Emerging roles of RNA modification: m(6)A and U-tail.

Although more than 100 types of RNA modification have been described thus far, most of them were thought to be rare in mRNAs and in regulatory noncoding RNAs. Recent developments have unveiled that at least some of the modifications are considerably abundant and widely conserved. This Minireview summarizes the molecular machineries and biological functions of methylation (N6-methyladenosine, m(6)A) and uridylation (U-tail).

In vivo profiling of the Zucchini proximal proteome in the Drosophila ovary.

PIWI-interacting RNAs (piRNAs) are small RNAs that play a conserved role in genome defense. The piRNA processing pathway is dependent on the sequestration of RNA precursors and protein factors in specific subcellular compartments. Therefore, a highly resolved spatial proteomics approach can help identify the local interactions and elucidate the unknown aspects of piRNA biogenesis. Herein, we performed TurboID proximity labeling to investigate the interactome of Zucchini (Zuc), a key factor of piRNA biogenesis in germline cells and somatic follicle cells of the Drosophila ovary. Quantitative mass spectrometry analysis of biotinylated proteins defined the Zuc-proximal proteome, including the well-known partners of Zuc. Many of these were enriched in the outer mitochondrial membrane (OMM), where Zuc was specifically localized. The proximal proteome of Zuc showed a distinct set of proteins compared with that of Tom20, a representative OMM protein, indicating that chaperone function-related and endomembrane system/vesicle transport proteins are previously unreported interacting partners of Zuc. The functional relevance of several candidates in piRNA biogenesis was validated by derepression of transposable elements after knockdown. Our results present potential Zuc-interacting proteins, suggesting unrecognized biological processes.

Terminal Uridylyltransferases Execute Programmed Clearance of Maternal Transcriptome in Vertebrate Embryos.

During the maternal-to-zygotic transition (MZT), maternal RNAs are actively degraded and replaced by newly synthesized zygotic transcripts in a highly coordinated manner. However, it remains largely unknown how maternal mRNA decay is triggered in early vertebrate embryos. Here, through genome-wide profiling of RNA abundance and 3' modification, we show that uridylation is induced at the onset of maternal mRNA clearance. The temporal control of uridylation is conserved in vertebrates. When the homologs of terminal uridylyltransferases TUT4 and TUT7 (TUT4/7) are depleted in zebrafish and Xenopus, maternal mRNA clearance is significantly delayed, leading to developmental defects during gastrulation. Short-tailed mRNAs are selectively uridylated by TUT4/7, with the highly uridylated transcripts degraded faster during the MZT than those with unmodified poly(A) tails. Our study demonstrates that uridylation plays a crucial role in timely mRNA degradation, thereby allowing the progression of early development.

Optimal age to discontinue long-term surveillance of intraductal papillary mucinous neoplasms: comparative cost-effectiveness of surveillance by age.

OBJECTIVE: Current guidelines recommend long-term image-based surveillance for patients with low-risk intraductal papillary mucinous neoplasms (IPMNs). This simulation study aimed to examine the comparative cost-effectiveness of continued versus discontinued surveillance at different ages and define the optimal age to stop surveillance. DESIGN: We constructed a Markov model with a lifetime horizon to simulate the clinical course of patients with IPMNs receiving imaging-based surveillance. We calculated incremental cost-effectiveness ratios (ICERs) for continued versus discontinued surveillance at different ages to stop surveillance, stratified by sex and IPMN types (branch-duct vs mixed-type). We determined the optimal age to stop surveillance as the lowest age at which the ICER exceeded the willingness-to-pay threshold of US$100 000 per quality-adjusted life year. To estimate model parameters, we used a clinical cohort of 3000 patients with IPMNs and a national database including 40 166 patients with pancreatic cancer receiving pancreatectomy as well as published data. RESULTS: In male patients, the optimal age to stop surveillance was 76-78 years irrespective of the IPMN types, compared with 70, 73, 81, and 84 years for female patients with branch-duct IPMNs <20 mm, =20-29 mm, ≥30 mm and mixed-type IPMNs, respectively. The suggested ages became younger according to an increasing level of comorbidities. In cases with high comorbidity burden, the ICERs were above the willingness-to-pay threshold irrespective of sex and the size of branch-duct IPMNs. CONCLUSIONS: The cost-effectiveness of long-term IPMN surveillance depended on sex, IPMN types, and comorbidity levels, suggesting the potential to personalise patient management from the health economic perspective.

mTAIL-seq reveals dynamic poly(A) tail regulation in oocyte-to-embryo development.

Eukaryotic mRNAs are subject to multiple types of tailing that critically influence mRNA stability and translatability. To investigate RNA tails at the genomic scale, we previously developed TAIL-seq, but its low sensitivity precluded its application to biological materials of minute quantity. In this study, we report a new version of TAIL-seq (mRNA TAIL-seq [mTAIL-seq]) with enhanced sequencing depth for mRNAs (by ∼1000-fold compared with the previous version). The improved method allows us to investigate the regulation of poly(A) tails in Drosophila oocytes and embryos. We found that maternal mRNAs are polyadenylated mainly during late oogenesis, prior to fertilization, and that further modulation occurs upon egg activation. Wispy, a noncanonical poly(A) polymerase, adenylates the vast majority of maternal mRNAs, with a few intriguing exceptions such as ribosomal protein transcripts. By comparing mTAIL-seq data with ribosome profiling data, we found a strong coupling between poly(A) tail length and translational efficiency during egg activation. Our data suggest that regulation of poly(A) tails in oocytes shapes the translatomic landscape of embryos, thereby directing the onset of animal development. By virtue of the high sensitivity, low cost, technical robustness, and broad accessibility, mTAIL-seq will be a potent tool to improve our understanding of mRNA tailing in diverse biological systems.

ROS-induced PADI2 downregulation accelerates cellular senescence via the stimulation of SASP production and NFκB activation.

Cellular senescence is closely related to tissue aging including bone. Bone homeostasis is maintained by the tight balance between bone-forming osteoblasts and bone-resorbing osteoclasts, but it undergoes deregulation with age, causing age-associated osteoporosis, a main cause of which is osteoblast dysfunction. Oxidative stress caused by the accumulation of reactive oxygen species (ROS) in bone tissues with aging can accelerate osteoblast senescence and dysfunction. However, the regulatory mechanism that controls the ROS-induced senescence of osteoblasts is poorly understood. Here, we identified Peptidyl arginine deiminase 2 (PADI2), a post-translational modifying enzyme, as a regulator of ROS-accelerated senescence of osteoblasts via RNA-sequencing and further functional validations. PADI2 downregulation by treatment with H2O2 or its siRNA promoted cellular senescence and suppressed osteoblast differentiation. CCL2, 5, and 7 known as the elements of the senescence-associated secretory phenotype (SASP) which is a secretome including proinflammatory cytokines and chemokines emitted by senescent cells and a representative feature of senescence, were upregulated by H2O2 treatment or Padi2 knockdown. Furthermore, blocking these SASP factors with neutralizing antibodies or siRNAs alleviated the senescence and dysfunction of osteoblasts induced by H2O2 treatment or Padi2 knockdown. The elevated production of these SASP factors was mediated by the activation of NFκB signaling pathway. The inhibition of NFκB using the pharmacological inhibitor or siRNA effectively relieved H2O2 treatment- or Padi2 knockdown-induced senescence and osteoblast dysfunction. Together, our study for the first time uncover the role of PADI2 in ROS-accelerated cellular senescence of osteoblasts and provide new mechanistic and therapeutic insights into excessive ROS-promoted cellular senescence and aging-related bone diseases.

The conformational signature of ß-arrestin2 predicts its trafficking and signalling functions.

Arrestins are cytosolic proteins that regulate G-protein-coupled receptor (GPCR) desensitization, internalization, trafficking and signalling. Arrestin recruitment uncouples GPCRs from heterotrimeric G proteins, and targets the proteins for internalization via clathrin-coated pits. Arrestins also function as ligand-regulated scaffolds that recruit multiple non-G-protein effectors into GPCR-based 'signalsomes'. Although the dominant function(s) of arrestins vary between receptors, the mechanism whereby different GPCRs specify these divergent functions is unclear. Using a panel of intramolecular fluorescein arsenical hairpin (FlAsH) bioluminescence resonance energy transfer (BRET) reporters to monitor conformational changes in ß-arrestin2, here we show that GPCRs impose distinctive arrestin 'conformational signatures' that reflect the stability of the receptor-arrestin complex and role of ß-arrestin2 in activating or dampening downstream signalling events. The predictive value of these signatures extends to structurally distinct ligands activating the same GPCR, such that the innate properties of the ligand are reflected as changes in ß-arrestin2 conformation. Our findings demonstrate that information about ligand-receptor conformation is encoded within the population average ß-arrestin2 conformation, and provide insight into how different GPCRs can use a common effector for different purposes. This approach may have application in the characterization and development of functionally selective GPCR ligands and in identifying factors that dictate arrestin conformation and function.

Adenylation of maternally inherited microRNAs by Wispy.

Early development depends heavily on accurate control of maternally inherited mRNAs, and yet it remains unknown how maternal microRNAs are regulated during maternal-to-zygotic transition (MZT). We here find that maternal microRNAs are highly adenylated at their 3' ends in mature oocytes and early embryos. Maternal microRNA adenylation is widely conserved in fly, sea urchin, and mouse. We identify Wispy, a noncanonical poly(A) polymerase, as the enzyme responsible for microRNA adenylation in flies. Knockout of wispy abrogates adenylation and results in microRNA accumulation in eggs, whereas overexpression of Wispy increases adenylation and reduces microRNA levels in S2 cells. Wispy interacts with Ago1 through protein-protein interaction, which may allow the effective and selective adenylation of microRNAs. Thus, adenylation may contribute to the clearance of maternally deposited microRNAs during MZT. Our work provides mechanistic insights into the regulation of maternal microRNAs and illustrates the importance of RNA tailing in development.

Photochemical oxidants and ambulance dispatches for asthmatic symptoms in Tokyo.

While photochemical oxidants (Ox = O3+ NO2) are known to increase asthma flare-ups, there is a paucity of studies of the Japanese population, especially for Tokyo residents. We used data on asthma cases (n = 7,455) from ambulance dispatches in Tokyo, 2015-2016. Variables included date and time of incidence, age, sex, occurrence location at the ward (ku) level, and the symptom/cause of dispatch as recorded by paramedics. Ox data were obtained from the nearest air quality monitoring station to the occurrence location, then linked them with the outcomes based on occurrence date. We directly incorporated a distributed lag model into a bi-directional case-crossover study design controlling for ambient temperature and day of week. A 10-ppb increase in Ox for lag days 0-3 was associated with a 5.51% (95% CI: 0.13 to 11.18) increase in ambulance dispatches related to asthma. The association was strongest on lag day 1 (4.67%, 95% CI: 0.51 to 9.00). Exposure to high levels of Ox was associated with increased ambulance dispatches related to asthma exacerbations in Tokyo, Japan.

APEX Proximity Labeling as a Versatile Tool for Biological Research.

Most proteins are specifically localized in membrane-encapsulated organelles or non-membrane-bound compartments. The subcellular localization of proteins facilitates their functions and integration into functional networks; therefore, protein localization is tightly regulated in diverse biological contexts. However, protein localization has been mainly analyzed through immunohistochemistry or the fractionation of subcellular compartments, each of which has major drawbacks. Immunohistochemistry can examine only a handful of proteins at a time, and fractionation inevitably relies on the lysis of cells, which disrupts native cellular conditions. Recently, an engineered ascorbate peroxidase (APEX)-based proximity labeling technique combined with mass spectrometry was developed, which allows for temporally and spatially resolved proteomic mapping. In the presence of H2O2, engineered APEX oxidizes biotin-phenols into biotin-phenoxyl radicals, and these short-lived radicals biotinylate electron-rich amino acids within a radius of several nanometers. Biotinylated proteins are subsequently enriched by streptavidin and identified by mass spectrometry. This permits the sensitive and efficient labeling of proximal proteins around locally expressed APEX. Through the targeted expression of APEX in the subcellular region of interest, proteomic profiling of submitochondrial spaces, the outer mitochondrial membrane, the endoplasmic reticulum (ER)-mitochondrial contact, and the ER membrane has been performed. Furthermore, this method has been modified to define interaction networks in the vicinity of target proteins and has also been applied to analyze the spatial transcriptome. In this Perspective, we provide an outline of this newly developed technique and discuss its potential applications to address diverse biological questions.

Development of Multiplexed Immuno-N-Terminomics to Reveal the Landscape of Proteolytic Processing in Early Embryogenesis of Drosophila melanogaster.

Protein expression levels are regulated through both translation and degradation mechanisms. Levels of degradation intermediates, that is, partially degraded proteins, cannot be distinguished from those of intact proteins by global proteomics analysis, which quantify total protein abundance levels. This study aimed to develop a tool for assessing the aspects of degradation regulation via proteolytic processing through a new multiplexed N-terminomics method involving selective isobaric labeling of protein N-termini and immunoaffinity capture of the labeled N-terminal peptides. Our method allows for not only identification of proteolytic cleavage sites, but also highly multiplexed quantification of proteolytic processing. We profiled a number of potential cleavage sites by signal peptidase and provided experimental confirmation of predicted cleavage sites of signal peptide. Furthermore, the present method uniquely represents the landscape of proteomic proteolytic processing rate during early embryogenesis in Drosophila melanogaster, revealing the underlying mechanism of stringent decay regulation of zygotically expressed proteins during early stages of embryogenesis.

An association between oil spill clean-up work and cardiovascular disease.

BACKGROUND: In December 2007, Taean, South Korea, experienced the largest oil spill in Korean history. After about 10 years of follow-up, we evaluated the long-term effect of the disaster on the cardiovascular health of residents and clean-up workers/volunteers. OBJECTIVE: We examined the relationship between the duration of oil clean-up work and the risk of incident angina and myocardial infarction (MI). METHODS: We used data from a prospective cohort study, the Health Effects Research of Oil Spill (HEROS); we included adult cohort members free from cardiovascular disease who completed at least the first two surveys (n = 1737). At baseline, members reported the number of days they participated in oil clean-up work; during the subsequent surveys, they reported newly diagnosed cases of angina or MI. We fitted a time-varying interval-censored proportional hazard model, controlling for age, sex, body mass index, smoking status, monthly household income, and distance from the affected seashore to residence. RESULTS: The risk of incident angina or MI was greater in those with more than 15 days' exposure; those with 15-59 days showed a hazard ratio (HR) of 1.34 (95% confidence interval [CI]: 0.87, 2.06) those with 60-179 days had an HR of 1.31 (0.95, 1.79), and those worked longest (180 or more days) showed the strongest association with a HR of 1.75 (95% CI: 1.17, 2.61). CONCLUSION: We found that a greater duration of clean-up work was associated with an increased risk of incident angina or MI.

DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Chronic lung inflammation is linked to the pathogenesis of IPF. DROSHA, a class 2 ribonuclease III enzyme, has an important role in the biogenesis of microRNA (miRNA). The function of miRNAs has been identified in the regulation of the target gene or protein related to inflammatory responses via degradation of mRNA or inhibition of translation. The absent-in-melanoma-2 (AIM2) inflammasome is critical for inflammatory responses against cytosolic double stranded DNA (dsDNA) from pathogen-associated molecular patterns (PAMPs) and self-DNA from danger-associated molecular patterns (DAMPs). The AIM2 inflammasome senses double strand DNA (dsDNA) and interacts with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which recruits pro-caspase-1 and regulates the maturation and secretion of interleukin (IL)-1ß and IL-18. A recent study showed that inflammasome activation contributes to lung inflammation and fibrogenesis during IPF. In the current review, we discuss recent advances in our understanding of the DROSHA-miRNA-AIM2 inflammasome axis in the pathogenesis of IPF.

Regulatory Mechanism of MicroRNA Expression in Cancer.

Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3' UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization.

HDL normally transports about 50-70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.

Ambient Temperature and Sudden Infant Death Syndrome in the United States.

BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear. METHODS: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities. We applied a time-stratified case-crossover analysis to determine the effect of ambient temperature on the risk of SIDS by season. We stratified the analysis by race, infant age, and climate. RESULTS: There were a total of 60,364 SIDS cases during our study period. A 5.6°C (10°F) higher daily temperature on the same day was associated with an increased SIDS risk of 8.6% (95% confidence interval [CI] = 3.6%, 13.8%) in the summer, compared with a 3.1% decrease (95% CI = -5.0%, -1.3%) in the winter. Summer risks were greater among black infants (18.5%; 95% CI = 9.3%, 28.5%) than white infants (3.6%; 95% CI = -2.3%, 9.9%), and among infants 3-11 months old (16.9%; 95% CI = 8.9%, 25.5%) than infants 0-2 months old (2.7%; 95% CI = -3.5%, 9.2%). The temperature-SIDS association was stronger in climate clusters in the Midwest and surrounding northern regions. CONCLUSIONS: Temperature increases were associated with an elevated risk of SIDS in the summer, particularly among infants who were black, 3 months old and older, and living in the Midwest and surrounding northern regions.

Doubly Robust Additive Hazards Models to Estimate Effects of a Continuous Exposure on Survival.

BACKGROUND: The effect of an exposure on survival can be biased when the regression model is misspecified. Hazard difference is easier to use in risk assessment than hazard ratio and has a clearer interpretation in the assessment of effect modifications. METHODS: We proposed two doubly robust additive hazards models to estimate the causal hazard difference of a continuous exposure on survival. The first model is an inverse probability-weighted additive hazards regression. The second model is an extension of the doubly robust estimator for binary exposures by categorizing the continuous exposure. We compared these with the marginal structural model and outcome regression with correct and incorrect model specifications using simulations. We applied doubly robust additive hazard models to the estimation of hazard difference of long-term exposure to PM2.5 (particulate matter with an aerodynamic diameter less than or equal to 2.5 microns) on survival using a large cohort of 13 million older adults residing in seven states of the Southeastern United States. RESULTS: We showed that the proposed approaches are doubly robust. We found that each 1 µg m increase in annual PM2.5 exposure was associated with a causal hazard difference in mortality of 8.0 × 10 (95% confidence interval 7.4 × 10, 8.7 × 10), which was modified by age, medical history, socioeconomic status, and urbanicity. The overall hazard difference translates to approximately 5.5 (5.1, 6.0) thousand deaths per year in the study population. CONCLUSIONS: The proposed approaches improve the robustness of the additive hazards model and produce a novel additive causal estimate of PM2.5 on survival and several additive effect modifications, including social inequality.

Long-term Exposure to PM2.5 and Mortality Among Older Adults in the Southeastern US.

BACKGROUND: Little is known about what factors modify the effect of long-term exposure to PM2.5 on mortality, in part because in most previous studies certain groups such as rural residents and individuals with lower socioeconomic status (SES) are under-represented. METHODS: We studied 13.1 million Medicare beneficiaries (age ≥65) residing in seven southeastern US states during 2000-2013 with 95 million person-years of follow-up. We predicted annual average of PM2.5 in each zip code tabulation area (ZCTA) using a hybrid spatiotemporal model. We fit Cox proportional hazards models to estimate the association between long-term PM2.5 and mortality. We tested effect modification by individual-level covariates (race, sex, eligibility for both Medicare and Medicaid, and medical history), neighborhood-level covariates (urbanicity, percentage below poverty level, lower education, median income, and median home value), mean summer temperature, and mass fraction of 11 PM2.5 components. RESULTS: The hazard ratio (HR) for death was 1.021 (95% confidence interval: 1.019, 1.022) per 1 µg m increase in annual PM2.5. The HR decreased with age. It was higher among males, non-whites, dual-eligible individuals, and beneficiaries with previous hospital admissions. It was higher in neighborhoods with lower SES or higher urbanicity. The HR increased with mean summer temperature. The risk associated with PM2.5 increased with relative concentration of elemental carbon, vanadium, copper, calcium, and iron and decreased with nitrate, organic carbon, and sulfate. CONCLUSIONS: Associations between long-term PM2.5 exposure and death were modified by individual-level, neighborhood-level variables, temperature, and chemical compositions.

Seasonal patterns of dengue fever and associated climate factors in 4 provinces in Vietnam from 1994 to 2013.

BACKGROUND: In Vietnam, dengue fever (DF) is still a leading cause of hospitalization. The main objective of this study was to evaluate the seasonality and association with climate factors (temperature and precipitation) on the incidences of DF in four provinces where the highest incidence rates were observed from 1994 to 2013 in Vietnam. METHODS: Incidence rates (per 100,000) were calculated on a monthly basis from during the study period. The seasonal-decomposition procedure based on loess (STL) was used in order to assess the trend and seasonality of DF. In addition, a seasonal cycle subseries (SCS) plot and univariate negative binomial regression (NBR) model were used to evaluate the monthly variability with statistical analysis. Lastly, a generalized estimating equation (GEE) was used to assess the relationship between monthly incidence rates and weather factors (temperature and precipitation). RESULTS: We found that increased incidence rates were observed in the second half of each year (from May through December) which is the rainy season in each province. In Hanoi, the final model showed that 1 °C rise of temperature corresponded to an increase of 13% in the monthly incidence rate of DF. In Khanh Hoa, the final model displayed that 1 °C increase in temperature corresponded to an increase of 17% while 100 mm increase in precipitation corresponded to an increase of 11% of DF incidence rate. For Ho Chi Minh City, none of variables were significant in the model. In An Giang, the final model showed that 100 mm increase of precipitation in the preceding and same months corresponded to an increase of 30% and 22% of DF incidence rate. CONCLUSION: Our findings provide insight into understanding the seasonal pattern and associated climate risk factors.

12/10-Helical ß-Peptide with Dynamic Folding Propensity: Coexistence of Right- and Left-Handed Helices in an Enantiomeric Foldamer.

We present the first examples of atomic-resolution crystal data for the ß-peptide 12/10-helix from oligomers of cis-2-aminocyclohexane carboxylic acid (cis-ACHC) with alternating chirality. The local conformations of two enantiomeric cis-ACHC dimer units suggested that a chiral ß-peptide may adopt both right-handed and left-handed helical conformations in solution. To probe the conformational behavior of 12/10-helical ß-peptides, the two reference helices with a single handedness were synthesized with a more rigidified cis-ACHC derivative. Comparison with these reference helices at low temperature revealed that a chiral cis-ACHC oligomer with alternating chirality indeed displays 12/10-helical conformations with both handedness that equilibrate rapidly in solution. This is a very rare example of chiral oligomers with helix inversion ability. The 12/10-helical backbone should be a valuable addition to potential scaffolds for applications involving helices with dynamic folding propensity.