Molecular Arrays Research Articles

Blood‐based SNAP‐25 and VAMP‐2 in Alzheimer’s disease; relation to cognition, atrophy and synaptic density.

AbstractBackgroundA hallmark of neurodegenerative disorders is synaptic dysfunction and degeneration. This makes the presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25) and the Vesicle‐associated membrane protein 2 (VAMP‐2) targets of interest and importance. Previously, these proteins have only been measurable in cerebrospinal fluid (CSF) and are increased in Alzheimer’s disease (AD) patients. Considering the advancement of blood‐based detection of phosphorylated tau (p‐tau), neurofilament light (NfL) and amyloid‐β (Aβ42/40), a measure of synaptic degeneration in blood would be important for disease prognosis and clinical trial outcome. In this study, we describe results from novel single molecular arrays (Simoa) for blood SNAP‐25 and VAMP‐2.MethodPrototype Simoa assays for N‐terminal SNAP‐25 and VAMP‐2 were developed as more sensitive versions of previously validated in‐house CSF assays with diluent suited for both plasma and CSF. We examined 110 participants (54 AD and 56 healthy controls) from the Swedish BioFINDER pilot study. The mean age of patients was 75.9 years (7.1 SD) and there was an even distribution of sex. We examined group differences by the Wilcoxon rank sum test and associations between these two blood biomarkers and Aβ‐PET, tau‐PET, MRI and MMSE were determined by linear regression, adjusting for age and sex.ResultSNAP‐25 was significantly increased in patients with AD (mean [SD], 0.81 pg/mL [0.27]; p < 0.001) as compared to controls (0.60 pg/mL [0.22]). SNAP‐25 distinguished AD patients from controls with an area under the curve of 0.74 (95% CI = 0.65‐0.83). SNAP‐25 showed association with Aβ PET (β = 0.10, p = 0.007) but not tau PET. SNAP‐25 associated with cortical thickness (β = ‐0.05, p = 0.009) and MMSE (β = ‐6.69, p = 0.001). No significant associations were found when analysing the AD group alone. VAMP‐2 showed no significant association with any of the mentioned parameters above.ConclusionThis novel ultra‐sensitive immunoassay demonstrates an increase of plasma SNAP‐25 in AD patients, and a significant relationship with cognition and cortical atrophy. Further studies will verify these changes in independent cohorts and explore the relationship between plasma SNAP‐25 and VAMP‐2 with synaptic vesicle glycoprotein 2A (SV2A) PET in a broad range of neurodegenerative disorders.

Alzheimer’s disease plasma markers and depressive symptoms: an IPD meta‐analysis

AbstractBackgroundDepression has been associated with an increased risk of Alzheimer’s disease (AD), but the biological mechanisms are still not fully understood. Plasma biomarkers, such as amyloid‐beta, tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), have been associated with AD pathophysiology. However, the relationship with depression is unclear. Assessing these biomarkers in the blood allows for the opportunity to assess if AD pathology is related to depressive symptoms on a large‐scale. We hypothesized if depression is part of the AD process, then these markers will be associated with depressive symptoms.MethodA two‐stage IPD meta‐analysis was performed based on eight cohorts of individuals without dementia as part of the Netherlands Consortium of Dementia Cohorts (NCDC). We examined the cross‐sectional association between each plasma marker for AD (amyloid‐beta42/40 ratio, p‐tau181, NfL, and GFAP) with depressive symptoms (the GDS‐15, PHQ‐9, CES‐D, and SF‐36). Plasma markers were assessed using Single Molecular Array (Simoa; Quanterix) assays. Both plasma markers and depressive symptoms were standardized. We estimated the effect per plasma marker with depressive symptoms using linear regressions, correcting for age, sex, education, and APOE e4 allele presence, in each cohort. The effect estimates were entered into a random‐effects meta‐analysis. We also performed subgroup analyses assessing sex differences and between those with and without an APOE e4 allele.ResultThis study involved 7210 participants with an age range of 38 to 102 years. Based on clinical cut‐offs per questionnaire, high depressive symptomology ranged from one to 22% per cohort. None of the plasma markers were associated with depressive symptoms in the meta‐analysis. However, subgroup analyses found an association with NfL and depressive symptoms in women (beta 0.07; 95% CI: 0.03‐0.10, p < 0.001) and in those with an APOE e4 allele (beta 0.11; 95% CI: 0.05‐0.17, p = 0.001).ConclusionAD pathology did not show an overall relationship with depressive symptoms. However, in women and in those with a genetic risk for AD, NfL showed an association. As NfL is a marker of overall neurodegeneration, this pathology in plasma may be specific to depressive symptoms in certain subgroups.

Plasma SNAP‐25 as a potential Alzheimer’s disease biomarker

AbstractBackgroundSynaptic degeneration and dysfunction are hallmarks of several neurodegenerative diseases, including Alzheimer’s disease (AD). Several studies have shown that the presynaptic protein, synaptosomal‐associated‐protein‐25 (SNAP‐25), is increased in the cerebrospinal fluid (CSF) of AD patients. In the era of ultra‐sensitive immunoassays, the quantification of SNAP‐25 concentration in blood could provide an easily accessible measure of synaptic integrity in AD.MethodIn this pilot study, we investigated 42 participants (n = 23 cognitively unimpaired [CU]; n = 19 MCI or AD dementia patients [CI]) from Geneva University Hospital. A total of 27 participants underwent amyloid positron emission tomography (PET) scans and 14 underwent tau PET scans within 1 year. Global cognition was assessed with Mini Mental State Examination (MMSE). Mann‐Whitney tests were used to assess differences in plasma SNAP25 levels between diagnostic, amyloid (A+/‐) and tau (T+/‐) classification. Furthermore, we used Pearson correlations to assess the association between SNAP25, amyloid centiloid, Tau SUVr and MMSE.ResultThe mean age was 66.9 years +/‐ 7.6 years and 57% were female. SNAP‐25 was significantly increased in CI patients (0.87 pg/mL ±/‐ 0.19) compared to CU participants (0.59 pg/mL ±/‐ 0.11; p>0.001). SNAP‐25 levels were also significantly increased in A+ (0.89 pg/mL ±/‐ 0.18) and T+ (0.92 pg/mL ±/‐ 0.19) individuals compared to A‐ (0.65 pg/mL ±/‐ 0.09; p<0.001) and T‐ (0.717 pg/mL ±/‐ 0.07; p = 0.041). Moreover, we observed a significant correlation between the SNAP‐25 levels and amyloid centiloid (p = 0.016, rho = 0.48), while the correlation was not significant between SNAP‐25 and tau SUVr (p = 0.146, rho = 0.41). Finally, we observed a significant correlation between SNAP‐25 levels and MMSE score (p = 0.033, rho = ‐0.35).ConclusionThe novel plasma single molecular array (Simoa) can accurately quantify SNAP‐25 in blood plasma. In a pilot study, we observed significantly elevated plasma SNAP‐25 levels in cognitively impaired individuals and amyloid and tau positive individuals. Our findings suggest that SNAP‐25 is a potential biomarker indexing synaptic loss in AD. Further results will extend to a memory clinic cohort of >350 participants to assess its diagnostic and prognostic power and relationship to amyloid, tau, MRI and CSF biomarkers.

Local probe-induced structural isomerization in a one-dimensional molecular array

Synthesis of one-dimensional molecular arrays with tailored stereoisomers is challenging yet has great potential for application in molecular opto-, electronic- and magnetic-devices, where the local array structure plays a decisive role in the functional properties. Here, we demonstrate the construction and characterization of dehydroazulene isomer and diradical units in three-dimensional organometallic compounds on Ag(111) with a combination of low-temperature scanning tunneling microscopy and density functional theory calculations. Tip-induced voltage pulses firstly result in the formation of a diradical species via successive homolytic fission of two C-Br bonds in the naphthyl groups, which are subsequently transformed into chiral dehydroazulene moieties. The delicate balance of the reaction rates among the diradical and two stereoisomers, arising from an in-line configuration of tip and molecular unit, allows directional azulene-to-azulene and azulene-to-diradical local probe structural isomerization in a controlled manner. Furthermore, our theoretical calculations suggest that the diradical moiety hosts an open-shell singlet with antiferromagnetic coupling between the unpaired electrons, which can undergo an inelastic spin transition of 91 meV to the ferromagnetically coupled triplet state.

Clinical and biological relevance of glial fibrillary acidic protein in Alzheimer’s disease

IntroductionThere is a tremendous need for identifying reliable blood-based biomarkers for Alzheimer’s disease (AD) that are tied to the biological ATN (amyloid, tau and neurodegeneration) framework as well as clinical assessment and progression.MethodsOne hundred forty-four elderly participants underwent 18F-AV45 positron emission tomography (PET) scan, structural magnetic resonance imaging (MRI) scan, and blood sample collection. The composite standardized uptake value ratio (SUVR) was derived from 18F-AV45 PET to assess brain amyloid burden, and the hippocampal volume was determined from structural MRI scans. Plasma glial fibrillary acidic protein (GFAP), phosphorylated tau-181 (ptau-181), and neurofilament light (NfL) measured by single molecular array (SIMOA) technology were assessed with respect to ATN framework, genetic risk factor, age, clinical assessment, and future functional decline among the participants.ResultsAmong the three plasma markers, GFAP best discriminated participants stratified by clinical diagnosis and brain amyloid status. Age was strongly associated with NfL, followed by GFAP and ptau-181 at much weaker extent. Brain amyloid was strongly associated with plasma GFAP and ptau-181 and to a lesser extent with plasma NfL. Moderate association was observed between plasma markers. Hippocampal volume was weakly associated with all three markers. Elevated GFAP and ptau-181 were associated with worse cognition, and plasma GFAP was the most predictive of future functional decline. Combining GFAP and ptau-181 together was the best model to predict brain amyloid status across all participants (AUC = 0.86) or within cognitively impaired participants (AUC = 0.93); adding NfL as an additional predictor only had a marginal improvement.ConclusionOur findings indicate that GFAP is of potential clinical utility in screening amyloid pathology and predicting future cognitive decline. GFAP, NfL, and ptau-181 were moderately associated with each other, with discrepant relevance to age, sex, and AD genetic risk, suggesting their relevant but differential roles for AD assessment. The combination of GFAP with ptau-181 provides an accurate model to predict brain amyloid status, with the superior performance of GFAP over ptau-181 when the prediction is limited to cognitively impaired participants.

Curcuminoids Modulated the IL-6/JAK/STAT3 Signaling Pathway in LoVo and HT-29 Colorectal Cancer Cells.

Curcuminoids, including curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin, are natural polyphenolic compounds that exhibit various biological properties, such as antioxidant, anti-inflammatory, and anticancer activities. Dysregulation of the interleukin (IL)-6-mediated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway is closely associated with the development of colorectal cancer (CRC). Here, we have evaluated the modulation of the IL-6/JAK/STAT3 pathway of curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin in LoVo and HT-29 colorectal cancer cells with a single molecular array (Simoa), western blot analysis, real-time polymerase chain reaction (PCR), and pathway analysis system. The study showed that curcuminoids suppressed the amount of IL-6 in LoVo and HT-29 colorectal cancer cells. Meanwhile, curcuminoids inhibited the expression of inflammation regulator-related microRNA (miRNA). We also found that the expression of total STAT3 was downregulated by curcuminoids. Moreover, the pathway analysis system showed that curcuminoids inactivated the JAK/STAT3 signaling pathway. Taken together, we demonstrated that the anti-cancer activities of curcuminoids against colorectal cancer are due to the modulation of the IL-6/JAK/STAT3 cascade. Curcuminoids could be a promising anti-cancer agent for the treatment of human colorectal cancer.

Olfactory function, neurofilament light chain, and cognitive trajectory: A 12-year follow-up of the Shanghai Aging Study.

This study aimed to determine whether blood neurofilament light chain (NfL) modifies the association of olfactory dysfunction (OD) with long-term cognitive decline. A total of 1125 non-demented older adults in the Shanghai Aging Study were evaluated for baseline olfaction (12-item Sniffin' Sticks Smell Test) and cognitive trajectory by a 12-year follow-up. Baseline blood NfL was quantified using Single Molecular Array assay, and dichotomized into low and high levels based on the median value of concentration. The Mini-Mental StateExamination (MMSE) and Telephone Interview for Cognitive Status-40 were used to assess participants' cognitive function. Cognitive decline was ascertained when dementia was diagnosed or documented in the medical record during follow-up, or the MMSE declining rate (slope) was 1.0 SD larger than the group mean. OD participants presented a steeper trajectory of MMSE score (p interaction=0.004) and a high risk of cognitive decline (adjusted HR [95% CI], 1.82 [1.11, 2.98]) only in those with high NfL. Participants with combined OD and high NfL showed the highest risk of cognitive decline (adjusted HR, 2.43 [1.20, 4.92]). OD, especially in combination with high blood NfL concentration, may be able to identify individuals who later incur cognitive deterioration.

Forces and Flows at Cell Surfaces.

Flow is an important physiological signal and modulates a variety of cell functions. However, the molecular mechanisms that cells use to sense flow have remained surprisingly opaque. The first steps in flow sensing are likely to occur at the plasma membrane, the fluid barrier between the inside and outside of a cell. This membrane is an organized, two-dimensional molecular array that has both solid and fluid properties. The mobility of membrane proteins and lipids is constrained by complex interactions with the cytoskeletal protein network that supports the membrane. Physiologically relevant flows can only generate tiny forces on individual proteins, smaller than those from thermal noise. However, cells could overcome this problem by sensing micron-scale concentration gradients of extracellular membrane proteins. This is possible in cell plasma membranes because their particular physical state allows flow to sort membrane proteins laterally over the extracellular surface.

Photoinduced Processes in Molecular and Supramolecular Arrays Based on Porphyrins and Acridinium Units

Multichromophoric arrays based on porphyrins are of high interest for their mimicry of naturally occurring photoinduced energy and electron transfer processes leading to energy collection and conversion. [1] Moreover, the rich photophysics and electrochemistry of porphyrins make them suitable components of molecular wires, switches or chemical sensors. [2] In this perspective, it is interesting to pursue the combination of porphyrins with units that can act as multiresponsive components by modifying their chemical and electronic structure upon chemical or redox stimuli. N-acridinium ions have been recently explored as a new class of switches that respond to various orthogonal stimulations (pH or electrochemical/photochemical inputs) that trigger their reversible conversion into the non-aromatic acridane form. [3] Few examples reporting the association of acridinium units and porphyrins indicate that these systems are characterized by fast photoinduced electron transfer reactions between the porphyrin donor and the acridinium acceptor. [4,5]We recently investigated the photophysical properties of molecular and supramolecular arrays based on porphyrins and acridinium units, where the type of porphyrin (free-base or metallated) and/or the form of the switchable component (acridinium or acridane) has been varied (Figure 1). We found that the association of porphyrins and acridinium ions always leads to ultrafast electron transfer processes, and that these reactions can be altered by changing the temperature or by converting the acridinium electron acceptor into an acridane energy donor. Moreover, the combination of two Zn-porphyrins with two acridinium/acridane units results in switchable molecular receptors able to coordinate suitable hosts. The photophysics of the arrays and of the complexes, analyzed by means of steady-state and time-resolved luminescence techniques and ultrafast transient absorption spectroscopy, will be herein presented and discussed.The work is supported by the H2020-MSCA-ITN-2017-765297 project “NOAH” and by the H2020-LC-SC3-2020-RES-RIA-101006839 project “CONDOR”.[1] M. Beyler, L. Flamigni, V. Heitz, J.-P. Sauvage, B. Ventura, Photochem. Photobiol. 2014, 90, 275-286.[2] Beletskaya I, Tyurin VS, Tsivadze AY, Guilard R, Stern C. Chem. Rev. 2009, 109, 1659-1713.[3] H.-P. J. de Rouville, J. Hu, V. Heitz, ChemPlusChem, 2021, 86, 110-129.[4] A. Edo-Osagie, D. Sánchez-Resa, D. Serillon, E. Bandini, C. Gourlaouen, H.-P. Jacquot de Rouville, B. Ventura, V. Heitz, C. R. Chim. 2021, 24, 1-9.[5] H. Kotani, K. Ohkubo, M. J. Crossley, S. Fukuzumi, J. Am. Chem. Soc., 2011, 133, 11092-11095.Figure 1. Structures of the studied arrays and schemes of the occurring photoinduced processes: a) bisacridinium-Zn(II) porphyrin conjugate, b) bisacridinium-diphenylporphyrin conjugate, c) bis(acridinium/acridane)-Zn(II) porphyrin receptors. Figure 1

(Invited) Diameter-Dependent Stacking of Squaraine Dye Molecules inside Chirality-Sorted Single-Wall Carbon Nanotubes

Filling of single-wall carbon nanotubes (SWCNTs) with organic dye molecules is a promising strategy to add new functionalities, for instance by aligning dipolar dyes in a one-dimensional (1D) head-to-tail coupled chain to obtain a giant enhancement of their nonlinear optical response,[1] or by photo-sensitizing the tubes in new wavelength ranges by excitation energy transfer (EET) from the dye to the SWCNTs, useful for photo-conversion applications.[2] The 1D stacking of molecules inside SWCNTs modulates both the properties of the molecules and of the SWCNTs. We found that the EET of squaraine-dye-filled SWCNTs reveals a pronounced SWCNT-diameter-dependence of the dye absorption, indicating a diameter-dependent stacking. By performing IR fluorescence excitation spectroscopy on a range of chirality-enriched samples of dye-filled SWCNTs with different chirality distributions, each shifted dye absorption wavelength observed through the EET can be unambiguously assigned to a specific encapsulating SWCNT chirality.[3] This reveals a systematic trend with diameter that can be associated with the J-aggregate- and H-aggregate-like interactions expected in close-packed single- and double-file stackings, as corroborated by a simple geometric model, and enables tuning of the optical properties of the 1D molecular arrays through the selection of proper SWCNT diameters.[1] S. Cambré, J. Campo, C. Beirnaert, C. Verlackt, P. Cool, W. Wenseleers, Nature Nanotechnol. 10(3) 248-252 (2015). [2] S. van Bezouw, D.H. Arias, R. Ihly, S. Cambré, A.J. Ferguson, J. Campo, J.C. Johnson, J. Defillet, W. Wenseleers, J.L. Blackburn, ACS Nano 12(7) 6881-6894 (2018). [3] S. Forel, H. Li, S. van Bezouw, J. Campo, L. Wieland, W. Wenseleers, B.S. Flavel, S. Cambré, Nanoscale 14, 8385-8397 (2022).

Depression and HIV: a scoping review in search of neuroimmune biomarkers.

People with HIV are at increased risk for depression, though the neurobiological mechanisms underlying this are unclear. In the last decade, there has been a substantial rise in interest in the contribution of (neuro)inflammation to depression, coupled with rapid advancements in the resolution and sensitivity of biomarker assays such as Luminex, single molecular array and newly developed positron emission tomography radioligands. Numerous pre-clinical and clinical studies have recently leveraged these next-generation immunoassays to identify biomarkers that may be associated with HIV and depression (separately), though few studies have explored these biomarkers in co-occurring HIV and depression. Using a systematic search, we detected 33 publications involving a cumulative N = 10 590 participants which tested for associations between depressive symptoms and 55 biomarkers of inflammation and related processes in participants living with HIV. Formal meta-analyses were not possible as statistical reporting in the field was highly variable; future studies must fully report test statistics and effect size estimates. The majority of included studies were carried out in the United States, with samples that were primarily older and primarily men. Substantial further work is necessary to diversify the geographical, age, and sex distribution of samples in the field. This review finds that alterations in concentrations of certain biomarkers of neuroinflammation (interleukin-6, tumour necrosis factor-α, neopterin) may influence the association between HIV and depression. Equally, the chemokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) or the metabolic index kynurenine:tryptophan (Kyn:Trp), which have been the focus of several studies, do not appear to be associated with depressive symptoms amongst people living with HIV, as all (MCP-1) or most (IL-8 and Kyn:Trp) available studies of these biomarkers reported non-significant associations. We propose a biomarker-driven hypothesis of the neuroimmunometabolic mechanisms that may precipitate the increased risk of depression among people with HIV. Chronically activated microglia, which trigger key neuroinflammatory cascades shown to be upregulated in people with HIV, may be the central link connecting HIV infection in the central nervous system with depressive symptoms. Findings from this review may inform research design in future studies of HIV-associated depression and enable concerted efforts towards biomarker discovery.

A qualitative investigation of paediatric intensive care staff attitudes towards the diagnosis of lower respiratory tract infection in the molecular diagnostics era

BackgroundIn the past decade, molecular diagnostic syndromic arrays incorporating a range of bacterial and viral pathogens have been described. It is unclear how paediatric intensive care unit (PICU) staff diagnose lower respiratory tract infection (LRTI) and integrate diagnostic array results into antimicrobial decision-making.MethodsAn online survey with eleven questions was distributed throughout paediatric intensive care societies in the UK, continental Europe and Australasia with a total of 755 members. Participants were asked to rate the clinical factors and investigations they used when prescribing for LRTI. Semi-structured interviews were undertaken with staff who participated in a single-centre observational study of a 52-pathogen diagnostic array.ResultsSeventy-two survey responses were received; most responses were from senior doctors. Whilst diagnostic arrays were used less frequently than routine investigations (i.e. microbiological culture), they were of comparable perceived utility when making antimicrobial decisions. Prescribers reported that for arrays to be clinically impactful, they would need to deliver results within 6 h for stable patients and within 1 h for unstable patients to inform their immediate decision to prescribe antimicrobials. From 16 staff interviews, we identified that arrays were helpful for the diagnosis and screening of bacterial LRTI. Staff reported it could be challenging to interpret results in some cases due to the high sensitivity of the test. Therefore, results were considered within the context of the patient and discussed within the multidisciplinary team.ConclusionsDiagnostic arrays were considered of comparable value to microbiological investigations by PICU prescribers. Our findings support the need for further clinical and economic evaluation of diagnostic arrays in a randomised control trial.Trial registrationClinicaltrials.gov, NCT04233268. Registered on 18 January 2020.

A Comparison of Two Analytical Approaches for the Quantification of Neurofilament Light Chain, a Biomarker of Axonal Damage in Multiple Sclerosis.

Neurofilament light chain (NfL), is a neuron-specific cytoskeletal protein detected in extracellular fluid following axonal damage. Extensive research has focused on NfL quantification in CSF, establishing it as a prognostic biomarker of disability progression in Multiple Sclerosis (MS). Our study used a new commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit and Single Molecular Array (Simoa) advanced technology to assess serum NfL levels in MS patients and Healthy Controls (HC). Verifying the most accurate, cost-effective methodology will benefit its application in clinical settings. Blood samples were collected from 54 MS patients and 30 HC. Protocols accompanying the kits were followed. The ELISA thershold was set as 3 S.D. above the mean of the HC. For Simoa, the Z-score calculation created by Jens Kuhle's group was applied (with permission). Samples exceeding the threshold or z-score ≥1.5 indicated subclinical disease activity. To our knowledge, this is the first study to find strong-positive correlation between ELISA and Simoa for the quantification of NfL in serum (r = 0.919). Despite the strong correlation, Simoa has better analytical sensitivity and can detect small changes in samples making it valuable in clinical settings. Further research is required to evaluate whether serum NfL quantification using ELISA could be utilized to predict disability progression.

Deflecting and routing nematicons via orientation programmable liquid crystal array.

By designing a liquid crystal cell with comb electrode structure, the alignment modulation of nematic liquid crystal in the cell can be realized after the electric field is applied. In different orientation regions, the incident laser beam can deflect at different angles. At the same time, by changing the incident angle of the laser beam, the reflection modulation of the laser beam on the interface of the liquid crystal molecular orientation change can be realized. Based on the above discussion, we then demonstrate the modulation of liquid crystal molecular orientation arrays on nematicon pairs. In different orientation regions of liquid crystal molecules, nematicon pairs can exhibit various combinations of deflections, and these deflection angles are modulable under external fields. Deflection and modulation of nematicon pairs have potential applications in optical routing and optical communication.

Lipid bilayer-coated nanoparticles: mimetism for biomedical applications

Living organisms are made of self-assembled nanostructures. Therefore, the control of sizes, shapes, textures, or chemical functions during chemical synthesis, as managed by nanotechnology, leads to a myriad of possibilities in the field of biomedical applications. One of the main approaches in this area, also known as nanomedicine, is the production of biomimetic nanoparticles, which take profit from either natural products or bioinspired materials. Cell-cell communications are strongly dependent on molecular arrays displayed at the cell surface in the context of lipid bilayers. Therefore, the mimicry of such coatings has gained great interest during the last decades. Herein we summarize the rationale and the methodologies related to this approach, with a special focus on the delivery of drugs and vaccines. The challenges and opportunities in this area, along with some selected examples will be discussed as well.

Data-driven design of a multiplexed, peptide-sensitized transistor to detect breath VOC markers of COVID-19.

Exhaled human breath contains a rich mixture of volatile organic compounds (VOCs) whose concentration can vary in response to disease or other stressors. Using simulated odorant-binding proteins (OBPs) and machine learning methods, we designed a multiplex of short VOC- and carbon-binding peptide probes that detect a characteristic "VOC fingerprint". Specifically, we target VOCs associated with COVID-19 in a compact, molecular sensor array that directly transduces vapor composition into multi-channel electrical signals. Rapidly synthesizable, chimeric VOC- and solid-binding peptides were derived from selected OBPs using multi-sequence alignment with protein database structures. Selective peptide binding to targeted VOCs and sensor surfaces was validated using surface plasmon resonance spectroscopy and quartz crystal microbalance. VOC sensing was demonstrated by peptide-sensitized, exposed-channel carbon nanotube transistors. The data-to-device pipeline enables the development of novel devices for non-invasive monitoring, diagnostics of diseases, and environmental exposure assessment.

Surface-Mediated Spin Locking and Thermal Unlocking in a 2D Molecular Array.

Molecule-based functional devices may take advantage of surface-mediated spin state bistability. Whereas different spin states in conventional spin crossover complexes are only accessible at temperatures well below room temperature, and the lifetimes of the high-spin state are relatively short, a different behavior exhibited by prototypical nickel phthalocyanine is shown here. Direct interaction of the organometallic complex with a copper metal electrode mediates the coexistence of a high spin and a low spin state within the 2D molecular array. The spin state bistability is extremely non-volatile, since no external stimuli are required to preserve it. It originates from the surface-induced axial displacement of the functional nickel cores, which generates two stable local minima. Spin state unlocking and the full conversion to the low spin state are only possible by a high temperature stimulus. This spin state transition is accompanied by distinct changes in the molecular electronic structure that might facilitate the state readout at room temperature, as evidenced by valence spectroscopy. The non-volatility of the high spin state up to elevated temperatures and the controllable spin bistability render the system extremely intriguing for applications in molecule-based information storage devices.

Acacia senegal Budmunchiamines as a Potential Adjuvant for Rejuvenating Phenicol Activities towards Escherichia coli-Resistant Strains.

The continuous emergence of bacterial resistance alters the activities of different antibiotic families and requires appropriate strategies to solve therapeutic impasses. Medicinal plants are an attractive source for researching alternative and original therapeutic molecules. In this study, the fractionation of natural extracts from A. senegal and the determination of antibacterial activities are associated with molecular networking and tandem mass spectrometry (MS/MS) data used to characterize active molecule(s). The activities of the combinations, which included various fractions plus an antibiotic, were investigated using the "chessboard" test. Bio-guided fractionation allowed the authors to obtain individually active or synergistic fractions with chloramphenicol activity. An LC-MS/MS analysis of the fraction of interest and molecular array reorganization showed that most identified compounds are Budmunchiamines (macrocyclic alkaloids). This study describes an interesting source of bioactive secondary metabolites structurally related to Budmunchiamines that are able to rejuvenate a significant chloramphenicol activity in strains that produce an AcrB efflux pump. They will pave the way for researching new active molecules for restoring the activity of antibiotics that are substrates of efflux pumps in enterobacterial-resistant strains.

Review of Endometrial Receptivity Array: A Personalized Approach to Embryo Transfer and Its Clinical Applications.

Successful outcomes of in vitro fertilization (IVF) rely on both the formation of a chromosomally normal embryo and its implantation in a receptive endometrium. Pre-implantation genetic testing for aneuploidy (PGT-A) has been widely accepted as a tool to assess the viability of an embryo. In 2011, the endometrial receptivity array (ERA) was first published as a tool to determine when the endometrium is most receptive to an embryo, commonly referred to as the "window of implantation" (WOI). The ERA uses molecular arrays to assess proliferation and differentiation in the endometrium and screens for inflammatory markers. Unlike PGT-A, there has been dissent within the field concerning the efficacy of the ERA. Many studies that contest the success of the ERA found that it did not improve pregnancy outcomes in patients with an already-good prognosis. Alternatively, studies that utilized the ERA in patients with repeated implantation failure (RIF) and transfer of known euploid embryos demonstrated improved outcomes. This review aims to describe the ERA as a novel technique, review the various settings that the ERA may be used in, such as natural frozen embryo transfer (nFET) and hormone replacement therapy frozen embryo transfer (HRT-FET), and provide a summary of the recent clinical data for embryo transfers in patients with RIF utilizing the ERA.

Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. MethodsExome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. ResultsWe identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. ConclusionsWe have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and ImplicationsA rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.