SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

APOBEC2 safeguards skeletal muscle cell fate through binding chromatin and regulating transcription of non-muscle genes during myoblast differentiation.

The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide (APOBEC) family is composed of nucleic acid editors with roles ranging from antibody diversification to RNA editing. APOBEC2, a member of this family with an evolutionarily conserved nucleic acid-binding cytidine deaminase domain, has neither an established substrate nor function. Using a cellular model of muscle differentiation where APOBEC2 is inducibly expressed, we confirmed that APOBEC2 does not have the attributed molecular functions of the APOBEC family, such as RNA editing, DNA demethylation, and DNA mutation. Instead, we found that during muscle differentiation APOBEC2 occupied a specific motif within promoter regions; its removal from those regions resulted in transcriptional changes. Mechanistically, these changes reflect the direct interaction of APOBEC2 with histone deacetylase (HDAC) transcriptional corepressor complexes. We also found that APOBEC2 could bind DNA directly, in a sequence-specific fashion, suggesting that it functions as a recruiter of HDAC to specific genes whose promoters it occupies. These genes are normally suppressed during muscle cell differentiation, and their suppression may contribute to the safeguarding of muscle cell fate. Altogether, our results reveal a unique role for APOBEC2 within the APOBEC family.

Squidpy: a scalable framework for spatial omics analysis.

Spatial omics data are advancing the study of tissue organization and cellular communication at an unprecedented scale. Flexible tools are required to store, integrate and visualize the large diversity of spatial omics data. Here, we present Squidpy, a Python framework that brings together tools from omics and image analysis to enable scalable description of spatial molecular data, such as transcriptome or multivariate proteins. Squidpy provides efficient infrastructure and numerous analysis methods that allow to efficiently store, manipulate and interactively visualize spatial omics data. Squidpy is extensible and can be interfaced with a variety of already existing libraries for the scalable analysis of spatial omics data.

Predicting cellular responses to complex perturbations in high-throughput screens.

Recent advances in multiplexed single-cell transcriptomics experiments facilitate the high-throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible. Therefore, computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder (CPA), which combines the interpretability of linear models with the flexibility of deep-learning approaches for single-cell response modeling. CPA learns to in silico predict transcriptional perturbation response at the single-cell level for unseen dosages, cell types, time points, and species. Using newly generated single-cell drug combination data, we validate that CPA can predict unseen drug combinations while outperforming baseline models. Additionally, the architecture's modularity enables incorporating the chemical representation of the drugs, allowing the prediction of cellular response to completely unseen drugs. Furthermore, CPA is also applicable to genetic combinatorial screens. We demonstrate this by imputing in silico 5,329 missing combinations (97.6% of all possibilities) in a single-cell Perturb-seq experiment with diverse genetic interactions. We envision CPA will facilitate efficient experimental design and hypothesis generation by enabling in silico response prediction at the single-cell level and thus accelerate therapeutic applications using single-cell technologies.

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention.

MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

O2 activation by subnanometer Re-Pt clusters supported on TiO2(110): exploring adsorption sites.

Activation of O2 by subnanometer metal clusters is a fundamental step in the reactivity and oxidation processes of single-cluster catalysts. In this work, we examine the adsorption and dissociation of O2 on RenPtm (n + m = 5) clusters supported on rutile TiO2(110) using DFT calculations. The adhesion energies of RenPtm clusters on the support are high, indicating significant stability of the supported clusters. Furthermore, the bimetallic Re-Pt clusters attach to the surface through the Re atoms. The oxygen molecule was adsorbed on three sites of the supported systems: the metal cluster, the surface, and the interface. At the metal cluster site, the O2 molecule binds strongly to RenPtm clusters, especially on the Re-rich clusters. O2 activation occurs by charge transfer from the metal atoms to the molecule. The dissociation of O2 on the RenPtm clusters is an exothermic process with low barriers. As a result, sub-nanometer Re-Pt clusters can be susceptible to oxidation. Similar results are obtained at the metal-support interface, where both the surface and cluster transfer charge to O2. To surface sites, molecular oxygen is adsorbed onto the Ti5c atoms with moderate adsorption energies. The polarons, which are produced by the interaction between the metal cluster and the surface, participate in the activation of the molecule. However, dissociating O2 in these sites is challenging due to the endothermic nature of the process and the high energy barriers involved. Our findings provide novel insights into the reactivity of supported clusters, specifically regarding the O2 activation by Re-Pt clusters on rutile TiO2(110).

A chiral metal cluster triggers enantiospecific electronic transport.

Chirality is a geometric property of matter that can be present at different scales, especially at the nanoscale. Here, we investigate the manifestation of chirality in electronic transport through a molecular junction. Spinless electronic transport through a chiral molecular junction is not enantiospecific. However, when a chiral metal cluster, C3-Au34, is attached to the source electrode, a different response is obtained in spinless electronic transport between R and L systems: this indicates the crucial role of chiral clusters in triggering enantiospecific spinless electronic transport. In contrast, when an achiral metal cluster, C3v-Au34, is attached, no change in conductance occurs between enantiomeric systems. Using the non-equilibrium green's function method, we characterized this phenomenon by calculating the transmission and conductance of spin-unpolarized electrons. Our theoretical results highlight the importance of metal clusters with specific sizes and chiral structures in electronic transport and support previously published experimental results that exhibited enantiospecific scanning tunneling measurements with intrinsically chiral tips.

Educational disparities in brain health and dementia across Latin America and the United States.

BACKGROUND: Education influences brain health and dementia. However, its impact across regions, specifically Latin America (LA) and the United States (US), is unknown. METHODS: A total of 1412 participants comprising controls, patients with Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) from LA and the US were included. We studied the association of education with brain volume and functional connectivity while controlling for imaging quality and variability, age, sex, total intracranial volume (TIV), and recording type. RESULTS: Education influenced brain measures, explaining 24%-98% of the geographical differences. The educational disparities between LA and the US were associated with gray matter volume and connectivity variations, especially in LA and AD patients. Education emerged as a critical factor in classifying aging and dementia across regions. DISCUSSION: The results underscore the impact of education on brain structure and function in LA, highlighting the importance of incorporating educational factors into diagnosing, care, and prevention, and emphasizing the need for global diversity in research. HIGHLIGHTS: Lower education was linked to reduced brain volume and connectivity in healthy controls (HCs), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Latin American cohorts have lower educational levels compared to the those in the United States. Educational disparities majorly drive brain health differences between regions. Educational differences were significant in both conditions, but more in AD than FTLD. Education stands as a critical factor in classifying aging and dementia across regions.

Comparative chromatin accessibility upon BDNF stimulation delineates neuronal regulatory elements.

Neuronal stimulation induced by the brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences affect BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and the heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal stimulation.

Interaction Mechanisms and Interface Configuration of Cysteine Adsorbed on Gold, Silver, and Copper Nanoparticles.

Cysteine-protected metal nanoparticles (NPs) have shown interesting physicochemical properties of potential utility in biomedical applications and in the understanding of protein folding. Herein, cysteine interaction with gold, silver, and copper NPs is characterized by Raman spectroscopy and density functional theory calculations to elucidate the molecular conformation and adsorption sites for each metal. The experimental analysis of Raman spectra upon adsorption with respect to free cysteine indicates that while the C-S bond and carboxyl group are similarly affected by adsorption on the three metal NPs, the amino group is sterically influenced by the electronegativity of each metal, causing a greater modification in the case of gold NPs. A theoretical approach that takes into consideration intermolecular interactions using two cysteine molecules is proposed using a S-metal-S interface motif anchored to the metal surface. These interactions generate the stabilization of an organo-metallic complex that combines gauche (PH) and anti (PC) rotameric conformers of cysteine on the surface of all three metals. Similarities between the calculated Raman spectra and experimental data confirm the thiol and carboxyl as adsorption groups for gold, silver, and copper NPs and suggest the formation of monomeric "staple motifs" that have been found in the protecting monolayer of atomic-precise thiolate-capped metal nanoclusters.

Bucket handle meniscus tears in low-resource settings can be successfully treated with a cost-effective technique.

PURPOSE: In regions of the world where resources can limit medical care (limited-resource settings, LRS), most meniscal tears are often treated with meniscectomy. A simple, low-cost option for meniscal repair has been developed. We sought to evaluate patient reported outcomes (PROMs) and clinical failure rates of bucket handle meniscus tears (BHTs) treated with meniscal repair in a LRS. METHODS: We prospectively enrolled patients over 18 who were treated for BHT with meniscal repair in a LRS. Meniscal repair was primarily accomplished using an outside-in technique. Pre-injury and final follow-up PROMs were recorded. Clinical failure was defined as the need for re-operation or symptoms that prevented the patient from returning to recreational activities or work responsibilities. RESULTS: Nineteen patients with a mean age of 25.4 years were eligible. Two patients sustained a clinical failure (10.5%). At mean follow-up of 40.6 months, there was significant improvement in all PROMs from baseline. Subgroup analysis revealed no significant difference in the failure group compared to the success group in number of knots used, pre-injury Tegner score, number of devices used, suture type, or technique. CONCLUSION: Bucket-handle meniscal tears can be repaired using a low-cost technique resulting in satisfactory healing rates and excellent outcomes.

Effect of the Metal-Ligand Interface on the Chiroptical Activity of Cysteine-Protected Nanoparticles.

Gold, silver, and copper small nanoparticles (NPs), with average size ≈2 nm, are synthesized and afterward protected with l- and d-cysteine, demonstrating emergence of chiroptical activity in the wavelength range of 250-400 nm for all three metals with respect to the bare nanoparticles and ligands alone. Silver-cysteine (Ag-Cys) NPs display the higher anisotropy factor, whereas gold-cysteine (Au-Cys) NPs show optical and chiroptical signatures slightly more displaced to the visible range. A larger number of circular dichroism (CD) bands with smaller intensity, as compared to gold and silver, is observed for the first time for copper-cysteine (Cu-Cys) NPs. The manifestation of optical and chiroptical responses upon cysteine adsorption and the differences between the spectra corresponding to each metal are mainly dictated by the metal-ligand interface, as supported by a comparison with calculations of the oscillatory and rotatory strengths based on time-dependent density functional theory, using a metal-ligand interface motif model, which closely resembles the experimental absorption and CD spectra. These results are useful to demonstrate the relevance of the interface between chiral ligands and the metal surfaces of Au, Ag, and Cu NPs, and provide evidence and further insights into the origin of the transfer mechanisms and induction of extrinsic chirality.

Combined secondary compounds naturally found in nectars enhance honeybee cognition and survival.

The alkaloid caffeine and the amino acid arginine are present as secondary compounds in nectars of some flower species visited by pollinators. Each of these compounds affects honeybee appetitive behaviours by improving foraging activity and learning. While caffeine potentiates responses of mushroom body neurons involved in honeybee learning processes, arginine acts as precursor of nitric oxide, enhancing the protein synthesis involved in memory formation. Despite existing evidence on how these compounds affect honeybee cognitive ability individually, their combined effect on this is still unknown. We evaluated acquisition and memory retention in a classical olfactory conditioning procedure, in which the reward (sucrose solution) contained traces of caffeine, arginine or a mixture of the two. The results indicate that the presence of the single compounds and their most concentrated mixture increases bees' learning performance. However, memory retention, measured in the short and long term, increases significantly only in those treatments offering combinations of the two compounds in the reward. Additionally, the most concentrated mixture triggers a significant survival rate in the conditioned bees. Thus, some nectar compounds, when combined, show synergistic effects on cognitive ability and survival in an insect.

Chiral-Icosahedral ( I) Symmetry in Ubiquitous Metallic Cluster Compounds (145A,60X): Structure and Bonding Principles.

There exists a special kind of perfection-in symmetry, simplicity, and stability-attainable for structures generated from precisely 60 ligands (all of a single type) that protect 145 metal-atom sites. The symmetry in question is icosahedral ( Ih), generally, and chiral icosahedral ( I) in particular. A 60-fold equivalence of the ligands is the smallest number to allow this kind of perfection. Known cluster compounds that approximate this structural ideal include palladium-carbonyls, Ih-Pd145(CO)60; gold-thiolates, I-Au144(SR)60; and gold-alkynyls, I-Au144(C2R)60. Many other variants are suspected. The Pd145 compound established the basic achiral structure-type. However, the Au144-thiolate archetype is prominent, historically in its abundance and ease of preparation and handling, in its proliferation in many laboratories and application areas, and ultimately in the intrinsic chirality of its geometrical structure and organization of its bonding network or connectivity. As discovered by mass spectrometry (the "30-k anomaly") in 1995, it appeared as a broad single peak, as solitary and symmetrical as Mount Fuji, centered near 30 kDa (∼150 Au atoms), provoking these thoughts: Surely this phenomenon requires a unique explanation. It appears to be the Buckminsterfullerene (carbon-60) of gold-cluster chemistry. Herein we provide an elementary account of the unexpected discovery, in which the Pd145-structure played a critical role, that led to the identification and prediction, in 2008, of a fascinating new molecular structure-type, evidently the first one of chiral icosahedral symmetry. Rigorous confirmation of this prediction occurred in early spring 2018, when two single-crystal X-ray crystallography reports were submitted, each one distinguishing both enantiomeric structures and noting profound chirality for the surface (ligand) layer. The emphasis here is on the structure and bonding principles and how these have been elucidated. Our aim has been to present this story in simplest terms, consistent with the radical simplicity of the structure itself. Because it combines intrinsic profound chirality, at several levels, with the highest possible symmetry-type (icosahedral), the structure may attract broader interest also from educators, especially if studied in tandem with the analysis of hollow (shell) metallic systems that exhibit the same chirality and symmetry. Because the shortest (stiffest) bonds follow the chiral 3-way weave pattern of the traditional South-Asian reed football, this cultural artifact may be used to introduce chiral-icosahedral symmetry in a pleasant and memorable way. One may also appreciate easily the bonding and excitations in I-symmetry metallic nanostructures via the golden fullerenes, that is, the proposed hollow Au60,72 spheres. Beyond any aesthetic or pedagogical value, we aim that our Account may provide a firm foundation upon which others may address open questions and the opportunities they present. This Account can scarcely hint at the prospects for further fundamental understanding of these compounds, as well as a widening sphere of applications (chemical, electronic, imaging). The compounds remain crucial to a wider field presently under intense development.

Head to Tail Distortion Wave Characterizes the Enantiomerization of Helicenes.

A fresh look on helicenes' enantiomerization process with a focus on ring conformation reveals that it can be described as a step-by-step mechanism in which maximal distortion is consecutively transferred along the helicene skeleton, head to tail. Density functional theory methods were used to compute the enantiomerization pathway, and continuous symmetry measures were applied to quantify the distortion of even-number helicenes with 8-14 rings. Our findings show that the distortion wave is additive-the process always starts from one edge of the helicene and progresses along the rings until the other edge is reached. As more rings are added to the helicene, extra steps are appended to the distortion wave. Implications of this fundamental process are discussed in light of similar natural phenomena from polymer dynamics to snake locomotion.

CeO2(111) electronic reducibility tuned by ultra-small supported bimetallic Pt-Cu clusters.

Controlling Ce4+ to Ce3+ electronic reducibility in a rare-earth binary oxide such as CeO2 has enormous applications in heterogeneous catalysis, where a profound understanding of reactivity and selectivity at the atomic level is yet to be reached. Thus, in this work we report an extensive DFT-based Basin Hopping global optimization study to find the most stable bimetallic Pt-Cu clusters supported on the CeO2(111) oxide surface, involving up to 5 atoms in size for all compositions. Our PBE+U global optimization calculations indicate a preference for Pt-Cu clusters to adopt 2D planar geometries parallel to the oxide surface, due to the formation of strong metal bonds to oxygen surface sites and charge transfer effects. The calculated adsorption energy values (Eads) for both mono- and bimetallic systems are of the order of 1.79 up to 4.07 eV, implying a strong metal cluster interaction with the oxide surface. Our calculations indicate that at such sub-nanometer sizes, the number of Ce4+ surface atoms reduced to Ce3+ cations is mediated by the amount of Cu atoms within the cluster, reaching a maximum of three Ce3+ for a supported Cu5 cluster. Our computational results have critical implications on the continuous understanding of the strong metal-support interactions over reducible oxides such as CeO2, as well as the advancement of frontier research areas such as heterogeneous single-atom catalysts (SAC) and single-cluster catalysts (SCC).

Mechanical Vibrations of Atomically Defined Metal Clusters: From Nano- to Molecular-Size Oscillators.

Acoustic vibrations of small nanoparticles are still ruled by continuum mechanics laws down to diameters of a few nanometers. The elastic behavior at lower sizes (<1-2 nm), where nanoparticles become molecular clusters made by few tens to few atoms, is still little explored. The question remains to which extent the transition from small continuous-mass solids to discrete-atom molecular clusters affects their specific low-frequency vibrational modes, whose period is classically expected to linearly scale with diameter. Here, we investigate experimentally by ultrafast time-resolved optical spectroscopy the acoustic response of atomically defined ligand-protected metal clusters Au n(SR) m with a number n of atoms ranging from 10 to 102 (0.5-1.5 nm diameter range). Two periods, corresponding to fundamental breathing- and quadrupolar-like acoustic modes, are detected, with the latter scaling linearly with cluster diameters and the former taking a constant value. Theoretical calculations based on density functional theory (DFT) predict in the case of bare clusters vibrational periods scaling with size down to diatomic molecules. For ligand-protected clusters, they show a pronounced effect of the ligand molecules on the breathing-like mode vibrational period at the origin of its constant value. This deviation from classical elasticity predictions results from mechanical mass-loading effects due to the protecting layer. This study shows that clusters characteristic vibrational frequencies are compatible with extrapolation of continuum mechanics model down to few atoms, which is in agreement with DFT computations.

CO2 adsorption on gas-phase Cu4-xPtx (x = 0-4) clusters: a DFT study.

Transition and noble metal clusters have proven to be critical novel materials, potentially offering major advantages over conventional catalysts in a range of value-added catalytic processess such as carbon dioxide transformation to methanol. In this work, a systematic computational study of CO2 adsorption on gas-phase Cu4-xPtx (x = 0-4) clusters is performed. An exhaustive potential energy surface exploration is initially performed using our recent density functional theory basin-hopping global optimization implementation. Ground-state and low-lying energy isomers are identified for Cu4-xPtx clusters. Secondly, a CO2 molecule adsorption process is analyzed on the ground-state Cu4-xPtx configurations, as a function of cluster composition. Our results show that the gas-phase linear CO2 molecule is deformed upon adsorption, with its bend angle varying from about 132° to 139°. Cu4-xPtx cluster geometries remain unchanged after CO2 adsorption, with the exception of Cu3Pt1 and Pt4 clusters. For these particular cases, a structural conversion between the ground-state geometry and the corresponding first isomer configurations is found to be assisted by the CO2 adsorption. For all clusters, the energy barriers between the ground-state and first isomer structures are explored. Our calculated CO2 adsorption energies are found to be larger for Pt-rich clusters, exhibiting a volcano-type plot. The overall effect of a hybrid functional including dispersion forces is also discussed.

Lysenin Toxin Membrane Insertion Is pH-Dependent but Independent of Neighboring Lysenins.

Pore-forming toxins form a family of proteins that act as virulence factors of pathogenic bacteria, but similar proteins are found in all kingdoms of life, including the vertebrate immune system. They are secreted as soluble monomers that oligomerize on target membranes in the so-called prepore state; after activation, they insert into the membrane and adopt the pore state. Lysenin is a pore-forming toxin from the earthworm Eisenida foetida, of which both the soluble and membrane-inserted structures are solved. However, the activation and membrane-insertion mechanisms have remained elusive. Here, we used high-speed atomic force microscopy to directly visualize the membrane-insertion mechanism. Changing the environmental pH from pH 7.5 to below pH 6.0 favored membrane insertion. We detected a short α-helix in the soluble structure that comprised three glutamic acids (Glu92, Glu94, and Glu97) that we hypothesized may represent a pH-sensor (as in similar toxins, e.g., Listeriolysin). Mutant lysenin still can form pores, but mutating these glutamic acids to glutamines rendered the toxin pH-insensitive. On the other hand, toxins in the pore state did not favor insertion of neighboring prepores; indeed, pore insertion breaks the hexagonal ordered domains of prepores and separates from neighboring molecules in the membrane. pH-dependent activation of toxins may represent a common feature of pore-forming toxins. High-speed atomic force microscopy with single-molecule resolution at high temporal resolution and the possibility of exchanging buffers during the experiments presents itself as a unique tool for the study of toxin-state conversion.

Diverse Chiral Scaffolds from Diethynylspiranes: All-Carbon Double Helices and Flexible Shape-Persistent Macrocycles.

State-of-the-art chiroptical spectroscopies are valuable tools for structural elucidation. However, the potential of these spectroscopies for everyday applications has not been exploited to date partially due to the lack of sufficiently stable and efficient chiroptical systems. To this end, the development of suitable chiroptical structures is essential. Herein, we present the synthesis of spiro-compounds (P2 )-1 and (P4 )-2 as well as (M2 )-1 and (M4 )-2 exhibiting remarkable chiroptical responses. Theoretical simulations show that (P2 )-1, constituted by two (P)-configured spiranic chiral axes, presents an all-carbon double helix structure with (M)-helicity. On the other hand, molecular dynamic simulations reveal (P4 )-2 to have a single path for geometry-modification along its flat conformational space, certifying it as a chiral flexible shape-persistent macrocycle. Geometric quantification of chirality has been used to compare the spiranic derivatives presented herein.