Biology subjects

Sandoval, R.

Publications and source records attributed to Sandoval, R..

3 recordsLinked to original sources

bioRxiv2026

Expanding Threat of Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae in Peru: Genomic and Phenotypic Evidence of High-Risk Clones Dissemination

Carbapenemase-producing Enterobacterales represent a growing global threat due to their extensive antimicrobial resistance and rapid dissemination. This study characterized the phenotypic and genomic features of Escherichia coli and Klebsiella pneumoniae isolates collected between 2020 and 2022 from four healthcare institutions in Lima, Peru. A total of 320 non-redundant isolates (61 E. coli and 259 K. pneumoniae) were analyzed through antimicrobial susceptibility testing, polymerase chain reaction, and whole-genome sequencing. The most frequent carbapenemase gene was blaNDM (69%), followed by blaKPC (16.9%) and blaOXA-48-like (4.6%). Eleven K. pneumoniae isolates co-produced NDM and KPC, and one E. coli isolate co-harbored NDM and OXA-48-like. All isolates were multidrug resistant, and 5% were pandrug resistant. Novel {beta}-lactam/{beta}-lactamase inhibitor combinations such as aztreonam/avibactam and cefiderocol showed complete activity against all classes of carbapenemases. Genomic analysis revealed predominant E. coli sequence types ST167 and ST410 and K. pneumoniae lineages ST147, ST15, ST45, and ST273. The blaNDM-5 allele was detected for the first time in Peru, mostly in E. coli ST167, carried on multireplicon IncF-type plasmids. In K. pneumoniae, ST147 was identified as a dominant clone associated with blaNDM-1, indicating sustained local dissemination of high-risk clonal groups. The coexistence of multiple carbapenemases and plasmid backbones highlights the ongoing evolution of resistance mechanisms. These findings provide actionable evidence to guide treatment strategies in settings with high prevalence of metallo-{beta}-lactamases and underscores the need for continuous genomic surveillance and antimicrobial stewardship to mitigate their clinical and epidemiological impact.

microbiology↗

bioRxiv2024

Mammalian RNAi represses pericentromeric lncRNAs to maintain genome stability

Mammalian pericentromeric tandem repeats produce long noncoding RNAs (lncRNAs) that are dysregulated in cancer and linked to genomic instability. Identifying the basic molecular characteristics of these lncRNAs and their regulation is important to understanding their biological function. Here, we determine that the Argonaute (Ago) proteins of the RNA interference (RNAi) pathway directly and uniformly repress bidirectional pericentromeric lncRNAs in a Dicer-dependent manner in mouse embryonic and adult stem cells. Ago-dependent and Dicer-dependent autoregulatory small RNAs were identified within pericentromeric lncRNA degradation intermediates. We develop an RNase H cleavage assay to determine the relative proportions and lengths of the pericentromeric lncRNA targets. We find that 5-phosphate and non-polyadenylated bidirectional pericentromeric lncRNAs are expressed at similar proportions. These lncRNAs can span up to 9 repeats, with transcription from the reverse strand template yielding the longer products. Using pericentromeric repeat RNA reporters, we determine that Ago represses pericentromeric lncRNAs after S phase transcription. Upon loss of Ago, pericentromeric lncRNA dysregulation results in delayed cell cycle progression, a defective mitotic spindle assembly checkpoint (SAC) and genomic instability. These results show that an evolutionarily conserved Ago activity at pericentromeres contributes to mammalian genome stability.

molecular biology↗

bioRxiv2022

Dorsal Hippocampus To Nucleus Accumbens Projections Drive Reinforcement Via Activation of Accumbal Dynorphin Neurons.

The hippocampus represents a key structure in the integration of emotional processing, learning and memory, and reward-related behaviors. While the ventral subdivision of the hippocampus (vHPC) is involved in processing emotional values of salient stimuli and goal-directed behaviors, the dorsal hippocampus (dHPC) plays a critical role in episodic, spatial, and associative memory. In addition, it has been shown that the dHPC is necessary for context- and cue-associated reward behaviors, including the expression of reward seeking. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli and its activity is sufficient to drive aversive and appetitive behaviors. Recent evidence has demonstrated that dHPC[->]Nucleus Accumbens (NAc) pathway is necessary for expression of a conditioned place preference. However, despite years of groundbreaking research and identification of direct projections from the dHPC to the NAc, the sufficiency for dHPC[->]NAC inputs to drive reinforcement and reward associated behavior remains to be determined. Here using a wide range of complementary and cutting-edge techniques including behavior, in-vivo manipulation using optogenetics, chemogenetics, brain clearing, local field potential and fiber photometry recordings, we demonstrate that activation of excitatory projections from the CA1 subregion of the dHPC (dCA1) is sufficient to drive reinforcing behaviors. In addition, we provide strong evidence that this reinforcing behavior is driven by 1) a direct projection from the dCA1 to the NAc and 2) enhanced glutamatergic signaling within the NAc. Furthermore, we uncovered that while dCA1 stimulation increases the activity of both enkephalin- and dynorphin-containing medium spiny neurons in the NAc, the selective activity of dynorphin-containing neurons is necessary for the expression of this reinforcing behavior. Our findings shed light on a novel pathway governing reinforcement and further extend the role of the dHPC on reward seeking.

neuroscience↗