Mixed-dimensional moiré systems of twisted graphitic thin films.

Moiré patterns formed by stacking atomically thin van der Waals crystals with a relative twist angle can give rise to notable new physical properties1,2. The study of moiré materials has so far been limited to structures comprising no more than a few van der Waals sheets, because a moiré pattern localized to a single two-dimensional interface is generally assumed to be incapable of appreciably modifying the properties of a bulk three-dimensional crystal. Here, we perform transport measurements of dual-gated devices constructed by slightly rotating a monolayer graphene sheet atop a thin bulk graphite crystal. We find that the moiré potential transforms the electronic properties of the entire bulk graphitic thin film. At zero and in small magnetic fields, transport is mediated by a combination of gate-tuneable moiré and graphite surface states, as well as coexisting semimetallic bulk states that do not respond to gating. At high field, the moiré potential hybridizes with the graphitic bulk states due to the unique properties of the two lowest Landau bands of graphite. These Landau bands facilitate the formation of a single quasi-two-dimensional hybrid structure in which the moiré and bulk graphite states are inextricably mixed. Our results establish twisted graphene-graphite as the first in a new class of mixed-dimensional moiré materials.

Three-dimensional quantum Hall effect and metal-insulator transition in ZrTe5.

The discovery of the quantum Hall effect (QHE)1,2 in two-dimensional electronic systems has given topology a central role in condensed matter physics. Although the possibility of generalizing the QHE to three-dimensional (3D) electronic systems3,4 was proposed decades ago, it has not been demonstrated experimentally. Here we report the experimental realization of the 3D QHE in bulk zirconium pentatelluride (ZrTe5) crystals. We perform low-temperature electric-transport measurements on bulk ZrTe5 crystals under a magnetic field and achieve the extreme quantum limit, where only the lowest Landau level is occupied, at relatively low magnetic fields. In this regime, we observe a dissipationless longitudinal resistivity close to zero, accompanied by a well-developed Hall resistivity plateau proportional to half of the Fermi wavelength along the field direction. This response is the signature of the 3D QHE and strongly suggests a Fermi surface instability driven by enhanced interaction effects in the extreme quantum limit. By further increasing the magnetic field, both the longitudinal and Hall resistivity increase considerably and display a metal-insulator transition, which represents another magnetic-field-driven quantum phase transition. Our findings provide experimental evidence of the 3D QHE and a promising platform for further exploration of exotic quantum phases and transitions in 3D systems.

Light-Driven Spontaneous Phonon Chirality and Magnetization in Paramagnets.

Spin-phonon coupling enables the mutual manipulation of phonon and spin degrees of freedom in solids. In this study, we reveal the inherent nonlinearity within this coupling. Using a paramagnet as an illustration, we demonstrate the nonlinearity by unveiling spontaneous symmetry breaking under a periodic drive. The drive originates from linearly polarized light, respecting a mirror reflection symmetry of the system. However, this symmetry is spontaneously broken in the steady state, manifested in the emergence of coherent chiral phonons accompanied by a nonzero magnetization. We establish an analytical self-consistency equation to find the parameter regime where spontaneous symmetry breaking occurs. Furthermore, we estimate realistic parameters and discuss potential materials that could exhibit this behavior. Our findings shed light on the exploration of nonlinear phenomena in magnetic materials and present possibilities for on-demand control of magnetization.

Electrically Controlled Anomalous Hall Effect and Orbital Magnetization in Topological Magnet MnBi_{2}Te_{4}.

We propose an intrinsic mechanism to understand the even-odd effect, namely, opposite signs of anomalous Hall resistance and different shapes of hysteresis loops for even and odd septuple layers (SLs), of MBE-grown MnBi_{2}Te_{4} thin films with electron doping. The nonzero hysteresis loops in the anomalous Hall effect and magnetic circular dichroism for even-SLs MnBi_{2}Te_{4} films originate from two different antiferromagnetic (AFM) configurations with different zeroth Landau level energies of surface states. The complex form of the anomalous Hall hysteresis loop can be understood from two magnetic transitions, a transition between two AFM states followed by a second transition to the ferromagnetic state. Our model also clarifies the relationship and distinction between axion parameter and magnetoelectric coefficient, and shows an even-odd oscillation behavior of magnetoelectric coefficients in MnBi_{2}Te_{4} films.

Gate-Tunable Phonon Magnetic Moment in Bilayer Graphene.

We develop a first-principles quantum scheme to calculate the phonon magnetic moment in solids. As a showcase example, we apply our method to study gated bilayer graphene, a material with strong covalent bonds. According to the classical theory based on the Born effective charge, the phonon magnetic moment in this system should vanish, yet our quantum mechanical calculations find significant phonon magnetic moments. Furthermore, the magnetic moment is highly tunable by changing the gate voltage. Our results firmly establish the necessity of the quantum mechanical treatment, and identify small-gap covalent materials as a promising platform for studying tunable phonon magnetic moment.

Gate-Tunable Anomalous Hall Effect in a 3D Topological Insulator/2D Magnet van der Waals Heterostructure.

We demonstrate advantages of samples made by mechanical stacking of exfoliated van der Waals materials for controlling the topological surface state of a three-dimensional topological insulator (TI) via interaction with an adjacent magnet layer. We assemble bilayers with pristine interfaces using exfoliated flakes of the TI BiSbTeSe2 and the magnet Cr2Ge2Te6, thereby avoiding problems caused by interdiffusion that can affect interfaces made by top-down deposition methods. The samples exhibit an anomalous Hall effect (AHE) with abrupt hysteretic switching. For the first time in samples composed of a TI and a separate ferromagnetic layer, we demonstrate that the amplitude of the AHE can be tuned via gate voltage with a strong peak near the Dirac point. This is the signature expected for the AHE due to Berry curvature associated with an exchange gap induced by interaction between the topological surface state and an out-of-plane-oriented magnet.

Phonon Magnetic Moment from Electronic Topological Magnetization.

The traditional theory of magnetic moments for chiral phonons is based on the picture of the circular motion of the Born effective charge, typically yielding a small fractional value of the nuclear magneton. Here we investigate the adiabatic evolution of electronic states induced by the lattice vibration of a chiral phonon and obtain an electronic orbital magnetization in the form of a topological second Chern form. We find that the traditional theory needs to be refined by introducing a k resolved Born effective charge, and identify another contribution from the phonon-modified electronic energy together with the momentum-space Berry curvature. The second Chern form can diverge when there is a Yang's monopole near the parameter space of interest as illustrated by considering a phonon at the Brillouin zone corner in a gapped graphene model. We also find large magnetic moments for the optical phonon in bulk topological materials where nontopological contribution is also important. Our results agree with recent observations in experiments.

WKB Estimate of Bilayer Graphene's Magic Twist Angles.

Graphene bilayers exhibit zero-energy flatbands at a discrete series of magic twist angles. In the absence of intrasublattice interlayer hopping, zero-energy states satisfy a Dirac equation with a non-Abelian SU(2) gauge potential that cannot be diagonalized globally. We develop a semiclassical WKB approximation scheme for this Dirac equation by introducing a dimensionless Planck's constant proportional to the twist angle, solving the linearized Dirac equation around AB and BA turning points, and connecting Airy function solutions via bulk WKB wave functions. We find zero-energy solutions at a discrete set of values of the dimensionless Planck's constant, which we obtain analytically. Our analytic flatband twist angles correspond closely to those determined numerically in previous work.

Orbital Chern Insulator and Quantum Phase Diagram of a Kagome Electron System with Half-Filled Flat Bands.

We study the quantum phase diagram of electrons on kagome lattice with half-filled lowest flat bands by considering the antiferromagnetic Heisenberg interaction J, and short-range Coulomb interaction V. In the weak J regime, we identify a fully spin-polarized phase. The presence of finite V drives a spontaneous chiral current, which makes the system an orbital Chern insulator by contributing an orbital magnetization. Such an out-of-plane orbital magnetization allows the presence of a Chern insulating phase independent of the spin orientation in contrast to the spin-orbit coupling induced Chern insulator that disappears with in-plane ferromagnetism constrained by symmetry. Such a symmetry difference provides a criterion to distinguish the physical origin of topological responses in kagome systems. The orbital Chern insulator is robust against small coupling J. By further increasing J, we find that the ferromagnetic topological phase is suppressed, which first becomes partially polarized and then enters a nonmagnetic phase with spin and charge nematicity. The frustrated flat band allows the spin and Coulomb interaction to play an essential role in determining the quantum phases.

Engineering Corner States from Two-Dimensional Topological Insulators.

We theoretically demonstrate that the second-order topological insulator with robust corner states can be realized in two-dimensional Z_{2} topological insulators by applying an in-plane Zeeman field. The Zeeman field breaks the time-reversal symmetry and thus destroys the Z_{2} topological phase. Nevertheless, it respects some crystalline symmetries and thus can protect the higher-order topological phase. By taking the Kane-Mele model as a concrete example, we find that spin-helical edge states along zigzag boundaries are gapped out by the Zeeman field whereas the in-gap corner state at the intersection between two zigzag edges arises, which is independent of the field orientation. We further show that the corner states are robust against the out-of-plane Zeeman field, staggered sublattice potentials, Rashba spin-orbit coupling, and the buckling of honeycomb lattices, making them experimentally feasible. Similar behaviors can also be found in the well-known Bernevig-Hughes-Zhang model.

Topological phases in two-dimensional materials: a review.

Topological phases with insulating bulk and gapless surface or edge modes have attracted intensive attention because of their fundamental physics implications and potential applications in dissipationless electronics and spintronics. In this review, we mainly focus on recent progress in the engineering of topologically nontrivial phases (such as [Formula: see text] topological insulators, quantum anomalous Hall effects, quantum valley Hall effects etc) in two-dimensional systems, including quantum wells, atomic crystal layers of elements from group III to group VII, and the transition metal compounds.

Electroacupuncture inhibits hippocampal neuronal apoptosis and improves cognitive dysfunction in mice with vascular dementia via the JNK signaling pathway.

BACKGROUND: Electroacupuncture (EA) has been shown to reduce cognitive impairment in vascular dementia (VaD) patients. However, the mechanism of action remains unknown. OBJECTIVE: The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in apoptosis. Herein, we focused on whether EA can inhibit apoptosis and alleviate cognitive impairment by regulating the JNK signaling pathway using a mouse model of VaD induced by modified bilateral common carotid artery occlusion (BCCAo). METHODS: In experiment I, 60 mice were randomly divided into a Sham group, BCCAo group, BCCAo + EA group, BCCAo + Sham-EA group, BCCAo + SP group (receiving the selective JNK inhibitor SP600125) and BCCAo + SP + EA group. Morris water maze tests, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining and flow cytometry were used to evaluate the effect of the EA intervention on VaD. In experiment II, 30 mice were randomly divided into a Sham group, BCCAo group, BCCAo + EA group, BCCAo + SP group and BCCAo + SP + EA group. Western blotting and real-time reverse transcription polymerase chain reaction were used to detect protein and mRNA expression of key factors in the JNK signaling pathway in the hippocampus. RESULTS: EA, SP600125 and EA + SP600125 significantly inhibited hippocampal apoptosis and improved cognitive impairment in VaD model mice. There were no significant differences between the BCCAo group and the BCCAo + Sham-EA group. EA, EA + SP600125 and SP600125 inhibited the phosphorylation of JNK and caspase-3. EA and EA + SP600125 promoted protein and mRNA expression of B-cell lymphoma 2 (Bcl-2) in the hippocampus of VaD mice and inhibited protein and mRNA expression of activator protein (AP)-1, p53 and Bax. CONCLUSION: EA can reverse cognitive deficits and inhibit hippocampal neuronal apoptosis in VaD model mice, at least partially through inhibition of the JNK signaling pathway and regulation of apoptosis signals.

Overexpression of SmMYC2 enhances salt resistance in Arabidopsis thaliana and Salvia miltiorrhiza hairy roots.

Soil salinity significantly affects both Salvia miltiorrhiza growth and development as well as seed germination throughout field cultivation and production. The basic helix-loop-helix (bHLH) transcription factor (TF) MYC2 contributes significantly to plant stress resistance as a key regulator of the jasmonic acid signaling pathway. In transgenic S. miltiorrhiza hairy roots, SmMYC2 has been shown to promote the accumulation of tanshinone and salvianolic acid, but its role in S. miltiorrhiza of resistance to abiotic stress is unclear. Herein, we found methyl jasmonate (MeJA), NaCl, and PEG treatment all significantly increased SmMYC2 expression. In response to salt stress, SmMYC2 overexpression in yeast increased its rate of growth. Additionally, overexpression of SmMYC2 transgenic Arabidopsis thaliana and S. miltiorrhiza hairy root showed that it might improve salt resistance in transgenic plant. In particular, compared to WT, overexpression of SmMYC2 transgenic Arabidopsis had higher levels of three antioxidant enzymes (superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT)), proline (Pro) content, and ABA-dependent and ABA-independent genes expression. They also had lower levels of malondialdehyde (MDA) and reactive oxygen species (ROS) accumulation. What's more, overexpression of SmMYC2 increases the expression of flavonoid synthesis genes and the accumulation of related components in Arabidopsis. These findings imply that SmMYC2 functions as a positive regulator that regulates plant tolerance to salt through ABA-dependent and independent signaling pathways.

Tunable interaction between excitons and hybridized magnons in a layered semiconductor.

The interaction between distinct excitations in solids is of both fundamental interest and technological importance. One such interaction is the coupling between an exciton, a Coulomb bound electron-hole pair, and a magnon, a collective spin excitation. The recent emergence of van der Waals magnetic semiconductors1 provides a platform to explore these exciton-magnon interactions and their fundamental properties, such as strong correlation2, as well as their photospintronic and quantum transduction3 applications. Here we demonstrate the precise control of coherent exciton-magnon interactions in the layered magnetic semiconductor CrSBr. We varied the direction of an applied magnetic field relative to the crystal axes, and thus the rotational symmetry of the magnetic system4. Thereby, we tuned not only the exciton coupling to the bright magnon, but also to an optically dark mode via magnon-magnon hybridization. We further modulated the exciton-magnon coupling and the associated magnon dispersion curves through the application of uniaxial strain. At a critical strain, a dispersionless dark magnon band emerged. Our results demonstrate an unprecedented level of control of the opto-mechanical-magnonic coupling, and a step towards the predictable and controllable implementation of hybrid quantum magnonics5-11.

An aquaporin gene MdPIP1;2 from Malus domestica confers salt tolerance in transgenic Arabidopsis.

Aquaporins are known as water channel proteins. In this study, an aquaporin gene MdPIP1;2 was cloned from Malus domestica cv. Qinguan encoding a protein of 289 amino acids that formed the typical structure of aquaporin by six transmembrane domains, two asparagine-proline-alanine motifs, aromatic/arginine filter, and Forger's position. MdPIP1;2 was highly expressed in the water-sensitive or water-requiring tissues, and upregulated by salt and PEG stresses. MdPIP1;2 transgenic Arabidopsis exhibited enhanced salt stress tolerance with less Na + accumulation, lower malondialdehyde (MDA) content, lower electrolyte leakage (EL) level, and higher superoxide dismutase (SOD) and peroxidase (POD) activities compared with WT plants. Additionally, transcriptome analysis indicated MdPIP1;2 transgenic Arabidopsis could present healthier growth and development condition probably through regulating morphological structures and accumulating specific secondary metabolites under salt stress. Our results are a useful reference for better understanding the biological function of aquaporin in apple tree, especially in plant response to abiotic stress.

Phytochemistry and bioactivities of the main constituents of Polyporus umbellatus (Pers.) Fries.

BACKGROUND: Edible fungi resources have good application prospects in the research and development of food, medicine, and health products. Polyporus umbellatus (Pers.) Fries, as a precious edible and medicinal fungus, has long been used by Chinese medicine to treat urinary systems and related kidney diseases. PURPOSE: In recent years, researchers have discovered and isolated a variety of active compounds from P. umbellatus. Modern phytochemical and pharmacological experiments showed that the crude extract of P. umbellatus had many biological functions and could be widely used in the fields of food, pharmaceutical and cosmetics. This paper summarizes the active components of P. umbellatus, through elaborating its mechanism of action, further clarify the action substances, in order to improve the utilization rate of P. umbellatus, promote the development and application of P. umbellatus in food, pharmaceutical and cosmetics industry. METHODS: In this paper, the literatures related to P. umbellatus were summarized and classified by "China National Knowledge Instructure (CNKI)", "Google Scholar" and "Web of Science". Compared with other articles, this work systematically sorted out all the active substances with clear structures in P. umbellatus. On this basis, combined with the chemical composition of P. umbellatus, its functional efficacy was expounded, and the effects of different types of active substances in P. umbellatus were further presented. RESULTS: The main chemical constituents of P. umbellatus include polysaccharide and sterol, and the secondary compounds include fatty acids, phenols and other small molecules. These active substances endowed P. umbellatus anti-cancer, antibacterial, diuretic, antioxidant, enhance immune system, promote hair growth and other pharmacological activities, which has been verified many times in vivo and in vitro experiments. CONCLUSION: Modern in vitro or in vivo pharmacological experiments and clinical practice for the efficacy of P. umbellatus provides a strong support, and the separation of compounds in P. umbellatus has also deepened people's understanding of this traditional Chinese medicine, greatly promoted the development and application of P. umbellatus. However, the complex active substances of poring also hinder the research of P. umbellatus to some extent, and the mechanism of action and potential synergistic or antagonistic effect of the mixture of various active ingredients have not been clearly analyzed. How to use the bioactivity-guided separation strategy to identify more bioactive components and analyze the molecular mechanism of the main active components have become the main problems of P. umbellatus research, but also provides a direction for the further study of it.

Effects of bilirubin on perioperative myocardial infarction and its long-term prognosis in patients undergoing percutaneous coronary intervention.

BACKGROUND: Although bilirubin is known to be an antioxidant, any relationship with coronary heart disease remains controversial. To the best of our knowledge, no previous study has investigated the association between bilirubin and perioperative myocardial infarction (PMI), including its long-term prognosis. AIM: To investigate the impact of bilirubin levels on PMI in patients undergoing percutaneous coronary intervention (PCI), and long-term prognosis in post-PMI patients. METHODS: Between January 2014 and September 2018, 10236 patients undergoing elective PCI were enrolled in the present study. Total bilirubin (TB) and cardiac troponin I (cTnI) levels were measured prior to PCI and cTnI at further time-points, 8, 16 and 24 h after PCI. Participants were stratified by pre-PCI TB levels and divided into three groups: < 10.2; 10.2-14.4 and > 14.4 µmol/L. PMI was defined as producing a post-procedural cTnI level of > 5 × upper limit of normal (ULN) with normal baseline cTnI. Major adverse cardiovascular events (MACEs) included cardiac death, MI, stroke and revascularization during a maximum 5-year follow-up. RESULTS: PMI was detected in 526 (15.3%), 431 (12.7%) and 424 (12.5%) of patients with pre-PCI TB levels of < 10.2, 10.2-14.4 and > 14.4 µmol/L (P = 0.001), respectively. Multivariate logistical analysis indicated that patients with TB 10.2-14.4 and > 14.4 µmol/L had a lower incidence of PMI [TB 10.2-14.4 µmol/L: Odds ratio (OR): 0.854; 95% confidence interval (CI): 0.739-0.987; P = 0.032; TB > 14.4 µmol/L: OR: 0.846; 95%CI: 0.735-0.975; P = 0.021] compared with patients with TB < 10.2 µmol/L. Construction of a Kaplan-Meier curve demonstrated a higher MACE-free survival time for patients with higher TB than for those with lower TB (log-rank P = 0.022). After adjustment for cardiovascular risk factors and angiographic characteristics, multivariate Cox analysis showed that a TB level > 14.4 µmol/L was associated with a reduced risk of MACEs compared with a TB level < 10.2 µmol/L (hazard ratio 0. 667; 95%CI: 0.485-0.918; P = 0.013). CONCLUSION: Bilirubin was a protective factor in PMI prediction. For post-PMI patients, elevated bilirubin levels were independently associated with a reduced risk of MACEs during long-term follow-up.

Assessment of Genetic Diversity of the Salangid, Neosalanx taihuensis, Based on the Mitochondrial COI Gene in Different Chinese River Basins.

The salangid Neosalanx taihuensis (Salangidae) is a commercially important economical fish endemic to China and restricted to large freshwater systems with a wide-ranging distribution. This fish species has continuous distribution ranges and a long-introduced aquaculture history in Chinese basins. However, the research on its population genetic differentiation within and between basins is very limited. In this regard, 197 individuals were sampled from 11 populations in the Nenjiang River Basin (A1-A4), Songhua River Basin (B1), Yellow River Basin (C1-C2), Yangtze River Basin (D1), Lanchang River Basin (E1-E2) and Huaihe River Basin (F1). Based on the COI sequence, the N.taihuensis population's genetic difference within and between river basins was investigated. The haplotypes and their frequency distributions were strongly skewed, with most haplotypes (n = 13) represented only in single samples each and thus restricted to a single population. The most common haplotype (H4, 67/197) was found in all individuals. The analysis of molecular variance (AMOVA) revealed a random pattern in the distribution of genetic diversity, which is inconsistent with contemporary hydrological structure. The mismatch between the distribution and neutrality tests supported the evidence of a population expansion, which occurred during the late Pleistocene (0.041-0.051 million years ago). Significant levels of genetic subdivision were detected among populations within basins rather than between the six basins. Population history dynamics showed that N. taihuensis experienced an expansion during the glacial period in the late Pleistocene. Therefore, different populations should be considered as different management units to achieve effective conservation and management purposes. These results have great significance for the evaluation and exploitation of the germplasm resources of N. taihuensis.

Genetic Diversity Evaluation and Conservation of Topmouth Culter (Culter alburnus) Germplasm in Five River Basins in China.

To study the genetic diversity of Culter alburnus (C. alburnus) populations, we analyzed the genetic diversity of five C. alburnus populations from Songhua Lake (SH), Huaihe River (HH), Changjiang River (CJ), Taihu Lake (TH), and Gehu Lake (GH) based on mitochondrial COI gene sequences. The results showed that the average contents of bases T, C, A, and G in the 526 bp COI gene sequence were 25.3%, 18.1%, 28.1%, and 28.6%, respectively, which showed AT bias. A total of 115 polymorphic sites were detected in the five populations, and 11 haplotypes (Hap) were defined. The nucleotide diversity (Pi) of the five populations ranged from 0.00053 to 0.01834, and the haplotype diversity (Hd) ranged from 0.280 to 0.746, with the highest genetic diversity in the TH population, followed by the SH population, with lower genetic diversity in the HH, CJ and GH populations. The analysis of the fixation index (Fst) and the genetic distance between populations showed that there was significant genetic differentiation between the SH population and the other populations, and the genetic distances between all of them were far; the genetic diversity within populations was higher than that between populations. Neutral tests, mismatch distributions, and Bayesian skyline plot (BSP) analyses showed that the C. alburnus populations have not experienced population expansion and are relatively stable in historical dynamics.

Non-Invasive Skin Imaging Assessment of Human Stress During Head-Down Bed Rest Using a Portable Handheld Two-Photon Microscope.

Spaceflight presents a series of physiological and pathological challenges to astronauts resulting from ionizing radiation, microgravity, isolation, and other spaceflight hazards. These risks cause a series of aging-related diseases associated with increased oxidative stress and mitochondria dysfunction. The skin contains many autofluorescent substances, such as nicotinamide adenine dinucleotide phosphate (NAD(P)H), keratin, melanin, elastin, and collagen, which reflect physiological and pathological changes in vivo. In this study, we used a portable handheld two-photon microscope to conduct high-resolution in vivo skin imaging on volunteers during 15 days of head-down bed rest. The two-photon microscope, equipped with a flexible handheld scanning head, was used to measure two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) images of the left forearm, left front chest, and forehead of volunteers. Changes in TPEF, SHG, and the extended SHG-to-AF(TPEF) aging index of the dermis (SAAID) were measured. It was found that TPEF intensity increased during bed rest and was restored to normal levels after recovery. Meanwhile, SHG increased slightly during bed rest, and the skin aging index increased. Moreover, we found the skin TPEF signals of the left forearm were significantly negatively associated with the oxidative stress marker malondialdehyde (MDA) and DNA damage marker 8-hydroxy-2'-desoxyguanosine (8-OHdG) values of subjects during head-down bed rest. Meanwhile, the SHG signals were also significantly negatively correlated with MDA and 8-OHDG. A significant negative correlation between the extended SAAID of the left chest and serum antioxidant superoxide dismutase (SOD) levels was also found. These results demonstrate that skin autofluorescence signals can reflect changes in human oxidant status. This study provides evidence for in-orbit monitoring of changes in human stress using a portable handheld two-photon microscope for skin imaging.