The APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of proteins have diverse and important functions in human health and disease. These proteins have an intrinsic ability to ...bind to both RNA and single-stranded (ss) DNA. Both function and tissue-specific expression varies widely for each APOBEC protein. We are beginning to understand that the activity of APOBEC proteins is regulated through genetic alterations, changes in their transcription and mRNA processing, and through their interactions with other macromolecules in the cell. Loss of cellular control of APOBEC activities leads to DNA hypermutation and promiscuous RNA editing associated with the development of cancer or viral drug resistance, underscoring the importance of understanding how APOBEC proteins are regulated.
The APOBEC family of proteins do not have a common RNA or DNA substrate for cytidine/deoxycytidine deamination and in fact it appears that not all the predicted cytidine deaminase domains are catalytically active.
A consensus is emerging that nucleic acid substrates are coordinated for deamination using amino acid residues flanking the catalytic domain.
APOBECs are not essential proteins for development and growth but several play crucial roles in the maintenance of long-term health such as in metabolism and immunity (innate and acquired).
APOBECs are controlled through transcription, the expression of alternative spliced mRNAs as well as via localization, post-translational modification, turnover, and interactions with other proteins or RNAs.
Overexpression of APOBECs and APOBEC variants has been observed in several malignancies suggesting an association with cancer initiation and/or progression.
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► APOBEC deaminases edit RNA and DNA. ► APOBEC regulation. ► APOBEC restrict foreign genetic elements.
APOBEC1 is a cytidine deaminase that edits messenger RNAs and was the first ...enzyme in the APOBEC family to be functionally characterized. Under appropriate conditions APOBEC1 also deaminates deoxycytidine in single-stranded DNA (ssDNA). The other ten members of the APOBEC family have not been fully characterized however several have deoxycytidine deaminase activity on ssDNAs. Despite the nucleic acid substrate preferences of different APOBEC proteins, a common feature appears to be their intrinsic ability to bind to RNA as well as to ssDNA. RNA binding to APOBEC proteins together with protein–protein interactions, post-translation modifications and subcellular localization serve as biological modulators controlling the DNA mutagenic activity of these potentially genotoxic proteins.
The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease ...burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized.
This article analyzes mismatches between syntactic and prosodic constituency in Irish and attempts to understand those mismatches in terms of recent proposals about the nature of the syntax-prosody ...interface. It argues in particular that such mismatches are best understood in terms of Selkirk's (2011) Match Theory, working in concert with constraints concerned with rhythm and phonological balance. An apparently anomalous rightward movement that seems to target certain pronouns and shift them rightward is shown to be fundamentally a phonological process: a prosodic response to a prosodic dilemma. The article thereby adds to a growing body of evidence for the role of phonological factors in shaping constituent order.
Multimodal integration is the formation of a coherent percept from different sensory inputs such as vision, audition, and somatosensation. Most research on multimodal integration in speech perception ...has focused on audio-visual integration. In recent years, audio-tactile integration has also been investigated, and it has been established that puffs of air applied to the skin and timed with listening tasks shift the perception of voicing by naive listeners. The current study has replicated and extended these findings by testing the effect of air puffs on gradations of voice onset time along a continuum rather than the voiced and voiceless endpoints of the original work. Three continua were tested: bilabial (“pa/ba”), velar (“ka/ga”), and a vowel continuum (“head/hid”) used as a control. The presence of air puffs was found to significantly increase the likelihood of choosing voiceless responses for the two VOT continua but had no effect on choices for the vowel continuum. Analysis of response times revealed that the presence of air puffs lengthened responses for intermediate (ambiguous) stimuli and shortened them for endpoint (non-ambiguous) stimuli. The slowest response times were observed for the intermediate steps for all three continua, but for the bilabial continuum this effect interacted with the presence of air puffs: responses were slower in the presence of air puffs, and faster in their absence. This suggests that during integration auditory and aero-tactile inputs are weighted differently by the perceptual system, with the latter exerting greater influence in those cases where the auditory cues for voicing are ambiguous.
Following the development of Prosodic Hierarchy Theory (Selkirk 1984; Nespor & Vogel 1986), evidence has accumulated that prosodic categories may be recursively self-embedded (e.g. Selkirk 1995; ...Truckenbrodt 1999; Wagner 2010; Itô & Mester 2013, etc.). However, this conclusion is not universally accepted (e.g. Vogel 2009a), and even the need for prosodic categories has been recently disputed (e.g. Scheer 2012b).In this article I argue that the prefixal phonology of Kaqchikel provides clear and convincing evidence for unbounded (iterable) recursion of the prosodic word ω. Patterns of ʔ-insertion and degemination receive a simple, elegant treatment if recursion of the prosodic word is permitted. Theories of prosodic phonology which do without recursion are forced to resort to ad hoc stipulations to account for the same facts. Both derivational (e.g. Kiparsky 1982) and transderivational (e.g. Benua 2000) analyses of these patterns fail on morphological grounds. The overall conclusion is that both abstract prosodic structure and recursion of the prosodic word are indispensable parts of any theory of word-level phonology.
Sangivamycin (S) is an adenosine (A) nucleoside analog with low nanomolar antiviral activity against SARS-CoV-2 in vitro. Previously, low nanomolar antiviral efficacy was revealed when tested against ...multiple viral variants in several cell types. SARS-CoV-2 RNA isolated from live virus infected cells and the virions released from these cells was analyzed by mass spectrometry (MS) for S incorporation. Dose-dependent incorporation occurred up to 1.8 S per 1,000 nucleotides (49 S per genome) throughout the viral genomes isolated from both infected cells and viral particles, but this incorporation did not change the viral mutation rate. In contrast, host mRNA, affinity purified from the same infected and treated cells, contained little or no S. Sangivamycin triphosphate (STP) was synthesized to evaluate its incorporation into RNA by recombinant SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) under defined in vitro conditions. SARS-CoV-2 RdRp showed that S was not a chain terminator and S containing oligonucleotides templated as A. Though the antiviral mechanism remains to be determined, the data suggests that SARS-CoV-2 RdRp incorporates STP into SARS-CoV-2 RNA, which does not significantly impair viral RNA synthesis or the mutation rate.
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•Sangivamycin is an antiviral nucleoside analog preferentially incorporated into SARS-CoV-2 RNA by the viral polymerase.•Sangivamycin templates as an A and is not a chain terminator or a viral mutator.•Viral genomes containing sangivamycin are packaged into virions.
A dichotomy between the additions of organolithiums and lithium amides to cyclobutenediones is described wherein the former give carbonyl addition products while the latter induce ring opening by ...enone cleavage
via O
- to
C
-lithium transfer. This distinct mode of ring scission gives access to 2-oxobut-3-enamides and tetrasubstituted furans.
The addition of lithium amides to cyclobutenediones provides access to 2-oxo-but-3-enamides and tetrasubstituted furans
via
a new mode of ring opening involving enone cleavage
via O
- to
C
-lithium transfer.
The infectivity of HIV depends on overcoming APOBEC3 (A3) innate immunity, predominantly through the expression of the viral protein Vif, which induces A3 degradation in the proteasome. Disruption of ...the functional interactions of Vif enables A3 mutagenesis of the HIV genome during viral replication, which can result in a broadly neutralizing antiviral effect. Vif function requires self-association along with interactions with A3 proteins, protein chaperones, and factors of the ubiquitination machinery and these are described here as a potential platform for novel antiviral drug discovery. This Review will examine the current state of development of Vif inhibitors that we believe to have therapeutic and functional cure potential.
Both model systems and clinical data suggest that the interactions between HIV Vif and APOBEC3 innate immunity are critical for HIV infection and have antiretroviral therapeutic potential.
There are multiple protein–protein interactions required for HIV Vif to block APOBEC3 antiviral activity.
Diverse small-molecule Vif inhibitors targeting different interactions establish proof-of-concept for antiviral sites for drug development.
Vif inhibitors could have the potential to enhance HIV treatment options and might be part of future prevention and cure initiatives.
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