Protein post-translational modifications (PTMs), such as ADP-ribosylation and phosphorylation, regulate multiple fundamental biological processes in cells. During bacterial infection, effector proteins are delivered into host cells through dedicated bacterial secretion systems and can modulate important cellular pathways by covalently modifying their host targets. These strategies enable intruding bacteria to subvert various host processes, thereby promoting their own survival and proliferation. Despite rapid expansion of our understanding of effector-mediated PTMs in host cells, analytical measurements of these molecular events still pose significant challenges in the study of host-pathogen interactions. Nevertheless, with major technical breakthroughs in the last two decades, mass spectrometry (MS) has evolved to be a valuable tool for detecting protein PTMs and mapping modification sites. Additionally, large-scale PTM profiling, facilitated by different enrichment strategies prior to MS analysis, allows high-throughput screening of host enzymatic substrates of bacterial effectors. In this review, we summarize the advances in the studies of two representative PTMs (i.e., ADP-ribosylation and phosphorylation) catalyzed by bacterial effectors during infection. Importantly, we will discuss the ever increasing role of MS in understanding these molecular events and how the latest MS-based tools can aid in future studies of this booming area of pathogenic bacteria-host interactions.

Background and Purpose: Blood-brain barrier (BBB) breakdown is one of the most crucial pathological changes of cerebral ischemia-reperfusion (I/R) injury. Trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect against cerebral I/R injury as demonstrated in our previous study. This study was designed to investigate the effect of TLB on disruption of BBB after cerebral I/R injury. Experimental Approach: Rats with focal cerebral ischemia caused by transient middle cerebral artery occlusion (MCAO) and brain microvascular endothelial cells along with human astrocytes to mimic blood brain barrier (BBB) injury caused by oxygen and glucose deprivation (OGD) followed by reoxygenation (OGD/R). Key results: The results showed that TLB effectively maintained the integrity of BBB and inhibited neuronal loss following cerebral I/R challenge. Furthermore, TLB dramatically increased tight junction proteins including ZO-1, occludin and claudin 5, as well as decreased the levels of apolipoprotein E (APOE) 4, cyclophilin A (CypA), and phosphorylated nuclear factor kappa B (NF-κB), thereby reduced proinflammatory cytokines. In addition, TLB also decreased Bax/Bcl-2 ratio and cleaved-caspase 3 level along with reduced the number of apoptotic neurons. Intriguingly, molecular docking and transcriptomics predicted MMP9 was a prominent gene evoked by TLB treatment. Furthermore, the protective effect of TLB on OGD/R-induced the loss of BBB integrity in human brain microvascular endothelial cell and astrocyte co-cultures in vitro was markedly reinforced by knockdown of MMP9. Conclusions and implications: Our findings reveal a novel property of TLB: saving BBB disruption following cerebral I/R via targeting MMP9 and inhibiting APOE4/CypA/NF-κB axis.

We describe a case of a 2-month-old female displaying clinical phenotype of HIES related disease with severe eczematous dermatitis recalcitrant to corticosteroids. Genetic panel showed a variant of unknown significance in key immune regulator of PGM3. Patient achieved nearly complete response from off-label use of dupilumab.

By integrating the Four Switch Buck-Boost (FSBB) PFC and full-bridge LLC resonant converter, a novel single-stage FSBB-LLC AC-DC converter is proposed. Moreover, a dual-loop feedback control strategy based on PFM/PWM hybrid modulation is proposed for obtaining the desired bus voltage and stable output voltage. The bus voltage feedback loop is utilized to regulate the bus voltage by selecting the boost or buck-boost mode; the output voltage feedback loop is employed to stabilize the output voltage by adjusting the switching frequency or phase shifting angle. Furthermore, an optimal parameter design based on power balance principle is also derived. The experimental results of an 85~300V input, 12V/25A output prototype demonstrate that: (1) low and narrow bus voltage of 240~340V is achieved under the entire input and output condition; (2) the LLC cell operates as a DCX converter over the whole load range as the input voltage exceeds 120V; (3) the output voltage is well regulated even under the no-load condition; (4) ZVS feature for the shared main switches is still maintained; (5) a peak efficiency of 90.9% and PF values above 0.987 are achieved.

We present a method to use a birefringent crystal for generating two illumination beams in a digital scanned laser light-sheet microscopy (DSLM) system. Upon this, a conventional confocal DSLM can be easily upgraded to a dual-slit confocal DSLM with two-fold imaging speed. We have implemented this method to our bidirectional DSLM system, locating two identical calcite crystals on both illumination paths from both sides of the sample. The neurons of in vivo larval zebrafish have been fast imaged with sterling image quality, especially ~2.5 times higher contrast, compared to the conventional DSLM.

Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here, we systematically gathered the vast evidence of the role of dopamine in the simplest forms of aversive learning: classical fear conditioning and extinction. In the past, crude methods were used to augment or inhibit dopamine to study its relationship with fear conditioning and extinction. More advanced techniques such as conditional genetic, chemogenic, and optogenetic approaches now provide causal evidence for dopamine's role in these learning processes. Dopamine neurons encode conditioned stimuli during fear conditioning and extinction, and convey the signal via activation of D1-4 receptor sites particularly in the amygdala, prefrontal cortex, and striatum. The coordinated activation of dopamine receptors allows for the continuous formation, consolidation, retrieval, and updating of fear and extinction memory in a dynamic and reciprocal manner. Based on the reviewed literature, we conclude that dopamine is crucial for the encoding of classical fear conditioning and extinction and contributes in a way that is comparable to its role in encoding reward.

Objectives: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children. We aimed to analyze the factors affecting the estimation of RSV-related disease burden, and furthermore, to provide evidence to help establish a surveillance system. Methods: We searched for literature published in English or Chinese between 1 January, 2010 and 2 June, 2022. The quality of the included articles was assessed using the Agency for Healthcare Research and Quality scale. Random-effects models were used for data synthesis and subgroup analyses. This review was registered in the Prospective Register of Systematic Reviews (PROSPERO: CRD42022372972). Results: We included 44 studies (149,321,171 participants), all of which were of medium or high quality. The pooled RSV-associated disease incidence, hospitalization rate, in-hospital mortality, and overall mortality rates in children aged 5 years and younger were 9.0% (95% confidence interval [CI]: 7.0–11.0%), 1.68% (95% CI: 1.30–2.05%), 0.45% (95% CI: 0.38–0.52%), and 0.05% (95% CI: 0.04–0.06%), respectively. Age, economics, surveillance types, case definition, and data source were all influencing factors. Conclusions: A standardized and unified RSV surveillance system is required. Case definition and surveillance types should be fully considered for surveillance of different age groups.

It is impossible to address the many complex needs of respiratory virus surveillance with a single system. Therefore, multiple surveillance systems and complementary studies must fit together as tiles in a “mosaic” to provide a complete picture of the risk, transmission, severity, and impact of respiratory viruses of epidemic and pandemic potential. Below we present a framework to assist national authorities to identify priority respiratory virus surveillance objectives and the best approaches to meet them; to develop implementation plans according to national context and resources; and to prioritize and target technical assistance and financial investments to meet most pressing needs.

Early in the 2022 Mpox (MPX) global outbreak, caseloads in the New York Metropolitan area climbed rapidly before other US urban areas. This case series summarizes the authors’ clinical experience detecting and treating MPX, during a quickly evolving outbreak. Clinical outcomes were recorded with a focus on varied clinical presentation and outcomes such as complications and response to experimental tecovirimat therapy. A focal or multifocal rash was the most common presenting symptom in 91% of patients. Almost two thirds (62%) of patients had anogenital involvement. Proctitis was one of the most painful presentations with 75% requiring antiviral treatment and 3 patients needing hospitalization for pain management. Most patients responded promptly to antiviral treatment with tecovirimat. Five out of 10 patients treated with tecovirimat reported symptom resolution within 48 – 72 hours of therapy and another 3 saw resolution within first 96 hours. Two patients had poor response to tecovirimat. This series includes the only reported case of an HIV positive, immunocompetent patient who experienced recurrent anal ulcers due to Mpox and required a second course of tecovirimat. Other unique presentations included urethritis, abscess formation and MPX infection post-vaccination. Control of this current Mpox outbreak was possible due to timely diagnosis and the availability of both a licensed vaccine and an investigational drug.

Interventions to promote deprescribing are an important focus of research. Key decisions for such interventions are whether to target one or multiple medicines, and whether the intervention scope is deprescribing, or also extends to other aspects of medicines optimisation. This article reflects on how these decisions impact on developing interventions and measuring outcomes. Many behavioural strategies are common to deprescribing and medicines optimisation, however operationalisation may differ. Aspects to consider include the burden of multiple simple interventions versus one complex intervention, the extent to which the approach to deprescribing can be specified as part of the intervention, and variability in how the intervention is delivered across patients and providers. Outcomes should be selected based on the intervention target and scope and the audience for whom evidence is being produced. These may include medication changes, and process outcomes to assess intervention delivery. Targeting single medications may allow for a focus on specific clinical or symptom-related outcomes, rather than more general outcomes such as adverse drug reactions. Cost-related outcomes are also important to inform implementation decisions, and modelling approaches may be more feasible for interventions targeting single medications.

Significant racial disparities in prostate cancer incidence and mortality have been reported between African American Men (AAM) who are at increased risk for prostate cancer, and European American Men (EAM). In most of the studies carried out on prostate cancer, this population is underrepresented. With the advancement of genome-wide association studies (GWAS), several genetic predictor models of prostate cancer risk have been elaborated, as well as numerous studies that identify both germline and somatic mutations with clinical utility. Despite significant advances, the AAM population continues to be underrepresented in genomic studies, which can limit their generalizability and potentially widen disparities. Here we outline racial disparities in currently available genomic applications that are used to estimate the risk of individuals developing prostate cancer and to identify personalized oncology treatment strategies. While the incidence and mortality of prostate cancer are different between AAM and EAM. the biological features and differences of prostate tumors in AAM and EAM are still being described. Samples from AAM remain to be unrepresented in different studies. This disparity impacts the available genomic data on prostate cancer. As a result, the disparity can limit the predictive utility of the genomic applications that have been developed and may lead to widening disparities. More studies with substantially higher recruitment and engagement of African American patients are necessary to overcome this disparity.

Lead-acid battery system is designed to perform optimally at ambient temperature (25 °C) in terms of capacity and cyclability. However, varying climate zones enforce harsher conditions on the automotive lead acid batteries. Hence, they age faster and exhibit low performance when operated at either extremity of the optimum ambient conditions. In this work, a systematic study was conducted to analyze the effect of varying temperatures (-10, 0, 25 and 40 °C) on the sealed lead acid. Enersys® Cyclon (2V, 5Ah) cells were cycled at C/10 rate using battery testing system. The environmental aging results in shorter cycle life due to the degradation of electrode, and grid materials at higher temperature (25 and 40 °C), while at lower temperature (-10 and 0 °C) negligible degradation was observed due to slower kinetics and reduced available capacity. Electrochemical impedance spectroscopy, X-ray diffraction and Energy-dispersive X-ray spectroscopy analysis were used to evaluate the degradation mechanism, chemical and morphological changes.

Nonwoven membranes are highly engineered fibrous materials that can be manufactured on a large scale from a wide range of different polymers, and their surfaces can be modified using a large variety of different chemistries and ligands. The fiber diameters, surface areas, pore sizes, total porosities, and thicknesses of the nonwoven mats can be carefully controlled, providing many opportunities for creative approaches for the development of novel membranes with unique properties to meet the needs of the future of downstream processing. Fibrous membranes are already finding use in ultrafiltration, microfiltration, depth filtration, and, more recently, in membrane chromatography for product capture and impurity removal. This article summarizes the various methods of manufacturing nonwoven fabrics, and the many methods available for the modification of the fiber surfaces. It also reviews recent studies focused on the use of nonwoven fabric devices in membrane chromatography and provides some perspectives on the challenges that need to be overcome to increase binding capacities, decrease residence times, and reduce pressure drops so that eventually they can replace resin column chromatography in downstream process operations.

Severe BPD can be associated with clinical and histologic features that are similar to ACD without evidence of FOXF1 genetic disease.  Importantly, lung FOXF1 and TMEM100 gene expression is markedly decreased in severe BPD, suggesting that impaired FOXF1 signaling may contribute to abnormal lung growth and refractory pulmonary hypertension in BPD.

Background: Repositioning a traumatized tooth involves, first, replacing and second stabilizing it. Stabilization, on the other hand, usually requires flexible splints. Occasionally the immediate replacement may be impossible being necessary to use other procedure. Methods: When complete replacement is not possible,

Meglumine gadoterate induces immunoglobulin-independent human mast cell activation and MRGPRX2 internalizationTo the Editor,Gadolinium-based contrast agents (GBCA) are intravenous drugs used to enhance resolution in magnetic resonance imaging. They can induce immediate hypersensitivity reactions, yet their pathogenic mechanisms remain poorly characterized. This hampers the ability to predict which patients are at risk of developing them.1 In fact, affected patients usually show negative skin-tests and can react upon the first known GBCA exposure, which implies that IgE-independent mechanisms might be driving this inflammatory response.The Mas-related G protein-coupled receptor member X2 (MRGPRX2) has been recently associated with non-IgE mediated immediate hypersensitivity reactions.2 Some drugs, such as fluoroquinolones, vancomycin, neuromuscular blockade agents, icatibant, morphine, leuprolide and iodinated contrast media, have been reported to activate MRGPRX2, which is highly expressed in mast cells (MCs).3To assess the ability of GBCA to induce non-IgE-mediated hypersensitivity reactions, we stimulated the human MC line LAD2 with several commercial GBCA, namely, meglumine gadoterate, gadobutrol, gadoxetate disodium and gadoteridol. Then, we determined cell viability and degranulation by flow cytometry4 (see a detailed material and methods section in this article´s online supplementary ).Of the GBCA tested, only meglumine gadoterate was able to induce significant MC activation (Figure 1A ) without compromising cell viability (Figure 1B ), as compared to unstimulated MCs. We further assessed MRGPRX2 expression on LAD2 cells by flow cytometry, as well as changes in its expression following stimulations with either meglumine gadoterate or vancomycin (a known agonist of MRGPRX2).5 Under basal conditions, LAD2 cells expressed high levels of MRGPRX2 (Figure 1C ). Following incubation with vancomycin, the level of MRGPRX2 expression was reduced, as compared to untreated LAD2 cells. Interestingly, we observed a similar decrease in MRGPRX2 expression levels upon meglumine gadoterate and vancomycin challenges, as compared to controls, suggesting both the signaling and the internalization of this receptor (Figure 1D ).Meglumine gadoterate is an ionic macrocyclic paramagnetic contrast media. It is composed by gadolinium, which together with the chelating agent tetraxetan (also known as DOTA), yields gadoteric acid. The base meglumine and gadoteric acid form the salt meglumine gadoterate (Figure 2A ). Given that MRGPRX2 has affinity for cationic amphiphilic compounds,6 we ascertained the ability of meglumine to induce MC activation. Meglumine itself induced MC degranulation without affecting cell viability, as compared to untreated cells (Figure 2B ), although a reduction in MRGPX2 expression could not be confirmed (data not shown). Interestingly, meglumine caused MC activation at lower concentrations than meglumine gadoterate, according to the half maximal effective concentration (EC50) of both substances (Figure 2C ). The logarithmically transformed EC50 for meglumine gadoterate was 2.04 (R2= 0.75), and for meglumine was about one order of magnitude lower (1.06; R2= 0.71). Considering the EC50 for meglumine and its proportion in meglumine gadoterate (~26%), meglumine could be its main component responsible for MC degranulation.In conclusion, our study demonstrates the ability of meglumine gadoterate to induce MC activation, by an immunoglobulin-independent mechanism that is likely mediated by MRGPRX2. Furthermore, we have delved into the meglumine gadoterate components that are involved in MC activation, and identified meglumine as a potential causative of non-IgE mediated hypersensitivity reactions. These data raise the possibility that immediate hypersensitivity reactions following intravascular administration of ionic iodinated contrast media may be at least partly mediated by meglumine. Further studies should be performed to define clinically relevant interactions between diverse radiological contrast media and MRGPRX2.Authors: Paula H. Ruiz de Azcárate,1#Rodrigo Jiménez-Saiz,1-4 #* Celia López-Sanz,1 Azahara López-Raigada,5Francisco Vega,5 Carlos Blanco,5*# First authors* Corresponding authorsAffiliations: 1Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain.2Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain.3Faculty of Experimental Sciences, Universidad Francisco de Vitoria (UFV), Madrid, Spain.4Department of Medicine, McMaster Immunology Research Centre (MIRC), Schroeder Allergy and Immunology Research Institute (SAIRI), McMaster University, Hamilton, ON, Canada.5Department of Allergy, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain.*Co-correspondence to :1) Rodrigo Jiménez-Saiz, Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Diego de León 62, 28006, Madrid, Spain. Email address: [email protected]) Carlos Blanco, Department of Allergy, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Diego de León 62, 28006, Madrid, Spain. Email address: [email protected] Funding information: RJS reports grants by the FSE/FEDER through the Instituto de Salud Carlos III (CP20/00043; PI22/00236; Spain), The Nutricia Research Foundation (NRF-2021-13; The Netherlands), New Frontiers in Research Fund (NFRFE-2019-00083; Canada) and SEAIC (BECA20A9; Spain). PHR is supported by the INVESTIGO Program of the Community of Madrid (Spain), which is funded by “Plan de Recuperación, Transformación y Resiliencia” and “NextGenerationEU” of the European Union (09-PIN1-00015.6/2022).Conflict of interest : All the authors have no significant conflicts of interest to declare in relation to this manuscript.References1. Vega F, Lopez-Raigada A, Mugica MV, Blanco C. Fast challenge tests with gadolinium-based contrast agents to search for an alternative contrast media in allergic patients. Allergy.2022;77(10):3151-3153.2. Kolkhir P, Ali H, Babina M, et al. MRGPRX2 in drug allergy: What we know and what we do not know. J Allergy Clin Immunol. 2022.3. Foer D, Wien M, Karlson EW, Song W, Boyce JA, Brennan PJ. Patient Characteristics Associated With Reactions to Mrgprx2-Activating Drugs in an Electronic Health Record-Linked Biobank. J Allergy Clin Immunol Pract. 2022.4. López-Sanz C, Sánchez-Martínez E, Jiménez-Saiz R. Protocol to desensitize human and murine mast cells after polyclonal IgE sensitization. STAR Protocols. 2022;3(4):101755.5. Navines-Ferrer A, Serrano-Candelas E, Lafuente A, Munoz-Cano R, Martin M, Gastaminza G. MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia. Sci Rep.2018;8(1):11628.6. Wolf K, Kühn H, Boehm F, et al. A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice. J Allergy Clin Immunol. 2021;148(2):506-522.e508.

In this paper, an enclosing control problem is investigated for nonholonomic mobile agents with a moving target of unknown velocity. An adaptive observer containing two internal variables is first designed for each agent to compensate for the lack of the target velocity information. One variable is designed to estimate the unknown target velocity and further its estimation error is assessed by the other internal variable to subsequently guarantee the control performance. Then using the estimated information from the adaptive observer, a dynamic control law for circular formation of nonholonomic agents around the moving target is designed by a backstepping process. The global asymptotical stability of the closed-loop system is achieved under the proposed dynamic control law with the adaptive observer. Finally, a simulation is conducted to demonstrate the effectiveness of the proposed approach.

Herein, we have developed a strategy of Rh(III)-catalyzed C–H activation of N-nitrosoanilines and iodonium ylides to construct novel tetralydrocarbzol-4-one scaffolds, which provided valuable templates for sequential C-H functionalization such as alkylation, alkenyla-tion, amidation and (hetero)arylation at C5-position of tetralydrocarbzol-4-one with different coupling partners. Gram-scale synthesis and further transformation of tetralydrocarbzol-4-one derivatives to Ondansetron and its analogues demonstrated the utility of this protocol, which enabled the concise and diverse construction of biologically active molecules.