Macroscopic changes in aquaporin-4 underlie blast traumatic brain injury-related impairment in glymphatic function.

Mild traumatic brain injury (mTBI) has emerged as a potential risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy. Blast mTBI, caused by exposure to a pressure wave from an explosion, is predominantly experienced by military personnel and has increased in prevalence and severity in recent decades. Yet the underlying pathology of blast mTBI is largely unknown. We examined the expression and localization of AQP4 in human post-mortem frontal cortex and observed distinct laminar differences in AQP4 expression following blast exposure. We also observed similar laminar changes in AQP4 expression and localization and delayed impairment of glymphatic function that emerged 28 days following blast injury in a mouse model of repetitive blast mTBI. In a cohort of veterans with blast mTBI, we observed that blast exposure was associated with an increased burden of frontal cortical MRI-visible perivascular spaces, a putative neuroimaging marker of glymphatic perivascular dysfunction. These findings suggest that changes in AQP4 and delayed glymphatic impairment following blast injury may render the post-traumatic brain vulnerable to post-concussive symptoms and chronic neurodegeneration.

Longitudinal Sleep Patterns and Cognitive Impairment in Older Adults.

Importance: Sleep disturbances and clinical sleep disorders are associated with all-cause dementia and neurodegenerative conditions, but it remains unclear how longitudinal changes in sleep impact the incidence of cognitive impairment. Objective: To evaluate the association of longitudinal sleep patterns with age-related changes in cognitive function in healthy older adults. Design, Setting, and Participants: This cross-sectional study is a retrospective longitudinal analyses of the Seattle Longitudinal Study (SLS), which evaluated self-reported sleep duration (1993-2012) and cognitive performance (1997-2020) in older adults. Participants within the SLS were enrolled as part of a community-based cohort from the Group Health Cooperative of Puget Sound and Health Maintenance Organization of Washington between 1956 and 2020. Data analysis was performed from September 2020 to May 2023. Main Outcomes and Measures: The main outcome for this study was cognitive impairment, as defined by subthreshold performance on both the Mini-Mental State Examination and the Mattis Dementia Rating Scale. Sleep duration was defined by self-report of median nightly sleep duration over the last week and was assessed longitudinally over multiple time points. Median sleep duration, sleep phenotype (short sleep, median ≤7 hours; medium sleep, median = 7 hour; long sleep, median ≥7 hours), change in sleep duration (slope), and variability in sleep duration (SD of median sleep duration, or sleep variability) were evaluated. Results: Of the participants enrolled in SLS, only 1104 participants who were administered both the Health Behavior Questionnaire and the neuropsychologic battery were included for analysis in this study. A total of 826 individuals (mean [SD] age, 76.3 [11.8] years; 468 women [56.7%]; 217 apolipoprotein E ε4 allele carriers [26.3%]) had complete demographic information and were included in the study. Analysis using a Cox proportional hazard regression model (concordance, 0.76) showed that status as a short sleeper (hazard ratio, 3.67; 95% CI, 1.59-8.50) and higher sleep variability (hazard ratio, 3.06; 95% CI, 1.14-5.49) were significantly associated with the incidence of cognitive impairment. Conclusions and Relevance: In this community-based longitudinal study of the association between sleep patterns and cognitive performance, the short sleep phenotype was significantly associated with impaired cognitive performance. Furthermore, high sleep variability in longitudinal sleep duration was significantly associated with the incidence of cognitive impairment, highlighting the possibility that instability in sleep duration over long periods of time may impact cognitive decline in older adults.

Isotopic Control of the Boron-Vacancy Spin Defect in Hexagonal Boron Nitride.

We report on electron spin resonance (ESR) spectroscopy of boron-vacancy (V_{B}^{-}) centers hosted in isotopically engineered hexagonal boron nitride (hBN) crystals. We first show that isotopic purification of hBN with ^{15}N yields a simplified and well-resolved hyperfine structure of V_{B}^{-} centers, while purification with ^{10}B leads to narrower ESR linewidths. These results establish isotopically purified h^{10}B^{15}N crystals as the optimal host material for future use of V_{B}^{-} spin defects in quantum technologies. Capitalizing on these findings, we then demonstrate optically induced polarization of ^{15}N nuclei in h^{10}B^{15}N, whose mechanism relies on electron-nuclear spin mixing in the V_{B}^{-} ground state. This work opens up new prospects for future developments of spin-based quantum sensors and simulators on a two-dimensional material platform.

Control of the Bright-Dark Exciton Splitting Using the Lamb Shift in a Two-Dimensional Semiconductor.

We investigate the exciton fine structure in atomically thin WSe_{2}-based van der Waals heterostructures where the density of optical modes at the location of the semiconductor monolayer can be tuned. The energy splitting Δ between the bright and dark exciton is measured by photoluminescence spectroscopy. We demonstrate that Δ can be tuned by a few meV as a result of a significant Lamb shift of the optically active exciton that arises from emission and absorption of virtual photons triggered by the vacuum fluctuations of the electromagnetic field. We also measure strong variations of the bright exciton radiative linewidth as a result of the Purcell effect. All these experimental results illustrate the strong sensitivity of the excitons to local vacuum field fluctuations. We find a very good agreement with a model that demonstrates the equivalence, for our system, of a classical electrodynamical transfer matrix formalism and quantum-electrodynamical approach. The bright-dark splitting control we demonstrate here in the weak light-matter coupling regime should apply to any semiconductor structures.

Optically Active Spin Defects in Few-Layer Thick Hexagonal Boron Nitride.

Optically active spin defects in hexagonal boron nitride (hBN) are promising quantum systems for the design of two-dimensional quantum sensing units offering optimal proximity to the sample being probed. In this Letter, we first demonstrate that the electron spin resonance frequencies of boron vacancy centers (V_{B}^{-}) can be detected optically in the limit of few-atomic-layer thick hBN flakes despite the nanoscale proximity of the crystal surface that often leads to a degradation of the stability of solid-state spin defects. We then analyze the variations of the electronic spin properties of V_{B}^{-} centers with the hBN thickness with a focus on (i) the zero-field splitting parameters, (ii) the optically induced spin polarization rate and (iii) the longitudinal spin relaxation time. This Letter provides important insights into the properties of V_{B}^{-} centers embedded in ultrathin hBN flakes, which are valuable for future developments of foil-based quantum sensing technologies.

Instability in longitudinal sleep duration predicts cognitive impairment in aged participants of the Seattle Longitudinal Study.

Importance: Sleep disturbances and clinical sleep disorders are associated with all-cause dementia and neurodegenerative conditions. It remains unclear how longitudinal changes in sleep impact the incidence of cognitive impairment. Objective: To evaluate how longitudinal sleep patterns contribute to age-related changes in cognitive function in healthy adults. Design Setting Participants: This study utilizes retrospective longitudinal analyses of a community-based study within Seattle, evaluating self-reported sleep (1993-2012) and cognitive performance (1997-2020) in aged adults. Main Outcomes and Measures: The main outcome is cognitive impairment as defined by sub-threshold performance on 2 of 4 neuropsychological batteries: Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, Trail Making Test, and Wechsler Adult Intelligent Scale (Revised). Sleep duration was defined through self-report of 'average nightly sleep duration over the last week' and assessed longitudinally. Median sleep duration, change in sleep duration (slope), variability in sleep duration (standard deviation, Sleep Variability), and sleep phenotype ("Short Sleep" median ≤7hrs.; "Medium Sleep" median = 7hrs; "Long Sleep" median ≥7hrs.). Results: A total of 822 individuals (mean age of 76.2 years [11.8]; 466 women [56.7%]; 216 APOE allele positive [26.3%]) were included in the study. Analysis using a Cox Proportional Hazard Regression model (concordance 0.70) showed that increased Sleep Variability (95% CI [1.27,3.86]) was significantly associated with the incidence of cognitive impairment. Further analysis using linear regression prediction analysis (R2=0.201, F (10, 168)=6.010, p=2.67E-07) showed that high Sleep Variability (ß=0.3491; p=0.048) was a significant predictor of cognitive impairment over a 10-year period. Conclusions and Relevance: High variability in longitudinal sleep duration was significantly associated with the incidence of cognitive impairment and predictive of decline in cognitive performance ten years later. These data highlight that instability in longitudinal sleep duration may contribute to age-related cognitive decline.

The effect of aquaporin-4 mis-localization on Aß deposition in mice.

The reduced clearance of amyloid-ß (Aß) is thought to contribute to the development of the pathology associated with Alzheimer's disease (AD), which is characterized by the deposition of Aß plaques. Previous studies have shown that Aß is cleared via the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is dependent upon the water channel aquaporin-4 (AQP4), localized at astrocytic endfeet. While prior studies have shown that both the loss and mislocalization of AQP4 slow Aß clearance and promote Aß plaque formation, the relative impact of the loss or mislocalization of AQP4 on Aß deposition has never been directly compared. In this study, we evaluated how the deposition of Aß plaques within the 5XFAD mouse line is impacted by either Aqp4 gene deletion or the loss of AQP4 localization in the α-syntrophin (Snta1) knockout mouse. We observed that both the absence (Aqp4 KO) and mislocalization (Snta1 KO) of AQP4 significantly increases the parenchymal Aß plaque and microvascular Aß deposition across the brain, when compared with 5XFAD littermate controls. Further, the mislocalization of AQP4 had a more pronounced impact on Aß plaque deposition than did global Aqp4 gene deletion, perhaps pointing to a key role that mislocalization of perivascular AQP4 plays in AD pathogenesis.

Optical Detection of Long Electron Spin Transport Lengths in a Monolayer Semiconductor.

Using a spatially resolved optical pump-probe experiment, we measure the lateral transport of spin-valley polarized electrons over very long distances (tens of micrometers) in a single WSe_{2} monolayer. By locally pumping the Fermi sea of 2D electrons to a high degree of spin-valley polarization (up to 75%) using circularly polarized light, the lateral diffusion of the electron polarization can be mapped out via the photoluminescence induced by a spatially separated and linearly polarized probe laser. Up to 25% spin-valley polarization is observed at pump-probe separations up to 20 µm. Characteristic spin-valley diffusion lengths of 18±3 µm are revealed at low temperatures. The dependence on temperature, pump helicity, pump intensity, and electron density highlight the key roles played by spin relaxation time and pumping efficiency on polarized electron transport in monolayer semiconductors possessing spin-valley locking.

Role of endothelium-pericyte signaling in capillary blood flow response to neuronal activity.

Local blood flow in the brain is tightly coupled to metabolic demands, a phenomenon termed functional hyperemia. Both capillaries and arterioles contribute to the hyperemic response to neuronal activity via different mechanisms and timescales. The nature and specific signaling involved in the hyperemic response of capillaries versus arterioles, and their temporal relationship are not fully defined. We determined the time-dependent changes in capillary flux and diameter versus arteriolar velocity and flow following whisker stimulation using optical microangiography (OMAG) and two-photon microscopy. We further characterized depth-resolved responses of individual capillaries versus capillary networks. We hypothesized that capillaries respond first to neuronal activation, and that they exhibit a coordinated response mediated via endothelial-derived epoxyeicosatrienoates (EETs) acting on pericytes. To visualize peri-capillary pericytes, we used Tie2-GFP/NG2-DsRed mice, and to determine the role of endothelial-derived EETs, we compared cerebrovascular responses to whisker stimulation between wild-type mice and mice with lower endothelial EETs (Tie2-hsEH). We found that capillaries respond immediately to neuronal activation in an orchestrated network-level manner, a response attenuated in Tie2-hsEH and inhibited by blocking EETs action on pericytes. These results demonstrate that capillaries are first responders during functional hyperemia, and that they exhibit a network-level response mediated via endothelial-derived EETs' action on peri-capillary pericytes.

Measurement of Conduction and Valence Bands g-Factors in a Transition Metal Dichalcogenide Monolayer.

The electron valley and spin degree of freedom in monolayer transition-metal dichalcogenides can be manipulated in optical and transport measurements performed in magnetic fields. The key parameter for determining the Zeeman splitting, namely, the separate contribution of the electron and hole g factor, is inaccessible in most measurements. Here we present an original method that gives access to the respective contribution of the conduction and valence band to the measured Zeeman splitting. It exploits the optical selection rules of exciton complexes, in particular the ones involving intervalley phonons, avoiding strong renormalization effects that compromise single particle g-factor determination in transport experiments. These studies yield a direct determination of single band g factors. We measure g_{c1}=0.86±0.1, g_{c2}=3.84±0.1 for the bottom (top) conduction bands and g_{v}=6.1±0.1 for the valence band of monolayer WSe_{2}. These measurements are helpful for quantitative interpretation of optical and transport measurements performed in magnetic fields. In addition, the measured g factors are valuable input parameters for optimizing band structure calculations of these 2D materials.

Measurement of the spin-forbidden dark excitons in MoS2 and MoSe2 monolayers.

Excitons with binding energies of a few hundreds of meV control the optical properties of transition metal dichalcogenide monolayers. Knowledge of the fine structure of these excitons is therefore essential to understand the optoelectronic properties of these 2D materials. Here we measure the exciton fine structure of MoS2 and MoSe2 monolayers encapsulated in boron nitride by magneto-photoluminescence spectroscopy in magnetic fields up to 30 T. The experiments performed in transverse magnetic field reveal a brightening of the spin-forbidden dark excitons in MoS2 monolayer: we find that the dark excitons appear at 14 meV below the bright ones. Measurements performed in tilted magnetic field provide a conceivable description of the neutral exciton fine structure. The experimental results are in agreement with a model taking into account the effect of the exchange interaction on both the bright and dark exciton states as well as the interaction with the magnetic field.

Revealing exciton masses and dielectric properties of monolayer semiconductors with high magnetic fields.

In semiconductor physics, many essential optoelectronic material parameters can be experimentally revealed via optical spectroscopy in sufficiently large magnetic fields. For monolayer transition-metal dichalcogenide semiconductors, this field scale is substantial-tens of teslas or more-due to heavy carrier masses and huge exciton binding energies. Here we report absorption spectroscopy of monolayer [Formula: see text], and [Formula: see text] in very high magnetic fields to 91 T. We follow the diamagnetic shifts and valley Zeeman splittings of not only the exciton's [Formula: see text] ground state but also its excited [Formula: see text] Rydberg states. This provides a direct experimental measure of the effective (reduced) exciton masses and dielectric properties. Exciton binding energies, exciton radii, and free-particle bandgaps are also determined. The measured exciton masses are heavier than theoretically predicted, especially for Mo-based monolayers. These results provide essential and quantitative parameters for the rational design of opto-electronic van der Waals heterostructures incorporating 2D semiconductors.

Control of the Exciton Radiative Lifetime in van der Waals Heterostructures.

Optical properties of atomically thin transition metal dichalcogenides are controlled by robust excitons characterized by a very large oscillator strengths. Encapsulation of monolayers such as MoSe_{2} in hexagonal boron nitride (hBN) yields narrow optical transitions approaching the homogenous exciton linewidth. We demonstrate that the exciton radiative rate in these van der Waals heterostructures can be tailored by a simple change of the hBN encapsulation layer thickness as a consequence of the Purcell effect. The time-resolved photoluminescence measurements show that the neutral exciton spontaneous emission time can be tuned by one order of magnitude depending on the thickness of the surrounding hBN layers. The inhibition of the radiative recombination can yield spontaneous emission time up to 10 ps. These results are in very good agreement with the calculated recombination rate in the weak exciton-photon coupling regime. The analysis shows that we are also able to observe a sizable enhancement of the exciton radiative decay rate. Understanding the role of these electrodynamical effects allows us to elucidate the complex dynamics of relaxation and recombination for both neutral and charged excitons.

Characteristics of Frequent Users of Emergency Medical Services in Singapore.

OBJECTIVES: This study aims to describe frequent users of Emergency Medical Services (EMS) conveyed to a Singapore tertiary hospital, focusing on a comparison between younger users (age <65) and older users in diagnoses and admission rates. METHODS: All patients conveyed by EMS to a tertiary hospital 4 times or more over a 1-year period in 2015 had their EMS ambulance charts and Emergency Department (ED) electronic records retrospectively analyzed (n = 243), with admission the primary outcome. RESULTS: The 243 frequent users were analyzed with a combined total of 1,705 visits, out of a total of 10,183 patients with 12,839 visits conveyed by EMS to Singapore General Hospital (SGH) in 2015. Younger frequent users (<65 years age) were found to be predominantly male (79.6%, p = 0.001) and were on average responsible for more visits than elderly frequent users (8.6 vs. 5.7, p = 0.004). Medical co-morbidities were significantly more prevalent in older users. Younger frequent users were more likely to be smokers (60.2% vs. 22.3%), heavy drinkers (51.3% vs. 8.5%), substance abusers (12.4% vs. 0.8%), and bad debtors (49.6% vs. 20.0%, p < 0.001). A larger proportion presented with altered mental states (11.7% vs. 5.4%, p < 0.001) and alcohol related diagnoses (34.7% vs. 5.3%, p < 0.001). Many were picked up from public areas (45.5% vs. 19.6%, p < 0.001), and had lower acuity triage scores at both EMS (p < 0.001) and ED (p = 0.001). They had lower admission rates (40.5% vs. 78.7%, p < 0.001) and shorter length of stay (4.3 vs. 5.9 days, p < 0.001). Univariable and multivariable analysis showed alcohol related diagnoses, history of alcohol abuse and lower triage scores were less likely to require admissions. CONCLUSION: Frequent EMS users consume a disproportionate amount of healthcare resources. Two broad subgroups of patients were identified: younger patients with social issues and older patients with multiple medical conditions. EMS usage by older patients was significantly associated with higher rates of admission.

Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology.

The deposition of misfolded proteins, including amyloid beta plaques and neurofibrillary tangles is the histopathological hallmark of Alzheimer's disease (AD). The glymphatic system, a brain-wide network of perivascular pathways that supports interstitial solute clearance, is dependent upon expression of the perivascular astroglial water channel aquaporin-4 (AQP4). Impairment of glymphatic function in the aging rodent brain is associated with reduced perivascular AQP4 localization, and in human subjects, reduced perivascular AQP4 localization is associated with AD diagnosis and pathology. Using human transcriptomic data, we demonstrate that expression of perivascular astroglial gene products dystroglycan (DAG1), dystrobrevin (DTNA) and alpha-syntrophin (SNTA1), are associated with dementia status and phosphorylated tau (P-tau) levels in temporal cortex. Gene correlation analysis reveals altered expression of a cluster of potential astrocytic endfoot components in human subjects with dementia, with increased expression associated with temporal cortical P-tau levels. The association between perivascular astroglial gene products, including DTNA and megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) with AD status was confirmed in a second human transcriptomic dataset and in human autopsy tissue by Western blot. This suggests changes in the astroglial endfoot domain may underlie vulnerability to protein aggregation in AD.

Enabling valley selective exciton scattering in monolayer WSe2 through upconversion.

Excitons, Coulomb bound electron-hole pairs, are composite bosons and their interactions in traditional semiconductors lead to condensation and light amplification. The much stronger Coulomb interaction in transition metal dichalcogenides such as WSe2 monolayers combined with the presence of the valley degree of freedom is expected to provide new opportunities for controlling excitonic effects. But so far the bosonic character of exciton scattering processes remains largely unexplored in these two-dimensional materials. Here we show that scattering between B-excitons and A-excitons preferably happens within the same valley in momentum space. This leads to power dependent, negative polarization of the hot B-exciton emission. We use a selective upconversion technique for efficient generation of B-excitons in the presence of resonantly excited A-excitons at lower energy; we also observe the excited A-excitons state 2s. Detuning of the continuous wave, low-power laser excitation outside the A-exciton resonance (with a full width at half maximum of 4 meV) results in vanishing upconversion signal.

Gate-Controlled Spin-Valley Locking of Resident Carriers in WSe_{2} Monolayers.

Using time-resolved Kerr rotation, we measure the spin-valley dynamics of resident electrons and holes in single charge-tunable monolayers of the archetypal transition-metal dichalcogenide (TMD) semiconductor WSe_{2}. In the n-type regime, we observe long (∼130 ns) polarization relaxation of electrons that is sensitive to in-plane magnetic fields B_{y}, indicating spin relaxation. In marked contrast, extraordinarily long (∼2 µs) polarization relaxation of holes is revealed in the p-type regime, which is unaffected by B_{y}, directly confirming long-standing expectations of strong spin-valley locking of holes in the valence band of monolayer TMDs. Supported by continuous-wave Kerr spectroscopy and Hanle measurements, these studies provide a unified picture of carrier polarization dynamics in monolayer TMDs, which can guide design principles for future valleytronic devices.

In-Plane Propagation of Light in Transition Metal Dichalcogenide Monolayers: Optical Selection Rules.

The optical selection rules for interband transitions in WSe_{2}, WS_{2}, and MoSe_{2} transition metal dichalcogenide monolayers are investigated by polarization-resolved photoluminescence experiments with a signal collection from the sample edge. These measurements reveal a strong polarization dependence of the emission lines. We see clear signatures of the emitted light with the electric field oriented perpendicular to the monolayer plane, corresponding to an interband optical transition forbidden at normal incidence used in standard optical spectroscopy measurements. The experimental results are in agreement with the optical selection rules deduced from group theory analysis, highlighting the key role played by the different symmetries of the conduction and valence bands split by the spin-orbit interaction. These studies yield a direct determination of the bright-dark exciton splitting, for which we measure 40±1 meV and 55±2 meV in WSe_{2} and WS_{2} monolayer, respectively.

Control of Exciton Valley Coherence in Transition Metal Dichalcogenide Monolayers.

The direct gap interband transitions in transition metal dichalcogenide monolayers are governed by chiral optical selection rules. Determined by laser helicity, optical transitions in either the K^{+} or K^{-} valley in momentum space are induced. Linearly polarized laser excitation prepares a coherent superposition of valley states. Here, we demonstrate the control of the exciton valley coherence in monolayer WSe_{2} by tuning the applied magnetic field perpendicular to the monolayer plane. We show rotation of this coherent superposition of valley states by angles as large as 30° in applied fields up to 9 T. This exciton valley coherence control on the ps time scale could be an important step towards complete control of qubits based on the valley degree of freedom.

Double resonant Raman scattering and valley coherence generation in monolayer WSe_{2}.

The electronic states at the direct band gap of monolayer transition metal dichalcogenides such as WSe_{2} at the K^{+} and K^{-} valleys are related by time reversal and may be viewed as pseudospins. The corresponding optical interband transitions are governed by robust excitons. Excitation with linearly polarized light yields the coherent superposition of exciton pseudospin states, referred to as coherent valley states. Here, we uncover how and why valley coherence can be generated efficiently. In double resonant Raman spectroscopy, we show that the optically generated 2s exciton state differs from the 1s state by exactly the energy of the combination of several prominent phonons. Superimposed on the exciton photoluminescence (PL), we observe the double resonant Raman signal. This spectrally narrow peak shifts with the excitation laser energy as incoming photons match the 2s and outgoing photons the 1s exciton transition. The multiphonon resonance has important consequences: following linearly polarized excitation of the 2s exciton, a superposition of valley states is efficiently transferred from the 2s to 1s state. This explains the high degree of valley coherence measured for the 1s exciton PL.