Large oscillatory thermal hall effect in kagome metals.

The thermal Hall effect recently provided intriguing probes to the ground state of exotic quantum matters. These observations of transverse thermal Hall signals lead to the debate on the fermionic versus bosonic origins of these phenomena. The recent report of quantum oscillations (QOs) in Kitaev spin liquid points to a possible resolution. The Landau level quantization would most likely capture only the fermionic thermal transport effect. However, the QOs in the thermal Hall effect are generally hard to detect. In this work, we report the observation of a large oscillatory thermal Hall effect of correlated Kagome metals. We detect a 180-degree phase change of the oscillation and demonstrate the phase flip as an essential feature for QOs in the thermal transport properties. More importantly, the QOs in the thermal Hall channel are more profound than those in the electrical Hall channel, which strongly violates the Wiedemann-Franz (WF) law for QOs. This result presents the oscillatory thermal Hall effect as a powerful probe to the correlated quantum materials.

TNIK Inhibition Sensitizes TNIK-Overexpressing Lung Squamous Cell Carcinoma to Radiotherapy.

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited because of dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for patients with LSCC. Moreover, other options for chemotherapy-ineligible patients are limited. As such, there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. In this study, we investigated inhibiting TRAF2- and NCK-interacting protein kinase (TNIK), which is amplified in 40% of patients with LSCC, as a strategy to sensitize LSCC tumors to chemotherapy and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in patients with LSCC with high TNIK expression.

Exergaming and cognitive functions in people with mild cognitive impairment and dementia: a meta-analysis.

Exergaming is a combination of exercise and gaming. Evidence shows an association between exercise and cognition in older people. However, previous studies showed inconsistent results on the cognitive benefits of exergaming in people with cognitive impairment. Therefore, this study aims to examine the effect of exergaming intervention on cognitive functions in people with MCI or dementia. A systematic literature search was conducted via OVID databases. Randomized controlled trials (RCTs) examined the effect of an exergaming intervention on cognitive functions in people with MCI or dementia were included. Subgroup analyses were conducted according to the type of intervention and training duration. Twenty RCTs with 1152 participants were identified, including 14 trials for MCI and 6 trials for dementia. In people with MCI, 13 studies used virtual-reality (VR)-based exergaming. Those who received VR-based exergaming showed significantly better global cognitive function [SMD (95%CI) = 0.67 (0.23-1.11)], learning and memory [immediate recall test: 0.79 (0.31-1.27); delayed recall test: 0.75 (0.20-1.31)], working memory [5.83 (2.27-9.39)], verbal fluency [0.58 (0.12-1.03)], and faster in executive function than the controls. For people with dementia, all studies used video-based exergaming intervention. Participants with exergaming intervention showed significantly better global cognitive function than the controls [0.38 (0.10-0.67)]. Subgroup analyses showed that longer training duration generated larger effects. The findings suggest that exergaming impacts cognitive functions in people with MCI and dementia. Cognitive benefits are demonstrated for those with a longer training duration. With technological advancement, VR-based exergaming attracts the attention of people with MCI and performs well in improving cognitive functions.

TNIK inhibition sensitizes TNIK-overexpressing lung squamous cell carcinoma to radiotherapy.

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited due to dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for LSCC patients. Moreover, other options for chemotherapy-ineligible patients are also limited. As such there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. Here, we investigated inhibiting TRAF2 and NCK-interacting protein kinase (TNIK), which is amplified in 40% of LSCC patients, as a strategy to sensitize LSCC tumors to chemo- and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in LSCC patients with high TNIK expression.

Quantum oscillations evidence for topological bands in kagome metal ScV6Sn6.

Metals with kagome lattice provide bulk materials to host both the flat-band and Dirac electronic dispersions. A new family of kagome metals is recently discovered inAV6Sn6. The Dirac electronic structures of this material needs more experimental evidence to confirm. In the manuscript, we investigate this problem by resolving the quantum oscillations in both electrical transport and magnetization in ScV6Sn6. The revealed orbits are consistent with the electronic band structure models. Furthermore, the Berry phase of a dominating orbit is revealed to be aroundπ, providing direct evidence for the topological band structure, which is consistent with calculations. Our results demonstrate a rich physics and shed light on the correlated topological ground state of this kagome metal.

Computerized cognitive training for memory functions in mild cognitive impairment or dementia: a systematic review and meta-analysis.

Dementia is a common medical condition in the ageing population, and cognitive intervention is a non-pharmacologic strategy to improve cognitive functions. This meta-analysis evaluated the benefits of computerized cognitive training (CCT) on memory functions in individuals with MCI or dementia. The study was registered prospectively with PROSPERO under CRD42022363715 and received no funding. The search was conducted on MEDLINE, Embase, and PsycINFO on Sept 19, 2022, and Google Scholar on May 9, 2023, to identify randomized controlled trials that examined the effects of CCT on memory outcomes in individuals with MCI or dementia. Mean differences and standard deviations of neuropsychological assessment scores were extracted to derive standardized mean differences. Our search identified 10,678 studies, of which 35 studies were included. Among 1489 participants with MCI, CCT showed improvements in verbal memory (SMD (95%CI) = 0.55 (0.35-0.74)), visual memory (0.36 (0.12-0.60)), and working memory (0.37 (0.10-0.64)). Supervised CCT showed improvements in verbal memory (0.72 (0.45-0.98)), visual memory (0.51 (0.22-0.79)), and working memory (0.33 (0.01-0.66)). Unsupervised CCT showed improvement in verbal memory (0.21 (0.04-0.38)) only. Among 371 participants with dementia, CCT showed improvement in verbal memory (0.64 (0.02-1.27)) only. Inconsistency due to heterogeneity (as indicated by I2 values) is observed, which reduces our confidence in MCI outcomes to a moderate level and dementia outcomes to a low level. The results suggest that CCT is efficacious on various memory domains in individuals with MCI. Although the supervised approach showed greater effects, the unsupervised approach can improve verbal memory while allowing users to receive CCT at home without engaging as many healthcare resources.

Assessing care quality in general practice: a qualitative study of GPs in Ireland.

BACKGROUND: It is estimated that each year in Ireland, approximately 29 million consultations occur in general practice with a patient satisfaction level of 90%. To date, research has been lacking on how GPs assess the quality of care. AIM: To examine how GPs assess care quality during routine practice with respect to the following pillars of quality improvement: effectiveness, safety, timeliness, equity, efficiency, sustainability, and person-centredness. DESIGN & SETTING: Qualitative study of GPs in Ireland. METHOD: In this qualitative study, semi-structured interviews were conducted with 10 GPs who were recruited via a snowball sampling strategy. Interviews were recorded, transcribed, and analysed. Quality 'assessment points' were identified and themes were synthesised to produce a theoretical framework. RESULTS: Five female and five male GPs practising in a variety of settings were interviewed. The age range was 33-68 years. In total, 122 assessment points emerged from the data and were collated into the following eight themes: the GP as a professional person factors; the patient and coproduction factors; care team factors; direct care factors; outcome factors; practice environment and organisation factors; external environment factors; and improvement approach factors. CONCLUSION: This is the first study to examine how GPs in Ireland assess care quality as a holistic construct during daily care. The qualitative approach applied yielded rich and diverse insights into the many assessment points that GPs use to inform their approach and actions as clinicians, managers, collaborators, and leaders to maximise patient care. The theory produced is likely useful and applicable for practising GPs, healthcare administration, policymakers, and funders in planning and executing changes for quality improvement.

TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment.

PURPOSE: Despite well-informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure-function and clinical impact of TP53 mutations in mCSPC. PATIENTS AND METHODS: We performed an international retrospective review of men with mCSPC who underwent next-generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression-free survival (rPFS) and overall survival (OS) evaluated with Kaplan-Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR-246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t-tests and ANOVA. RESULTS: Dominant-negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI]: 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI: 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner. CONCLUSIONS: DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.

Evaluation of an Isothermal Amplification HPV Assay on Self-Collected Vaginal Samples as Compared to Clinician-Collected Cervical Samples.

This study aimed to evaluate the concordance of HPV results between the SentisTM HPV assay (Sentis) (BGI Group, Shenzhen, China), an isothermal amplification-based HPV assay, on self-collected and clinician-collected samples and the agreement of Sentis on self-collected samples with the BD OnclarityTM HPV assay (Onclarity) (Becton, Dickinson, and Company, Franklin Lakes, New Jersey, USA), a PCR-based HPV assay, on clinician-collected samples. This was a prospective study of 104 women attending the colposcopy clinic for abnormal smears. After informed consent, participants self-collected vaginal samples before having clinician-collected cervical samples. Self-collected samples underwent HPV testing with Sentis (Self-Sentis HPV) and clinician-collected samples were tested with Sentis (Clinician-Sentis HPV) and Onclarity (Clinician-Onclarity), which was used as a reference standard. The concordance was assessed using Cohen's kappa. The prevalence of HPV and the acceptability of self-sampling were also evaluated. The concordance rate between Self-Sentis HPV and Clinician-Sentis HPV was 89.8% with a kappa of 0.769. The concordance rate between Self-Sentis HPV and Clinician-Onclarity was 84.4% with a kappa of 0.643. The prevalence of HPV was 26.0% on Clinician-Onclarity, 29.3% on Clinician-Sentis HPV, and 35.6% on Self-Sentis HPV. Overall, 65% of participants would undergo self-sampling again. This was attributed to mainly not feeling embarrassed (68%) and being convenient (58%). Our study showed a substantial agreement between Self-Sentis HPV with Clinician-Sentis HPV and Clinician-Onclarity. Self-sampling was also shown to be a generally well-accepted method of screening.

Sacral Chordoma Presenting as Back Pain in the Chiropractic Clinic: A Case Report.

Cases of lumbar and gluteal pain are commonly encountered in chiropractic clinics, with a broad differential diagnosis primarily centered on musculoskeletal conditions. This report presents the second documented case of sacral chordoma diagnosed at a chiropractic clinic and emphasizes the importance of considering alternative diagnoses and interdisciplinary collaboration in patient care. A 42-year-old man presented to a chiropractic clinic with complaints of lumbar and gluteal pain. The initial conservative management based on a presumptive musculoskeletal diagnosis was ineffective. Suspicion of an alternative etiology prompted a referral for imaging, which revealed a sacral chordoma. An interdisciplinary collaboration involving orthopedic surgeons, oncologists, radiologists, and other healthcare professionals was initiated to optimize the treatment outcomes of this rare and aggressive tumor. This case report underscores the importance of maintaining a high index of suspicion in cases of musculoskeletal presentations in chiropractic clinics and the critical role of advanced imaging in establishing a definitive diagnosis. Interdisciplinary collaboration is essential for managing complex conditions such as sacral chordomas, ensuring the delivery of the highest quality of care, and optimizing patient outcomes. Chiropractors play a crucial role in identifying, referring, and contributing to the management of patients with complex presentations as part of a comprehensive multidisciplinary treatment plan.

Griseofulvin Radiosensitizes Non-Small Cell Lung Cancer Cells and Activates cGAS.

Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non-small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC.

Light induction of somatic embryogenesis in Arabidopsis is regulated by PHYTOCHROME E.

The requirement of light on somatic embryogenesis (SE) has been documented in many species; however, no mechanism of action has been elucidated. Using Arabidopsis SE as a model, the effect of red light (660 nm) during the induction phase corresponding to the formation of the embryogenic tissue was examined. Analyses of several phytochrome mutants revealed that red light signaling, conducive to SE, was mediated by PHYTOCHROME E (PHYE). Both phyE and darkness were sufficient to repress the formation of somatic embryos and reduced the expression of CONSTITUTIVE PHOTOMORPHIC DWARF 3 (CPD3), a rate limiting step in brassinosteroid (BR) biosynthesis, as well as AGAMOUS LIKE 15 (AGL15), a key inducer of many SE genes. We further integrated BR signaling and nitric oxide (NO) with PHYE by demonstrating that applications of both compounds to phyE explants and WT explants cultured in the dark partially restored AGL15 expression. These results demonstrate that SE induction by red light operates via PHYE through BR signaling and NO required to induce AGL15.

Obstructive Sleep Apnea in Men With Idiopathic Intracranial Hypertension: A Prospective Case-Control Study.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is uncommon in men. Previous studies reported on high frequency of obstructive sleep apnea (OSA) in men with IIH, but the pathophysiology of this association remains unclear. One possible culprit for increased intracranial pressure in patients with OSA is hypercapnia. The purpose of this study was to compare the rate of hypercapnia during polysomnography (PSG) study in men with and without IIH and to report on the rate and severity of OSA in men with IIH compared with control subjects of similar age and body mass index (BMI). METHODS: Prospective case-control study of male patients diagnosed with IIH underwent PSG with continuous oxygen and carbon dioxide monitoring overnight. Healthy control subjects with similar age and BMI also underwent PSG. The incidence of OSA diagnosis, rate of hypercapnia and hypoxia, and apnea hypopnea index (AHI) were compared between 2 groups. RESULTS: Eleven subjects with IIH and 10 controls underwent PSG. Both groups were similar regarding age and BMI on the Mann-Whitney U test ( P = 0.072 for age, P = 0.251 for BMI). Subjects for whom carbon dioxide data were not available for more than 50% of total sleep time were excluded from hypercapnia analysis. The mean age was 41.9 years, and the mean BMI was 33.8 kg/m 2 in subjects and controls. OSA was diagnosed in 9 of 11 men with IIH and 4 of 10 controls. There was no statistically significant difference in the rate of hypercapnia and hypoxia between 2 groups for whom the data were available. All patients with BMI over 30 kg/m 2 (7 of 7) and 50% (2 of 4) controls with BMI over 30 kg/m 2 were diagnosed with OSA compared with 50% (2 of 4) of cases and 33% (2 of 6) of controls with BMI less than 30 kg/m 2 . BMI was a significant predictor of total AHI ( P = 0.042) and OSA severity ( P = 0.023), but IIH diagnosis was not ( P > 0.05). CONCLUSIONS: There was no difference in hypercapnia rate between men with IIH and controls; thus, hypercapnia is an unlikely causative factor in pathophysiology of IIH. OSA on PSG was almost 2 times as prevalent in patients with IIH compared with controls; however, BMI was the strongest predictor of OSA diagnosis, and most patients (9 of 11) with BMI over 30 kg/m 2 had OSA on PSG. In men with BMI less than 30, the rate of OSA on PSG study was higher in men with IIH. Based on these data, we recommend that all men with the diagnosis of IIH should undergo PSG study.

Comparison of pre-formalin fixation and postfixation temporal artery biopsy lengths.

OBJECTIVE: To evaluate the difference in temporal artery biopsy length before and after formalin fixation and identify any correlations with pathologic diagnosis. DESIGN: Prospective case series. PARTICIPANTS: Patients undergoing temporal artery biopsy between June 2020 and October 2021. METHODS: The pre- and postfixation biopsy lengths were compared. The primary outcome was the difference in temporal artery length as measured before fixation by the surgeon versus the postfixation measurement by the pathologist. RESULTS: Forty-seven consecutive biopsies in 46 patients were included. One patient had a repeat biopsy. Mean age was 75.3 ± 8.4 years (range, 49-94 years); 74% of patients (34 of 46 patients) were female. Mean prefixation biopsy length was 2.36 ± 0.58 cm (range, 1.1-4.5 cm). Mean postfixation biopsy length was 2.09 ± 0.59 cm (range, 0.6-3.8 cm). Mean difference (postfixation shrinkage) was 0.27 ± 0.24 cm (p = 0.0298), and 36% of biopsies (17 of 47 biopsies) were positive. There was no significant difference in prefixation temporal artery biopsy length (p = 0.38) or postfixation shrinkage (p = 0.24) between positive and negative biopsies. In a univariate analysis, elevated erythrocyte sedimentation rate was 31.3 mm/h (range, 4-88 mm/h) in negative biopsies versus 54.5 mm/h (range, 29-98 mm/h) in positive biopsies (p = 0.01), C-reactive protein was 17.4 mg/L (range, 0.2-145 mg/L) in negative biopsies versus 78.56 mg/L (range, 5-244.4 mg/L) in positive biopsies (p = 0.003), and platelets were 254.9 × 109/L (range, 134-570 × 109/L) in negative biopsies versus 393.8 × 109/L (range, 210-593 × 109/L) in positive biopsies (p < 0.001), all associated with a positive pathologic diagnosis. CONCLUSIONS: The average temporal artery biopsy was approximately 0.27 cm shorter on pathologic reports compared with before fixation measurements. Surgeons should account for this shrinkage with a buffer of at least 0.3 cm, aiming for excision of at least 2.3 cm, if they desire a postfixation size of 2 cm.

Applications and Safety of Sentinel Lymph Node Biopsy in Endometrial Cancer.

Lymph node status is important in predicting the prognosis and guiding adjuvant treatment in endometrial cancer. However, previous studies showed that systematic lymphadenectomy conferred no therapeutic values in clinically early-stage endometrial cancer but might lead to substantial morbidity and impact on the quality of life of the patients. The sentinel lymph node is the first lymph node that tumor cells drain to, and sentinel lymph node biopsy has emerged as an acceptable alternative to full lymphadenectomy in both low-risk and high-risk endometrial cancer. Evidence has demonstrated a high detection rate, sensitivity and negative predictive value of sentinel lymph node biopsy. It can also reduce surgical morbidity and improve the detection of lymph node metastases compared with systematic lymphadenectomy. This review summarizes the current techniques of sentinel lymph node mapping, the applications and oncological outcomes of sentinel lymph node biopsy in low-risk and high-risk endometrial cancer, and the management of isolated tumor cells in sentinel lymph nodes. We also illustrate a revised sentinel lymph node biopsy algorithm and advocate to repeat the tracer injection and explore the presacral and paraaortic areas if sentinel lymph nodes are not found in the hemipelvis.

Structural insights into photosystem II assembly.

Biogenesis of photosystem II (PSII), nature's water-splitting catalyst, is assisted by auxiliary proteins that form transient complexes with PSII components to facilitate stepwise assembly events. Using cryo-electron microscopy, we solved the structure of such a PSII assembly intermediate from Thermosynechococcus elongatus at 2.94 Å resolution. It contains three assembly factors (Psb27, Psb28 and Psb34) and provides detailed insights into their molecular function. Binding of Psb28 induces large conformational changes at the PSII acceptor side, which distort the binding pocket of the mobile quinone (QB) and replace the bicarbonate ligand of non-haem iron with glutamate, a structural motif found in reaction centres of non-oxygenic photosynthetic bacteria. These results reveal mechanisms that protect PSII from damage during biogenesis until water splitting is activated. Our structure further demonstrates how the PSII active site is prepared for the incorporation of the Mn4CaO5 cluster, which performs the unique water-splitting reaction.

Complete unilateral vision loss and optic nerve cupping from metastatic prostate cancer to the optic canal.

A 71-year-old man, living with metastatic castrate-resistant prostate cancer to the lymph nodes, spine and skull, presented with acute on chronic left eye vision loss. Examination revealed no-light-perception vision, a relative afferent pupillary defect and optic disc cupping. MRI brain revealed optic canal narrowing from metastatic sphenoid bone expansion and extraosseous tumour compressing the intracanalicular optic nerve. The optic disc cupping and excavation without significant pallor of the remaining neuroretinal rim was likely secondary to chronic compression of the optic nerve. The patient was treated with radiation therapy, but did not regain vision and was referred to palliative care as his condition continued to worsen. As patients live longer with advanced cancer, there is a greater risk of metastasis to atypical areas of the body including the optic nerve. This case demonstrates the unique combination of optic disc cupping from optic canal metastasis due to prostate cancer.

Maternal immune activation targeted to a window of parvalbumin interneuron development improves spatial working memory: Implications for autism.

Maternal immune activation (MIA) increases risk for neuropsychiatric disorders such as autism spectrum disorder (ASD) in offspring later in life through unknown causal mechanisms. Growing evidence implicates parvalbumin-containing GABAergic interneurons as a key target in rodent MIA models. We targeted a specific neurodevelopmental window of parvalbumin interneurons in a mouse MIA model to examine effects on spatial working memory, a key domain in ASD that can manifest as either impairments or improvements both clinically and in animal models. Pregnant dams received three consecutive intraperitoneal injections of Polyinosinic:polycytidylic acid (poly(I:C), 5 mg/kg) at gestational days 13, 14 and 15. Spatial working memory was assessed in young adult offspring using touchscreen operant chambers and the Trial-Unique Non-matching to Location (TUNL) task. Anxiety, novelty seeking and short-term memory were assessed using Elevated Plus Maze (EPM) and Y-maze novelty preference tasks. Fluorescent immunohistochemistry was used to assess hippocampal parvalbumin cell density, intensity and co-expression with perineuronal nets. qPCR was used to assess the expression of putatively implicated gene pathways. MIA targeting a window of parvalbumin interneuron development increased spatial working memory performance on the TUNL touchscreen task which was not influenced by anxiety or novelty seeking behaviour. The model reduced fetal mRNA levels of Gad1 and adult hippocampal mRNA levels of Pvalb and the distribution of low intensity parvalbumin interneurons was altered. We speculate a specific timing window for parvalbumin interneuron development underpins the apparently paradoxical improved spatial working memory phenotype found both across several rodent models of autism and clinically in ASD.

Fabrication and chemical lift-off of sub-micron scale III-nitride LED structures.

Nanoscale light emitting diodes (nanoLEDs, diameter < 1 µm), with active and sacrificial multi-quantum well (MQW) layers epitaxially grown via metal organic chemical vapor deposition, were fabricated and released into solution using a combination of colloidal lithography and photoelectrochemical (PEC) etching of the sacrificial MQW layer. PEC etch conditions were optimized to minimize undercut roughness, and thus limit damage to the active MQW layer. NanoLED emission was blue-shifted ∼10 nm from as-grown (unpatterned) LED material, hinting at strain relaxation in the active InGaN MQW layer. X-ray diffraction also suggests that strain relaxation occurs upon nanopatterning, which likely results in less quantum confined Stark effect. Internal quantum efficiency of the lifted nanoLEDs was estimated at 29% by comparing photoluminescence at 292K and 14K. This work suggests that colloidal lithography, combined with chemical release, could be a viable route to produce solution-processable, high efficiency nanoscale light emitters.

An abscisic acid-responsive protein interaction network for sucrose non-fermenting related kinase1 in abiotic stress response.

Yeast Snf1 (Sucrose non-fermenting1), mammalian AMPK (5' AMP-activated protein kinase) and plant SnRK1 (Snf1-Related Kinase1) are conserved heterotrimeric kinase complexes that re-establish energy homeostasis following stress. The hormone abscisic acid (ABA) plays a crucial role in plant stress response. Activation of SnRK1 or ABA signaling results in overlapping transcriptional changes, suggesting these stress pathways share common targets. To investigate how SnRK1 and ABA interact during stress response in Arabidopsis thaliana, we screened the SnRK1 complex by yeast two-hybrid against a library of proteins encoded by 258 ABA-regulated genes. Here, we identify 125 SnRK1- interacting proteins (SnIPs). Network analysis indicates that a subset of SnIPs form signaling modules in response to abiotic stress. Functional studies show the involvement of SnRK1 and select SnIPs in abiotic stress responses. This targeted study uncovers the largest set of SnRK1 interactors, which can be used to further characterize SnRK1 role in plant survival under stress.