Overexpression of TIAM2S, a critical regulator for the hippocampal-medial prefrontal cortex network, progresses age-related spatial memory impairment.

TIAM Rac1 associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging, remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmarks expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor images analysis were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus-mPFC circuits, leading to age-related spatial memory impairment.

Depth-profiling alkyl chain order in unsaturated lipid monolayers on water.

Unsaturated lipids with C=C groups in their alkyl chains are widely present in the cell membrane and food. The C=C groups alter the lipid packing density, membrane stability, and persistence against lipid oxidation. Yet, molecular-level insights into the structure of the unsaturated lipids remain scarce. Here, we probe the molecular structure and organization of monolayers of unsaturated lipids on the water surface using heterodyne-detected sum-frequency generation (HD-SFG) spectroscopy. We vary the location of the C=C in the alkyl chain and find that at high lipid density, the location of the C=C group affects neither the interfacial water organization nor the tail of the alkyl chain. Based on this observation, we use the C=C stretch HD-SFG response to depth-profile the alkyl chain conformation of the unsaturated lipid. We find that the first 1/3 of carbon atoms from the headgroup are relatively rigid, oriented perpendicular to the surface. In contrast, the remaining carbon atoms can be approximated as free rotators, introducing the disordering of the alkyl chains.

Spontaneous Appearance of Triiodide Covering the Topmost Layer of the Iodide Solution Interface Without Photo-Oxidation.

Ions containing iodine atoms at the vapor-aqueous solution interfaces critically affect aerosol growth and atmospheric chemistry due to their complex chemical nature and multivalency. While the surface propensity of iodide ions has been intensely discussed in the context of the Hofmeister series, the stability of various ions containing iodine atoms at the vapor-water interface has been debated. Here, we combine surface-specific sum-frequency generation (SFG) vibrational spectroscopy with ab initio molecular dynamics simulations to examine the extent to which iodide ions cover the aqueous surface. The SFG probe of the free O-D stretch mode of heavy water indicates that the free O-D group density decreases drastically at the interface when the bulk NaI concentration exceeds ∼2 M. The decrease in the free O-D group density is attributed to the spontaneous appearance of triiodide that covers the topmost interface rather than to the surface adsorption of iodide. This finding demonstrates that iodide is not surface-active, yet the highly surface-active triiodide is generated spontaneously at the water-air interface, even under dark and oxygen-free conditions. Our study provides an important first step toward clarifying iodine chemistry and pathways for aerosol formation.

Does the Sum-Frequency Generation Signal of Aromatic C-H Vibrations Reflect Molecular Orientation?

Organic molecules with aromatic groups at the aqueous interfaces play a central role in atmospheric chemistry, green chemistry, and on-water synthesis. Insights into the organization of interfacial organic molecules can be obtained using surface-specific vibrational sum-frequency generation (SFG) spectroscopy. However, the origin of the aromatic C-H stretching mode peak is unknown, prohibiting us from connecting the SFG signal to the interfacial molecular structure. Here, we explore the origin of the aromatic C-H stretching response by heterodyne-detected SFG (HD-SFG) at the liquid/vapor interface of benzene derivatives and find that, irrespective of the molecular orientation, the sign of the aromatic C-H stretching signals is negative for all the studied solvents. Together with density functional theory (DFT) calculations, we reveal that the interfacial quadrupole contribution dominates, even for the symmetry-broken benzene derivatives, although the dipole contribution is non-negligible. We propose a simple evaluation of the molecular orientation based on the aromatic C-H peak area.

True Origin of Amide I Shifts Observed in Protein Spectra Obtained with Sum Frequency Generation Spectroscopy.

Accurate determination of protein structure at interfaces is critical for understanding protein interactions, which is directly relevant to a molecular-level understanding of interfacial proteins in biology and medicine. Vibrational sum frequency generation (VSFG) spectroscopy is often used for probing the protein amide I mode, which reports protein structures at interfaces. Observed peak shifts are attributed to conformational changes and often form the foundation of hypotheses explaining protein working mechanisms. Here, we investigate structurally diverse proteins using conventional and heterodyne-detected VSFG (HD-VSFG) spectroscopy as a function of solution pH. We reveal that blue-shifts of the amide I peak observed in conventional VSFG spectra upon lowering the pH are governed by the drastic change of the nonresonant contribution. Our results highlight that connecting changes in conventional VSFG spectra to conformational changes of interfacial proteins can be arbitrary, and that HD-VSFG measurements are required to draw unambiguous conclusions about structural changes in biomolecules.

Health Risk Exposure Assessment of Migration of Perfluorooctane Sulfonate and Perfluorooctanoic Acid from Paper and Cardboard in Contact with Food under Temperature Variations.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are extensively used in food-contact paper and cardboard. However, they may migrate from food-contact materials to food, and the migration rate may be increased at elevated temperatures. In addition, there is a positive association of PFOS/PFOA levels with total cholesterol. Therefore, this study aims to assess the human health risk of increased total cholesterol associated with long-term exposure to PFOS and PFOA migration from food-contact paper and cardboard under temperature variation scenarios in adults. An exposure assessment was performed using an uptake dose model to estimate the uptake doses of PFOS and PFOA for the high-, intermediate-, and low-exposure scenarios. Benchmark dose (BMD) modeling was conducted to describe the dose-response relationships between PFOS/PFOA and total cholesterol levels. Finally, a margin of exposure (MOE) approach was used to characterize the risk. The results of the exposure assessment showed that PFOS and PFOA uptake doses in the high-exposure scenarios were around one and two orders of magnitude greater than those in the intermediate- and low-exposure scenarios, respectively. Under high-exposure scenarios, the uptake levels of hundredth-percentile PFOS and PFOA at high temperatures may raise health concerns (MOE < 1). This study provides a methodology to assess the health risks associated with exposure to migration of food contaminants from various types of paper and cardboard that come into contact with food.

Ions Speciation at the Water-Air Interface.

In typical aqueous systems, including naturally occurring sweet and salt water and tap water, multiple ion species are co-solvated. At the water-air interface, these ions are known to affect the chemical reactivity, aerosol formation, climate, and water odor. Yet, the composition of ions at the water interface has remained enigmatic. Here, using surface-specific heterodyne-detected sum-frequency generation spectroscopy, we quantify the relative surface activity of two co-solvated ions in solution. We find that more hydrophobic ions are speciated to the interface due to the hydrophilic ions. Quantitative analysis shows that the interfacial hydrophobic ion population increases with decreasing interfacial hydrophilic ion population at the interface. Simulations show that the solvation energy difference between the ions and the intrinsic surface propensity of ions determine the extent of an ion's speciation by other ions. This mechanism provides a unified view of the speciation of monatomic and polyatomic ions at electrolyte solution interfaces.

Fibril formation and ordering of disordered FUS LC driven by hydrophobic interactions.

Biomolecular condensates, protein-rich and dynamic membrane-less organelles, play critical roles in a range of subcellular processes, including membrane trafficking and transcriptional regulation. However, aberrant phase transitions of intrinsically disordered proteins in biomolecular condensates can lead to the formation of irreversible fibrils and aggregates that are linked to neurodegenerative diseases. Despite the implications, the interactions underlying such transitions remain obscure. Here we investigate the role of hydrophobic interactions by studying the low-complexity domain of the disordered 'fused in sarcoma' (FUS) protein at the air/water interface. Using surface-specific microscopic and spectroscopic techniques, we find that a hydrophobic interface drives fibril formation and molecular ordering of FUS, resulting in solid-like film formation. This phase transition occurs at 600-fold lower FUS concentration than required for the canonical FUS low-complexity liquid droplet formation in bulk. These observations highlight the importance of hydrophobic effects for protein phase separation and suggest that interfacial properties drive distinct protein phase-separated structures.

On the Fresnel factor correction of sum-frequency generation spectra of interfacial water.

Insights into the microscopic structure of aqueous interfaces are essential for understanding the chemical and physical processes on the water surface, including chemical synthesis, atmospheric chemistry, and events in biomolecular systems. These aqueous interfaces have been probed by heterodyne-detected sum-frequency generation (HD-SFG) spectroscopy. To obtain the molecular response from the measured HD-SFG spectra, one needs to correct the measured ssp spectra for local electromagnetic field effects at the interface due to a spatially varying dielectric function. This so-called Fresnel factor correction can change the inferred response substantially, and different ways of performing this correction lead to different conclusions about the interfacial water response. Here, we compare the simulated and experimental spectra at the air/water interface. We use three previously developed models to compare the experiment with theory: an advanced approach taking into account the detailed inhomogeneous interfacial dielectric profile and the Lorentz and slab models to approximate the interfacial dielectric function. Using the advanced model, we obtain an excellent quantitative agreement between theory and experiment, in both spectral shape and amplitude. Remarkably, we find that for the Fresnel factor correction of the ssp spectra, the Lorentz model for the interfacial dielectric function is equally accurate in the hydrogen (H)-bonded region of the response, while the slab model underestimates this response significantly. The Lorentz model, thus, provides a straightforward method to obtain the molecular response from the measured spectra of aqueous interfaces in the H-bonded region.

Ligand free FeSn2 alloy nanoparticles for safe T2-weighted MR imaging of in vivo lung tumors.

Biosafety is a critical issue for the successful translocation of nanomaterial-based therapeutic/diagnostic agents from bench to bedside. For instance, after the withdrawal of clinically approved magnetic resonance (MR) imaging contrast agents (CAs) due to their biosafety issues, there is a massive demand for alternative, efficient, and biocompatible MR contrast agents for future MRI clinical applications. To this end, here we successfully demonstrate the in vivo MR contrast abilities and biocompatibilities of ligand-free FeSn2 alloy NPs for tracking in vivo lung tumors. In vitro and in vivo results reveal the FeSn2 alloy NPs acting as appreciable T2 weighted MR contrast agents to locate tumors. The construction of iron (Fe) on biocompatible tin (Sn) greatly facilitates the reduction of the intrinsic toxicities of Fe in vivo resulting in no significant abnormalities in liver and kidney functions. Therefore, we envision that constructing ligand-free alloy NPs will be a promising candidate for tracking in vivo tumors in future clinical applications.

Direct Probe of Electrochemical Pseudocapacitive pH Jump at a Graphene Electrode.

Molecular-level insight into interfacial water at a buried electrode interface is essential in electrochemistry, but spectroscopic probing of the interface remains challenging. Here, using surface-specific heterodyne-detected sum-frequency generation (HD-SFG) spectroscopy, we directly access the interfacial water in contact with the graphene electrode supported on calcium fluoride (CaF2 ). We find phase transition-like variations of the HD-SFG spectra vs. applied potentials, which arises not from the charging/discharging of graphene but from the charging/discharging of the CaF2 substrate through the pseudocapacitive process. The potential-dependent spectra are nearly identical to the pH-dependent spectra, evidencing that the pseudocapacitive behavior is associated with a substantial local pH change induced by water dissociation between the CaF2 and graphene. Our work evidences the local molecular-level effects of pseudocapacitive charging at an electrode/aqueous electrolyte interface.

Bulklike Vibrational Coupling of Surface Water Revealed by Sum-Frequency Generation Spectroscopy.

Vibrational coupling between interfacial water molecules is important for energy dissipation after on-water chemistry, yet intensely debated. Here, we quantify the interfacial vibrational coupling strength through the linewidth of surface-specific vibrational spectra of the water's O─H (O─D) stretch region for neat H_{2}O/D_{2}O and their isotopic mixtures. The local-field-effect-corrected experimental SFG spectra reveal that the vibrational coupling between hydrogen-bonded interfacial water O─H groups is comparable to that in bulk water, despite the effective density reduction at the interface.

The dielectric function profile across the water interface through surface-specific vibrational spectroscopy and simulations.

The dielectric properties of interfacial water on subnanometer length scales govern chemical reactions, carrier transfer, and ion transport at interfaces. Yet, the nature of the interfacial dielectric function has remained under debate as it is challenging to access the interfacial dielectric with subnanometer resolution. Here we use the vibrational response of interfacial water molecules probed using surface-specific sum-frequency generation (SFG) spectra to obtain exquisite depth resolution. Different responses originate from water molecules at different depths and report back on the local interfacial dielectric environment via their spectral amplitudes. From experimental and simulated SFG spectra at the air/water interface, we find that the interfacial dielectric constant changes drastically across an ∼1 Šthin interfacial water region. The strong gradient of the interfacial dielectric constant leads, at charged planar interfaces, to the formation of an electric triple layer that goes beyond the standard double-layer model.

Polarization-Dependent Heterodyne-Detected Sum-Frequency Generation Spectroscopy as a Tool to Explore Surface Molecular Orientation and Ångström-Scale Depth Profiling.

Sum-frequency generation (SFG) spectroscopy provides a unique optical probe for interfacial molecules with interface-specificity and molecular specificity. SFG measurements can be further carried out at different polarization combinations, but the target of the polarization-dependent SFG is conventionally limited to investigating the molecular orientation. Here, we explore the possibility of polarization-dependent SFG (PD-SFG) measurements with heterodyne detection (HD-PD-SFG). We stress that HD-PD-SFG enables accurate determination of the peak amplitude, a key factor of the PD-SFG data. Subsequently, we outline that HD-PD-SFG can be used not only for estimating the molecular orientation but also for investigating the interfacial dielectric profile and studying the depth profile of molecules. We further illustrate the variety of combined simulation and PD-SFG studies.

Polarization-Dependent Sum-Frequency Generation Spectroscopy for Ångstrom-Scale Depth Profiling of Molecules at Interfaces.

The three-dimensional spatial distribution of molecules at soft matter interfaces is crucial for processes ranging from membrane biophysics to atmospheric chemistry. While several techniques can access surface composition, obtaining information on the depth distribution is challenging. We develop a noninvasive, polarization-resolved, surface-specific sum-frequency generation spectroscopy providing quantitative depth information. We demonstrate the technique on formic acid molecules at the air-water interface. With increasing molar fraction from 2.5% to 10%, the formic acid molecules shift, on average, ∼0.9 Å into the bulk. The consistency with the simulation data manifests that the technique allows for probing the Ångstrom-scale depth profile.

Molecular Effects of Low-Intensity Shock Wave Therapy on L6 Dorsal Root Ganglion/Spinal Cord and Blood Oxygenation Level-Dependent (BOLD) Functional Magnetic Resonance Imaging (fMRI) Changes in Capsaicin-Induced Prostatitis Rat Models.

Neurogenic inflammation and central sensitization play a role in chronic prostatitis/chronic pelvic pain syndrome. We explore the molecular effects of low-intensity shock wave therapy (Li-ESWT) on central sensitization in a capsaicin-induced prostatitis rat model. Male Sprague-Dawley rats underwent intraprostatic capsaicin (10 mM, 0.1 cm3) injections. After injection, the prostate received Li-ESWT twice, one day apart. The L6 dorsal root ganglion (DRG)/spinal cord was harvested for histology and Western blotting on days 3 and 7. The brain blood oxygenation level-dependent (BOLD) functional images were evaluated using 9.4 T fMRI before the Li-ESWT and one day after. Intraprostatic capsaicin injection induced increased NGF-, BDNF-, and COX-2-positive neurons in the L6 DRG and increased COX-2, NGF, BDNF, receptor Trk-A, and TRPV1 protein expression in the L6 DRG and the dorsal horn of the L6 spinal cord, whose effects were significantly downregulated after Li-ESWT on the prostate. Intraprostatic capsaicin injection increased activity of BOLD fMRI responses in brain regions associated with pain-related responses, such as the caudate putamen, periaqueductal gray, and thalamus, whose BOLD signals were reduced after Li-ESWT. These findings suggest a potential mechanism of Li-ESWT on modulation of peripheral and central sensitization for treating CP/CPPS.

Magnetic, biocompatible FeCO3 nanoparticles for T2-weighted magnetic resonance imaging of in vivo lung tumors.

BACKGROUND: Late diagnosis of lung cancer is one of the leading causes of higher mortality in lung cancer patients worldwide. Significant research attention has focused on the use of magnetic resonance imaging (MRI) based nano contrast agents to efficiently locate cancer tumors for surgical removal or disease diagnostics. Although contrast agents offer significant advantages, further clinical applications require improvements in biocompatibility, biosafety and efficacy. RESULTS: To address these challenges, we fabricated ultra-fine Iron Carbonate Nanoparticles (FeCO3 NPs) for the first time via modified literature method. Synthesized NPs exhibit ultra-fine size (~ 17 nm), good dispersibility and excellent stability in both aqueous and biological media. We evaluated the MR contrast abilities of FeCO3 NPs and observed remarkable T2 weighted MRI contrast in a concentration dependent manner, with a transverse relaxivity (r2) value of 730.9 ± 4.8 mM-1 S-1at 9.4 T. Moreover, the r2 values of present FeCO3 NPs are respectively 1.95 and 2.3 times higher than the clinically approved contrast agents Resovist® and Friedx at same 9.4 T MR scanner. FeCO3 NPs demonstrate an enhanced T2 weighted contrast for in vivo lung tumors within 5 h of post intravenous administration with no apparent systemic toxicity or induction of inflammation observed in in vivo mice models. CONCLUSION: The excellent biocompatibility and T2 weighted contrast abilities of FeCO3 NPs suggest potential for future clinical use in early diagnosis of lung tumors.

Chemical Structure and Shape Enhance MR Imaging-Guided X-ray Therapy Following Marginative Delivery.

Ineffective site-specific delivery has seriously impeded the efficacy of nanoparticle-based drugs to a disease site. Here, we report the preparation of three different shapes (sphere, scroll, and oblate) to systematically evaluate the impact of the marginative delivery on the efficacy of magnetic resonance (MR) imaging-guided X-ray irradiation at a low dose of 1 Gy. In addition to the shape effect, the therapeutic efficacy is investigated for the first time to be strongly related to the structure effect that is associated with the chemical activity. The enhanced particle-vessel wall interaction of both the flat scroll and oblate following margination dynamics leads to greater accumulation in the lungs, resulting in superior performance over the sphere against lung tumor growth and suppression of lung metastasis. Furthermore, the impact of the structural discrepancy in nanoparticles on therapeutic efficacy is considered. The tetragonal oblate reveals that the feasibility of the charge-transfer process outperforms the orthorhombic scroll and cubic sphere to suppress tumors. Finally, surface area is also a crucial factor affecting the efficacy of X-ray treatments from the as-prepared particles.

Accurate molecular orientation at interfaces determined by multimode polarization-dependent heterodyne-detected sum-frequency generation spectroscopy via multidimensional orientational distribution function.

Many essential processes occur at soft interfaces, from chemical reactions on aqueous aerosols in the atmosphere to biochemical recognition and binding at the surface of cell membranes. The spatial arrangement of molecules specifically at these interfaces is crucial for many of such processes. The accurate determination of the interfacial molecular orientation has been challenging due to the low number of molecules at interfaces and the ambiguity of their orientational distribution. Here, we combine phase- and polarization-resolved sum-frequency generation (SFG) spectroscopy to obtain the molecular orientation at the interface. We extend an exponentially decaying orientational distribution to multiple dimensions, which, in conjunction with multiple SFG datasets obtained from the different vibrational modes, allows us to determine the molecular orientation. We apply this new approach to formic acid molecules at the air-water interface. The inferred orientation of formic acid agrees very well with ab initio molecular dynamics data. The phase-resolved SFG multimode analysis scheme using the multidimensional orientational distribution thus provides a universal approach for obtaining the interfacial molecular orientation.