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ObjectiveTo expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.MethodsParticipants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.ResultsWe expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2–38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.ConclusionsThe spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

Multiple nations and private entities are pushing to make landing humans on Mars a reality. The majority of proposed mission architectures envision ‘living off the land’ by leveraging Martian water-ice deposits for fuel production and other purposes. Fortunately for mission designers, water ice exists on Mars in plentiful volumes. The challenge is isolating accessible ice deposits within regions that optimize other preferred landing-site conditions. Here we present the first results of the Mars Subsurface Water Ice Mapping (SWIM) project, which has the aim of searching for buried ice resources across the mid-latitudes. Through the integration of orbital datasets in concert with new data-processing techniques, the SWIM project assesses the likelihood of ice by quantifying the consistency of multiple, independent data sources with the presence of ice. Concentrating our efforts across the majority of the northern hemisphere, our composite ice-consistency maps indicate that the broad plains of Arcadia and the extensive glacial networks across Deuteronilus Mensae match the greatest number of remote-sensing criteria for accessible ice-rich, subsurface material situated equatorwards of the contemporary ice-stability zone. The Mars Subsurface Water Ice Mapping (SWIM) project aims at determining the regions where near-surface ice is most likely to be present, according to the combination of all the available datasets. Focusing on the northern mid-latitudes, they identify in particular Deuteronilus Mensae and Arcadia Planitia as promising sites.

All amniotes reproduce either by egg-laying (oviparity), which is ancestral to vertebrates or by live-bearing (viviparity), which has evolved many times independently. However, the genetic basis of these parity modes has never been resolved and, consequently, its convergence across evolutionary scales is currently unknown. Here, we leveraged natural hybridizations between oviparous and viviparous common lizards (Zootoca vivipara) to describe the functional genes and genetic architecture of parity mode and its key traits, eggshell and gestation length, and compared our findings across vertebrates. In these lizards, parity trait genes were associated with progesterone-binding functions and enriched for tissue remodelling and immune system pathways. Viviparity involved more genes and complex gene networks than did oviparity. Angiogenesis, vascular endothelial growth and adrenoreceptor pathways were enriched in the viviparous female reproductive tissue, while pathways for transforming growth factor were enriched in the oviparous. Natural selection on these parity mode genes was evident genome-wide. Our comparison to seven independent origins of viviparity in mammals, squamates and fish showed that genes active in pregnancy were related to immunity, tissue remodelling and blood vessel generation. Therefore, our results suggest that pre-established regulatory networks are repeatedly recruited for viviparity and that these are shared at deep evolutionary scales.

The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen Candida albicans exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of β-glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating XOG1-mediated “shaving” of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion., The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen Candida albicans masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans masks β-1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced β-glucan “masking” pathway to promote β-1,3-glucan “shaving.” Inactivation of XOG1 blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines β-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes.

Objective: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily causes respiratory illness. However, neurological sequelae from novel coronavirus disease 2019 (COVID-19) can occur. Patients with neurological conditions may be at higher risk of developing worsening of their underlying problem. Here we document our initial experiences as neurologic consultants at a single center quaternary hospital at the epicenter of the COVID-19 pandemic. Methods: This was a retrospective case series of adult patients diagnosed with SARS-CoV-2 who required neurological evaluation in the form of a consultation or primary neurological care from March 13, 2020 to April 1, 2020. Results: Thirty-three patients (ages 17-88 years) with COVID-19 infection who required neurological or admission to a primary neurology team were included in this study. The encountered neurological problems associated with SARS-CoV-2 infection were encephalopathy (12 patients, 36.4%), seizure (9 patients, 27.2%), stroke (5 patients, 15.2%), recrudescence of prior neurological disease symptoms (4 patients, 12.1%), and neuromuscular (3 patients, 9.1%). The majority of patients who required evaluation by neurology had elevated inflammatory markers. Twenty-one (63.6%) patients were discharged from the hospital and 12 (36.4%) died from COVID-19 related complications. Conclusion: This small case series of our initial encounters with COVID-19 infection describes a range of neurological complications which are similar to presentations seen with other critical illnesses. COVID-19 infection did not change the overall management of neurological problems.

Candida albicans is a normal member of the human microbiome. It is also an opportunistic pathogen, which can cause life-threatening systemic infections in severely immunocompromized individuals. Despite the availability of antifungal drugs, mortality rates of systemic infections are high and new drugs are needed to overcome therapeutic challenges including the emergence of drug resistance. Targeting known disease pathways has been suggested as a promising avenue for the development of new antifungals. However

Candida albicans is a normal member of the human microbiome. It is also an opportunistic pathogen, which can cause life-threatening systemic infections in severely immunocompromized individuals. Despite the availability of antifungal drugs, mortality rates of systemic infections are high and new drugs are needed to overcome therapeutic challenges including the emergence of drug resistance. Targeting known disease pathways has been suggested as a promising avenue for the development of new antifungals. However

Objective: Performance validity tests (PVTs) are essential in neuropsychological evaluations; however, it has been questioned how PVTs function in the context of cognitive impairment, and whether cognitive impairment alone is sufficient to cause PVT failure. Further, there is concern that some clinicians will disregard failed PVTs due to their perception that failures represent false-positive errors secondary to cognitive impairment. This study examined patterns associated with cognitively impaired versus noncredible performance across a battery of PVTs and neuropsychological tests. Additionally, the impact of VA service-connection and disability-seeking status on test validity was investigated.Method: A mixed-clinical sample of 103 veterans were administered six PVTs and neuropsychological tests. Performance was compared across three groups: valid-cognitively unimpaired, valid-cognitively impaired, and noncredible.Results: Significant PVT score differences and failure rates emerged across the thr...

Assessment of performance validity is an essential part of a neuropsychological evaluation, with the inclusion of two or more performance validity tests (PVTs) becoming routine practice. Considering the time to administer multiple tests, there has been some support for use of the Test of Memory Malingering (TOMM) Trial 1 (T1) as an independent, “one and done” PVT. Notably, cutoffs for TOMM T1 need further validation, with an emphasis on minimizing false-positive classifications among those with bona fide cognitive impairment. In a clinically referred sample of 127 veterans, this study examined the role of cognitive impairment in TOMM performance and the utility of a TOMM T1 as an independent PVT. Examinees were administered the TOMM and three additional PVTs as part of a comprehensive neuropsychological battery. Sixty-eight percent of examinees were classified valid (35% of valid examinees were cognitively impaired). TOMM T1 ≤ 40 had excellent observed sensitivity (83%) and specificity (93%) overall, with minimal false-positive classification. TOMM T1 was also significantly correlated and concordant with other memory-based PVTs. Given score ranges and failure rates for TOMM T1 ≤ 40 among those with neurological/neurocognitive conditions, scores in the 37–40 range may merit administration of additional TOMM trials to maximize accuracy in identifying valid-cognitively impaired versus noncredible performance. Otherwise, an abbreviated TOMM administration (i.e., only T1) using a cutoff of ≤ 40—in conjunction with one or more additional PVTs—may be sufficient for detecting noncredible/invalid test performance in the absence of known or suspected neurological/neurocognitive disorders.

Supplemental Digital Content is available in the text., Background and Purpose— Although some evidence has found that the Mediterranean diet (MD) is protective for stroke risk, few studies have investigated whether this relationship differs by sex or cardiovascular disease risk. Methods— We investigated the relationship between adherence to the MD score, estimated using 7-day dietary diaries and risk of incident stroke in an observational prospective population-based cohort study of 23 232 men and women (54.5% women) aged 40 to 77 years who participated in the European Prospective Investigation into Cancer study in Norfolk, United Kingdom. Risk of incident stroke was calculated using multivariable Cox regression, in the whole population, and also stratified by sex and cardiovascular disease risk profile, using the Framingham risk score. Results— During 17.0 years of follow-up (395 048 total person-years), 2009 incident strokes occurred. Risk of stroke was significantly reduced with greater adherence to the MD score (quartile 4 versus quartile 1 hazard ratio [HR], 0.83; 95% CI, 0.74–0.94; P-trend

Protection and deprotection of organic compounds in multistep reactions using functional groups such as tert-butoxycarbonyl (Boc), is widely performed in synthetic organic chemistry. Reaction rate acceleration studies in spray-based ionization methods (electrosonic spray, paper spray, nanospray) have become increasingly common. Here, we demonstrate reaction rate acceleration of Boc deprotection using easy ambient sonic-spray ionization (EASI), a pneumatic technique which does not involve an applied voltage, in a teaching laboratory setting. The goal of this laboratory exercise was to explore acceleration in a previously unexplored spray-based reaction, while emphasizing in a pedagogic setting the importance of protecting groups for multistep synthesis. Rate acceleration factors of more than an order of magnitude were observed in the uncharged micron-sized droplets generated by EASI. The effect of reaction conditions on reaction acceleration was examined including changes in the type of acid, reagent concentration ratios and syringe pump flow rates. Student knowledge was assessed by pre-laboratory assignments, post-laboratory reports and oral interviews.

The mechanism of the Ritter-type C-H amination reaction of menthol with acetonitrile using CuBr2, Selectfluor, and Zn(OTf)2, first disclosed by Baran and coworkers in 2012, was studied using a combination of online electrospray ionization mass spectrometry, continuous UV/vis spectrometric monitoring, and density functional theory calculations. In addition to corroborating Baran's original mechanistic proposal, these studies uncovered a second pathway to product formation, which likely only occurs in microdroplets. DFT calculations show that neither pathway has a barrier that is greater than 6.8 kcal/mol, suggesting that both mechanisms are potentially operative under ambient conditions.

The nucleophilic opening of an epoxide is a classic organic reaction that has widespread utility in both academic and industrial applications. We have studied the reaction of limonene oxide with morpholine to form 1-methyl-2-morpholino-4-(prop-1-en-2-yl) cyclohexan-1-ol in bulk solution and in electrosprayed microdroplets with a 1:1 v/v water/methanol solvent system. We find that even after 90 min at room temperature, there is no product detected by nuclear magnetic resonance spectroscopy in bulk solution whereas in room-temperature microdroplets (2–3 μm in diameter), the yield is already 0.5% in a flight time of 1 ms as observed by mass spectrometry. This constitutes a rate acceleration of ~ 105 in the microdroplet environment, if we assume that as much as 5% of product is formed in bulk after 90 min of reaction time. We examine how the reaction rate depends on droplet size, solvent composition, sheath gas pressure, and applied voltage. These factors profoundly influence the extent of reaction. This dramatic acceleration is not limited to just one system. We have also found that the nucleophilic opening of cis-stilbene oxide by morpholine is similarly accelerated. Such large acceleration factors in reaction rates suggest the use of microdroplets for ring opening of epoxides in other systems, which may have practical significance if such a procedure could be scaled.

Vaccination is an important tool in poultry health, but is itself a stressor often resulting in a reduction in feed intake, body weight gain, and nutrient digestibility. In other species, vaccination is associated with an immediate acute-phase response. As an important immune parameter, the circulating heterophil/lymphocyte (H/L) ratio is a well-recognized parameter of stress in poultry. In this study, the effects of a routinely used commercial poultry vaccine on the acute phase response (APR) and H/L ratios in specific pathogen-free (SPF) layer chicks was examined to determine if post vaccination (PV) stress and an APR occur. A combined Newcastle disease and infectious bronchitis vaccine (Nobalis Ma5+Clone 30) was administered to SPF chicks by the intraocular route at age 7 d. Acute phase proteins (APP), alpha-1 acid glycoprotein (AGP) and serum amyloid A (SAA) were measured by enzyme-linked immunosorbent assays at d 0 (pre-vaccination) and d 0.5, 1, 2, 3, 4, 5, 6, and 21 PV. Stress was determined in the chicks by measurement of the H/L ratio. The immune response to the vaccine was estimated by measurement of the antibody (IgY) response to the vaccine at d 21.\ud \ud The antibody titer was significantly (P < 0.05) higher in the vaccinated group at 21 d PV, confirming stimulation of the immune system. The H/L ratio was also significantly higher in the vaccinated group at 1 to 2 d (P < 0.01) and at 3 d (P < 0.05) PV. The concentration of SAA increased by 2.8-fold, from 63.7 μg/mL in controls to 181 μg/mL in the vaccinated group, (P < 0.05) at 1 d PV. AGP increased 1.6-fold at 2 d PV, (from 0.75 g/mL in the control group to 1.24 g/mL in the vaccinated group, P < 0.05).\ud \ud In conclusion an immediate but mild APR occurred in the chicks following intraocular vaccination, whereas the stress response as measured by H/L ratio seemed to be more specific and sensitive. Measurement of these biomarkers of the host response could be a tool in vaccine development.

Aims To describe the gross motor function of individuals with HNRNPH2-related disorder (OMIM 300986, Mental Retardation, X-linked, Syndrome, Bain Type; MRXSB) and determine the associations between clinician-measured motor function and caregiver-reported mobility scores. Methods Developmental histories of 17 female participants with HNRNPH2-related disorder (mean age 11.2 years, range 2.7–37.1 years) with various genotypes within and adjacent to the nuclear localization sequence (NLS) were analyzed. Participants performed the Gross Motor Function Measure-88 (GMFM-88) and caregivers completed developmental histories and the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT). Results All participants had measurable and quantifiable motor impairments. A strong positive correlation between the clinician-measured GMFM-88 total score and the caregiver-reported PEDI-CAT mobility domain score was established. Motor deficits were noted more often in individuals who were nonverbal. The 2 participants with genotypes adjacent to the NLS appear to have milder motor phenotypes. Conclusions The GMFM-88 and PEDI-CAT are useful and feasible measures of mobility in individuals with HNRNPH2-related disorders. Convergent validity was established between the clinician-measured GMFM-88 raw scores and caregiver-reported PEDI-CAT mobility domain scores. Factors including verbal status and genotype may impact motor abilities.

Organic gunshot residues, specifically methyl centralite (1,3-dimethyl-1,3-diphenylurea) and ethyl centralite (1,3-diethyl-1,3-diphenylurea), are characteristic compounds for which forensic analysts test when determining if an individual has discharged a firearm. These distinctive compounds have long been analyzed by several instrumental techniques, many of which involve extensive sample preparation or have lengthy analysis times. Presented here is an ambient ionization method that requires no sample preparation, offers real-time analysis, and can be paired with a portable ion trap mass spectrometer for in-situ analysis. Swab touch spray ionization utilizes a rayon-tipped swab that has an aluminum wire handle which can simply be swabbed over the area of interest. After contacting the hands of the shooter, or other surfaces, the swab simply has solvent applied to the rayon tip and a high voltage applied to the aluminum handle. This process generates ions that the mass spectrometer will use to determine if the organic gunshot residues are present. Mass spectrometry allows for the direct confirmation of organic gunshot residue on suspects hands, confirmed through tandem mass spectrometry. Additional benefits of swab touch spray ionization are that the swabs are commercially available, they are sterile, and they are individually packaged to prevent contamination. The swabs are also forensically feasible because they are sealed prior to delivery by the vendor with a tamper-proof label. Here we have shown that this ambient ionization method allows for the direct swabbing of suspected shooters hands for trace residues and confirm the presence of the two organic gunshot residues investigated.

This study examined the Word Choice Test’s (WCT) utility as a performance validity test in a mixed clinical sample of veterans referred for neuropsychological evaluation. Participants completed Green’s Word Memory Test (WMT), WCT, and Test of Memory Malingering (TOMM) Trial 1. Using the WMT as the criterion for valid performance, logistic regressions examined the WCT and TOMM’s classification accuracy for those with and without cognitive impairment (CI). Receiver operating characteristic curves were used to establish cut scores which maximized the sensitivity/specificity of each measure. In those without CI, both tests showed good classification accuracy (86.7% and 85.0%, respectively). Among those with CI, the TOMM retained good classification accuracy (82.3%), while the WCT’s decreased considerably (69.4%). Optimal WCT cut scores differed based on impairment status, with a higher sensitivity/specificity trade-off among those with CI. Successful performance on the WCT appeared to rely more heavily on cognitive processes unrelated to performance validity.

The goal of this laboratory exercise was for students to understand the concept of chirality and how enantiomeric excess (ee) is experimentally determined using the analysis of ibuprofen as an example. Students determined the enantiomeric excess of the analyte by three different instrumental methods: mass spectrometry, nuclear magnetic resonance spectroscopy, and optical polarimetry. This laboratory exercise introduced mass spectrometry into the first-semester organic chemistry curriculum. Further, it allowed the students to compare and contrast the analytical figures of merit for each technique, a topic usually discussed later in chemistry courses. The ee resolution, sensitivity, limits of detection, and required sample preparation were considered. Furthermore, this laboratory experiment taught students how to use the kinetic method for chiral analysis by mass spectrometry, a new technique in a student laboratory exercise. Students’ knowledge of how to select the appropriate technique for enantiomeric ex...

This study cross-validated the Dot Counting Test (DCT) as a performance validity test (PVT) among a mixed clinical veteran sample. Completion time and error patterns also were examined by validity group and cognitive impairment status.This cross-sectional study included 77 veterans who completed the DCT during clinical evaluation. Seventy-four percent (N = 57) were classified as valid and 26% as noncredible (N = 20) via the Word Memory Test (WMT) and Test of Memory Malingering (TOMM). Among valid participants, 47% (N = 27) were cognitively impaired, and 53% (N = 30) were unimpaired.DCT performance was not significantly associated with age, education, or bilingualism. Seventy-five percent of the overall sample committed at least one error across the 12 stimulus cards; however, valid participants had a 27% higher rate of 0 errors, while noncredible participants had a 35% higher rate of ≥4 errors. Overall, noncredible individuals had significantly longer completion times, more errors, and higher E-scores. Conversely, those with cognitive impairment had longer completion times, but comparable errors to their unimpaired counterparts. Finally, DCT E-scores significantly predicted group membership with 83.1% classification accuracy and an area under the curve of .87 for identifying invalid performance. The optimal cut-score of 15 was associated with 70% sensitivity and 88% specificity.The DCT demonstrated good classification accuracy and sensitivity/specificity for identifying noncredible performance in this mixed clinical veteran sample, suggesting utility as a non-memory-based PVT with this population. Moreover, cognitive impairment significantly contributed to slower completion times, but not reduced accuracy.

Advances in chemical sampling using miniature mass spectrometer technology are used to monitor slow reactions at a frequency of ca. 180 h–1 (on the Mini 12) with no sample carryover and with inline derivatization in the case of poorly ionizing compounds. Moreover, we demonstrate high reproducibility with a relative error of less than 10% for major components. Monitoring is enabled using a continuous-flow nanoelectrospray (CF-nESI) probe contained in a custom-built 3D-printed rotary holder. The holder position is automatically set using a stepper motor controlled by a microcontroller. Reaction progress of up to six reactions, including hydrazone formation and Katritzky transamination, can be monitored simultaneously without carryover for several hours.

Current mass spectrometry techniques and applications, especially those which achieve high speed by using ambient ionization and/or miniature instruments are presented with emphasis on the nature of the instrumentation and methodology. This is done in the context of describing an intensive two-day workshop for upper division undergraduate students (9th annual meeting for the Center for Analytical Instrumentation Development, CAID, Purdue University). Six hands-on demonstrations are detailed. Multiple ionization sources, types of mass spectrometers, and ion manipulation techniques are covered. The meeting “State-of-the-Art Mass Spectrometry for Point-of-Care and other Applications” might serve as a model for intensive short courses that other institutions might wish to develop in their particular research specialties. A hallmark is the emphasis on methodology, fundamental theory, and current applications. The effectiveness of the CAID short course to deeply immerse, motivate, and educate students was confirmed through formal student assessment and feedback.

Previous reports have shown that reactions occurring in the microdroplets formed during electrospray ionization can, under the right conditions, exhibit significantly greater rates than the corresponding bulk solution-phase reactions. The observed acceleration under electrospray ionization could result from a solution-phase, a gas-phase, or an interfacial reaction. This study shows that a gas-phase ion/molecule (or ion/ion) reaction is not responsible for the observed rate enhancement in the particular case of the Fischer indole synthesis. The results show that the accelerated reaction proceeds in the microdroplets, and evidence is provided that an interfacial process is involved. Graphical Abstract!-- [INSERT GRAPHICAL ABSTRACT TEXT HERE] --.

Introduction/Objective Cutaneous adenolipoma is a rare, benign variant of solitary lipoma characterized by a mature adipocytic proliferation with entrapped eccrine or apocrine sweat glands. It is found predominately in middle-aged females, with a predilection for lower extremities including the thigh and gluteal regions. Cutaneous adenolipoma is presumed to be a hamartomatous process. Herein, we report a unique case of a cutaneous eccrine adenolipoma with a spindle cell component, namely, an early evolving spindle cell adenolipoma. Methods A 43-year-old female with a recurrent history of hidradenitis presented with a 2.7 cm x 1.5 cm x 0.7 cm soft, mobile nodule on the right posterior thigh. It had been present for at least four months and clinically resembled a lipoma. An excisional punch biopsy was performed for pathological evaluation. A concurrent nevus lipomatosus superficialis was diagnosed from the right perineum. Results Gross examination of the thigh nodule revealed fragments of a tan-yellow, lobulated, fatty lesion. Microscopic examination demonstrated a benign lipomatous proliferation with entrapped eccrine glands associated with a surrounding spindle cell stroma. Initial differential diagnosis included a cutaneous eccrine adenolipoma variant and a cutaneous mixed solitary hamartoma composed of admixed neural, eccrine and lipomatous components. Immunohistochemical staining showed uptake for CD34 and CD10 in the spindle cell stromal component, but negative for desmin and S100. Based on our histopathological findings, our diagnosis of an eccrine cutaneous adenolipoma with a spindle cell component was rendered. This unique lesion displayed features of an evolving spindle cell lipoma with entrapped sweat glands, which may be viewed as an early stage of a dermal spindle cell adenolipoma. Conclusion Cutaneous eccrine adenolipoma is a rare, benign lipomatous neoplasm with entrapped sweat glands that can also show a spindle cell component. We share this rare lesion exemplifying the histomorphological spectrum of a lipomatous hamartoma and to highlight the recognition of a cutaneous adenolipoma.

The fungal cell wall is an essential organelle that maintains cellular morphology and protects the fungus from environmental insults. For fungal pathogens such as Candida albicans, it provides a degree of protection against attack by host immune defences. However, the cell wall also presents key epitopes that trigger host immunity and attractive targets for antifungal drugs. Rather than being a rigid shield, it has become clear that the fungal cell wall is an elastic organelle that permits rapid changes in cell volume and the transit of large liposomal particles such as extracellular vesicles. The fungal cell wall is also flexible in that it adapts to local environmental inputs, thereby enhancing the fitness of the fungus in these microenvironments. Recent evidence indicates that this cell wall adaptation affects host-fungus interactions by altering the exposure of major cell wall epitopes that are recognised by innate immune cells. Therefore, we discuss the impact of environmental adaptation upon fungal cell wall structure, and how this affects immune recognition, focussing on C. albicans and drawing parallels with other fungal pathogens.

To colonise their host, pathogens must counter local environmental and immunological challenges. Here, we reveal that the fungal pathogen Candida albicans exploits diverse host-associated signals to promote immune evasion by masking of a major pathogen-associated molecular pattern (PAMP), β-glucan. Certain nutrients, stresses and antifungal drugs trigger β-glucan masking, whereas other inputs, such as nitrogen sources and quorum sensing molecules, exert limited effects on this PAMP. In particular, iron limitation triggers substantial changes in the cell wall that reduce β-glucan exposure. This correlates with reduced phagocytosis by macrophages and attenuated cytokine responses by peripheral blood mononuclear cells. Iron limitation-induced β-glucan masking depends on parallel signalling via the iron transceptor Ftr1 and the iron-responsive transcription factor Sef1, and the protein kinase A pathway. Our data reveal that C. albicans exploits a diverse range of specific host signals to trigger protective anticipatory responses against impending phagocytic attack and promote host colonisation., The authors show that the fungal pathogen Candida albicans exploits diverse host-associated signals, including specific nutrients and stresses, to promote immune evasion by masking cell wall β-glucan, a major pathogen-associated molecular pattern.

In human hosts, the opportunistic fungal pathogen Candida albicans primarily proliferates in nutrient diverse niches. Environmental condition sensing regulates several fungal cellular features including, but not limited to, metabolism, cell wall elasticity, and virulence. In addition, yeast cell division exposes pathogen-associated molecular patterns (PAMPs) at the cell surface that are known to be immune-stimulatory (e.g. β-glucan). While various host environmental signals and cell wall stressors have been implicated in PAMP exposure in vitro, little is known about the molecular mechanisms that modulate PAMP exposure. We have shown that lactate, an alternative carbon source present in mucosal niches and produced by activated innate immune cells, acts as a signalling molecule to reduce β-glucan exposure. However, it is unknown whether the reduction in β-glucan exposure is the result of PAMP camouflaging by other cell wall components, PAMP modification, or a combination of both processes. We characterized the downstream effectors affecting PAMP exposure in response to different carbon sources and environmental conditions that C. albicans encounters during transit through host niches. Using proteomics, gene deletion analysis, and pharmacological assays, we identified the downstream effectors involved in evading β-glucan recognition by the host pattern recognition receptor, Dectin-1. We can also show microscopic changes to the overall distribution of Dectin-1-recognised β-glucan on the cell surface in response to masking conditions as well as alterations to the interactions of masked cells with phagocytes. Finally, we are examining the impact of PAMP modulation and its inhibition on disease outcomes.

Background The cuticle is an invisible glycosylated protein layer that covers the outside of the eggshell and forms a barrier to the transmission of microorganisms. Cuticle-specific staining and in situ absorbance measurements have been used to quantify cuticle deposition in several pure breeds of chicken. For brown eggs, a pre-stain and a post-stain absorbance measurement is required to correct for intrinsic absorption by the natural pigment. For white eggs, a post-stain absorbance measurement alone is sufficient to estimate cuticle deposition. The objective of the research was to estimate genetic parameters and provide data to promote adoption of the technique to increase cuticle deposition and reduce vertical transmission of microorganisms. Results For all pure breeds examined here, i.e. Rhode Island Red, two White Leghorns, White Rock and a broiler breed, the estimate of heritability for cuticle deposition from a meta-analysis was moderately high (0.38 ± 0.04). In the Rhode Island Red breed, the estimate of the genetic correlation between measurements recorded at early and late times during the egg-laying period was ~ 1. There was no negative genetic correlation between cuticle deposition and production traits. Estimates of the genetic correlation of cuticle deposition with shell color ranged from negative values or 0 in brown-egg layers to positive values in white- or tinted-egg layers. Using the intrinsic fluorescence of tryptophan in the cuticle proteins to quantify the amount of cuticle deposition failed because of complex quenching processes. Tryptophan fluorescence intensity at 330 nm was moderately heritable, but there was no evidence of a non-zero genetic correlation with cuticle deposition. This was complicated furthermore by a negative genetic correlation of fluorescence with color in brown eggs, due to the quenching of tryptophan fluorescence by energy transfer to protoporphyrin pigment. We also confirmed that removal of the cuticle increased reflection of ultraviolet wavelengths from the egg. Conclusions These results provide additional evidence for the need to incorporate cuticle deposition into breeding programs of egg- and meat-type birds in order to reduce vertical and horizontal transmission of potentially pathogenic organisms and to help improve biosecurity in poultry. Electronic supplementary material The online version of this article (10.1186/s12711-019-0467-5) contains supplementary material, which is available to authorized users.

Use of multiple performance validity tests (PVTs) may best identify invalid performance, though few studies have examined the utility and accuracy of combining PVTs. This study examined the following PVTs in the Advanced Clinical Solutions (ACS) package to determine their utility alone and in concert: Word Choice Test (WCT), Reliable Digit Span (RDS), and Logical Memory Recognition (LMR). Ninety-three veterans participated in clinical neuropsychological evaluations to determine presence of cognitive impairment; 25% of the performances were deemed invalid via criterion PVTs. Classification accuracy of the ACS measures was assessed via receiver operating characteristic curves, while logistic regressions determined utility of combining these PVTs. The WCT demonstrated superior classification accuracy compared to the two embedded measures of the ACS, even in veterans with cognitive impairment. The two embedded measures (even when used in concert) exhibited inadequate classification accuracy. A combined model with all three ACS PVTs similarly demonstrated little benefit of the embedded indicators over the WCT alone. Results suggest the ACS WCT has utility for detecting invalid performance in a clinical sample with likely cognitive impairment, though the embedded ACS measures (RDS and LMR) may have limited incremental utility, particularly in individuals with cognitive impairment.

The fungal cell wall is an essential organelle that maintains cellular morphology and protects the fungus from environmental insults. For fungal pathogens such as Candida albicans, it provides a degree of protection against attack by host immune defences. However, the cell wall also presents key epitopes that trigger host immunity and attractive targets for antifungal drugs. Rather than being a rigid shield, it has become clear that the fungal cell wall is an elastic organelle that permits rapid changes in cell volume and the transit of large liposomal particles such as extracellular vesicles. The fungal cell wall is also flexible in that it adapts to local environmental inputs, thereby enhancing the fitness of the fungus in these microenvironments. Recent evidence indicates that this cell wall adaptation affects host-fungus interactions by altering the exposure of major cell wall epitopes that are recognised by innate immune cells. Therefore, we discuss the impact of environmental adaptation upon fungal cell wall structure, and how this affects immune recognition, focussing on C. albicans and drawing parallels with other fungal pathogens.

Background CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome.Methods In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1,2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 mu m(2)/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered.Findings We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, p(interaction)=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, p(interaction)=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low.Interpretation Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imagingto-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

The inflammatory response in chickens (Gallus Gallus domesticus) is an integral part of the bird's response to infection. Detailing proteomic changes occurring during infection would be beneficial to the poultry industry, offering opportunities for comparative pathophysiological analysis. The objective of this study was to quantify the changes in the plasma proteome in chickens challenged with lipopolysaccharide (LPS), a bacterial endotoxin known to stimulate the host innate immune system. Plasma from chicken (N = 6) challenged with Escherichia coli (LPS) (2 mg/kg body weight) was collected pre (0 h) and at 12, 24, 48, and 72 h post-injection along with plasma from a control group (N = 6) challenged with sterile saline. Samples were analysed by a quantitative Tandem Mass Tags approach using a Q-Exactive-Plus mass-spectrometer. Identification and relative quantification were performed using Proteome Discoverer, and data were analysed using R. Gene Ontology terms were analysed by Cytoscape based on the Gallus gallus database. Finally, 87 significantly regulated proteins were found, including serum-amyloid-A, ovotransferrin and alpha-1-acid-glycoprotein, showing a significant effect of time post-injection in the LPS-treated group. Different pathways related with protein activation cascade and heterotopic cell-cell adhesion were affected by LPS-challenge. LPS-challenged chickens demonstrate significant changes to the plasma proteome with both increases and decreases of individual proteins within 12 h of challenge. Significance The injection of chicken with bacterial lipopolysaccharide followed by sequential plasma and clinical analysis of the bird, is a long established and a widely used model for inflammation and infection studies. This study, utilising and combining proteomic and immunoassay analysis with bioinformatic analysis, revealed that several biological pathways are modulated during this early period of inflammation. In addition, proteins with biomarker potential were identified and successfully validated. This experimental model also demonstrated potential for pathophysiological mechanism investigation and as an inflammatory model for biomedical research. There is, despite plasma being an easily accessible biological matrix which is representative of the health status of the bird, scarce data on the chicken plasma proteome. This research makes a positive contribution to the current field, generating significant data for continuing comparative analysis.

To understand child neurology care practices in telehealth (TH), we conducted an online survey interested in identifying which patients should be triaged for in-person evaluations in lieu of telehealth management. We also sought to identify provider and patient/parent limitations of the TH experience. One hundred fourteen clinicians completed the online survey. The majority of child neurologists transitioned within 3 weeks of the pandemic onset and found it inappropriate to evaluate a child under 1 year of age via TH. We identified specific disorders considered inappropriate for initial evaluation via TH, including neuromuscular disease, neuropathy, weakness, autoimmune disease and autism spectrum disorders. Patient and parent technical and economic issues are significant limitations of TH. We suggest quality improvement measures to provide additional training, focusing on particular disorders and increased access for those patients currently excluded from or limited in using or accessing TH.

Die bemerkenswerte Entdeckung, dass eine Reaktionsbeschleunigung in Losungen mit begrenztem Volumen erfolgt, wirft ein augenscheinliches Ratsel auf. Durch Spray-Ionisation gebildete Mikrotropfchen konnen genutzt werden, um den Verlauf von Reaktionen in der Bulkphase zu verfolgen und auserdem Reaktionen zwischen den Reagentien in solch einer Reaktion zu beschleunigen. In diesem Kurzaufsatz werden Beschleunigungsphanomene in Tropfchen und dunnen Filmen vorgestellt und moderne Methoden, die zur Untersuchung beschleunigter Reaktionen in Losungen mit begrenztem Volumen und groser Oberflache angewendet werden, zusammengefasst. Bedingungen, die entweder eine einfache Verfolgung oder eine Beschleunigung bestimmen, werden beim Auftreten von diskontinuierlicher und vollstandiger Desolvatisierung als Endpunkt der Tropfenentwicklung abgestimmt. Die gegensatzlichen Merkmale von Reaktionen in Mikrotropfchen und in Bulklosung werden in Verbindung mit moglichen Mechanismen, nach denen eine Reaktionsbeschleunigung in Mikrotropfchen erfolgt, beschrieben. Derzeitige Anwendungen von Tropfchen als Mikroreaktoren werden im Hinblick auf eine Reaktionsbeschleunigung in begrenzten Volumina und ein mogliches zukunftiges Scale-up angefuhrt.

Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.

RATIONALE Electrospray ionization-mass spectrometry (ESI-MS) is an emerging tool for reaction monitoring. It can be accompanied by reaction acceleration in charged droplets. METHODS The time course of the bulk reaction of indoline-2,3-dione with phenylhydrazine in methanol to produce 3-(2- phenylhydrazono)indolin-2-one was monitored by ESI. Both nanoESI and electrosonic spray ionization (ESSI) were used for this study as representing two common forms of ionization for reaction monitoring. The effect on product yield of the distance the droplets travel between the source and the MS inlet was varied and product/starting material ratios were examined. RESULTS Product yield is dramatically increased by increasing the distance. At short distances reaction monitoring can be performed without acceleration and at greater distances reaction acceleration occurs. This distance effect over the course of the reaction roughly parallels the time dependence of the bulk-phase reaction. CONCLUSIONS Reaction acceleration in droplets is attributed to solvent evaporation leading to increased surface to volume ratios. An acceleration factor of 10(4) , measured relative to the bulk reaction at short times, is readily achieved by simply increasing the droplet distance of flight showing that the same ionization source can be used to monitor reactions with or without acceleration. Copyright © 2016 John Wiley & Sons, Ltd.

Inductive electrospray ionization (iESI) is an ambient ionization method that is particularly well-suited to online reaction monitoring. It allows the potential of electrospray mass spectrometry (MS) to be realized as a routine process analytical technology (PAT) tool to monitor practical synthetic reactions in real time. In this study, a synthetic route to Anagliptin (target API) was successfully monitored using online iESI-MS. Starting materials not seen by traditional reaction monitoring tools (HPLC-UV/Vis and GC-FID) were observed, as well as water-sensitive reagents and intermediates which cannot easily be followed by other methods. Online tandem mass spectrometry (MS/MS) was used to characterize chemical species in the reaction mixture. Impurities and byproducts were identified, and information on the progress of byproduct formation enabled implementation of strategies to eliminate these byproducts in the course of the reaction. This work demonstrates how iESI-MS can be employed to obtain comprehens...

Date Presented 03/27/20 Variants in the HNRNPH2 gene are associated with a neurodevelopmental disorder, including developmental delay, intellectual disability, autism and autistic features, tone abnormalities, and other multisystem problems. A battery of OT assessments to explore OT needs were added to an HNRNPH2 natural history study. Findings indicate further research is necessary in the implementation of OT-based assessments that possess heightened sensitivity to discern disease-specific qualities for this condition. Primary Author and Speaker: Donnielle Rome-Martin Additional Authors and Speakers: Olivia Thornburg Contributing Authors: Jennifer Bain

The Abu Dabbab rare-metal granite in the Central Eastern Desert of Egypt is a peraluminous alkali-feldspar leucogranite stock with minimummelt composition of albite-rich haplogranite and is characterized by economic resources of columbite group minerals (CGM) and cassiterite. The bulk-rock trace element composition is characterized by very low Sr, Ba, REE+Y, Zr, Ti, Ni, Cr concentrations, elevated Li and F, and very high Sn, Ta and Ga. The non-chondritic, low Y/Ho ratios and extremely low Nb/Ta and Zr/Hf ratios of the Abu Dabbab granite are consistent with highly evolved peraluminous granites. The chondrite-normalized REE patterns with significant tetrad effects (TE1,3 ~ 1.6–2.6) and strongly negative Eu anomalies are indicative of the magmatic to hydrothermal transition. Heterogeneous 147Sm/144Nd (0.20411–0.51923) and 143Nd/144Nd (0.512968–0.514056) values of the bulk-rock reflect a disturbed Sm-Nd isotope system. Nevertheless, the initial eNd values calculated for a wide range of Neoproterozoic ages (500–700 Ma) are consistently positive, suggesting a juvenile source. Laser ablation ICP-MS analyses of the CGM, cassiterite, wolframite and Mn-ilmenite show elevated rare metal concentrations and complex REE tetrad patterns, reflecting fluid-melt interactions. The metasomatic fluids associated with the Abu Dabbab rare-metal granite were primarily low-salinity (

The Department of Veterans Affairs Polytrauma Transitional Rehabilitation Program was established to extend the rehabilitation of veterans and active duty service members past the acute phase and reintegrate them into the community. Effective community reintegration is best achieved with a diverse interdisciplinary team that treats patients' physical, cognitive, and psychological deficits in a collaborative approach. Barriers, such as lack of accurate awareness of functional limitations and premorbid psychosocial stressors, can limit the recovery process. Recovery from polytrauma injuries is often a lifelong process, with the goal of maximizing functional independence and quality of life.

Standards for neuromonitoring during extracorporeal membrane oxygenation support do not currently exist, and there is wide variability in practice. We present our institutional experience at an academic children's hospital since establishment of a continuous electroencephalography monitoring protocol for extracorporeal membrane oxygenation patients.Retrospective, single-center study.Neonatal ICU and PICU in an urban, quaternary care center.All neonatal and pediatric patients requiring extracorporeal membrane oxygenation.None.During the study period, 70 patients were cannulated for extracorporeal membrane oxygenation and had continuous electroencephalography monitoring for greater than 24 hours. Electroencephalographic seizures were observed in 16 of 70 patients (23%), including five patients (7%) who were in status epilepticus. Among patients with continuous electroencephalography seizures, nine (56%) had subclinical nonconvulsive status epilepticus and eight (50%) had seizures in the initial 24 hours of extracorporeal membrane oxygenation support. Survival to hospital discharge was significantly greater for extracorporeal membrane oxygenation patients without seizures (74% vs 44%; p = 0.02).Seizures occur in a significant proportion of pediatric and neonatal extracorporeal membrane oxygenation patients, frequently in the initial 24 hours after extracorporeal membrane oxygenation cannulation. Because seizures are associated with significantly decreased survival, neuromonitoring early in the extracorporeal membrane oxygenation course is important and useful. Further studies are needed to correlate electroencephalography findings with neurologic outcome.