Structure-Activity Relationship Study of Splicing Modulators on Hsh155/SF3B1 through Chemical Synthesis and Yeast Genetics.

Meayamycins are synthetic analogs of the natural product FR901464 and exhibit potent anticancer activity against human cancers. They bind SF3B1 and PHF5A, components of the human spliceosome, and they alter pre-mRNA splicing. Detailed analysis of the active site led us to investigate a narrow pocket within the binding site that surrounds the α,β-unsaturated amide portion of meayamycin.

Love thy neighbour: Feral buffalos show greater space use, resource overlap and encounters during the wet season in the Northern Territory.

Managing feral water buffalo in the Northern Territory is a formidable challenge. As an introduced species, buffalo are associated with a myriad of biosecurity, economic, cultural and environmental issues ranging from overgrazing, decreased water quality, disease vectors to the destruction of cultural assets. Nevertheless, the buffalo are also a harvestable resource that can support economic development of the region.

Dynamics and Evolutionary Conservation of B Complex Protein Recruitment During Spliceosome Activation.

Spliceosome assembly and catalytic site formation (called activation) involve dozens of protein and snRNA binding and unbinding events. The B-complex specific proteins Prp38, Snu23, and Spp381 have critical roles in stabilizing the spliceosome during conformational changes essential for activation. While these proteins are conserved, different mechanisms have been proposed for their recruitment to spliceosomes.

Mechanisms and regulation of spliceosome-mediated pre-mRNA splicing in Saccharomyces cerevisiae.

Pre-mRNA splicing, the removal of introns and ligation of flanking exons, is a crucial step in eukaryotic gene expression. The spliceosome, a macromolecular complex made up of five small nuclear RNAs (snRNAs) and dozens of proteins, assembles on introns via a complex pathway before catalyzing the two transesterification reactions necessary for splicing. All of these steps have the potential to be highly regulated to ensure correct mRNA isoform production for proper cellular function.

Control of 3' splice site selection by the yeast splicing factor Fyv6.

Pre-mRNA splicing is catalyzed in two steps: 5' splice site (SS) cleavage and exon ligation. A number of proteins transiently associate with spliceosomes to specifically impact these steps (1 and 2 step factors). We recently identified Fyv6 (FAM192A in humans) as a 2 step factor in ; however, we did not determine how widespread Fyv6's impact is on the transcriptome.

Functional analysis of the zinc finger modules of the splicing factor Luc7.

Identification of splice sites is a critical step in pre-messenger RNA (pre-mRNA) splicing because the definition of the exon/intron boundaries controls what nucleotides are incorporated into mature mRNAs. The intron boundary with the upstream exon is initially identified through interactions with the U1 small nuclear ribonucleoprotein (snRNP). This involves both base-pairing between the U1 snRNA and the pre-mRNA as well as snRNP proteins interacting with the 5' splice site (5'ss)/snRNA duplex.

Prediction of viral spillover risk based on the mass action principle.

Infectious zoonotic disease emergence, through spillover events, is of global concern and has the potential to cause significant harm to society, as recently demonstrated by COVID-19. More than 70% of the 400 infectious diseases that emerged in the past five decades have a zoonotic origin, including all recent pandemics. There have been several approaches used to predict the risk of spillover through some of the known or suspected infectious disease emergence drivers, largely using correlative approaches.

Global trends and scenarios for terrestrial biodiversity and ecosystem services from 1900 to 2050.

Based on an extensive model intercomparison, we assessed trends in biodiversity and ecosystem services from historical reconstructions and future scenarios of land-use and climate change. During the 20th century, biodiversity declined globally by 2 to 11%, as estimated by a range of indicators. Provisioning ecosystem services increased several fold, and regulating services decreased moderately.

A Sequential Binding Mechanism for 5' Splice Site Recognition and Modulation for the Human U1 snRNP.

Splice site recognition is essential for defining the transcriptome. Drugs like risdiplam and branaplam change how U1 snRNP recognizes particular 5' splice sites (5'SS) and promote U1 snRNP binding and splicing at these locations. Despite the therapeutic potential of 5'SS modulators, the complexity of their interactions and snRNP substrates have precluded defining a mechanism for 5'SS modulation.

Functional Analysis of the Zinc Finger Modules of the Splicing Factor Luc7.

Identification of splice sites is a critical step in pre-mRNA splicing since definition of the exon/intron boundaries controls what nucleotides are incorporated into mature mRNAs. The intron boundary with the upstream exon is initially identified through interactions with the U1 snRNP. This involves both base pairing between the U1 snRNA and the pre-mRNA as well as snRNP proteins interacting with the 5' splice site/snRNA duplex.

Complete genome sequences of phages Spelly and Phredrick.

We present the complete genome sequences of two viruses with siphovirus morphology, isolated from soils collected in Southwestern Indiana using the host . Spelly is a BE2 cluster phage with a 131,347-bp genome. Phredrick is a BK1 cluster phage with a 128,873-bp genome.

Biochemical and genetic evidence supports Fyv6 as a second-step splicing factor in .

Precursor mRNA (pre-mRNA) splicing is an essential process for gene expression in eukaryotes catalyzed by the spliceosome in two transesterification steps. The spliceosome is a large, highly dynamic complex composed of five small nuclear RNAs and dozens of proteins, some of which are needed throughout the splicing reaction while others only act during specific stages. The human protein FAM192A was recently proposed to be a splicing factor that functions during the second transesterification step, exon ligation, based on analysis of cryo-electron microscopy (cryo-EM) density.

Pre-mRNA splicing-associated diseases and therapies.

Precursor mRNA (pre-mRNA) splicing is an essential step in human gene expression and is carried out by a large macromolecular machine called the spliceosome. Given the spliceosome's role in shaping the cellular transcriptome, it is not surprising that mutations in the splicing machinery can result in a range of human diseases and disorders (spliceosomopathies). This review serves as an introduction into the main features of the pre-mRNA splicing machinery in humans and how changes in the function of its components can lead to diseases ranging from blindness to cancers.

Effects of Specialist Palliative Care for Patients Undergoing Major Abdominal Surgery for Cancer: A Randomized Clinical Trial.

Importance: Specialist palliative care benefits patients undergoing medical treatment of cancer; however, data are lacking on whether patients undergoing surgery for cancer similarly benefit from specialist palliative care.

Objective: To determine the effect of a specialist palliative care intervention on patients undergoing surgery for cure or durable control of cancer.

Design, Setting, And Participants: This was a single-center randomized clinical trial conducted from March 1, 2018, to October 28, 2021.

Hepatitis B immune status of staff in smaller acute healthcare facilities.

Objective To determine the proportion of staff employed in smaller Victorian public acute healthcare facilities with evidence of immunity to hepatitis B. Methods For optimal long-term immunity, a completed hepatitis B vaccination course and post vaccination hepatitis B surface antibody (anti-HBs) level ≥10 mIU/mL is desirable for all high-risk staff employed in healthcare facilities. For the financial years 2016/17-2019/20, a standardised surveillance module developed by the Victorian Healthcare Associated Infection Surveillance System (VICNISS) Coordinating Centre was completed by the smaller Victorian public acute healthcare facilities (individual hospitals with Results A total of 88 healthcare facilities reported hepatitis B immunity status of high-risk (Category A) staff (n  = 29 920) at least once over 5 years; 55 healthcare facilities reported more than once.

Japanese Encephalitis Enzootic and Epidemic Risks across Australia.

Japanese encephalitis virus (JEV) is an arboviral, encephalitogenic, zoonotic flavivirus characterized by its complex epidemiology whose transmission cycle involves reservoir and amplifying hosts, competent vector species and optimal environmental conditions. Although typically endemic in Asia and parts of the Pacific Islands, unprecedented outbreaks in both humans and domestic pigs in southeastern Australia emphasize the virus' expanding geographical range. To estimate areas at highest risk of JEV transmission in Australia, ecological niche models of vectors and waterbirds, a sample of piggery coordinates and feral pig population density models were combined using mathematical and geospatial mapping techniques.

Biochemical and Genetic Evidence Supports Fyv6 as a Second-Step Splicing Factor in .

Precursor mRNA (pre-mRNA) splicing is an essential process for gene expression in eukaryotes catalyzed by the spliceosome in two transesterification steps. The spliceosome is a large, highly dynamic complex composed of 5 small nuclear RNAs and dozens of proteins, some of which are needed throughout the splicing reaction while others only act during specific stages. The human protein FAM192A was recently proposed to be a splicing factor that functions during the second transesterification step, exon ligation, based on analysis of cryo-electron microscopy (cryo-EM) density.

Cellular composition and circuit organization of the locus coeruleus of adult mice.

The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions, including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multipatch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions.

Estimating the Distribution of Japanese Encephalitis Vectors in Australia Using Ecological Niche Modelling.

Recent Japanese encephalitis virus (JEV) outbreaks in southeastern Australia have sparked interest into epidemiological factors surrounding the virus' novel emergence in this region. Here, the geographic distribution of mosquito species known to be competent JEV vectors in the country was estimated by combining known mosquito occurrences and ecological drivers of distribution to reveal insights into communities at highest risk of infectious disease transmission. Species distribution models predicted that and presence was mostly likely along Australia's eastern and northern coastline, while presence was estimated to be most likely near inland regions of southern Australia as well as coastal regions of Western Australia.

Identification of transient intermediates during spliceosome activation by single molecule fluorescence microscopy.

Spliceosome activation is the process of creating the catalytic site for RNA splicing and occurs de novo on each intron following spliceosome assembly. Dozens of factors bind to or are released from the activating spliceosome including the Lsm2-8 heteroheptameric ring that binds the U6 small nuclear RNA 3'-end. Lsm2-8 must be released to permit active site stabilization by the Prp19-containing complex (NineTeen Complex, NTC); however, little is known about the temporal order of events and dynamic interactions that lead up to and follow Lsm2-8 release.

Genetic and Rare Diseases Information Center (GARD).

The Genetic and Rare Diseases Information Center (GARD) is a database dedicated to aiding anyone who may be seeking assistance and knowledge regarding rare diseases. This public health resource was put into motion by the Rare Diseases Act of 2002, and uses Translational Science to enhance research procedures. People can use this resource to find support, disease facts, ongoing research information, and available treatments.

Yeast U6 snRNA made by RNA polymerase II is less stable but functional.

U6 small nuclear (sn)RNA is the shortest and most conserved snRNA in the spliceosome and forms a substantial portion of its active site. Unlike the other four spliceosomal snRNAs, which are synthesized by RNA polymerase (RNAP) II, U6 is made by RNAP III. To determine if some aspect of U6 function is incompatible with synthesis by RNAP II, we created a U6 snRNA gene with RNAP II promoter and terminator sequences.