bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased H2O2 levels and p53 stabilization lead to mitochondrial dysfunction in XPC-deficient cells
Authors: Freire T S , Mori M P , Miranda J N F A , Muta L Y M , Machado F T , Moreno N C , Souza-Pinto N C
Published: August 2021

XPC deficiency is associated with mitochondrial dysfunction, increased mitochondrial H2O2 production and sensitivity to the Complex III inhibitor antimycin A (AA), through a yet unclear mechanism. We found an imbalanced expression of several proteins that participate in important mitochondrial function and increased expression and phosphorylation of the tumor suppressor p53 in Xeroderma pigmentosum complementation group C (XP-C) (XPC-null) cells compared with an isogenic line corrected in locus with wild-type XPC (XPC-wt). Interestingly, inhibition of p53 nuclear import reversed the overexpression of mitochondrial proteins, whereas AA treatment increased p53 expression more strongly in the XP-C cells. However, inhibition of p53 substantially increased XP-C cellular sensitivity to AA treatment, suggesting that p53 is a critical factor mediating the cellular response to mitochondrial stress. On the other hand, treatment with the antioxidant N-acetylcysteine increased glutathione concentration and decreased basal H2O2 production, p53 levels and sensitivity to AA treatment in the XPC-null back to the levels found in XPC-wt cells. Thus, the results suggest a critical role for mitochondrially generated H2O2 in the regulation of p53 expression, which in turn modulates XP-C sensitivity to agents that cause mitochondrial stress.
Recognition Memory is Associated with Distinct Patterns of Regional Gray Matter Volumes in Young and Aged Monkeys
Authors: Cooper C’iana P , Shafer Andrea T , Armstrong Nicole M , Rossi Sharyn L , Young Jennifer , Herold Christa , Gu Hong , Yang Yihong , Stein Elliot A , Resnick Susan M , Rapp Peter R
Published: August 2021

Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. Consistent with expectations from a long history of neuropsychological research, DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Less anticipated correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan, consistent with the perspective that the aged primate brain retains a substantial capacity for structural reorganization.
Standardized measurement of coronary inflammation using cardiovascular computed tomography: integration in clinical care as a prognostic medical device
Authors: Oikonomou Evangelos K , Antonopoulos Alexios S , Schottlander David , Marwan Mohammad , Mathers Chris , Tomlins Pete , Siddique Muhammad , Klüner Laura V , Shirodaria Cheerag , Mavrogiannis Michail C , Thomas Sheena , Fava Agostina , Deanfield John , Channon Keith M , Neubauer Stefan , Desai Milind Y , Achenbach Stephan , Antoniades Charalambos
Published: August 2021

Aims

Coronary computed tomography angiography (CCTA) is a first-line modality in the investigation of suspected coronary artery disease (CAD). Mapping of perivascular fat attenuation index (FAI) on routine CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which integrates standardized FAI mapping together with clinical risk factors and plaque metrics to provide individualized cardiovascular risk prediction.

Methods and results

The study included 3912 consecutive patients undergoing CCTA as part of clinical care in the USA (n = 2040) and Europe (n = 1872). These cohorts were used to generate age-specific nomograms and percentile curves as reference maps for the standardized interpretation of FAI. The first output of CaRi-Heart® is the FAI-Score of each coronary artery, which provides a measure of coronary inflammation adjusted for technical, biological, and anatomical characteristics. FAI-Score is then incorporated into a risk prediction algorithm together with clinical risk factors and CCTA-derived coronary plaque metrics to generate the CaRi-Heart® Risk that predicts the likelihood of a fatal cardiac event at 8 years. CaRi-Heart® Risk was trained in the US population and its performance was validated externally in the European population. It improved risk discrimination over a clinical risk factor-based model [Δ(C-statistic) of 0.085, P = 0.01 in the US Cohort and 0.149, P < 0.001 in the European cohort] and had a consistent net clinical benefit on decision curve analysis above a baseline traditional risk factor-based model across the spectrum of cardiac risk.

Conclusion

Mapping of perivascular FAI on CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which allows standardized measurement of coronary inflammation by calculating the FAI-Score of each coronary artery. The CaRi-Heart® device provides a reliable prediction of the patient's absolute risk for a fatal cardiac event by incorporating traditional cardiovascular risk factors along with comprehensive CCTA coronary plaque and perivascular adipose tissue phenotyping. This integration advances the prognostic utility of CCTA for individual patients and paves the way for its use as a dual diagnostic and prognostic tool among patients referred for CCTA.
Coherence for nutrition: insights from nutrition-relevant policies and programmes in Burkina Faso and Nigeria
Authors: Billings Lucy , Pradeilles Rebecca , Gillespie Stuart , Vanderkooy Anna , Diatta Dieynab , Toure Mariama , Diatta Ampa Dogui , Verstraeten Roos
Published: August 2021

There is consensus that policy coherence is necessary for implementing effective and sustainable approaches to tackle malnutrition. We look at whether policies and programmes provide a coherent pathway to address nutrition priorities and if programmes are designed to deliver interventions aligned to the nutrition policy agenda in Nigeria and Burkina Faso. A systematic desk review was performed on nutrition-relevant policy and programme documents, obtained through grey literature searches and expert recommendations. We developed a framework with an impact pathway structure that includes five process steps, which was used to guide coding, data reduction and synthesis and structure the analysis. We assessed internal coherence along process steps within a given document and external coherence across process steps for explicitly linked policy/programme pairs. The majority of policies and programmes had partial internal coherence for both countries. The identification of relevant nutrition interventions to address challenges and reach objectives was the strongest connection within policies (16 out of 45 had complete coherence), while among programmes, the strongest connection was coverage indicators that measure interventions (9 out of 21 had complete coherence). Eight programmes explicitly referenced at least one nutrition-relevant policy, with a total of 16 linked policy/programme pairs (13 pairs for Burkina Faso and 3 for Nigeria) across health, nutrition, agriculture and social focus areas. However, none of the linked pairs were assessed to have complete external coherence, suggesting that priorities at the policy level are not fully realized nor translated at the programme level. This study offers a new approach for the assessment of policy and programme coherence and specifically examines policy and programme linkages. We conclude that improved leadership on country priority setting and better alignment for nutrition within and across sectors is needed to enhance the effectiveness of nutrition investments.
Characterization of an Anti-Ebola Virus Hyperimmune Globulin Derived From Convalescent Plasma
Authors: Ciencewicki Jonathan M , Herbert Andrew S , Storm Nadia , Josleyn Nicole M , Huie Kathleen E , McKay Lindsay G A , Griffiths Anthony , Dye John M , Willis Todd , Arora Vikram
Published: August 2021

Background

Convalescent plasma has been used to treat many viral diseases including Ebola. The manufacture of a purified anti-Ebola virus (EBOV) intravenous immunoglobulin (IVIG) from pooled convalescent plasma is described in this paper.

Methods

An enzyme-linked immunosorbent assay (ELISA) targeting an EBOV surface glycoprotein antigen was used to determine the immunoglobulin titer of pooled plasma and purified anti-EBOV IVIG. Anti-EBOV IVIG was also tested in neutralization assays using a vesicular stomatitis virus pseudovirion expressing EBOV glycoprotein on its surface and with live EBOV. Finally, the efficacy of the anti-EBOV IVIG was assessed in a mouse model of EBOV infection.

Results

In the ELISA, the anti-EBOV IVIG was shown to have a 7-fold increase in immunoglobulin G (IgG) titer over pooled convalescent plasma. In both the pseudovirion and live virus assays, the anti-EBOV IVIG showed approximately 5- to 6-fold increased potency over pooled plasma. Anti-EBOV IVIG also significantly improved survivability in mice infected with the virus when administered concurrently or 2 days after infection.

Conclusions

These data support this purified anti-EBOV IVIG merits additional investigation and clinical trials for treatment and postexposure prophylaxis of Ebola virus disease. The experience gained can be applied to manufacture hyperimmune globulins against other emerging viruses.
A drug candidate for Alzheimer’s and Huntington’s disease, PBT2, can be repurposed to render Neisseria gonorrhoeae susceptible to natural cationic antimicrobial peptides
Authors: Jen Freda E -C , El-Deeb Ibrahim M , Zalucki Yaramah M , Edwards Jennifer L , Walker Mark J , von Itzstein Mark , Jennings Michael P
Published: August 2021

Background

Neisseria gonorrhoeae is a Gram-negative bacterial pathogen that causes gonorrhoea. No vaccine is available to prevent gonorrhoea and the emergence of MDR N. gonorrhoeae strains represents an immediate public health threat.

Objectives

To evaluate whether PBT2/zinc may sensitize MDR N. gonorrhoeae to natural cationic antimicrobial peptides.

Methods

MDR strains that contain differing resistance mechanisms against numerous antibiotics were tested in MIC assays. MIC assays were performed using the broth microdilution method according to CLSI guidelines in a microtitre plate. Serially diluted LL-37 or PG-1 was tested in combination with a sub-inhibitory concentration of PBT2/zinc. Serially diluted tetracycline was also tested with sub-inhibitory concentrations of PBT2/zinc and LL-37. SWATH-MS proteomic analysis of N. gonorrhoeae treated with PBT2/zinc, LL-37 and/or tetracycline was performed to determine the mechanism(s) of N. gonorrhoeae susceptibility to antibiotics and peptides.

Results

Sub-inhibitory concentrations of LL-37 and PBT2/zinc synergized to render strain WHO-Z susceptible to tetracycline, whereas the killing effect of PG-1 and PBT2/zinc was additive. SWATH-MS proteomic analysis suggested that PBT2/zinc most likely leads to a loss of membrane integrity and increased protein misfolding and, in turn, results in bacterial death.

Conclusions

Here we show that PBT2, a candidate Alzheimer’s and Huntington’s disease drug, can be repurposed to render MDR N. gonorrhoeae more susceptible to the endogenous antimicrobial peptides LL-37 and PG-1. In the presence of LL-37, PBT2/zinc can synergize with tetracycline to restore tetracycline susceptibility to gonococci resistant to this antibiotic.
Use of 2-hydroxy-4-(methylthio)-butanoic acid to inhibit Salmonella and Listeria in raw meat for feline diets and palatability in domestic cats
Authors: Owens Tiana G , King Broghan A , Radford Devon R , Strange Philip , Arvaj Laura , Guazzelli Pezzali Julia , Edwards Anne Michelle , Ganesh Daniel , DeVries Trevor J , McBride Brian W , Balamurugan Sampathkumar , Shoveller Anna K
Published: August 2021

While the raw pet food market continues to grow, the risk of bacterial contamination in these types of diets is a major concern, with Salmonella enterica and Listeria monocytogenes being the most frequently associated pathogens in raw pet food product recalls. dl-Methionine is included in some commercial feline kibble and canned diets to improve protein quality; however, an alternative to this is a liquid methionine supplement, 2-hydroxy-4-(methylthio)-butanoic acid (HMTBa), which is also an organic acid. 2-Hydroxy-4-(methylthio)-butanoic acid has previously demonstrated similar efficacy to formic acid against pathogens in a liquid environment and may be a good candidate to inhibit S. enterica and L. monocytogenes in raw ground meat. First, the minimum inhibitory concentration and minimum bactericidal concentration of HMTBa against these pathogens under laboratory growth conditions were determined by measuring growth of pathogens over 36 h when exposed to 10 concentrations of HMTBa (0.10% to 1.00%) mixed with tryptic soy broth. 2-Hydroxy-4-(methylthio)-butanoic acid included at ≥0.50% was bactericidal to S. enterica and L. monocytogenes (P < 0.05). Next, five levels of HMTBa (0.50% to 1.25%) were included in raw ground meat mixtures inoculated with cocktails of S. enterica or L. monocytogenes, and contamination levels were determined at four timepoints: immediately, and after refrigerated storage (4 °C) at 24, 48, and 72 h after removal from freezer (24 h at −20 °C). 2-Hydroxy-4-(methylthio)-butanoic acid included as 1.25% of the meat mixture reduced S. enterica and L. monocytogenes compared with the control (P < 0.05); however, it did not result in total kill of either of these pathogens. Following this, feeding behaviors of seven domestic cats were assessed when offered a raw chicken diet treated with or without 1.25% HMTBa for 5 d each, after which a 2-d 2-choice preference test was conducted. Cats demonstrated a preference for raw diets without HMTBa, but still readily consumed diets with 1.25% HMTBa, suggesting that such a diet was still palatable to them.
A Liberating-Engagement Theory of Consumer Fun
Authors: Oh Travis Tae , Pham Michel Tuan
Published: August 2021

The experience of fun plays a major role in the consumer society. Drawing on a grounded theory approach, we advance a psychological theory of consumer fun. Through an integration of in-depth interviews, narrative analyses, controlled experiments, structural equation modeling, and a photo-ethnography, our multimethod investigation makes four main contributions. First, we show that the experience of fun rests on the combination of two psychological pillars: hedonic engagement and a sense of liberation. Fun is an experience of liberating engagement—a temporary release from psychological restriction via a hedonically engaging activity. Second, we identify four situational facilitators—novelty, social connectedness, spontaneity, and spatial/temporal boundedness—that promote the experience of fun through their effects on hedonic engagement and the sense of liberation. Third, we show that although the psychology of fun is not consumption specific, there is an intimate connection between fun and consumption. Finally, we clarify the relation and distinction between fun and happiness. We discuss implications for our understanding of consumption experiences, business practices related to the engineering of fun, and consumers’ own pursuits of fun and happiness.
Multicancer Early Detection: Learning From the Past to Meet the Future
Authors: Etzioni Ruth , Gulati Roman , Weiss Noel S
Published: August 2021

Multicancer early detection (MCED) tests may soon be available to screen for many cancers using a single blood test, yet little is known about these tests beyond their diagnostic performance. Taking lessons from the history of cancer early detection, we highlight 3 factors that influence how performance of early detection tests translates into benefit and benefit-harm trade-offs: the ability to readily confirm a cancer signal, the population testing strategy, and the natural histories of the targeted cancers. We explain why critical gaps in our current knowledge about each factor prevent reliably projecting the expected clinical impact of MCED testing at this point in time. Our goal is to communicate how much uncertainty there is about the possible effects of MCED tests on population health so that patients, providers, regulatory agencies, and the public are well informed about what is reasonable to expect from this potentially important technological advance. We also urge the community to invest in a coordinated effort to collect data on MCED test dissemination and outcomes so that these can be tracked and studied while the tests are rigorously evaluated for benefit, harm, and cost.
Warming increases soil carbon input in aSibiraea angustata-dominated alpine shrub ecosystem
Authors: Liu Mei , Wen Jia-Hao , Chen Ya-Mei , Xu Wen-Juan , Wang Qiong , Ma Zhi-Liang
Published: August 2021

Plant-derived carbon (C) inputs via foliar litter, root litter and root exudates are key drivers of soil organic C stocks. However, the responses of these three input pathways to climate warming have rarely been studied in alpine shrublands. By employing a 3-year warming experiment (increased by 1.3 °C), we investigated the effects of warming on the relative C contributions from foliar litter, root litter and root exudates from Sibiraea angustata, a dominant shrub species in an alpine shrubland on the eastern Qinghai-Tibetan Plateau. The soil organic C inputs from foliar litter, root litter and root exudates were 77.45, 90.58 and 26.94 g C m−2, respectively. Warming only slightly increased the soil organic C inputs from foliar litter and root litter by 8.04 and 11.13 g C m−2, but significantly increased the root exudate C input by 15.40 g C m−2. Warming significantly increased the relative C contributions of root exudates to total C inputs by 4.6% but slightly decreased those of foliar litter and root litter by 2.5% and 2.1%, respectively. Our results highlight that climate warming may stimulate plant-derived C inputs into soils mainly through root exudates rather than litter in alpine shrublands on the Qinghai-Tibetan Plateau.
Establishing new diffuse interstellar band correlations to identify common carriers
Authors: Smith Fraser M , Harriott Tina A , Majaess Daniel , Massa Lou , Matta Chérif F
Published: August 2021

Observations from the Apache Point Observatory Catalog of Optical Diffuse Interstellar Bands (DIBs) were analysed to establish highly correlated pairs in terms of their equivalent widths (EWs) (r > 0.95), which importantly facilitate the identification of common carriers. A total of 154 846 possible DIB pairs were originally examined, yet only those with a sufficient number of sightlines (n > 9) that included EW uncertainties were subsequently investigated. The highest correlations for the resulting 56 893 DIB pairs are 6284.05–6203.58 Å (r = 0.990 ± 0.001), 6203.58–5780.64 Å (r = 0.986 ± 0.001), 6993.12–6269.89 Å (r = 0.984 ± 0.001), 6843.76–6792.51 Å (r = 0.984 ± 0.005), 6203.58–5487.64 Å (r = 0.983 ± 0.002), and 5061.50–4969.12 Å (r = 0.983 ± 0.009). The bands 5363.77, 5780.64, 6203.58, and 6284.05 Å appear most frequently. Novel relations linked to those DIBs and others warrant further research, in particular those pairs that involve one or both DIBs with low EWs (e.g. 5609.82, 6269.89, 6993.12, and 7224.16 Å). Numerous DIBs correlated with the prominent 4429.33 Å band were also discovered. The intriguing proposal of anionic hydrogen clusters as possible DIB carriers is also discussed.
Towards an advanced testing strategy for genotoxicity using image-based 2D and 3D HepG2 DNA damage response fluorescent protein reporters
Authors: ter Braak Bas , Niemeijer Marije , Wolters Liesanne , Le Dévédec Sylvia , Bouwman Peter , van de Water Bob
Published: August 2021

In vitro assessment of mutagenicity is an essential component in the chemical risk assessment. Given the diverse modes of action by which chemicals can induce DNA damage, it is essential that these in vitro assays are carefully evaluated for their possibilities and limitations. In this study, we used a fluorescent protein HepG2 reporter test system in combination with high content imaging. To measure induction of the DNA damage response (DDR), we used three different green fluorescent protein reporters for p53 pathway activation. These allowed for accurate quantification of p53, p21 and BTG2 (BTG anti-proliferation factor 2) protein expression and cell viability parameters at a single cell or spheroid resolution. The reporter lines were cultured as 2D monolayers and as 3D spheroids. Furthermore, liver maturity and cytochrome P450 enzyme expression were increased by culturing in an amino acid-rich (AAGLY) medium. We found that culture conditions that support a sustained proliferative state (2D culturing with normal DMEM medium) give superior sensitivity when genotoxic compounds are tested that do not require metabolisation and of which the mutagenic mode of action is dependent on replication. For compounds, which are metabolically converted to mutagenic metabolites, more differentiated HepG2 DDR reporters (e.g. 3D cultures) showed a higher sensitivity. This study stratifies how different culture methods of HepG2 DDR reporter cells can influence the sensitivity towards diverse genotoxicants and how this provides opportunities for a tiered genotoxicity testing strategy.
Kinetics of protein-assisted nucleic acid interconversion monitored by transient time resolved fluorescence in microfluidic droplets
Authors: Grytsyk Natalia , Cianfarani Damien , Crégut Olivier , Richert Ludovic , Boudier Christian , Humbert Nicolas , Didier Pascal , Mély Yves , Léonard Jérémie
Published: August 2021

Interconversions between nucleic acid structures play an important role in transcriptional and translational regulation and also in repair and recombination. These interconversions are frequently promoted by nucleic acid chaperone proteins. To monitor their kinetics, Förster resonance energy transfer (FRET) is widely exploited using ensemble fluorescence intensity measurements in pre-steady-state stopped-flow experiments. Such experiments only provide a weighted average of the emission of all species in solution and consume large quantities of materials. Herein, we lift these limitations by combining time-resolved fluorescence (TRF) with droplet microfluidics (DmF). We validate the innovative TRF-DmF approach by investigating the well characterized annealing of the HIV-1 (+)/(–) Primer Binding Sequences (PBS) promoted by a HIV-1 nucleocapsid peptide. Upon rapid mixing of the FRET-labelled (–)PBS with its complementary (+)PBS sequence inside microdroplets, the TRF-DmF set-up enables resolving the time evolution of sub-populations of reacting species and reveals an early intermediate with a ∼50 ps donor fluorescence lifetime never identified so far. TRF-DmF also favorably compares with single molecule experiments, as it offers an accurate control of concentrations with no upper limit, no need to graft one partner on a surface and no photobleaching issues.
Volatility Risk Pass-Through
Authors: Colacito Riccardo , Croce Mariano M , Liu Yang , Shaliastovich Ivan
Published: August 2021

We develop a novel measure of volatility pass-through to assess international propagation of output volatility shocks to macroeconomic aggregates, equity prices, and currencies. An increase in country’s output volatility is associated with a decrease in its output, consumption, and net exports. The average consumption pass-through is 50% (a 1% increase in output volatility increases consumption volatility by 0.5%) and it increases to 70% for shocks originating in smaller countries. The equity volatility pass-through is larger and in the order of 90%. A novel channel of risk sharing of volatility risks can explain our empirical findings.
Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
Authors: Dorst Daphne N , Rijpkema Mark , Buitinga Mijke , Walgreen Birgitte , Helsen Monique M A , Brennan Evan , Klein Christian , Laverman Peter , Ramming Andreas , Schmidkonz Christian , Kuwert Torsten , Schett Georg , van der Kraan Peter M , Gotthardt Martin , Koenders Marije I
Published: August 2021

Objective

Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using 68Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants.

Methods

Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received 68Ga-FAPI-04 and was scanned using PET/CT imaging.

Results

In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts.

Conclusion

In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.
Integrated application of metabolomics and RNA‐seq reveals thermogenic regulation in goat brown adipose tissues
Authors: Wang Yan , Chen Xingyue , Fan Wenli , Zhang Xujia , Zhan Siyuan , Zhong Tao , Guo Jiazhong , Cao Jiaxue , Li Li , Zhang Hongping , Wang Linjie
Published: August 2021

Brown adipose tissue (BAT) plays an important role on no shivering thermogenesis during cold exposure to maintain animal body temperature and energy homeostasis. However, knowledge of the cellular transition from white adipose tissue (WAT) to BAT is still limited. In this study, we provided a comprehensive metabolomics and transcriptional signatures of goat BAT and WAT. A total of 157 metabolites were significantly changed, including 81 upregulated and 76 downregulated metabolites. In addition, we identified the citric acid cycle, fatty acid elongation, and degradation pathways as coordinately activated in BAT. Interestingly, five unsaturated fatty acids (Eicosadienoic Acid, C20:2; γ‐Linolenic acid, C20:3; Arachidonic Acid, C20:4; Adrenic acid, C22:4; Docosahexaenoic acid, C22:6), Succinate, L‐carnitine, and L‐palmitoyl‐carnitine were found to be abundant in BAT. Furthermore, L‐carnitine, an intermediate of fatty acid degradation, is required for goat brown adipocyte differentiation and thermogenesis through activating AMPK pathway. However, L‐carnitine decreased lipid accumulation through inducing lipolysis and thermogenesis in white adipocytes. These results revealed that there are the significant alterations in transcriptomic and metabolomic profiles between goat WAT and BAT, which may contribute to better understanding the roles of metabolites in BAT thermogenesis process.
Endothelium‐dependent contraction: The non‐classical action of endothelial prostacyclin, its underlying mechanisms, and implications
Authors: Liu Bin , Zhou Yingbi
Published: August 2021

Although commonly thought to produce prostacyclin (prostaglandin I2; PGI2) that evokes vasodilatation and protects vessels from the development of diseases, the endothelial cyclooxygenase (COX)‐mediated metabolism has also been found to release substance(s) called endothelium‐derived contracting factor(s) (EDCF) that causes endothelium‐dependent contraction and implicates in endothelial dysfunction of disease conditions. Various mechanisms have been proposed for the process; however, the major endothelial COX metabolite PGI2, which has been classically considered to activate the I prostanoid receptor (IP) that mediates vasodilatation and opposes the effects of thromboxane (Tx) A2 produced by COX in platelets, emerges as a major EDCF in health and disease conditions. Our recent studies from genetically altered mice further suggest that vasomotor reactions to PGI2 are collectively modulated by IP, the vasoconstrictor Tx‐prostanoid receptor (TP; the prototype receptor of TxA2) and E prostanoid receptor‐3 (EP3; a vasoconstrictor receptor of PGE2) although with differences in potency and efficacy; a contraction to PGI2 reflects activities of TP and/or EP3 outweighing that of the concurrently activated IP. Here, we discuss the history of endothelium‐dependent contraction, evidences that support the above hypothesis, proposed mechanisms for the varied reactions to endothelial PGI2 synthesis as well as the relation of its dilator activity to the effect of another NO‐independent vasodilator mechanism, the endothelium‐derived hyperpolarizing factor. Also, we address the possible pathological and therapeutic implications as well as questions remaining to be resolved or limitations of our above findings obtained from genetically altered mouse models.
Two‐photon AMPK and ATP imaging reveals the bias between rods and cones in glycolysis utility
Authors: He Jiazhou , Yamamoto Masamichi , Sumiyama Kenta , Konagaya Yumi , Terai Kenta , Matsuda Michiyuki , Sato Shinya
Published: August 2021

In vertebrates, retinal rod and cone photoreceptor cells rely significantly on glycolysis. Lactate released from photoreceptor cells fuels neighboring retinal pigment epithelium cells and Müller glial cells through oxidative phosphorylation. To understand this highly heterogeneous metabolic environment around photoreceptor cells, single‐cell analysis is needed. Here, we visualized cellular AMP‐activated protein kinase (AMPK) activity and ATP levels in the retina by two‐photon microscopy. Transgenic mice expressing a hyBRET‐AMPK biosensor were used for measuring the AMPK activity. GO‐ATeam2 transgenic mice were used for measuring the ATP level. Temporal metabolic responses were successfully detected in the live retinal explants upon drug perfusion. A glycolysis inhibitor, 2‐deoxy‐d‐glucose (2‐DG), activated AMPK and reduced ATP. These effects were clearly stronger in rods than in cones. Notably, rod AMPK and ATP started to recover at 30 min from the onset of 2‐DG perfusion. Consistent with these findings, ex vivo electroretinogram recordings showed a transient slowdown in rod dim flash responses during a 60‐min 2‐DG perfusion, whereas cone responses were not affected. Based on these results, we propose that cones surrounded by highly glycolytic rods become less dependent on glycolysis, and rods also become less dependent on glycolysis within 60 min upon the glycolysis inhibition.
Defusing aggressive behavior in the healthcare setting
Authors: Homotoff Kerry
Published: August 2021

Up to 80% of healthcare professionals, particularly those working in emergency medicine, have experienced workplace violence. However, many clinicians lack proper training for handling these situations. Workplace violence is one factor contributing to burnout, job dissatisfaction, and mental health issues. This article describes how to identify and manage aggression and violence in the healthcare setting using simple interventions to de-escalate aggressive behaviors.
ICU survivorship
Authors: LaRosa Nicolette
Published: August 2021

The number of people surviving critical illnesses is larger than ever. Many of these patients will rely on physician assistants (PAs) to facilitate their care after discharge from the ICU. As a result, PAs must be able to recognize and treat the numerous short- and long-term challenges this vulnerable population faces, especially given the recent surge of critically ill patients resulting from the COVID-19 pandemic.
Combination Therapy of Pulsed Dye Laser With Intense Pulsed Light in Port-Wine Stain Treatment: A Prospective Side-by-Side Comparison
Authors: Yu Wenxin , Cen Qingqing , Chen Yanyu , Zhu Jiafang , Lin Xiaoxi
Published: August 2021

BACKGROUND

Pulsed dye laser (PDL) treatment currently represents the mainstream choice for port-wine stain (PWS) treatment in accordance with selective photothermolysis. However, most PWS lesions cannot be removed despite several treatments. Intense pulsed light (IPL) is reportedly an effective alternative to PDL for PWS treatment. No studies have thus far been reported on the combination therapy of PDL with IPL in PWS treatment.

OBJECTIVE

This study evaluated the efficacy and safety of PDL with IPL for PWS treatment.

METHODS

A total of 33 PWS lesions underwent 3 treatment sessions. Each PWS was divided into IPL + PDL, PDL, and untreated sites. Therapeutic outcomes were evaluated by visual assessment and chromametric assessment 3 months after the final treatment.

RESULTS

The overall average blanching rates were 36.2% and 32.6% at the sites treated with IPL + PDL and PDL, respectively (p > .05). No permanent side effects were reported.

CONCLUSION

In this laser setting, although IPL + PDL is a safe and effective PWS treatment, no significant improvement in the efficacy was observed using IPL + PDL in contrast to PDL alone.
Dexmedetomidine Exerts a Negative Chronotropic Action on Sinoatrial Node Cells Through the Activation of Imidazoline Receptors
Authors: Ishihara Mariko , Kojima Akiko , Ding Wei-Guang , Kitagawa Hirotoshi , Matsuura Hiroshi
Published: August 2021

Dexmedetomidine (DEX), an α2-adrenoreceptor (α2-AR) and imidazoline receptor agonist, is most often used for the sedation of patients in the intensive care unit. Its administration is associated with an increased incidence of bradycardia; however, the precise mechanism of DEX-induced bradycardia has yet to be fully elucidated. This study was undertaken to examine whether DEX modifies pacemaker activity and the underlying ionic channel function through α2-AR and imidazoline receptors. The whole-cell patch-clamp techniques were used to record action potentials and related ionic currents of sinoatrial node cells in guinea pigs. DEX (≥10 nM) reduced sinoatrial node automaticity and the diastolic depolarization rate. DEX reduced the amplitude of hyperpolarization-activated cation current (I
f or I
h) the pacemaker current, even within the physiological pacemaker potential range. DEX slowed the I
f current activation kinetics and caused a significant shift in the voltage dependence of channel activation to negative potentials. In addition, efaroxan, an α2-AR and imidazoline I1 receptor antagonist, attenuated the inhibitory effects of DEX on sinoatrial node automaticity and I
f current activity, whereas yohimbine, an α2-AR–selective antagonist, did not. DEX did not affect the current activities of other channels, including rapidly and slowly activating delayed rectifier K+ currents (I
Kr and I
Ks), L-type Ca2+ current (I
Ca,L), Na+/Ca2+ exchange current (I
NCX), and muscarinic K+ current (I
K,ACh). Our results indicate that DEX, at clinically relevant concentrations, induced a negative chronotropic effect on the sinoatrial node function through the downregulation of I
f current through an imidazoline I1 receptor other than the α2-AR in the clinical setting.
The Etiology of Childhood Pneumonia in Bangladesh
Authors: Brooks W. Abdullah , Zaman Khalequ , Goswami Doli , Prosperi Christine , Endtz Hubert P. , Hossain Lokman , Rahman Mustafizur , Ahmed Dilruba , Rahman Mohammed Ziaur , Banu Sayera , Shikder Arif Uddin , Jahan Yasmin , Nahar Kamrun , Chisti Mohammod Jobayer , Yunus Mohammed , Khan Muhammad Alfazal , Matin Fariha Bushra , Mazumder Razib , Shahriar Bin Elahi Mohammad , Saifullah Muhammad , Alam Muntasir , Bin Shahid Abu Sadat Mohammad Sayeem , Haque Fahim , Sultana Sabiha , Higdon Melissa M. , Haddix Meredith , Feikin Daniel R. , Murdoch David R. , Hammitt Laura L. , O’Brien Katherine L. , Deloria Knoll Maria
Published: August 2021

Background:

Pneumonia remains the leading infectious cause of death among children <5 years, but its cause in most children is unknown. We estimated etiology for each child in 2 Bangladesh sites that represent rural and urban South Asian settings with moderate child mortality.

Methods:

As part of the Pneumonia Etiology Research for Child Health study, we enrolled children 1–59 months of age with World Health Organization–defined severe and very severe pneumonia, plus age-frequency-matched controls, in Matlab and Dhaka, Bangladesh. We applied microbiologic methods to nasopharyngeal/oropharyngeal swabs, blood, induced sputum, gastric and lung aspirates. Etiology was estimated using Bayesian methods that integrated case and control data and accounted for imperfect sensitivity and specificity of the measurements.

Results:

We enrolled 525 cases and 772 controls over 24 months. Of the cases, 9.1% had very severe pneumonia and 42.0% (N = 219) had infiltrates on chest radiograph. Three cases (1.5%) had positive blood cultures (2 Salmonella typhi, 1 Escherichia coli and Klebsiella pneumoniae). All 4 lung aspirates were negative. The etiology among chest radiograph–positive cases was predominantly viral [77.7%, 95% credible interval (CrI): 65.3–88.6], primarily respiratory syncytial virus (31.2%, 95% CrI: 24.7–39.3). Influenza virus had very low estimated etiology (0.6%, 95% CrI: 0.0–2.3). Mycobacterium tuberculosis (3.6%, 95% CrI: 0.5–11.0), Enterobacteriaceae (3.0%, 95% CrI: 0.5–10.0) and Streptococcus pneumoniae (1.8%, 95% CrI: 0.0–5.9) were the only nonviral pathogens in the top 10 etiologies.

Conclusions:

Childhood severe and very severe pneumonia in young children in Bangladesh is predominantly viral, notably respiratory syncytial virus.
The Etiology of Pneumonia in HIV-1-infected South African Children in the Era of Antiretroviral Treatment
Authors: Moore David P. , Baillie Vicky L. , Mudau Azwifarwi , Wadula Jeannette , Adams Tanja , Mangera Shafeeka , Verwey Charl , Sipambo Nosisa , Liberty Afaaf , Prosperi Christine , Higdon Melissa M. , Haddix Meredith , Hammitt Laura L. , Feikin Daniel R. , O’Brien Katherine L. , Deloria Knoll Maria , Murdoch David R. , Simões Eric A. F. , Madhi Shabir A.
Published: August 2021

Background:

HIV-1 infection predisposes to an increased burden of pneumonia caused by community-acquired and opportunistic pathogens.

Methods:

Within the context of the Pneumonia Etiology Research for Child Health case-control study of under 5 pneumonia, we investigated the etiology of World Health Organization-defined severe/very severe pneumonia requiring hospitalization in South African HIV-infected children. Nasopharyngeal-oropharyngeal swabs and blood, collected from cases and age- and season-matched HIV-infected controls attending outpatient antiretroviral therapy (ART) clinics, were analyzed using molecular diagnostic methods. Cases were also investigated for tuberculosis. Etiologic fractions among cases with radiologically confirmed pneumonia were derived using Bayesian analytic techniques.

Results:

Of 115 HIV-infected cases, 89 (77.4%) had radiologically confirmed pneumonia. Severe immunosuppression (adjusted odds ratio, 32.60; 95% confidence interval, 7.25–146.64) was significantly associated with radiologically confirmed pneumonia. Cotrimoxazole prophylaxis (46.4% vs. 77.4%) and ART (28.2% vs. 83.1%) coverage were significantly lower in cases compared with ART-clinic controls. An etiologic agent was identified in 99.0% of the radiologically confirmed cases. The ‘top 4’ pathogens associated with radiologically confirmed pneumonia werePneumocystis jirovecii[23.0%; 95% credible interval (CrI), 12.4%–31.5%],Staphylococcus aureus(10.6%; 95% CrI, 2.2%–20.2%), pneumococcus (9.5%; 95% CrI, 2.2%–18.0%) and respiratory syncytial virus (9.3%; 95% CrI, 2.2%–14.6%). Bacteremia (6.7%) and in-hospital death (10.1%) were frequent among those with radiologically confirmed disease.

Conclusions:

Pneumocystis jirovecii,S. aureus, pneumococcus and respiratory syncytial virus contribute a considerable burden of radiologically confirmed pneumonia in South African HIV-infected children under 5 years. Expediting access to ART and cotrimoxazole prophylaxis would decrease the burden of pneumonia in these children.
The Etiology of Pneumonia in Zambian Children
Authors: Mwananyanda Lawrence , Thea Donald M. , Chipeta James , Kwenda Geoffrey , Mulindwa Justin M. , Mwenechanya Musaku , Prosperi Christine , Higdon Melissa M. , Haddix Meredith , Hammitt Laura L. , Feikin Daniel R. , Murdoch David R. , O’Brien Katherine L. , Deloria Knoll Maria , Mwansa James , Wa Somwe Somwe , Seidenberg Phil
Published: August 2021

Background:

Childhood pneumonia in developing countries is the foremost cause of morbidity and death. Fresh information on etiology is needed, considering the changing epidemiology of pneumonia in the setting of greater availability of effective vaccines, changing antibiotic use and improved access to care. We report here the Zambia site results of the Pneumonia Etiology Research for Child Health study on the etiology of pneumonia among HIV-uninfected children in Lusaka, Zambia.

Methods:

We conducted a case–control study of HIV-uninfected children age 1–59 months admitted with World Health Organization-defined severe or very severe pneumonia to a large tertiary care hospital in Lusaka. History, physical examination, chest radiographs (CXRs), blood cultures and nasopharyngeal/oropharyngeal swabs were obtained and tested by polymerase chain reaction and routine microbiology for the presence of 30 bacteria and viruses. From age and seasonally matched controls, we tested blood and nasopharyngeal/oropharyngeal samples. We used the Pneumonia Etiology Research for Child Health integrated analysis to determine the individual and population etiologic fraction for individual pathogens as the cause of pneumonia.

Results:

Among the 514 HIV-uninfected case children, 208 (40.5%) had abnormal CXRs (61 of 514 children were missing CXR), 8 (3.8%) of which had positive blood cultures. The overall mortality was 16.0% (82 deaths). The etiologic fraction was highest for respiratory syncytial virus [26.1%, 95% credible interval (CrI): 17.0–37.7], Mycobacterium tuberculosis (12.8%, 95% CrI: 4.3–25.3) and human metapneumovirus (12.8%, CrI: 6.1–21.8).

Conclusions:

Childhood pneumonia in Zambia among HIV-uninfected children is most frequently caused by respiratory syncytial virus, M. tuberculosis and human metapneumovirus, and the mortality remains high.
Etiology and Clinical Characteristics of Severe Pneumonia Among Young Children in Thailand
Authors: Bunthi Charatdao , Rhodes Julia , Thamthitiwat Somsak , Higdon Melissa M. , Chuananon Somchai , Amorninthapichet Tussanee , Paveenkittiporn Wantana , Chittaganpitch Malinee , Sawatwong Pongpun , Hammitt Laura L. , Feikin Daniel R. , Murdoch David R. , Deloria-Knoll Maria , O’Brien Katherine L. , Prosperi Christine , Maloney Susan A. , Baggett Henry C. , Akarasewi Pasakorn
Published: August 2021

Background:

Pneumonia remains the leading cause of death among children <5 years of age beyond the neonatal period in Thailand. Using data from the Pneumonia Etiology Research for Child Health (PERCH) Study, we provide a detailed description of pneumonia cases and etiology in Thailand to inform local treatment and prevention strategies in this age group.

Methods:

PERCH, a multi-country case–control study, evaluated the etiology of hospitalized cases of severe and very severe pneumonia among children 1–59 months of age. The Thailand site enrolled children for 24 consecutive months during January 2012–February 2014 with staggered start dates in 2 provinces. Cases were children hospitalized with pre-2013 WHO-defined severe or very severe pneumonia. Community controls were randomly selected from health services registries in each province. Analyses were restricted to HIV-negative cases and controls. We calculated adjusted odds ratios (ORs) and 95% CIs comparing organism prevalence detected by nasopharyngeal/oropharyngeal (NP/OP) polymerase chain reaction between cases and controls. The PERCH Integrated Analysis (PIA) used Bayesian latent variable analysis to estimate pathogen-specific etiologic fractions and 95% credible intervals.

Results:

Over 96% of both cases (n = 223) and controls (n = 659) had at least 1 organism detected; multiple organisms were detected in 86% of cases and 88% of controls. Among 98 chest Radiograph positive (CXR+) cases, respiratory syncytial virus (RSV) had the highest NP/OP prevalence (22.9%) and the strongest association with case status (OR 20.5; 95% CI: 10.2, 41.3) and accounted for 34.6% of the total etiologic fraction. Tuberculosis (TB) accounted for 10% (95% CrI: 1.6–26%) of the etiologic fraction among CXR+ cases.

Discussion:

More than one-third of hospitalized cases of severe and very severe CXR+ pneumonia among children 1–59 months of age in Thailand were attributable to RSV. TB accounted for 10% of cases, supporting evaluation for TB among children hospitalized with pneumonia in high-burden settings. Similarities in pneumonia etiology in Thailand and other PERCH sites suggest that global control strategies based on PERCH study findings are relevant to Thailand and similar settings.
Advanced Practice Providers and the Dermatology Literature
Authors: Laughter Melissa R. , Maymone Mayra B. C. , Presley Colby L. , Nodine Sarah , Szeto Mindy D. , Jones John D. , Robertson Kara , Wilkey Melissa , Yang Ronald , Anand Pratibha , Dellavalle Robert P. , Hugh Jeremy , Dunnick Cory A.
Published: August 2021

Numbers and roles of advanced practice providers (APPs) in dermatology have expanded tremendously over the last five decades. Although the imbalance between demand for dermatology services and available dermatologists may contribute to this increase, little research has been done to examine the evolving roles of APPs and ongoing trends as represented by scientific publications. To analyze publication trends, key topics, and perceptions related to APPs, the PubMed database was searched for all articles related to APPs in dermatology published from 1973 to 2018. The number of publications, citation counts, and favorability toward APPs were assessed and scored by two independent evaluators. Increased prevalence of APPs in dermatology mirrors a substantial increase in the total number of APP-related publications, whereas the proportion of publications showing positive perceptions of APPs was found to decrease over time. Top-cited articles focused on dermatology workforce shortages, roles of APPs, and comparisons of efficacy among providers. We hope this study will offer insight to all healthcare providers with considerations regarding the evolving roles of APPs in dermatology.