Symmetry Breaking and Spin-Orbit Coupling for Individual Vacancy-Induced In-Gap States in MoS2 Monolayers.

Spins confined to point defects in atomically thin semiconductors constitute well-defined atomic-scale quantum systems that are being explored as single-photon emitters and spin qubits. Here, we investigate the in-gap electronic structure of individual sulfur vacancies in molybdenum disulfide (MoS2) monolayers using resonant tunneling scanning probe spectroscopy in the Coulomb blockade regime. Spectroscopic mapping of defect wave functions reveals an interplay of local symmetry breaking by a charge-state-dependent Jahn-Teller lattice distortion that, when combined with strong (≃100 meV) spin-orbit coupling, leads to a locking of an unpaired spin-1/2 magnetic moment to the lattice at low temperature, susceptible to lattice strain. Our results provide new insights into the spin and electronic structure of vacancy-induced in-gap states toward their application as electrically and optically addressable quantum systems.

Pilot Implementation of a Nutrition-Focused Community-Health-Worker Intervention among Formerly Chronically Homeless Adults in Permanent Supportive Housing.

Food insecurity is a known health equity threat for formerly chronically homeless populations even after they transition into permanent housing. This project utilized a human-centered design methodology to plan and implement a nutrition-focused community-health-worker (CHW) intervention in permanent supportive housing (PSH). The project aimed to increase access to healthy foods, improve nutritional literacy, healthy cooking/eating practices, and build community/social connectedness among 140 PSH residents. Validated food-security screening conducted by CHWs identified low or very low food security among 64% of 83 residents who completed the baseline survey, which is similar to rates found in a previous study among formerly homeless populations placed in PSH. Major themes identified through an analysis of resident feedback include (1) lack of needed kitchenware/appliances for food preparation, (2) knowledge gaps on how to purchase and prepare healthier food, (3) positive perceptions of healthy food options, (4) expanded preferences for healthy, easy-to-prepare foods, (5) regaining cooking skills lost during homelessness, (6) positive experiences participating in group activities, (7) community re-entry, and (8) resident ownership. Preliminary findings suggest the use of a human-centered design methodology for planning and implementing this multi-level CHW intervention helped reduce food insecurity, engaged participants in learning and adopting healthy and safe cooking and eating practices, and fostered social connectedness and feelings of community among formerly chronically homeless PSH residents.

Protocol for measuring protein synthesis in specific cell types in the mouse brain using in vivo non-canonical amino acid tagging.

The fluorescent non-canonical amino acid tagging (FUNCAT) technique has been used to visualize newly synthesized proteins in cell lines and tissues. Here, we present a protocol for measuring protein synthesis in specific cell types in the mouse brain using in vivo FUNCAT. We describe steps for metabolically labeling newly synthesized proteins with azidohomoalanine, which introduces an azide group into the polypeptide. We then detail procedures for binding a fluorophore-conjugated alkyne to the azide group to allow its visualization. For complete details on the use and execution of this protocol, please refer to tom Dieck et al. (2012)1 and Hooshmandi et al. (2023).2.

4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling.

Activation of the mechanistic target of rapamycin complex 1 (mTORC1) contributes to the development of chronic pain. However, the specific mechanisms by which mTORC1 causes hypersensitivity remain elusive. The eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is a key mTORC1 downstream effector that represses translation initiation. Here, we show that nociceptor-specific deletion of 4E-BP1, mimicking activation of mTORC1-dependent translation, is sufficient to cause mechanical hypersensitivity. Using translating ribosome affinity purification in nociceptors lacking 4E-BP1, we identified a pronounced translational up-regulation of tripartite motif-containing protein 32 (TRIM32), an E3 ubiquitin ligase that promotes interferon signaling. Down-regulation of TRIM32 in nociceptors or blocking type I interferon signaling reversed the mechanical hypersensitivity in mice lacking 4E-BP1. Furthermore, nociceptor-specific ablation of TRIM32 alleviated mechanical hypersensitivity caused by tissue inflammation. These results show that mTORC1 in nociceptors promotes hypersensitivity via 4E-BP1-dependent up-regulation of TRIM32/interferon signaling and identify TRIM32 as a therapeutic target in inflammatory pain.

Topical Spironolactone in the Treatment of Ocular Graft-Versus-Host Disease.

INTRODUCTION: This two-part study aimed to investigate the therapeutic potential of topical spironolactone in ocular graft-versus-host disease (oGVHD). While off-label use of topical spironolactone has been described in dry eye, its efficacy in managing signs and symptoms of oGVHD remains unstudied. Preclinically, we tested the hypothesis that spironolactone induces corneal lipid synthesis in a mouse model. Clinically, we assessed patient response to spironolactone with a retrospective observational design. METHODS: Both immortalized and primary human corneal epithelial cells were stained with oil red O after 9 days of treatment with spironolactone. C57BL/6 mice were dosed thrice daily with one drop in each eye for 18 days. Corneal tissue was stained with oil red O and BODIPY™. Twenty eyes with oGVHD, as defined by the International Chronic oGVHD Consensus Group, were studied. Corneal fluorescein staining, lid margin vascularity, meibomian gland obstruction, meibum turbidity, zone A posterior lid margin vascularity, and oGVHD diagnostic criteria severity grading were compared in a pre-post study. Follow-up times ranged from 7 to 21 weeks, with a median time of 12 weeks. Statistical analysis was done with STATA 17 by fitting data to a non-parametric model. RESULTS:  In vitro results showed an increased number and density of oil red O staining granules in the treatment group versus control in both primary and immortalized human corneal epithelium. In vivo, results showed translation to the mouse model with increased corneal epithelial BODIPY™ signal compared to untreated control. oGVHD patients had improved lid margin vascularity (p = 0.046), corneal fluorescein staining (p = 0.021), and International oGVHD Consensus Group severity scores (p = 0.011) after treatment with topical spironolactone. Minimal adverse effects were noted, the most common being mild stinging lasting less than a minute after instillation. CONCLUSION: The improved severity scores, lid margin inflammation, and corneal fluorescein staining after weeks of treatment support the rationale that topical spironolactone may benefit oGVHD. The observed lipid production by the corneal epithelium is thought to contribute to this protective effect against ocular surface erosive disease in oGVHD. A mineralocorticoid receptor antagonist, spironolactone may offer therapeutic benefits in oGVHD while avoiding undesirable side effects of topical or systemic glucocorticoids.

Paracentral Bitemporal Hemianopsia and Acquired Supranuclear Ocular Motor Paresis Following Cardiac Surgery.

Acquired supranuclear ocular motor paresis (ASOMP) is a rare complication following cardiac surgery, characterized by limited voluntary eye motility. The exact cause and development of ASOMP after cardiac surgery remain unclear. We report a case of ASOMP with paracentral bitemporal hemianopsia with optic atrophy after cardiac surgery, which, to our knowledge, is novel. The patient demonstrated bilateral ophthalmoplegia, with gradual improvement in voluntary smooth pursuit but persistent impairment in saccadic eye movements. Interestingly, the patient showed improved proprioceptive-driven pursuit of their own hand compared to pursuit or saccades following an examiner's hand. The visual field examination revealed a bilateral paracentral temporal hemianopic field defect. The underlying mechanisms of ASOMP and potential chiasmal ischemia in this case remain unknown. Clinicians should be aware of the possibility of ASOMP following cardiac surgery, with potential slow improvement over time.

Topical Spironolactone in the Treatment of Evaporative Dry Eye Disease.

Meibomian gland dysfunction (MGD) is associated with evaporative dry eye syndrome, which is characterized by a reduction in meibum secretion and tear film instability. Present treatments provide only temporary relief, thereby necessitating the exploration of novel therapeutic strategies for chronic treatment. This study aims to evaluate topical spironolactone, a medication with anti-mineralocorticoid, anti-androgenic, and anti-inflammatory properties, in treating dry eye. A retrospective observational study was performed on the medical records of 102 patients diagnosed with dry eye disease. These patients were categorized into two groups based on their Schirmer's tear test scores. Various clinical indicators, including subjective global assessment scores, visual acuity, keratitis, conjunctival staining scores, and lid margin health, were evaluated prior to and following treatment with topical spironolactone eye drops. The group with higher Schirmer's scores exhibited improvement in self-reported global assessment scores after treatment. Significant improvements were also observed in keratitis and conjunctival staining scores, visual acuity, and lid margin inflammation. Similarly, the group with lower Schirmer's scores demonstrated improvements in self-reported global assessment scores and visual acuity after treatment. Topical spironolactone may improve tear film quality and address the inflammatory processes associated with MGD and evaporative dry eye. Moreover, the topical administration of spironolactone in an ocular vehicle appears to be well tolerated and may mitigate the risk of systemic adverse effects. Further studies are warranted to explore the long-term effects of topical spironolactone in the treatment of evaporative dry eye disease.

Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome.

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.

Demographic and Socioeconomic Factors in Prospective Retina-Focused Clinical Trial Screening and Enrollment.

Historically marginalized populations are disproportionately affected by many diseases that commonly affect the retina, yet they have been traditionally underrepresented in prospective clinical trials. This study explores whether this disparity affects the clinical trial enrollment process in the retina field and aims to inform future trial recruitment and enrollment. Age, gender, race, ethnicity, preferred language, insurance status, social security number (SSN) status, and median household income (estimated using street address and zip code) for patients referred to at least one prospective, retina-focused clinical trial at a large, urban, retina-based practice were retrospectively extracted using electronic medical records. Data were collected for the 12-month period from 1 January 2022, through 31 December 2022. Recruitment status was categorized as Enrolled, Declined, Communication (defined as patients who were not contacted, were contacted with no response, were waiting for a follow-up, or were scheduled for screening following a clinical trial referral.), and Did Not Qualify (DNQ). Univariable and multivariable analyses were used to determine significant relationships between the Enrolled and Declined groups. Among the 1477 patients, the mean age was 68.5 years old, 647 (43.9%) were male, 900 (61.7%) were White, 139 (9.5%) were Black, and 275 (18.7%) were Hispanic. The distribution of recruitment status was: 635 (43.0%) Enrolled, 232 (15.7%) Declined, 290 (19.6%) Communication, and 320 (21.7%) DNQ. In comparing socioeconomic factors between the Enrolled and Declined groups, significant odds ratios were observed for age (p < 0.02, odds ratio (OR) = 0.98, 95% confidence interval (CI) [0.97, 1.00]), and between patients who preferred English versus Spanish (p = 0.004, OR = 0.35, 95% CI [0.17, 0.72]. Significant differences between the Enrolled and Declined groups were also observed for age (p < 0.05), ethnicity (p = 0.01), preferred language (p < 0.05), insurance status (p = 0.001), and SSN status (p < 0.001). These factors may contribute to patient participation in retina-focused clinical trials. An awareness of these demographic and socioeconomic disparities may be valuable to consider when attempting to make clinical trial enrollment an equitable process for all patients, and strategies may be useful to help address these challenges.

Liquid-Metal-Printed Ultrathin Oxides for Atomically Smooth 2D Material Heterostructures.

Two-dimensional (2D) semiconductors are promising channel materials for continued downscaling of complementary metal-oxide-semiconductor (CMOS) logic circuits. However, their full potential continues to be limited by a lack of scalable high-k dielectrics that can achieve atomically smooth interfaces, small equivalent oxide thicknesses (EOTs), excellent gate control, and low leakage currents. Here, large-area liquid-metal-printed ultrathin Ga2O3 dielectrics for 2D electronics and optoelectronics are reported. The atomically smooth Ga2O3/WS2 interfaces enabled by the conformal nature of liquid metal printing are directly visualized. Atomic layer deposition compatibility with high-k Ga2O3/HfO2 top-gate dielectric stacks on a chemical-vapor-deposition-grown monolayer WS2 is demonstrated, achieving EOTs of ∼1 nm and subthreshold swings down to 84.9 mV/dec. Gate leakage currents are well within requirements for ultrascaled low-power logic circuits. These results show that liquid-metal-printed oxides can bridge a crucial gap in dielectric integration of 2D materials for next-generation nanoelectronics.

Computed tomography assessment of hypodontia and crown size in hemifacial microsomia.

OBJECTIVE: Our aims were to assess the prevalence of hypodontia in unilateral hemifacial microsomia (HFM), and to compare tooth (crown) size between affected and unaffected sides. DESIGN: In a retrospective cross-sectional study of South Australians, computed tomography (CT) scans were used to assess hypodontia and crown size (mesiodistal length, buccolingual width and crown height). The inclusion criteria were the absence of other congenital anomalies and the availability of CT scans. The exclusion criteria were the lack of extraction history or reproducible landmarks for morphometric assessment. The final sample comprised 41 participants in both dentitions, including 32 children and 9 adults (median age 13.9 years, range 0.4 - 47.6 years; 19 males and 22 females). Hypodontia was assessed in all participants, and the permanent crown size in 30 (73.2%) participants. Linear mixed-effects models were performed to determine if crown size was significantly different between the two sides, controlling for sex, HFM severity, and tooth and jaw type. RESULTS: Hypodontia occurred in none of the participants in the primary dentition, but in 6/30 (20%) participants in the permanent dentition (3/30 each on the affected and unaffected sides). There was no significant difference in the mean crown dimensions between the two sides, but the crown size was larger in males (p < 0.05), except for mesiodistal length, and became progressively smaller with increased HFM severity (p < 0.05). CONCLUSIONS: Hypodontia spared the primary dentition but featured prominently in the permanent dentition. The permanent crown dimensions were unaltered between the two sides.

Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1.

MAPK interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterized substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that, whereas deletion of Mnk1/2 (Mnk double knockout) impairs synaptic plasticity and memory in mice, ablation of phospho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between the Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 because Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk double knockout mice. Knockdown of Syngap1 reversed memory deficits in Mnk double knockout mice and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.

Parvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice.

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here, we show that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a proapoptotic protein, mitochondrial anchored protein ligase (MAPL), selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood.

Miniaturizing color-sensitive photodetectors via hybrid nanoantennas toward submicrometer dimensions.

Digital camera sensors use color filters on photodiodes to achieve color selectivity. As the color filters and photosensitive silicon layers are separate elements, these sensors suffer from optical cross-talk, which sets limits to the minimum pixel size. Here, we report hybrid silicon-aluminum nanostructures in the extreme limit of zero distance between color filters and sensors. This design could essentially achieve submicrometer pixel dimensions and minimize the optical cross-talk arising from tilt illuminations. The designed hybrid silicon-aluminum nanostructure has dual functionalities. Crucially, it supports a hybrid Mie-plasmon resonance of magnetic dipole to achieve color-selective light absorption, generating electron hole pairs. Simultaneously, the silicon-aluminum interface forms a Schottky barrier for charge separation and photodetection. This design potentially replaces the traditional dye-based filters for camera sensors at ultrahigh pixel densities with advanced functionalities in sensing polarization and directionality, and UV selectivity via interband plasmons of silicon.

Microglia-mediated degradation of perineuronal nets promotes pain.

Activation of microglia in the spinal cord dorsal horn after peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that after peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.

mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation.

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long-lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.

Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain.

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.

The landscape of antibiotic usage among COVID-19 patients in the early phase of pandemic: a Malaysian national perspective.

BACKGROUND: During the early phase of the COVID-19 pandemic, antibiotic usage among COVID-19 patients was noted to be high in many countries. The objective of this study was to determine the prevalence of antibiotic usage and factors affecting antibiotic usage among COVID-19 patients during the early phase of the COVID-19 pandemic in Malaysia. METHODS: This was a cross-sectional study that involved reviewing medical records of COVID-19 Malaysian patients aged 12 and above who were diagnosed with COVID-19 and received treatment in 18 COVID-19 hospitals from February to April 2020. A minimum sample of 375 patients was required. A binary logistic regression analysis was performed to determine factors associated with antibiotic usage. Variables with p < 0.05 were considered statistically significant. RESULTS: A total of 4043 cases were included for analysis. The majority of the patients (87.6%) were non-smokers, male (65.0%), and had at least one comorbidity (37.0%). The median age was 35 years (IQR: 38). The prevalence of antibiotic usage was 17.1%, with 5.5% of them being prescribed with two or more types of antibiotics. The most frequent antibiotics prescribed were amoxicillin/clavulanic acid (37.8%), ceftriaxone (12.3%), piperacillin/tazobactam (13.3%), azithromycin (8.3%), and meropenem (7.0%). Male patients (adjusted OR 1.53), who had a comorbidity (adjusted OR 1.36), associated with more severe stage of COVID-19 (adjusted OR 6.50-37.06), out-of-normal range inflammatory blood parameters for neutrophils, lymphocytes, and C-reactive protein (adjusted OR 2.04-3.93), corticosteroid use (adjusted OR 3.05), and ICU/HDU admission (adjusted OR 2.73) had higher odds of antibiotic use. CONCLUSIONS: The prevalence of antibiotic usage in the early phase of the COVID-19 pandemic was low, with amoxicillin/clavulanic acid as the most common antibiotic of choice. The study showed that clinicians rationalized antibiotic usage based on clinical assessment, supported by relevant laboratory parameters.

Gate-Defined Quantum Confinement in CVD 2D WS2.

Temperature-dependent transport measurements are performed on the same set of chemical vapor deposition (CVD)-grown WS2 single- and bilayer devices before and after atomic layer deposition (ALD) of HfO2 . This isolates the influence of HfO2 deposition on low-temperature carrier transport and shows that carrier mobility is not charge impurity limited as commonly thought, but due to another important but commonly overlooked factor: interface roughness. This finding is corroborated by circular dichroic photoluminescence spectroscopy, X-ray photoemission spectroscopy, cross-sectional scanning transmission electron microscopy, carrier-transport modeling, and density functional modeling. Finally, electrostatic gate-defined quantum confinement is demonstrated using a scalable approach of large-area CVD-grown bilayer WS2 and ALD-grown HfO2 . The high dielectric constant and low leakage current enabled by HfO2 allows an estimated quantum dot size as small as 58 nm. The ability to lithographically define increasingly smaller devices is especially important for transition metal dichalcogenides due to their large effective masses, and should pave the way toward their use in quantum information processing applications.