Elife. 2023 Feb 3;12:e83140. doi: 10.7554/eLife.83140. Online ahead of print.

ABSTRACT

Drug metabolism by the microbiome can influence anti-cancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host's chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor's chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria-drug interactions can have local and systemic influence on drug activity.

PMID:36734518 | DOI:10.7554/eLife.83140

Elife. 2023 Feb 3;12:e80100. doi: 10.7554/eLife.80100. Online ahead of print.

ABSTRACT

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 multi-patch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these mature LC neurons connected via gap junction at a rate similar to their early developmental stage and comparable to other brain regions. Most electrical connections form between dendrites and are restricted to narrowly spaced pairs or small clusters of neurons of the same type. In addition, more than two electrically coupled cell pairs were often identified across a cohort of neurons from individual multi-cell recording sets that followed a chain-like organizational pattern. The assembly of LC noradrenergic neurons thus follows a spatial and cell type-specific wiring principle that may be imposed by a unique chain-like rule.

PMID:36734517 | DOI:10.7554/eLife.80100

Elife. 2023 Feb 3;12:e79854. doi: 10.7554/eLife.79854. Online ahead of print.

ABSTRACT

Computational models starting from large ensembles of evolutionarily related protein sequences capture a representation of protein families and learn constraints associated to protein structure and function. They thus open the possibility for generating novel sequences belonging to protein families. Protein language models trained on multiple sequence alignments, such as MSA Transformer, are highly attractive candidates to this end. We propose and test an iterative method that directly employs the masked language modeling objective to generate sequences using MSA Transformer. We demonstrate that the resulting sequences score as well as natural sequences, for homology, coevolution and structure-based measures. For large protein families, our synthetic sequences have similar or better properties compared to sequences generated by Potts models, including experimentally-validated ones. Moreover, for small protein families, our generation method based on MSA Transformer outperforms Potts models. Our method also more accurately reproduces the higher-order statistics and the distribution of sequences in sequence space of natural data than Potts models. MSA Transformer is thus a strong candidate for protein sequence generation and protein design.

PMID:36734516 | DOI:10.7554/eLife.79854

Chembiochem. 2023 Feb 3. doi: 10.1002/cbic.202200802. Online ahead of print.

ABSTRACT

The emergence of drug resistant pathogens necessitates development of new countermeasures. In this regard, the introduction of probiotics to directly attack or competitively exclude pathogens presents a useful strategy. Application of this approach requires an understanding of how a probiotic and its target pathogen interact. A key means of probiotic-pathogen interaction involves the production of small molecules called natural products (NPs). Here, we report use of whole-cell matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectrometry for characterization of NP production by candidate probiotics (mouse airway microbiome isolates) when co-cultured with respiratory pathogen Burkholderia. We found that a Bacillus velezensis strain inhibits growth of and elicits NP production by B. thailandensis. Dereplication of known NPs detected in the metabolome of this B. velezensis strain suggests that a previously unannotated bioactive compound is involved. Thus, we present use of whole-cell MALDI as a broadly applicable method for screening of NP composition of microbial co-cultures, which can be combined with other -omics methods for characterization of probiotic-pathogen, and other microbe-microbe, interactions.

PMID:36734186 | DOI:10.1002/cbic.202200802

Cancer Res. 2023 Feb 3;83(3):351-353. doi: 10.1158/0008-5472.CAN-22-3537.

ABSTRACT

Adenosine-to-inosine (A-to-I) RNA editing is a major source of nucleotide diversification that has significant mechanistic implications in cancer progression and treatment response. However, its activity and prevalence have not yet been systematically determined at a single-cell resolution. Chan and colleagues revealed widespread A-to-I RNA editing events in single cancer cells through an in-depth analysis of a public lung adenocarcinoma single-cell transcriptome dataset. Edits significantly enriched in cancer cells compared to other cell types have the potential to inhibit innate immune response and to predict poor therapeutic response and prognosis in patients treated with targeted therapies. See related article by Chan et al., p. 374.

PMID:36734079 | DOI:10.1158/0008-5472.CAN-22-3537

Front Plant Sci. 2023 Jan 17;13:1074697. doi: 10.3389/fpls.2022.1074697. eCollection 2022.

ABSTRACT

In the Convolvulaceae family, around 1650 species belonging to 60 genera are widely distributed globally, mainly in the tropical and subtropical regions of America and Asia. Although a series of chloroplast genomes in Convolvulaceae were reported and investigated, the evolutionary and genetic relationships among the chloroplast genomes of the Convolvulaceae family have not been extensively elucidated till now. In this study, we first reported the complete chloroplast genome sequence of Ipomoea pes-caprae, a widely distributed coastal plant with medical values. The chloroplast genome of I. pes-caprae is 161667 bp in length, and the GC content is 37.56%. The chloroplastic DNA molecule of I. pes-caprae is a circular structure composed of LSC (large-single-copy), SSC (small-single-copy), and IR (inverted repeat) regions, with the size of the three regions being 88210 bp, 12117 bp, and 30670 bp, respectively. The chloroplast genome of I. pes-caprae contains 141 genes, and 35 SSRs are identified in the chloroplast genome. Our research results provide important genomic information for the molecular phylogeny of I. pes-caprae. The Phylogenetic analysis of 28 Convolvulaceae chloroplast genomes showed that the relationship of I. pes-caprae with I. involucrata or I. obscura was much closer than that with other Convolvulaccae species. Further comparative analyses between the Ipomoea species and Cuscuta species revealed the mechanism underlying the formation of parasitic characteristics of Cuscuta species from the perspective of the chloroplast genome.

PMID:36733590 | PMC:PMC9887335 | DOI:10.3389/fpls.2022.1074697

NAR Genom Bioinform. 2023 Jan 31;5(1):lqad008. doi: 10.1093/nargab/lqad008. eCollection 2023 Mar.

ABSTRACT

Metabolites regulate activity of proteins and thereby affect cellular processes in all organisms. Despite extensive efforts to catalogue the metabolite-protein interactome in different organisms by employing experimental and computational approaches, the coverage of such interactions remains fragmented, particularly for eukaryotes. Here, we make use of two most comprehensive collections, BioSnap and STITCH, of metabolite-protein interactions from seven eukaryotes as gold standards to train a deep learning model that relies on self- and cross-attention over protein sequences. This innovative protein-centric approach results in interaction-specific features derived from protein sequence alone. In addition, we designed and assessed a first double-blind evaluation protocol for metabolite-protein interactions, demonstrating the generalizability of the model. Our results indicated that the excellent performance of the proposed model over simpler alternatives and randomized baselines is due to the local and global features generated by the attention mechanisms. As a results, the predictions from the deep learning model provide a valuable resource for studying metabolite-protein interactions in eukaryotes.

PMID:36733400 | PMC:PMC9887643 | DOI:10.1093/nargab/lqad008

Front Behav Neurosci. 2023 Jan 17;17:1131920. doi: 10.3389/fnbeh.2023.1131920. eCollection 2023.

NO ABSTRACT

PMID:36733304 | PMC:PMC9887274 | DOI:10.3389/fnbeh.2023.1131920

PNAS Nexus. 2022 Jan 6;2(1):pgac299. doi: 10.1093/pnasnexus/pgac299. eCollection 2023 Jan.

ABSTRACT

Most animal cells are surrounded by a cell membrane and an underlying actomyosin cortex. Both structures are linked, and they are under tension. In-plane membrane tension and cortical tension both influence many cellular processes, including cell migration, division, and endocytosis. However, while actomyosin tension is regulated by substrate stiffness, how membrane tension responds to mechanical substrate properties is currently poorly understood. Here, we probed the effective membrane tension of neurons and fibroblasts cultured on glass and polyacrylamide substrates of varying stiffness using optical tweezers. In contrast to actomyosin-based traction forces, both peak forces and steady-state tether forces of cells cultured on hydrogels were independent of substrate stiffness and did not change after blocking myosin II activity using blebbistatin, indicating that tether and traction forces are not directly linked. Peak forces in fibroblasts on hydrogels were about twice as high as those in neurons, indicating stronger membrane-cortex adhesion in fibroblasts. Steady-state tether forces were generally higher in cells cultured on hydrogels than on glass, which we explain by a mechanical model. Our results provide new insights into the complex regulation of effective membrane tension and pave the way for a deeper understanding of the biological processes it instructs.

PMID:36733291 | PMC:PMC9887938 | DOI:10.1093/pnasnexus/pgac299

Cell Rep. 2023 Jan 31;42(1):111994. doi: 10.1016/j.celrep.2023.111994. Epub 2023 Jan 24.

ABSTRACT

Palmoplantar skin is structurally and functionally unique, but the transcriptional programs driving this specialization are unclear. Here, we use bulk and single-cell RNA sequencing of human palm, sole, and hip skin to describe the distinguishing characteristics of palmoplantar and non-palmoplantar skin while also uncovering differences between palmar and plantar sites. Our approach reveals an altered immune environment in palmoplantar skin, with downregulation of diverse immunological processes and decreased immune cell populations. Further, we identify specific fibroblast populations that appear to orchestrate key differences in cell-cell communication in palm, sole, and hip. Dedicated keratinocyte analysis highlights major differences in basal cell fraction among the three sites and demonstrates the existence of two spinous keratinocyte populations constituting parallel, site-selective epidermal differentiation trajectories. In summary, this deep characterization of highly adapted palmoplantar skin contributes key insights into the fundamental biology of human skin and provides a valuable data resource for further investigation.

PMID:36732947 | DOI:10.1016/j.celrep.2023.111994

Nat Commun. 2023 Feb 2;14(1):569. doi: 10.1038/s41467-023-36264-y.

NO ABSTRACT

PMID:36732511 | DOI:10.1038/s41467-023-36264-y

Nat Commun. 2023 Feb 2;14(1):574. doi: 10.1038/s41467-022-34256-y.

ABSTRACT

SARS-CoV-2 distribution and circulation dynamics are not well understood due to challenges in assessing genomic data from tissue samples. We develop experimental and computational workflows for high-depth viral sequencing and high-resolution genomic analyses from formalin-fixed, paraffin-embedded tissues and apply them to 120 specimens from six subjects with fatal COVID-19. To varying degrees, viral RNA is present in extrapulmonary tissues from all subjects. The majority of the 180 viral variants identified within subjects are unique to individual tissue samples. We find more high-frequency (>10%) minor variants in subjects with a longer disease course, with one subject harboring ten such variants, exclusively in extrapulmonary tissues. One tissue-specific high-frequency variant was a nonsynonymous mutation in the furin-cleavage site of the spike protein. Our findings suggest adaptation and/or compartmentalized infection, illuminating the basis of extrapulmonary COVID-19 symptoms and potential for viral reservoirs, and have broad utility for investigating human pathogens.

PMID:36732505 | DOI:10.1038/s41467-022-34256-y

Pharmacol Biochem Behav. 2023 Jan 30:173523. doi: 10.1016/j.pbb.2023.173523. Online ahead of print.

ABSTRACT

Approximately two-thirds of patients with major depressive disorder (MDD) fail to respond to conventional antidepressants, suggesting that additional mechanisms are involved in the MDD pathophysiology. In this scenario, the glutamatergic system represents a promising therapeutic target for treatment-resistant depression. To our knowledge, this is the first study using semantic approach with systems biology to identify potential targets involved in the fast-acting antidepressant effects of ketamine and its enantiomers as well as identifying specific targets of (R)-ketamine. We performed a systematic review, followed by a semantic analysis and functional gene enrichment to identify the main biological processes involved in the therapeutic effects of these agents. Protein-protein interaction networks were constructed, and the genes exclusively regulated by (R)-ketamine were explored. We found that the regulation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor subunits-Postsynaptic Protein 95 (PSD-95), Brain Derived Neurotrophic Factor (BDNF), and Tyrosine Receptor Kinase B (TrkB) are shared by the three-antidepressant agents, reinforcing the central role of the glutamatergic system and neurogenesis on its therapeutic effects. Differential regulation of Transforming Growth Factor Beta 1 (TGF-β1) receptors-Mitogen-Activated Protein Kinases (MAPK's), Receptor Activator of Nuclear Factor-Kappa Beta Ligand (RANKL), and Serotonin Transporter (SERT) seems to be particularly involved in (R)-ketamine antidepressant effects. Our data helps further studies investigating the relationship between these targets and the mechanisms of (R)-ketamine and searching for other therapeutic compounds that share the regulation of these specific biomolecules. Ultimately, this study could contribute to improve the fast management of depressive-like symptoms with less detrimental side effects than ketamine and (S)-ketamine.

PMID:36731751 | DOI:10.1016/j.pbb.2023.173523

Mol Metab. 2023 Jan 30:101682. doi: 10.1016/j.molmet.2023.101682. Online ahead of print.

ABSTRACT

OBJECTIVE: Dysfunctional, unhealthy expansion of white adipose tissue due to excess dietary intake is a process at the root of obesity and Type 2 Diabetes development. The objective of this study is to contribute to a better understanding of the underlying mechanism(s) regulating the early stages of adipose tissue expansion and adaptation to dietary stress due to an acute, high-fat diet (HFD) challenge, with a focus on the communication between adipocytes and other stromal cells.

METHODS: We profiled the early response to high-fat diet exposure in wildtype and adipocyte-specific GPS2-KO (GPS2-AKO) mice at cellular, tissue and organismal level. A multi-pronged approach was employed to disentangle the complex cellular interactions dictating tissue remodeling, via single-cell RNA sequencing and FACS profiling of the stromal fraction, and semi-quantitative proteomics of the adipocyte-derived exosomal cargo after 5 weeks of HFD feeding.

RESULTS: Our results indicate that loss of GPS2 in mature adipocytes leads to impaired adaptation to the metabolic stress imposed by HFD feeding. GPS2-AKO mice are significantly more inflamed, insulin resistant, and obese, compared to the WT counterparts. At the cellular level, lack of GPS2 in adipocytes impacts upon other stromal populations, with both the eWAT and scWAT depots exhibiting changes in the immune and non-immune compartments that contribute to an increase in inflammatory and anti-adipogenic cell types. Our studies also revealed that adipocyte to stromal cell communication is facilitated by exosomes, and that transcriptional rewiring of the exosomal cargo is crucial for tissue remodeling. Loss of GPS2 results in increased expression of secreted factors promoting a TGFβ-driven fibrotic microenvironment favoring unhealthy tissue remodeling and expansion.

CONCLUSIONS: Adipocytes serve as an intercellular signaling hub, communicating with the stromal compartment via paracrine signaling. Our study highlights the importance of proper regulation of the 'secretome' released by energetically stressed adipocytes at the onset of obesity. Altered transcriptional regulation of factors secreted via adipocyte-derived exosomes (AdExos), in the absence of GPS2, contributes to the establishment of an anti-adipogenic, pro-fibrotic adipose tissue environment, and to hastened progression towards a metabolically dysfunctional phenotype.

PMID:36731652 | DOI:10.1016/j.molmet.2023.101682

J Am Chem Soc. 2023 Feb 2. doi: 10.1021/jacs.2c13137. Online ahead of print.

ABSTRACT

We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product─along with a hypothesis about a biosynthetic relationship to related family members─inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis-to-trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama-Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C-N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.

PMID:36730688 | DOI:10.1021/jacs.2c13137

PLoS Comput Biol. 2023 Feb 2;19(2):e1010884. doi: 10.1371/journal.pcbi.1010884. Online ahead of print.

ABSTRACT

Infectious diseases of plants present an ongoing and increasing threat to international biosecurity, with wide-ranging implications. An important challenge in plant disease management is achieving early detection of invading pathogens, which requires effective surveillance through the implementation of appropriate monitoring programmes. However, when monitoring relies on visual inspection as a means of detection, surveillance is often hindered by a long incubation period (delay from infection to symptom onset) during which plants may be infectious but not displaying visible symptoms. 'Sentinel' plants-alternative susceptible host species that display visible symptoms of infection more rapidly-could be introduced to at-risk populations and included in monitoring programmes to act as early warning beacons for infection. However, while sentinel hosts exhibit faster disease progression and so allow pathogens to be detected earlier, this often comes at a cost: faster disease progression typically promotes earlier onward transmission. Here, we construct a computational model of pathogen transmission to explore this trade-off and investigate how including sentinel plants in monitoring programmes could facilitate earlier detection of invasive plant pathogens. Using Xylella fastidiosa infection in Olea europaea (European olive) as a current high profile case study, for which Catharanthus roseus (Madagascan periwinkle) is a candidate sentinel host, we apply a Bayesian optimisation algorithm to determine the optimal number of sentinel hosts to introduce for a given sampling effort, as well as the optimal division of limited surveillance resources between crop and sentinel plants. Our results demonstrate that including sentinel plants in monitoring programmes can reduce the expected prevalence of infection upon outbreak detection substantially, increasing the feasibility of local outbreak containment.

PMID:36730434 | DOI:10.1371/journal.pcbi.1010884

Cell Rep. 2023 Jan 31;42(2):112052. doi: 10.1016/j.celrep.2023.112052. Online ahead of print.

ABSTRACT

The notochord is a defining feature of all chordates. The transcription factors Zic and ETS regulate enhancer activity within the notochord. We conduct high-throughput screens of genomic elements within developing Ciona embryos to understand how Zic and ETS sites encode notochord activity. Our screen discovers an enhancer located near Lama, a gene critical for notochord development. Reversing the orientation of an ETS site within this enhancer abolishes expression, indicating that enhancer grammar is critical for notochord activity. Similarly organized clusters of Zic and ETS sites occur within mouse and human Lama1 introns. Within a Brachyury (Bra) enhancer, FoxA and Bra, in combination with Zic and ETS binding sites, are necessary and sufficient for notochord expression. This binding site logic also occurs within other Ciona and vertebrate Bra enhancers. Collectively, this study uncovers the importance of grammar within notochord enhancers and discovers signatures of enhancer logic and grammar conserved across chordates.

PMID:36729834 | DOI:10.1016/j.celrep.2023.112052

Mol Diagn Ther. 2023 Feb 2. doi: 10.1007/s40291-023-00640-7. Online ahead of print.

ABSTRACT

Breath analysis is a relatively recent field of research with much promise in scientific and clinical studies. Breath contains endogenously produced volatile organic components (VOCs) resulting from metabolites of ingested precursors, gut and air-passage bacteria, environmental contacts, etc. Numerous recent studies have suggested changes in breath composition during the course of many diseases, and breath analysis may lead to the diagnosis of such diseases. Therefore, it is important to identify the disease-specific variations in the concentration of breath to diagnose the diseases. In this review, we explore methods that are used to detect VOCs in laboratory settings, VOC constituents in exhaled air and other body fluids (e.g., sweat, saliva, skin, urine, blood, fecal matter, vaginal secretions, etc.), VOC identification in various diseases, and recently developed electronic (E)-nose-based sensors to detect VOCs. Identifying such VOCs and applying them as disease-specific biomarkers to obtain accurate, reproducible, and fast disease diagnosis could serve as an alternative to traditional invasive diagnosis methods. However, the success of VOC-based identification of diseases is limited to laboratory settings. Large-scale clinical data are warranted for establishing the robustness of disease diagnosis. Also, to identify specific VOCs associated with illness states, extensive clinical trials must be performed using both analytical instruments and electronic noses equipped with stable and precise sensors.

PMID:36729362 | DOI:10.1007/s40291-023-00640-7

Microbiol Spectr. 2023 Feb 2:e0473522. doi: 10.1128/spectrum.04735-22. Online ahead of print.

ABSTRACT

Colonization resistance, also known as pathogen interference, describes the ability of a colonizing microbe to interfere with the ability of an incoming microbe to establish infection, and in the case of pathogenic organisms, cause disease in a susceptible host. Furthermore, colonization-associated dysbiosis of the commensal microbiota can alter host immunocompetence and infection outcomes. Here, we investigated the role of Bordetella bronchiseptica nasal colonization and associated disruption of the nasal microbiota on the ability of influenza A virus to establish infection in the murine upper respiratory tract. Targeted sequencing of the microbial 16S rRNA gene revealed that B. bronchiseptica colonization of the nasal cavity efficiently displaced the resident commensal microbiota-the peak of this effect occurring 7 days postcolonization-and was associated with reduced influenza associated-morbidity and enhanced recovery from influenza-associated clinical disease. Anti-influenza A virus hemagglutinin-specific humoral immune responses were not affected by B. bronchiseptica colonization, although the cellular influenza PA-specific CD8+ immune responses were dampened. Notably, influenza A virus replication in the nasal cavity was negated in B. bronchiseptica-colonized mice. Collectively, this work demonstrates that B. bronchiseptica-mediated pathogen interference prevents influenza A virus replication in the murine nasal cavity. This may have direct implications for controlling influenza A virus replication in, and transmission events originating from, the upper respiratory tract. IMPORTANCE The interplay of microbial species in the upper respiratory tract is important for the ability of an incoming pathogen to establish and, in the case of pathogenic organisms, cause disease in a host. Here, we demonstrate that B. bronchiseptica efficiently colonizes and concurrently displaces the commensal nasal cavity microbiota, negating the ability of influenza A virus to establish infection. Furthermore, B. bronchiseptica colonization also reduced influenza-associated morbidity and enhanced recovery from influenza-associated disease. Collectively, this study indicates that B. bronchiseptica-mediated interference prevents influenza A virus replication in the upper respiratory tract. This result demonstrates the potential for respiratory pathogen-mediated interference to control replication and transmission dynamics of a clinically important respiratory pathogen like influenza A virus.

PMID:36728413 | DOI:10.1128/spectrum.04735-22

Am J Physiol Renal Physiol. 2023 Feb 2. doi: 10.1152/ajprenal.00231.2022. Online ahead of print.

ABSTRACT

Circadian variability in kidney function is well recognized but is often ignored as a potential confounding variable in physiological experiments. Here, we have created a data resource consisting of expression levels for mRNA transcripts in microdissected proximal tubule segments from mice as a function of the time of day. Small-sample RNA-sequencing (RNA-seq) was applied to microdissected S1 proximal convoluted tubules (PCTs) and S2 proximal straight tubules (PSTs). After stringent filtering, the data were analyzed using JTK-Cycle to detect periodicity. The dataset is provided as a user-friendly webpage at https://esbl.nhlbi.nih.gov/Databases/Circadian-Prox2/. In PCTs, 234 transcripts varied in a circadian manner (4.0 % of total). In PSTs, 334 transcripts varied in a circadian manner (5.3 %). Transcripts previously known to be associated with corticosteroid action and with increased flow were found to be overrepresented among circadian transcripts peaking during the "dark" portion of the day (Zeitgeber Time [ZT] 14-22), corresponding to the peak levels of corticosterone and glomerular filtration rate in mice. To ask whether there is time-of-day dependence of protein abundances in the kidney, we carried out LC-MS/MS-based proteomics in whole mouse kidneys at ZT12 and ZT0. The full data set (n=6546 proteins) is available at https://esbl.nhlbi.nih.gov/Databases/Circadian-Proteome/. Overall, 293 proteins were differentially expressed between ZT12 and ZT0 (197 greater at ZT12; 96 greater at ZT0). Among the regulated proteins, only 9 had been found to be periodic in the RNA-seq analysis, suggesting a high level of post-transcriptional regulation of protein abundances.

PMID:36727945 | DOI:10.1152/ajprenal.00231.2022