link between mitochondrial dysfunction, aging and metabolic disease.

Telomeres, the nucleolus and aging.

Reactivation of telomerase in cultured human cells extends their replicative life span beyond the Hayflick limit. How telomere shortening triggers cell senescence and whether it contributes to aging in vivo are under investigation. Studies in yeast have revealed another site critical to cellular aging: the nucleolus. The accumulation of ribosomal DNA circles is a cause of aging in this organism. The possible relevance of this mechanism to human aging is also being considered.

Daughter cells of Saccharomyces cerevisiae from old mothers display a reduced life span.

The yeast Saccharomyces cerevisiae typically divides asymmetrically to give a large mother cell and a smaller daughter cell. As mother cells become old, they enlarge and produce daughter cells that are larger than daughters derived from young mother cells. We found that occasional daughter cells were indistinguishable in size from their mothers, giving rise to a symmetric division. The frequency of symmetric divisions became greater as mother cells aged and reached a maximum occurrence of 30% in mothers undergoing their last cell division. Symmetric divisions occurred similarly in rad9 and ste12 mutants. Strikingly, daughters from old mothers, whether they arose from symmetric divisions or not, displayed reduced life spans relative to daughters from young mothers. Because daughters from old mothers were larger than daughters from young mothers, we investigated whether an increased size per se shortened life span and found that it did not. These findings are consistent with a model for aging that invokes a senescence substance which accumulates in old mother cells and is inherited by their daughters.

Yeast HAP2 and HAP3: transcriptional activators in a heteromeric complex.

Transcription of the yeast C upsilon C1 gene (iso-1-cytochrome c) is regulated in part by the upstream activation site UAS2. Activity of UAS2 requires both the HAP2 and HAP3 activators, which bind to UAS2 in an interdependent manner. To distinguish whether these factors bound to UAS2 cooperatively or formed a complex in the absence of DNA, HAP2 and HAP3 were tagged by gene fusion to LexA and beta-galactosidase, respectively, and purified through four chromatographic steps. The copurification of LexA-HAP2, HAP3 beta-galactosidase, and UAS2 binding activity shows that HAP2 and HAP3 associate in the absence of DNA to form a multisubunit activation complex.

Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae.

Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.

A technique for expressing eukaryotic genes in bacteria.

Methods are described that allow efficient expression in Escherichia coli of cloned eukaryotic genes. The methods require that the coding sequence of the gene in question be available in a form uninterrupted by intervening sequences (for example, as a complementary DNA clone). The gene products are synthesized unfused to other amino acid sequences. The genetic manipulations are simple, and require the plasmids described and commercially available enzymes.

Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants.

The SGS1 gene of yeast encodes a DNA helicase with homology to the human WRN gene. Mutations in WRN result in Werner's syndrome, a disease with symptoms resembling premature aging. Mutation of SGS1 is shown to cause premature aging in yeast mother cells on the basis of a shortened life-span and the aging-induced phenotypes of sterility and redistribution of the Sir3 silencing protein from telomeres to the nucleolus. Further, in old sgs1 cells the nucleolus is enlarged and fragmented-changes that also occur in old wild-type cells. These findings suggest a conserved mechanism of cellular aging that may be related to nucleolar structure.

Transcriptional coactivators in yeast and beyond.

Coactivators are a novel class of transcriptional activator required at many eukaryotic promoters. Several coactivators have now been isolated, their identification often facilitated by genetic studies in yeast. Some of the proposed mechanisms of coactivator function may help explain synergy between transcriptional activators at eukaryotic promoters.

Molecular mechanisms of yeast aging.

The life cycle of many organisms involves a progressive decline in fitness and fecundity with age, and yeast is no exception. Many theories have been proposed to explain the mortality of yeast cells, including the increase in cell size and accumulation of bud scars on the cell surface. None of these has survived closed scrutiny. However, recent discoveries might have validated one aging model in which the triggering of a molecular aging clock results in the replication and accumulation of a senescence factor that eventually overwhelms old cells.

Mechanisms of cellular senescence.

Aging is a near universal process, yet the molecular mechanisms that underlie cellular senescence have remained elusive. Recent progress in determining the roles of various genetic influences in controlling the rate of cellular aging has made this an exciting time in aging research. Genetic screens designed to isolate long-lived mutants in Saccharomyces cerevisiae and Caenorhabditis elegans have implicated factors involved in transcriptional silencing and the dauer pathway in the control of aging. The gene responsible for Werner's syndrome, a disease with symptoms of premature aging, was isolated and found to be a member of the RecQ subfamily of DNA helicases. The regulation of telomere length and its role in senescence and cellular immortalization has been found to be more complex than expected. In C. elegans, mutations have been isolated in maternal-effect genes that presumably control its biological clocks and can dramatically extend its lifespan. Indeed, aging research within the past year has implicated a variety of mechanisms ranging from the control of gene expression, stress resistance, and DNA metabolism to the overall 'rate of living'.

Synthetic enhancement in gene interaction: a genetic tool come of age.

Synthetic enhancement, in which one mutation exacerbates the severity of another, is a genetic interaction of increasing importance in biology. This review focuses on the logic of interpreting synthetic enhancement, and begins by comparing the phenomenon with genetic suppression.

SIR2 and aging--the exception that proves the rule.

One of the holy grails of medicine is the possibility of an increase in lifespan without a decrease in vitality. However, the causes and processes of human aging are still unclear. One evolutionary theory is that in the post-reproductive stage of life, selective forces decline allowing many vital systems to deteriorate. This suggests that intervention will be difficult, if not impossible. However, molecular geneticists propose an aging process that is programmed (like other developmental processes) and regulated by single genes, meaning that intervention could be possible. Here, I discuss a way of reconciling these two views that could have major implications for healthcare.

Conservation and evolution of transcriptional mechanisms in eukaryotes.

Eukaryotic transcriptional activators play key roles in controlling cell growth and specifying embryonic development. These activators can stimulate promoters from distances up to tens of kilobases by a mechanism that is remarkably conserved in eukaryotes ranging from yeast to humans. Although the primary sequence of certain activators has also been conserved in widely divergent organisms, the regulatory roles that these factors play have been altered over evolution to fit the specific needs of the host.

Genetic analysis of aging in Saccharomyces cerevisiae.

The natural limits to life span are poorly understood. Yeast is a good model organism for studies of the aging process because single cells can be followed for many cell divisions and their loss of division potential follows kinetics identical to mortality rates in complex organisms. Recent experimental approaches in yeast are beginning to lead to basic models of the factors that facilitate aging.

Dyskeratosis congenita, telomeres and human ageing.

As normal humans age, telomeres shorten in tissues that contain dividing cells, and this has been proposed both as a cause of ageing and as a tumor-suppressor mechanism. The surprising finding that cells from individuals with the rare inherited disorder dyskeratosis congenita (DKC) have reduced levels of telomerase and shortened telomeres might provide the first direct genetic test of the function of telomeres in intact humans.

The nine amino-terminal residues of delta-aminolevulinate synthase direct beta-galactosidase into the mitochondrial matrix.

delta-Aminolevulinate synthase, the first enzyme in the heme biosynthetic pathway, is encoded by the nuclear gene HEM1. The enzyme is synthesized as a precursor in the cytoplasm and imported into the matrix of the mitochondria, where it is processed to its mature form. Fusions of beta-galactosidase to various lengths of amino-terminal fragments of delta-aminolevulinate synthase were constructed and transformed into yeast cells. The subcellular location of the fusion proteins was determined by organelle fractionation. Fusion proteins were found to be associated with the mitochondria. Protease protection experiments involving the use of intact mitochondria or mitoplasts localized the fusion proteins to the mitochondrial matrix. This observation was confirmed by fractionation of the mitochondrial compartments and specific activity measurements of beta-galactosidase activity. The shortest fusion protein contains nine amino acid residues of delta-aminolevulinate synthase, indicating that nine amino-terminal residues are sufficient to localize beta-galactosidase to the mitochondrial matrix. The amino acid sequence deduced from the DNA sequence of HEM1 showed that the amino-terminal region of delta-aminolevulinate synthase was largely hydrophobic, with a few basic residues interspersed.

Organization of the regulatory region of the yeast CYC7 gene: multiple factors are involved in regulation.

Regulation of the CYC7 gene of Saccharomyces cerevisiae, encoding iso-2-cytochrome c, was studied. Expression was induced about 20-fold by heme and derepressed 4- to 8-fold by a shift from glucose medium to one containing a nonfermentable carbon source. Deletion analysis showed that induction by heme depends upon sequences between -250 and -228 (from the coding sequence) and upon the HAP1 activator gene, previously shown to be required for CYC1 expression (L. Guarente et al., Cell 36:503-511, 1984). Thus, HAP1 coordinates expression of CYC7 and CYC1, the two genes encoding isologs of cytochrome c in S. cerevisiae. HAP1-18, a mutant allele of HAP1, which increased CYC7 expression more than 10-fold, also acted through sequences between -250 and -228. In vitro binding studies showed that the HAP1 product binds to these sequences (see also K. Pfeifer, T. Prezant, and L. Guarente, Cell 49:19-28, 1987) and an additional factor binds to distal sequences that lie between -201 and -165. This latter site augmented CYC7 expression in vivo. Derepression of CYC7 expression in a medium containing nonfermentable carbon sources depended upon sequences between -354 and -295. The interplay of these multiple sites and the factors that bind to them are discussed.

Mutational analysis of upstream activation sequence 2 of the CYC1 gene of Saccharomyces cerevisiae: a HAP2-HAP3-responsive site.

We analyzed upstream activation sequence 2 (UAS2), one of two independent UAS elements in the CYC1 gene of Saccharomyces cerevisiae. Deletions and linker scanning mutations across the 87 base pairs previously defined as UAS2 showed two separate functional elements required for full activity. Region 1, from -230 to -200, contains the principal activation site and responds to the trans-acting regulatory loci HAP2 and HAP3. A portion of region 1 is homologous to two other HAP2-HAP3-responsive UASs and includes the G----A transition mutation UP1, which increases UAS2 activity. This consensus sequence TNATTGGT bears striking similarity to several CAAT box sequences of higher cells. Region 2, from -192 to -178, substantially enhances the activity of region 1, yet has little activity by itself. These regions bind distinct proteins found in crudely fractionated yeast extracts.