Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules.

Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology is inexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that upon environmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where they aberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated from the cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting this aberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stress-dependent molecular link across diverse CMT2 mutants and provide a conceptual framework for understanding genetic heterogeneity in light of environmental stress.

CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord.

Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.

Ret is a multifunctional coreceptor that integrates diffusible- and contact-axon guidance signals.

Growing axons encounter multiple guidance cues, but it is unclear how separate signals are resolved and integrated into coherent instructions for growth cone navigation. We report that glycosylphosphatidylinositol (GPI)-anchored ephrin-As function as "reverse" signaling receptors for motor axons when contacted by transmembrane EphAs present in the dorsal limb. Ephrin-A receptors are thought to depend on transmembrane coreceptors for transmitting signals intracellularly. We show that the receptor tyrosine kinase Ret is required for motor axon attraction mediated by ephrin-A reverse signaling. Ret also mediates GPI-anchored GFRα1 signaling in response to GDNF, a diffusible chemoattractant in the limb, indicating that Ret is a multifunctional coreceptor for guidance molecules. Axons respond synergistically to coactivation by GDNF and EphA ligands, and these cooperative interactions are gated by GFRα1 levels. Our studies uncover a hierarchical GPI-receptor signaling network that is constructed from combinatorial components and integrated through Ret using ligand coincidence detection.

Presenilin-dependent receptor processing is required for axon guidance.

The Alzheimer's disease-linked gene presenilin is required for intramembrane proteolysis of amyloid-ß precursor protein, contributing to the pathogenesis of neurodegeneration that is characterized by loss of neuronal connections, but the role of Presenilin in establishing neuronal connections is less clear. Through a forward genetic screen in mice for recessive genes affecting motor neurons, we identified the Columbus allele, which disrupts motor axon projections from the spinal cord. We mapped this mutation to the Presenilin-1 gene. Motor neurons and commissural interneurons in Columbus mutants lacking Presenilin-1 acquire an inappropriate attraction to Netrin produced by the floor plate because of an accumulation of DCC receptor fragments within the membrane that are insensitive to Slit/Robo silencing. Our findings reveal that Presenilin-dependent DCC receptor processing coordinates the interplay between Netrin/DCC and Slit/Robo signaling. Thus, Presenilin is a key neural circuit builder that gates the spatiotemporal pattern of guidance signaling, thereby ensuring neural projections occur with high fidelity.

Conserved NIMA kinases regulate multiple steps of endocytic trafficking.

Human NIMA-related kinases have primarily been studied for their roles in cell cycle progression (NEK1/2/6/7/9), checkpoint-DNA-damage control (NEK1/2/4/5/10/11), and ciliogenesis (NEK1/4/8). We previously showed that Caenorhabditis elegans NEKL-2 (NEK8/9 homolog) and NEKL-3 (NEK6/7 homolog) regulate apical clathrin-mediated endocytosis (CME) in the worm epidermis and are essential for molting. Here we show that NEKL-2 and NEKL-3 also have distinct roles in controlling endosome function and morphology. Specifically, loss of NEKL-2 led to enlarged early endosomes with long tubular extensions but showed minimal effects on other compartments. In contrast, NEKL-3 depletion caused pronounced defects in early, late, and recycling endosomes. Consistently, NEKL-2 was strongly localized to early endosomes, whereas NEKL-3 was localized to multiple endosomal compartments. Loss of NEKLs also led to variable defects in the recycling of two resident cargoes of the trans-Golgi network (TGN), MIG-14/Wntless and TGN-38/TGN38, which were missorted to lysosomes after NEKL depletion. In addition, defects were observed in the uptake of clathrin-dependent (SMA-6/Type I BMP receptor) and independent cargoes (DAF-4/Type II BMP receptor) from the basolateral surface of epidermal cells after NEKL-2 or NEKL-3 depletion. Complementary studies in human cell lines further showed that siRNA knockdown of the NEKL-3 orthologs NEK6 and NEK7 led to missorting of the mannose 6-phosphate receptor from endosomes. Moreover, in multiple human cell types, depletion of NEK6 or NEK7 disrupted both early and recycling endosomal compartments, including the presence of excess tubulation within recycling endosomes, a defect also observed after NEKL-3 depletion in worms. Thus, NIMA family kinases carry out multiple functions during endocytosis in both worms and humans, consistent with our previous observation that human NEKL-3 orthologs can rescue molting and trafficking defects in C. elegans nekl-3 mutants. Our findings suggest that trafficking defects could underlie some of the proposed roles for NEK kinases in human disease.

A spatiotemporal barrier formed by Follistatin is required for left-right patterning.

How left-right (LR) asymmetry emerges in a patterning field along the anterior-posterior axis remains an unresolved problem in developmental biology. Left-biased Nodal emanating from the LR organizer propagates from posterior to anterior (PA) and establishes the LR pattern of the whole embryo. However, little is known about the regulatory mechanism of the PA spread of Nodal and its asymmetric activation in the forebrain. Here, we identify bilaterally expressed Follistatin (Fst) as a regulator blocking the propagation of the zebrafish Nodal ortholog Southpaw (Spaw) in the right lateral plate mesoderm (LPM), and restricting Spaw transmission in the left LPM to facilitate the establishment of a robust LR asymmetric Nodal patterning. In addition, Fst inhibits the Activin-Nodal signaling pathway in the forebrain thus preventing Nodal activation prior to the arrival, at a later time, of Spaw emanating from the left LPM. This contributes to the orderly propagation of asymmetric Nodal activation along the PA axis. The LR regulation function of Fst is further confirmed in chick and frog embryos. Overall, our results suggest that a robust LR patterning emerges by counteracting a Fst barrier formed along the PA axis.

ZNF468 inhibits irradiation-induced G2/M cell cycle arrest and apoptosis by facilitating AURKA transcription in Esophageal Squamous Cell Carcinoma.

BACKGROUND: ZNF468 is a relatively unexplored gene that has been implicated in potential oncogenic properties in various cancer types. However, the exact role of ZNF468 in radiotherapy resistance of esophageal squamous cell carcinomas (ESCCs) is not well understood. METHODS: Bioinformatic analysis was performed using the TCGA database to assess ZNF468 expression and prognostic significance in pan-cancer and ESCC. Functional experiments were conducted using ZNF468 overexpressing and knockdown cell lines to assess its impact on cell survival, DNA damage response, cell cycle, and apoptosis upon radiation. A luciferase reporter assay was utilized to validate ZNF468 binding to the AURKA promoter. RESULTS: ZNF468 was significantly upregulated in diverse cancer types, including ESCC, and its high expression correlated with adverse prognosis in specific tumors. In the ESCC cohort, ZNF468 exhibited substantial upregulation in post-radiotherapy tissues, indicating its potential role in conferring radiotherapy resistance. Functional experiments revealed that ZNF468 enhances cell viability and facilitates DNA damage repair in radiotherapy-treated ESCC cells, while dampening the G2/M cell cycle arrest and apoptosis induced by radiation. Moreover, ZNF468 facilitated AURKA transcription, resulting in upregulated Aurora A expression, and subsequently inhibited P53 expression, unveiling key molecular mechanisms underlying radiotherapy resistance in ESCC. CONCLUSION: ZNF468 plays an oncogenic role in ESCC and contributes to radiotherapy resistance. It enhances cell survival while dampening radiation-induced G2/M cell cycle arrest and apoptosis. By modulating AURKA and P53 expression, ZNF468 represents a promising therapeutic target for enhancing radiotherapy efficacy in ESCC.

Unveiling the Adoption and Barriers of Telemedicine in US Hospitals: A Comprehensive Analysis (2017-2022).

BACKGROUND: Telemedicine has emerged as a vital healthcare delivery model, especially pronounced during the COVID-19 pandemic. Our study uniquely focuses on an institutional lens, examining US hospitals to offer targeted policy implications. OBJECTIVE: To investigate the trend in telemedicine adoption across US hospitals from 2017 to 2022 and analyze the institutional challenges they encounter, particularly in the realm of electronic health information exchange. DESIGN: Cross-sectional study leveraging data from the American Hospital Association's (AHA) annual surveys for the years 2017 to 2021 and the 2022 AHA IT Supplement Survey. SETTING: The study includes a national sample of US hospitals, covering a diverse range of hospital types including large, nonprofit, teaching, and system-affiliated institutions. PARTICIPANTS: US hospitals form the study's participants, with a substantial response rate to the surveys. MAIN MEASURES: Key metrics include the number of telemedicine patient encounters, percentage of hospitals offering telemedicine services, and institutional challenges to electronic health information exchange. KEY RESULTS: Telemedicine encounters saw a 75% increase, growing from approximately 111.4 million in 2020 to nearly 194.4 million in 2021. The percentage of hospitals offering at least one form of telemedicine service went from 46% in 2017 to 72% in 2021. Larger, nonprofit, and teaching hospitals were more prone to telehealth adoption, without notable urban-rural disparities. While over 90% of hospitals allow patients to view and download medical records, only 41% permit online data submission. Importantly, 25% of hospitals identified Certified Health IT Developers such as EHR vendor as frequent culprits in information blocking, with cost being the primary obstacle. CONCLUSIONS: The findings underscore the rapid yet uneven adoption of telemedicine services in U.S. hospitals. The results point to the need for comprehensive policy interventions to address the challenges identified and realize telemedicine's full potential in healthcare delivery and resilience.

Characteristics of Prescription Drug Fills Using Pharmacy-Pharmacy Benefit Manager Discount Programs: The "GoodRx" Model.

OBJECTIVES: This study aimed to characterize products using pharmacy-pharmacy benefit manager (PBM) discounts and to estimate the association among such discounts, prescription utilization, and out-of-pocket costs. METHODS: This is a retrospective cohort study using IQVIA's Formulary Impact Analyzer, which contains anonymized, individual-level pharmacy claims representing US retail pharmacy transactions. We focused on 20 products with the greatest number of transactions using a pharmacy-PBM discount. Our unit of analysis was a treatment episode, defined as the length of time from an incident fill to no continuous use for 60 consecutive days after allowing for indefinite stockpiling. Outcome measures included products with greatest pharmacy-PBM discount use, characteristics of treatment episodes, and out-of-pocket costs with and without pharmacy-PBM discount. RESULTS: Across all products, 3.82% of transactions and 7.69% of treatment episodes were accompanied by a pharmacy-PBM discount. Commonly discounted products included generic treatments for chronic disease (lisinopril, levothyroxine, metformin) and neuropsychiatric conditions (alprazolam, amphetamine, buprenorphine, hydrocodone). The median postdiscount out-of-pocket cost was >2.5-fold higher during treatment episodes with a discount than those without ($15.15, interquartile range [IQR] $8.53-32.00, vs $5.88, IQR $1.40-15.00). Median treatment episode duration was 249 days (IQR 132-418) with discount use compared with 236 days (IQR 121-396) without discount use, although treatment episodes that began with a discount had fewer transactions per treatment episode and were shorter (median 212 days, IQR 114-360) than those that did not (313 days, IQR 178-500). CONCLUSIONS: Pharmacy-PBM discounts may foster market competition and improve access for under- and uninsured individuals; however, these programs may not generate savings for many insured individuals.

Bacterial antigens and asthma: a comparative study of common respiratory pathogenic bacteria.

Objective: In a previous study we have shown that, in the presence of interleukin (IL)-33, repeated, per-nasal challenge of murine airways with Streptococcus pneumoniae (S. pneumoniae) organisms induces human asthma-like airways inflammation. It is not clear, however, whether this effect is unique or manifest in response to other common respiratory pathogens.Methods: To explore this, airways of BALB/c mice were repeatedly challenged per-nasally with formaldehyde-inactivated bacterial bodies in the presence or absence of murine recombinant IL-33. Serum concentrations of S.pneumoniae, Moraxella catarrhalis (M.catarrhalis) and Haemophilus influenzae (H.influenzae) lysates-specific IgE were measured in patients with asthma and control subjects.Results: We showed that in the presence of IL-33, repeated, per-nasal airways exposure to the bodies of these bacteria induced airways hyperresponsiveness (AHR) in the experimental mice. This was accompanied by cellular infiltration into bronchoalveolar lavage fluid (BALF), eosinophilic infiltration and mucous hypertrophy of the lung tissue, with elevated local expression of some type 2 cytokines and elevated, specific IgG and IgE in the serum. The precise characteristics of the inflammation evoked by exposure to each bacterial species were distinguishable.Conclusions: These results suggest that in the certain circumstances, inhaled or commensal bacterial body antigens of both Gram-positive (S. pneumoniae) and Gram-negative (M. catarrhalis and H. influenzae) respiratory tract bacteria may initiate type 2 inflammation typical of asthma in the airways. In addition, we demonstrated that human asthmatic patients manifest elevated serum concentrations of M.catarrhalis- and H.influenzae-specific IgE.

The evolution of parasitism from mutualism in wasps pollinating the fig, Ficus microcarpa, in Yunnan Province, China.

Theory identifies factors that can undermine the evolutionary stability of mutualisms. However, theory's relevance to mutualism stability in nature is controversial. Detailed comparative studies of parasitic species that are embedded within otherwise mutualistic taxa (e.g., fig pollinator wasps) can identify factors that potentially promote or undermine mutualism stability. We describe results from behavioral, morphological, phylogenetic, and experimental studies of two functionally distinct, but closely related, Eupristina wasp species associated with the monoecious host fig, Ficus microcarpa, in Yunnan Province, China. One (Eupristina verticillata) is a competent pollinator exhibiting morphologies and behaviors consistent with observed seed production. The other (Eupristina sp.) lacks these traits, and dramatically reduces both female and male reproductive success of its host. Furthermore, observations and experiments indicate that individuals of this parasitic species exhibit greater relative fitness than the pollinators, in both indirect competition (individual wasps in separate fig inflorescences) and direct competition (wasps of both species within the same fig). Moreover, phylogenetic analyses suggest that these two Eupristina species are sister taxa. By the strictest definition, the nonpollinating species represents a "cheater" that has descended from a beneficial pollinating mutualist. In sharp contrast to all 15 existing studies of actively pollinated figs and their wasps, the local F. microcarpa exhibit no evidence for host sanctions that effectively reduce the relative fitness of wasps that do not pollinate. We suggest that the lack of sanctions in the local hosts promotes the loss of specialized morphologies and behaviors crucial for pollination and, thereby, the evolution of cheating.

Screening and analysis of the targeted compounds in Choerospondias axillaris extract by receptor chromatographic column with immobilized angiotensin II type 1 receptor.

As a result of the lack of modern techniques, the study of Tibetan medicine has been hindered in identifying bioactive compounds. Herein, we established a chromatographic approach using an immobilized angiotensin II type 1 receptor (AT1R) via a one-step method triggered by haloalkane dehalogenase. The bioactive compounds from Choerospondias axillaris (Guangzao) were screened and identified using the immobilized AT1R followed by MS. Frontal analysis (FA) and adsorption energy distribution (AED) were used to evaluate the association constants. Molecular docking was used to investigate the binding configurations, and the surface efficiency index, binding efficiency index, and ligand-lipophilicity efficiency (LLE) were calculated to assess the drug-like properties. The results identified naringenin, pinocembrin, and chrysin as the compounds that specifically bind to AT1R in Guangzao. FA and AED confirmed that there is only one type of binding site between these compounds and AT1R. The association constants were (2.40 ± 0.02) × 104 M-1 for naringenin (5.22 ± 0.26) × 104 M-1 for pinocembrin, and (4.27 ± 0.14) × 104 M-1 for chrysin, respectively. These compounds can bind with AT1R through the orthosteric binding pocket. Naringenin exhibited better LLE than pinocembrin and chrysin. These results confirmed the feasibility of using the immobilized AT1R column for screening and analyzing bioactive compounds in Tibetan medicines.

Estimation of Tax Benefit of US Nonprofit Hospitals.

Importance: Nonprofit hospitals are under increasing scrutiny to justify the generous tax benefit they receive due to their tax-exempt status. Quantifying the value of the tax benefit they receive at the federal, state, and local levels is critical for designing informed public health policies and ensuring nonprofit hospitals' taxpayer accountability. Objective: To estimate the financial benefit that nonprofit hospitals derive from their tax-exempt status and assess how the benefit is distributed across state and local communities. Design, Setting, and Participants: Using methodologies and measures consistent with current tax law and practice and data from 2021 Medicare Cost Reports, this study calculated the total financial benefit from nonprofit hospitals' tax-exempt status for all US nonprofit hospitals with the required Cost Reports data. Main Outcomes and Measures: Nonprofit hospitals' total tax benefit, which equals the sum of federal and state income tax, sales tax, property tax, the fair market value of charitable contributions from donors, savings from tax exemptions on issued bonds, and federal unemployment tax. Results: A total of 2927 US nonprofit hospitals received a $37.4 billion total tax benefit in 2021 from federal income tax ($11.5 billion; 31%), sales tax ($9.1 billion; 24%), property tax ($7.8 billion; 21%), state income tax ($3.7 billion; 10%), charitable contributions ($3.2 billion; 8%), bond financing ($2.1 billion; 6%), and federal unemployment tax ($200 million; <1%). Tax benefit varied substantially across states, from $25 098 (Delaware) to $159 464 (Massachusetts) per hospital bed and from $19 (Alabama) to $275 (Massachusetts) per capita. Tax benefit was highly concentrated, with 7% (n = 212) of hospitals accounting for half of the total amount. Conclusion and Relevance: This study highlights the wide variation of nonprofit hospitals' tax benefit across states, its high concentration among a small number of hospitals, and the primary role played by state and local taxes. Policy efforts to strengthen nonprofit hospitals' taxpayer accountability are likely to be more effective when pursued at the local level. The detailed standardized estimation road map can be used by various stakeholders to estimate tax benefit for external valuation and reporting purposes, updated as laws change, and improved upon as better data sources become available.

Fabrication, characterization and simulated gastrointestinal digestion of sea buckthorn pulp oil microcapsule: effect of wall material and interfacial bilayer stabilization.

BACKGROUND: Sea buckthorn (Hippophae rhamnoides L.) pulp oil is rich in functional components; however, low water solubility and stability limit its applications. This study fabricated sea buckthorn pulp oil microcapsules using whey protein isolate (WPI), soy protein isolate (SPI), sodium caseinate (NaCN), gum arabic (GA), starch sodium octenylsuccinate (OSAS) and SPI mixed with chitosan (CHI). The influences of these wall materials on physicochemical properties, release behavior and digestibility were explored. RESULTS: Protein-based wall materials (WPI, NaCN, SPI) demonstrated lower bulk densities due to their porous structures and larger particle sizes, while GA and OSAS produced denser microcapsules. Encapsulation efficiency was the highest for protein-based microcapsules (79.41-89.12%) and the lowest for GA and OSAS. The surface oil percentage of protein-based microcapsules (1.41-4.40%) was lower than that of the other microcapsules. Protein-based microcapsules showed concave and cracked surfaces, while GA and OSAS microcapsules were spherical and smooth. CHI improved reconstitution performance, leading to faster dissolution. During simulated gastrointestinal digestion, protein-based microcapsules released more free fatty acids (FFAs) in the intestinal phase, while CHI-modified SPI microcapsules showed a delayed release pattern due to thicker walls. CONCLUSION: Protein-based wall materials were more effective for sea buckthorn pulp oil microencapsulation, providing higher encapsulation efficiency, better flow properties and releasing more FFAs. The addition of CHI led to the layer-by-layer self-assembly of the microcapsule wall and resulted in sustained release during in vitro intestinal digestion. These findings suggested the potential of protein-based microcapsules for targeted delivery and improved applications of bioactive oils in the food industry. © 2024 Society of Chemical Industry. Published by John Wiley & Sons Ltd.

Sources of Social Support and Depressive Symptoms Among Chinese Older Adults: A Moderated Mediation of Social Adaptation and Filial Piety.

This study examined the mediating effect of social adaptation on the associations between sources of social support and depressive symptoms among Chinese older adults, and explored how filial piety moderated these associations in different ways. Data were drawn from the China Longitudinal Aging Social Survey in 2018 (N = 6617). Regression analysis and bootstrap test were used to assess the mechanisms underlying the inconsistency between different sources of social support and depressive symptoms. We found that social support, except for pension, significantly affected depressive symptoms through social adaptation. Moreover, filial piety positively moderated the mediating effect of social adaptation on the association between social support inside the family and depressive symptoms, while negatively moderating it in regard to social support outside the family, except for pension, and depressive symptoms. The results showed filial piety may affect the extent to which older adults convert different sources of social support into personal subjective welfare.

Genome-wide analysis of long noncoding RNAs in response to salt stress in Nicotiana tabacum.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been shown to play important roles in the response of plants to various abiotic stresses, including drought, heat and salt stress. However, the identification and characterization of genome-wide salt-responsive lncRNAs in tobacco (Nicotiana tabacum L.) have been limited. Therefore, this study aimed to identify tobacco lncRNAs in roots and leaves in response to different durations of salt stress treatment. RESULTS: A total of 5,831 lncRNAs were discovered, with 2,428 classified as differentially expressed lncRNAs (DElncRNAs) in response to salt stress. Among these, only 214 DElncRNAs were shared between the 2,147 DElncRNAs in roots and the 495 DElncRNAs in leaves. KEGG pathway enrichment analysis revealed that these DElncRNAs were primarily associated with pathways involved in starch and sucrose metabolism in roots and cysteine and methionine metabolism pathway in leaves. Furthermore, weighted gene co-expression network analysis (WGCNA) identified 15 co-expression modules, with four modules strongly linked to salt stress across different treatment durations (MEsalmon, MElightgreen, MEgreenyellow and MEdarkred). Additionally, an lncRNA-miRNA-mRNA network was constructed, incorporating several known salt-associated miRNAs such as miR156, miR169 and miR396. CONCLUSIONS: This study enhances our understanding of the role of lncRNAs in the response of tobacco to salt stress. It provides valuable information on co-expression networks of lncRNA and mRNAs, as well as networks of lncRNAs-miRNAs-mRNAs. These findings identify important candidate lncRNAs that warrant further investigation in the study of plant-environment interactions.

Quantum Similarity Testing with Convolutional Neural Networks.

The task of testing whether two uncharacterized quantum devices behave in the same way is crucial for benchmarking near-term quantum computers and quantum simulators, but has so far remained open for continuous variable quantum systems. In this Letter, we develop a machine learning algorithm for comparing unknown continuous variable states using limited and noisy data. The algorithm works on non-Gaussian quantum states for which similarity testing could not be achieved with previous techniques. Our approach is based on a convolutional neural network that assesses the similarity of quantum states based on a lower-dimensional state representation built from measurement data. The network can be trained off-line with classically simulated data from a fiducial set of states sharing structural similarities with the states to be tested, with experimental data generated by measurements on the fiducial states, or with a combination of simulated and experimental data. We test the performance of the model on noisy cat states and states generated by arbitrary selective number-dependent phase gates. Our network can also be applied to the problem of comparing continuous variable states across different experimental platforms, with different sets of achievable measurements, and to the problem of experimentally testing whether two states are equivalent up to Gaussian unitary transformations.

U.S. Hospitals' Administrative Expenses Increased Sharply During COVID-19.

BACKGROUND: In response to the declining utilization and patient revenue due to the COVID-19 pandemic, the U.S. hospital industry furloughed at least 1.4 million health care workers to contain their clinical-related expenses. However, it remains unclear how hospitals responded by adjusting their administrative expenses, which account for more than a quarter of U.S. hospitals' spending, a proportion substantially higher than that of other industrialized countries. Examining changes in hospitals' administrative expenses during the COVID-19 pandemic is important for understanding hospitals' cost-containment behaviors under operational shocks during a pandemic. OBJECTIVE: To assess changes in hospitals' administrative expenses and clinical expenses during the COVID-19 pandemic in 2020. DESIGN: Time-series observational study. PARTICIPANTS: 1420 Medicare-certified general acute-care hospitals with fiscal years starting in January and continuously operating during 2016-2020. MAIN MEASURES: Hospitals' annual administrative expenses and clinical expenses. KEY RESULTS: Hospitals' median administrative and clinical expenses both increased consistently around 4% each year from 2016 to 2019. From 2019 to 2020, the median administrative expenses grew by 6.2% while the median clinical expenses grew by 0.6%. The interrupted time-series regression estimated an additional 6.4% (95% CI, 4.5 to 8.2%) increase in administrative expenses in 2020, relative to the pre-COVID annual increase of 3.9% (95% CI, 3.3 to 4.4%), while an additional increase in clinical expenses in 2020 (0.5%; 95% CI, -0.3 to 1.4%) did not differ from the pre-COVID annual increase of 3.7% (95% CI, 3.5 to 4%). Stratified analysis showed hospitals with larger utilization volume, located in states with lower COVID-19 burden, or situated in counties with higher median household income experienced larger increase in administrative expenses in 2020. CONCLUSIONS: In 2020, administrative expenses grew much faster than clinical expenses, resulting in a larger share of hospital financial resources allocated to administrative activities. Higher administrative expenses might reflect hospitals' operational effort in response to the pandemic or inefficient cost management.

Inducing root redundant development to release oxygen: An efficient natural oxygenation approach for subsurface flow constructed wetland.

Dissolved oxygen (DO) is a limiting factor affecting the purification efficiency of subsurface flow (SSF) constructed wetlands (CWs). To clarify the causes of oxygen environments and the response characteristics of plant oxygen release (POR) in SSF CWs, this study set three oxygen source treatments by limiting atmospheric reaeration (AR) and influent oxygen (IO) and compared the differences in plant physiological metabolism, DO distribution characteristics, and the purification effect of the SSF CWs at different depths. The results showed that limiting exogenous oxygen stimulated root redundancy of the wetland plants. The root volume and proportion of fibrous roots of the wetland plants increased significantly (p < 0.05). When only the POR existed, the root zone DO increased significantly to 2.05-4.37 mg/L (p < 0.05), and was positively correlated with the TN and TP removal rates (p < 0.05). Additionally, in the presence of POR only, the average removal rates of TN and TP in the top layer were 86.5% and 76.9%, respectively. The proportion of fibrous roots, root zone DO, and root-shoot ratio were key factors promoting the purification effect of the SSF CWs under limited exogenous oxygen sources. Enhancing POR by inducing root redundancy enhanced nitrification (hao, pmoABC-amoABC), plant absorption, and assimilation-related functional genes (nrtABC, nifKDH), and enriched nitrogen and phosphorus removal bacteria, such as Flavobacterium and Zoogloea. This consequently improved pollutant removal efficiency. Inducing root redundancy to strengthen POR produced an aerobic environment in the SSF CWs. This ensures the efficient and stable operation of the SSF CW and is an effective approach for natural oxygenation.

Root vertical spatial stress: A method for enhancing rhizosphere effect of plants in subsurface flow constructed wetland.

The depth of the substrate of subsurface flow (SSF) constructed wetlands (CWs) is closely related to their cost and operation stability. To explore the physiological regulation mechanism of wetland plants and pollutant removal potential of SSF CWs under "vertical spatial stress of roots" (by greatly reducing the depth of the substrate in SSF CWs to limit the vertical growth space of roots, VSSR), the physiological response and wetland purification effect of a 0.1 m Canna indica L. CW under VSSR were studied compared with conventional SSF CWs (0.6 m, 1.2 m). The results demonstrated that VSSR significantly enhanced the dissolved oxygen (DO) concentration (p < 0.05) within the SSF CWs, with the DO in 0.1 m CW remaining stable at over 3 mg/L. Under the same hydraulic retention time (HRT), VSSR significantly improved the removal effect of pollutants (p < 0.05). The removal rates of COD, NH4+-N, and total phosphorus (TP) remained above 87%, and the mean removal rates of total nitrogen (TN) reached 91.71%. VSSR promoted the morphological adaptation mechanisms of plants, such as significantly increased root-shoot ratio (p < 0.05), changed biomass allocation. Plants could maintain the stability of the photosynthetic mechanism by changing the distribution of light energy. The results of microbial community function prediction demonstrated that aerobic denitrification was the main mechanism of N transformation in the 0.1 m CW under VSSR. VSSR could induce the high root activity of plants, augment the concentration of root exudates, enhance the redox environment of the plant rhizosphere, further foster the enrichment of aerobic denitrifying bacteria, and strengthen the absorption efficiency of wetland plants and substrate, thus achieving an efficient pollutant removal capacity. Studies showed that VSSR was an effective means to enhance the rhizosphere effect of plants and pollutant removal in SSF CWs.