Evaluation of some acute phase proteins in cattle naturally infected with Babesia bigemina.

Abstract: Bovine babesiosis due to Babesia bigemina infection induces systemic inflammation, evidenced by increased sialic acid (SA) levels and declined cholinesterase activity. The current study was undertaken to assess further indicators of the systemic inflammation in the naturally infected cattle. To this end, serum levels of some selected acute phase-proteins (APPs) including serum amyloid A (SAA), haptoglobin (Hp), ceruloplasmin (Cp), and fibrinogen were measured. Additionally, sensitivity and specificity of the APPs were calculated by receiver operating characteristic curve. The correlation among APPs, SA and cholinesterase activity were also assessed. Our previous blood specimens were used to measure APPs. Briefly, the diseased animals were divided into two groups according to the parasitemia: 12 mildly (20 % <) and 8 severely (20 %>) infected animals. Moreover, 10 healthy animals as the control were included. The levels of all APPs were measured to be significantly elevated in a parasitemia burden-dependent fashion as compared to the control. Furthermore, all the APPs showed 100 % specificity, but only SAA and Cp had 100 % sensitivity. A strong and positive correlation was calculated between the APPs and SA; however, cholinesterase activity was inversely correlated with AAPs and SA. In conclusion, inﬂammatory reactions play a pivotal role in the pathogenesis of bovine babesiosis and APPs can be considered as the potential indicators of inflammation.

Acute phase protein
Cattle
Inflammation
B. bigemina


Continuous positive airway pressure in severe obstructive sleep apnea reduces pain sensitivity.

Abstract:
STUDY OBJECTIVE
To evaluate effects of CPAP on pain sensitivity in severe OSA patients.

DESIGN
Within-subject treatment study.

SETTING
Hospital-based sleep disorders center.

PATIENTS
Twelve severe OSA patients (7 men, 5 women), 50.2 ± 12.5 years, with no pain.

INTERVENTIONS
The morning after a diagnostic nocturnal polysomnogram (NPSG), patients underwent a training session of finger withdrawal latency (FWL) testing to a radiant heat stimulus, a validated human behavioral model of thermal nociception. Baseline FWL in seconds was obtained after the training session. CPAP pressure was titrated on a second night in the laboratory. Two nights after titration, patients returned to sleep in the laboratory on CPAP. FWL was tested in the morning after awakening, after 6-8 wks of CPAP use, and finally (within 6-8 weeks) after 2 nights of discontinuation of CPAP. Mean FWL in seconds (sec) was compared using MANOVAs with nights as the within subject variable.

RESULTS
Apnea-hypopnea index (AHI) decreased from 50.9 ± 14.5 to 1.4 ± 1.0 with CPAP, and sleep continuity improved. In parallel, FWL increased significantly from a mean baseline of 9.8 ± 1.3 sec to 13.7 ± 5.1 sec (P = 0.01) and with continued CPAP use (5.1 ± 2.3 h nightly) for 6-8 weeks FWL remained elevated (21.1 ± 16.2 sec). After the 2-night CPAP discontinuation, apnea/hypopneas returned and sleep was fragmented (AHI = 32.6 ± 19.8). FWL decreased to 11.6 ± 5.9 sec relative to intermediate-term CPAP use (P = 0.03).

CONCLUSION
CPAP treatment reduces pain sensitivity in OSA patients. Future studies will focus on patients with OSA and chronic pain and identify mediating mechanisms.

Khalid|Imran|I|
Roehrs|Timothy A|TA|
Hudgel|David W|DW|
Roth|Thomas|T|

D045422:Continuous Positive Airway Pressure

Pain sensitivity
CPAP treatment
obstructive sleep apnea syndrome


Expression of fibrosis-related molecules in the oral mucosa of six animal species: A reference for selecting animal models.

Abstract: Several animal models have been used in studies associated with oral submucous fibrosis (OSF); however, an appropriate model based on the histopathological characteristics of OSF is still needed. This study aimed to provide histological references for selecting a potential model. The expression intensities of collagen type I (Col I), type III (Col III), type IV (Col IV), fibronectin (FN), transforming growth factors β (TGF-β), and connective tissue growth factor (CCN2) in the oral mucosa of the human and six non-human animal species were measured by immunohistochemistry. There was little variation in the expression intensity of Col I while the expression of Col III, Col IV, and FN showed differences. The expression intensities of TGF-β in dog, rat, sheep, and pig oral mucosae, and those of CCN2 in dog, minipig, rat, and buffalo oral mucosae were equivalent to the expression intensities in human mucosa. The expression of fibrosis-related molecules in the dog oral mucosa optimally mimics the human condition, suggesting its suitability with regard to histopathology as an animal model for the study of OSF.

Sa|Guoliang|G| Xiong|Xuepeng|X| Ren|Jiangang|J| Zhao|Yifang|Y| He|Sangang|S|

Animal model
Oral submucous fibrosis
TGF-β
CCN2
Extracellular matrix


Evaluation of chemotherapeutic and cancer-protective properties of sphingosine and C2-ceramide in a human breast stem cell derived carcinogenesis model.

Abstract: The overall goal of the present study was to evaluate the chemotherapeutic and cancer‑protective properties of D‑erythro‑sphingosine (sphingosine) and C2‑ceramide using a human breast epithelial cell (HBEC) culture system, which represents multiple‑stages of breast carcinogenesis. The HBEC model includes Type I HBECs (normal stem), Type II HBECs (normal differentiated) and transformed cells (immortal/non‑tumorigenic cells and tumorigenic cells, which are transformed from the same parental normal stem cells). The results of the present study indicate that sphingosine preferentially inhibits proliferation and causes death of normal stem cells (Type I), tumorigenic cells, and MCF7 breast cancer cells, but not normal differentiated cells (Type II). In contrast to the selective anti‑proliferative effects of sphingosine, C2‑ceramide inhibits proliferation of normal differentiated cells as well as normal stem cells, tumorigenic cells, and MCF7 cancer cells with similar potency. Both sphingosine and C2‑ceramide induce apoptosis in tumorigenic cells. Among the sphingosine stereoisomers (D‑erythro, D‑threo, L‑erythro, and L‑threo) and sphinganine that were tested, L‑erythro‑sphingosine most potently inhibits proliferation of tumorigenic cells. The inhibition of breast tumorigenic/cancer cell proliferation by sphingosine was accompanied by inhibition of telomerase activity. Sphingosine at non‑cytotoxic concentrations, but not C2‑ceramide, induces differentiation of normal stem cells (Type I), thereby reducing the number of stem cells that are more susceptible to neoplastic transformation. To the best of our knowledge, the present study demonstrates one of the first results that sphingosine can be a potential chemotherapeutic and cancer‑protective agent, whereas C2‑ceramide is not an ideal chemotherapeutic and cancer‑protective agent due to its anti‑proliferative effects on Type II HBECs and its inability to induce the differentiation of Type I to Type II HBECs.

Ahn|Eun Hyun|EH|
Yang|Hong|H|
Hsieh|Ching-Yi|CY|
Sun|Wei|W|
Chang|Chia-Cheng|CC|
Schroeder|Joseph J|JJ|

sphingosine
stem cells
differentiation
proliferation
breast cancer
apoptosis
sphingosine stereoisomers
sphinganine
telomerase
ceramide


Stretchable Random Lasers with Tunable Coherent Loops.

Abstract: Stretchability represents a key feature for the emerging world of realistic applications in areas, including wearable gadgets, health monitors, and robotic skins. Many optical and electronic technologies that can respond to large strain deformations have been developed. Laser plays a very important role in our daily life since it was discovered, which is highly desirable for the development of stretchable devices. Herein, stretchable random lasers with tunable coherent loops are designed, fabricated, and demonstrated. To illustrate our working principle, the stretchable random laser is made possible by transferring unique ZnO nanobrushes on top of polydimethylsiloxane (PDMS) elastomer substrate. Apart from the traditional gain material of ZnO nanorods, ZnO nanobrushes were used as optical gain materials so they can serve as scattering centers and provide the Fabry-Perot cavity to enhance laser action. The stretchable PDMS substrate gives the degree of freedom to mechanically tune the coherent loops of the random laser action by changing the density of ZnO nanobrushes. It is found that the number of laser modes increases with increasing external strain applied on the PDMS substrate due to the enhanced possibility for the formation of coherent loops. The device can be stretched by up to 30% strain and subjected to more than 100 cycles without loss in laser action. The result shows a major advance for the further development of man-made smart stretchable devices.

Sun|Tzu-Min|TM| Wang|Cih-Su|CS| Liao|Chi-Shiun|CS| Lin|Shih-Yao|SY| Perumal|Packiyaraj|P| Chiang|Chia-Wei|CW| Chen|Yang-Fang|YF|

stretchable
random laser
tunable
coherent loop
Fabry−Perot resonance
ZnO nanostructure


Tidal drift removes the need for area-restricted search in foraging Atlantic puffins.

Abstract: Understanding how animals forage is a central objective in ecology. Theory suggests that where food is uniformly distributed, Brownian movement ensures the maximum prey encounter rate, but when prey is patchy, the optimal strategy resembles a Lévy walk where area-restricted search (ARS) is interspersed with commuting between prey patches. Such movement appears ubiquitous in high trophic-level marine predators. Here, we report foraging and diving behaviour in a seabird with a high cost of flight, the Atlantic puffin ( Fratercula arctica), and report a clear lack of Brownian or Levy flight and associated ARS. Instead, puffins foraged using tides to transport them through their feeding grounds. Energetic models suggest the cost of foraging trips using the drift strategy is 28-46% less than flying between patches. We suggest such alternative movement strategies are habitat-specific, but likely to be far more widespread than currently thought.

Bennison|Ashley|A|
Quinn|John L|JL|
Debney|Alison|A|
Jessopp|Mark|M|

area-restricted search
foraging
energetics
movement ecology


Antihypernociceptive and neuroprotective effects of Combretin A and Combretin B on streptozotocin-induced diabetic neuropathy in mice.

Abstract: Painful diabetic neuropathy (PDN) is known to adversely affect psychosocial functioning by enhancing levels of anxiety and depression. This study was designed to verify the antihypernociceptive, anxiolytic, and antidepressant-like effects of Combretin A and Combretin B (two triterpenes cycloartane-type isolated from the leaves of Combretum fragrans) in streptozotocin-induced diabetic neuropathy in mice. PDN was induced in mice by the administration of streptozotocin (STZ, 200 mg/kg, i.p.). The effect of oral administration of Combretin A (25 and 50 mg/kg) and Combretin B (25 and 50 mg/kg) on nociception (mechanical allodynia, thermal hyperalgesia, cold allodynia, and chemical hyperalgesia), anxiety (elevated plus maze, light-dark box test, social interaction), and depressant (open field test, forced swimming test, tail suspension test) was evaluated. Combretin A (25 and 50 mg/kg) and Combretin B (25 and 50 mg/kg) caused antihypernociceptive, anxiolytic, and antidepressant-like effects in in STZ-induced diabetic neuropathy in mice. Both compounds also caused a decrease in blood glucose and improved body weight in treated animals. They also significantly (p < 0.001) reduced tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), malondialdehyde (MDA), and nitric oxide (NO) production in serum and sciatic nerves, and, significantly (p < 0.001) increased superoxide dismutase (SOD) and catalase (CAT) activity in serum, sciatic nerves, and brain. Combretin A and Combretin B also showed a great systemic effect, conserving values of evaluated parameters close to normal in treated mice. The results of this study confirm the antihypernociceptive, antianxiety, and antidepressant activities of Combretin A and Combretin B.

Mbiantcha|Marius|M|0000-0001-8586-6150
Khalid|Rauf|R|
Dawe|Amadou|A|
Mehreen|Arif|A|
Atsamo|Donatien Albert|DA|
Ateufack|Gilbert|G|
Hamza|Dar|D|
Nana|William Yousseu|WY|
Bomba|Francis Tatsinkou Desire|FTD|
Naeem|Rehman Ur|RU|
Izhar|Ahmad|A|

Antihypernociceptive
Neuroprotective
Diabetic neuropathy
Combretins A and B


Aerobic scope does not predict the performance of a tropical eurythermal fish at elevated temperatures.

Abstract: Climate warming is predicted to negatively impact fish populations through impairment of oxygen transport systems when temperatures exceed those which are optimal for aerobic scope (AS). This concept of oxygen- and capacity-limited thermal tolerance (OCLTT) is rapidly gaining popularity within climate change research and has been applied to several fish species. Here, we evaluated the relevance of aerobic performance of juvenile barramundi (Lates calcarifer) in the context of thermal preference and tolerance by (1) measuring standard and maximum metabolic rates (SMR and MMR, respectively) and AS of fish acclimated to 29°C and acutely exposed to temperatures from 23 to 38°C, (2) allowing the fish to behaviourally select a preferred temperature between 29 and 38°C, and (3) quantifying alterations to AS after 5 weeks of acclimation to 29 and 38°C. SMR and MMR both increased continuously with temperature in acutely exposed fish, but the increase was greater for MMR such that AS was highest at 38°C, a temperature approaching the upper lethal limit (40-41°C). Despite 38°C eliciting maximum AS, when given the opportunity the fish selected a median temperature of 31.7 ± 0.5°C and spent only 10 ± 3% of their time at temperatures >36°C. Following acclimation to 38°C, AS measured at 38°C was decreased to the same level as 29°C-acclimated fish measured at 29°C, suggesting that AS may be dynamically modulated independent of temperature to accommodate the requirements of daily life. Together, these results reveal limited power of the OCLTT hypothesis in predicting optimal temperatures and effects of climate warming on juvenile barramundi.

Norin|Tommy|T|
Malte|Hans|H|
Clark|Timothy D|TD|

Oxygen- and capacity-limited thermal tolerance (OCLTT)


The passing of western civilization.

Abstract: Modern western civilization reached a pinnacle in the last half of the 20th century, spending over 200 years evolving and spreading throughout the world. A robust social contract, technological advancement and pervasive economic success in the context of democracy and capitalism propelled the project. Unfortunately, two underlying pillars of past success developed intensifying negative consequences, hastening socioeconomic decline: insatiable collective wants and global population growth. The rise and decline of civilizations in history is well documented, yet oddly ignored in today's dialogue. Contemporary civilization is assumed to be immune from forces that shaped cycles of past civilizations-that our age is somehow an exception. For the first time in human history planetary systems that seemed invisible until recently are sending us the message that our civilization is not exceptional, that there are finite limits to the thrust of humanity's present trajectory. Viable solutions curbing the effects of habitat destruction, diminishing biodiversity and climate change along with rising inequality, debt, conflict and refugee flows are known but unimplementable. The current essay examines underlying causes of socioeconomic deterioration and entrapment, suggesting a comprehensive collective intelligence enterprise be launched to prepare for the global transition facing humanity.

Western civilization
Population
Inequality
Debt
Anthropocene
Human nature
Liberal tradition


High-throughput receptor-based assay for the detection of spirolides by chemiluminescence.

Abstract: The spirolides are marine toxins that belong to a new class of macrocyclic imines produced by dinoflagellates. In this study a previously described solid-phase receptor-based assay for the detection of spirolides was optimized for high-throughput screening and prevalidated. This method is based on the competition between 13-desmethyl spirolide C and biotin-α-bungarotoxin immobilized on a streptavidin-coated surface, for binding to nicotinic acetylcholine receptors. In this inhibition assay the amount of nAChR bound to the well surface is quantified using a specific antibody, followed by a second anti-mouse IgG antibody labeled with horseradish peroxidase (HRP). The assay protocol was optimized for 384-well microplates, which allowed a reduction of the amount of reagents per sample and an increase of the number of samples per plate versus previously published receptor-based assays. The sensitivity of the assay for 13-desmethyl spirolide C ranged from 5 to 150 ng mL(-1). The performance of the assay in scallop extracts was adequate, with an estimated detection limit for 13-desmethyl spirolide C of 50 μg kg(-1) of shellfish meat. The recovery rate of 13-desmethyl spirolide C for spiked samples with this assay was 80% and the inter-assay coefficient of variation was 8%. This 384-well microplate, chemiluminescence method can be used as a high-throughput screening assay to detect 13-desmethyl spirolide C in shellfish meat in order to reduce the number of samples to be processed through bioassays or analytical methods.

Rodríguez|Laura P|LP|
Vilariño|Natalia|N|
Molgó|Jordi|J|
Aráoz|Rómulo|R|
Botana|Luis M|LM|

Nicotinic acetylcholine receptors
Nicotinic acetylcholine receptors
nAChR
horseradish peroxidase
HRP
coefficient of variation
BSA
Bovine serum albumin
CR
CV
Competition assay
Cyclic imines
LC–MS
LoD
MBA
MWCO
PBS
SD
SEM
Single-laboratory pre-validation
cross-reactivity
i.p.
intraperitoneal
limit of detection
liquid chromatography–mass spectrometry
molecular-weight-cutoff
mouse bioassay
nicotinic acetylcholine receptor
phosphate-buffered saline
standard deviation
standard error of the mean
α-BTX
α-bungarotoxin

P P P P P P U U U U R M U U U U U U U U U M U R U U M P U U M U U


Anti-aging effects of co-enzyme Q10 on periodontal tissues.

Abstract: Oxidative stress is associated with age-related reactions. The anti-oxidative effects of a reduced form of co-enzyme Q10 (rCoQ10) suppress oxidative stress, which may contribute to the prevention of age-related inflammatory reactions. We examined the effects of topically applied rCoQ10 on periodontal inflammatory reactions in a rat aging model. Male Fischer 344 rats, 2 (n = 6) and 4 mos (n = 18) of age, were used. All of the two-month-old rats and 6 of the four-month-old rats were sacrificed and 12 remaining four-month-old rats received topically applied ointment with or without 1% rCoQ10 on the gingival surface until they reached 6 mos of age. The rats showed an age-dependent increase in circulating oxidative stress. RCoQ10 decreased oxidative DNA damage and tartrate-resistant acid-phosphatase-positive osteoclasts in the periodontal tissue at 6 mos of age as compared with the control. The same conditions lowered gene expression of caspase-1 and interleukin-1β in the periodontal tissue. Furthermore, Nod-like receptor protein 3 inflammasomes were less activated in periodontal tissues from rCoQ10-treated rats as compared with the control rats. Our results suggest that rCoQ10 suppresses age-related inflammatory reactions and osteoclast differentiation by inhibiting oxidative stress.

Yoneda|T|T| Tomofuji|T|T| Ekuni|D|D| Azuma|T|T| Endo|Y|Y| Kasuyama|K|K| Machida|T|T| Morita|M|M|

D045222:Electron Transport Chain Complex Proteins

D000071199:NLR Family, Pyrin Domain-Containing 3 Protein

D018160:Receptors, Cytoplasmic and Nuclear

oxidative stress
aging
inflammasomes
coenzyme Q10
periodontium
preclinical drug evaluation


Women in science: a son's perspective.

Abstract: I am often asked how our mother inspired my sister Moriah and me to want to become scientists. She never directly suggested we should go down that path. Instead, she shared the aspects of the natural world, that she loved, with us while keeping the non-science aspects of her job separate from our lives at home. Now, I have learned that her perspective provides insights that spark innovative discoveries, some of which challenged the status quo. Her passion for research has allowed her to pursue what she believes to be worth studying. Her personality and collaborative nature allow her to be teased at home, facilitate a room of diverse opinions, and command a hall of hundreds of people. Her respect for those around her is inspiring. My mom's trust in her trainees and collaborators allows her to answer questions that could fundamentally not be answered had she pigeonholed herself to a single field. She managed to accomplish everything while being nothing other than my mom to me, and I am so glad that I am growing into a person who can truly appreciate the woman she is to everyone else.

Behaviour
Marla Sokolowski
development
foraging
genetics


Microelectromechanical Transducer to Monitor High-Doses of Nuclear Irradiation.

Abstract: This paper reports the design, fabrication and measured performance of a passive microelectromechanical transducer for the wireless monitoring of high irradiation doses in nuclear environments. The sensing device is composed of a polymer material (high-density polyethylene) sealed inside a cavity. Subjected to ionizing radiation, this material releases various gases, which increases the pressure inside the cavity and deflects a dielectric membrane. From the measurement of the deflection, the variation of the applied pressure can be estimated, and, in turn, the dose may be determined. The microelectromechanical structure can also be used to study and validate the radiolysis properties of the polymer through its gas emission yield factor. Measurement of the dielectric membrane deflection is performed here to validate on the one hand the required airtightness of the cavity exposed to doses about 4 MGy and on the other hand, the functionality of the fabricated dosimeter for doses up to 80 kGy. The selection of appropriate materials for the microelectromechanical device is discussed, and the outgassing properties of the selected high-density polyethylene are analysed. Moreover, the technological fabrication process of the transducer is detailed.

Philippe|Julien|J|0000-0002-1578-1693 Ferry|Muriel|M| Charlot|Samuel|S| Assié|Sandrine|S| Lecestre|Aurélie|A| Libaude|Guillaume|G| Ferrand|André|A| Pons|Patrick|P|0000-0002-7989-3272 Aubert|Hervé|H|0000-0002-6113-0648

microelectromechanical systems (MEMS) technology


Liquiritigenin ameliorates memory and cognitive impairment through cholinergic and BDNF pathways in the mouse hippocampus.

Abstract: Liquiritigenin (LQ), a flavonoid extracted from the radix of Glycyrrhiza, has anti-inflammatory and neuroprotective properties. In this study, we evaluated the cognitive enhancing effects of LQ on learning and memory impairments induced by scopolamine (0.5 mg/kg, i.p.), a muscarinic antagonist, using the Y-maze, passive avoidance, and novel object recognition tests. A single administration of LQ significantly improved scopolamine-induced cognitive impairments in these behavioral tests. In addition, LQ dramatically inhibited acetylcholinesterase and thiobarbituric acid reactive substance activities in the hippocampus of scopolamine-induced mice in a dose-dependent manner. Furthermore, LQ markedly increased the protein level of brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding (CREB) in the hippocampus of scopolamine-induced mice. Taken together, our results indicate that LQ may be useful for the treatment of learning and memory impairments, and that the beneficial effects of LQ are mediated, in part, by cholinergic and BDNF/ERK/CREB signaling enhancement and/or protection.

Ko|Yong-Hyun|YH| Kwon|Seung-Hwan|SH| Lee|Seok-Yong|SY| Jang|Choon-Gon|CG|

Liquiritigenin
Scopolamine
Brain-derived neurotrophic factor
Extracellular signal-regulated kinase
cAMP response element binding
Alzheimer’s disease


Adaptive Natural Killer Cell and Killer Cell Immunoglobulin-Like Receptor-Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transplantation.

Abstract: Cytomegalovirus (CMV) reactivates in >30% of CMV-seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of natural killer (NK) cells expressing NKG2C, CD57, and inhibitory killer cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation after HCT. These NK cells persist after the resolution of infection and display "adaptive" or memory properties. Despite these findings, the differential impact of persistent/inactive versus reactivated CMV on NK versus T cell maturation after HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pretransplantation CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an adaptive phenotype (NKG2C(+)CD57(+)). Compared with CMV-seronegative recipients, those who reactivated CMV had the highest adaptive cell frequencies, whereas intermediate frequencies were observed in CMV-seropositive recipients harboring persistent/nonreplicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV-seropositive recipients of sibling but not UCB grafts and were correlated with lower rates of CMV reactivation (sibling 33% versus UCB 51%; P < .01). These data suggest that persistent/nonreplicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation.

Davis|Zachary B|ZB|
Cooley|Sarah A|SA|
Cichocki|Frank|F|
Felices|Martin|M|
Wangen|Rose|R|
Luo|Xianghua|X|
DeFor|Todd E|TE|
Bryceson|Yenan T|YT|
Diamond|Don J|DJ|
Brunstein|Claudio|C|
Blazar|Bruce R|BR|
Wagner|John E|JE|
Weisdorf|Daniel J|DJ|
Horowitz|Amir|A|
Guethlein|Lisbeth A|LA|
Parham|Peter|P|
Verneris|Michael R|MR|
Miller|Jeffrey S|JS|

D036101:Cord Blood Stem Cell Transplantation

D018380:Hematopoietic Stem Cell Transplantation

Natural killer cells
Cytomegalovirus reactivation
Transplantation
Clinical outcomes


Structures of a Nonribosomal Peptide Synthetase Module Bound to MbtH-like Proteins Support a Highly Dynamic Domain Architecture.

Abstract: Nonribosomal peptide synthetases (NRPSs) produce a wide variety of peptide natural products. During synthesis, the multidomain NRPSs act as an assembly line, passing the growing product from one module to the next. Each module generally consists of an integrated peptidyl carrier protein, an amino acid-loading adenylation domain, and a condensation domain that catalyzes peptide bond formation. Some adenylation domains interact with small partner proteins called MbtH-like proteins (MLPs) that enhance solubility or activity. A structure of an MLP bound to an adenylation domain has been previously reported using a truncated adenylation domain, precluding any insight that might be derived from understanding the influence of the MLP on the intact adenylation domain or on the dynamics of the entire NRPS module. Here, we present the structures of the full-length NRPS EntF bound to the MLPs from Escherichia coli and Pseudomonas aeruginosa These new structures, along with biochemical and bioinformatics support, further elaborate the residues that define the MLP-adenylation domain interface. Additionally, the structures highlight the dynamic behavior of NRPS modules, including the module core formed by the adenylation and condensation domains as well as the orientation of the mobile thioesterase domain.

Miller|Bradley R|BR|
Drake|Eric J|EJ|
Shi|Ce|C|
Aldrich|Courtney C|CC|
Gulick|Andrew M|AM|

D004926:Escherichia coli
D010453:Peptide Synthases
D000072417:Protein Domains
D011550:Pseudomonas aeruginosa

acyl carrier protein (ACP)
bacterial metabolism
enzyme mechanism
enzyme mutation
multifunctional protein
natural product biosynthesis
siderophore
structural biology


Implementing the 27 PRISMA 2020 Statement items for systematic reviews in the sport and exercise medicine, musculoskeletal rehabilitation and sports science fields: the PERSiST (implementing Prisma in Exercise, Rehabilitation, Sport medicine and SporTs science) guidance.

Abstract: Poor reporting of medical and healthcare systematic reviews is a problem from which the sports and exercise medicine, musculoskeletal rehabilitation, and sports science fields are not immune. Transparent, accurate and comprehensive systematic review reporting helps researchers replicate methods, readers understand what was done and why, and clinicians and policy-makers implement results in practice. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement and its accompanying Explanation and Elaboration document provide general reporting examples for systematic reviews of healthcare interventions. However, implementation guidance for sport and exercise medicine, musculoskeletal rehabilitation, and sports science does not exist. The Prisma in Exercise, Rehabilitation, Sport medicine and SporTs science (PERSiST) guidance attempts to address this problem. Nineteen content experts collaborated with three methods experts to identify examples of exemplary reporting in systematic reviews in sport and exercise medicine (including physical activity), musculoskeletal rehabilitation (including physiotherapy), and sports science, for each of the PRISMA 2020 Statement items. PERSiST aims to help: (1) systematic reviewers improve the transparency and reporting of systematic reviews and (2) journal editors and peer reviewers make informed decisions about systematic review reporting quality.

implementation evaluation meta-analysis methodology


Crystal structure of [Co(NH3)6][Co(CO)4]2.

Abstract: Hexaamminecobalt(II) bis-[tetra-carbonyl-cobaltate(-I)], [Co(NH3)6][Co(CO)4]2, was synthesized by reaction of liquid ammonia with Co2(CO)8. The Co(II) atom is coordinated by six ammine ligands. The resulting polyhedron, the hexa-amminecobalt(II) cation, exhibits point group symmetry -3. The Co(-I) atom is coordinated by four carbonyl ligands, leading to a tetra-carbonyl-cobaltate(-I) anion in the shape of a slightly distorted tetra-hedron, with point group symmetry 3. The crystal structure is related to that of high-pressure BaC2 (space group R-3m), with the [Co(NH3)6](2+) cations replacing the Ba sites and the [Co(CO)4](-) anions replacing the C sites. N-H⋯O hydrogen bonds between cations and anions stabilize the structural set-up in the title compound.

crystal structure
ammonia
hydrogen bonding
cobalt carbonyl


Socioeconomic Disparities in the Acute Management of Stone Disease in the United States.

Abstract:
INTRODUCTION
Patients admitted to the hospital with an acute, noninfected episode of urolithiasis are candidates for medical expulsive therapy, ureteral stent placement, or upfront ureteroscopy (URS). We sought to assess socioeconomic factors influencing treatment decisions in managing urolithiasis and to determine differences in outcomes based on treatment modality.

MATERIALS AND METHODS
The Healthcare Cost and Utilization Project State Inpatient Database, State Ambulatory Surgery and Services Database, and State Emergency Department Database for California from 2007 to 2011 and for Florida from 2009 to 2014 were utilized. Patients who were admitted to the hospital with a primary diagnosis of kidney or ureteral stone were identified. The initial treatment modality utilized was assessed and factors that influenced that decision were analyzed. Multivariate logistic regression model was fit to determine factors independently associated with upfront URS. Lastly, outcomes of noninfected patients who underwent stent alone vs URS were compared.

RESULTS
We identified 146,199 patients who had an inpatient admission with urolithiasis. Overall, 45% of patients had no intervention at the time of their evaluation. Of the 55% of patients who underwent surgical intervention, 42% underwent stent alone, 44% underwent upfront URS, 1% had a PCN tube placement, 8% underwent extracorporeal shockwave lithotripsy, while 5% underwent PCNL. On multivariate logistic regression model, minorities, younger patients, publicly uninsured patients, more comorbid patients, those admitted on the weekends, and those admitted to an academic institution had significantly lower odds of undergoing upfront URS. Secondary analysis demonstrated clinical and economic advantages of upfront URS vs stent alone in eligible patients.

CONCLUSION
Upfront URS is an overlooked procedure that has clinical and cost-saving implications. Unfortunately, minorities, publicly insured patients, and those admitted on the weekend are less likely to undergo upfront URS, a disparity that should be addressed by urologist.

Kirshenbaum|Eric J|EJ|
Doshi|Chirag|C|
Dornbier|Ryan|R|
Blackwell|Robert H|RH|
Bajic|Petar|P|
Gupta|Gopal N|GN|
Gorbonos|Alex|A|
Turk|Thomas M T|TMT|
Flanigan|Robert C|RC|
Baldea|Kristin G|KG|

socioeconomic disparities
urolithiasis
ureteroscopy
kidney stones
weekend effect


Frequency of Growth Differentiation Factor 5 rs143383 and asporin D-repeat polymorphisms in patients with hand and knee osteoarthritis in Kurdistan province, Iran.

Abstract:
AIM
Osteoarthritis (OA) is the most common chronic joint disorder, resulting from the breakdown of joint cartilage. It occurs in the knees, hands, and hips, leading to pain, stiffness, inflammation, and swelling.

METHODS
In this study, 100 hand and knee OA patients, meeting the American College of Rheumatology criteria were included in the case group, and 100 healthy individuals were allocated to the control group. Blood samples were collected from the participants. After DNA extraction, genotyping was carried out for GDF5 rs143383 C/T polymorphism by allele-specific polymerase chain reaction (ASPCR) and for D-repeat alleles of asporin (ASPN) by conventional PCR assay.

RESULTS
The results showed that the frequency of the D14 allele of ASPN was significantly higher than other alleles in the case group (P = .0001). Also, the frequency of the D14 allele among women was significantly higher than in men (P = .004). Moreover, the frequency of the TT allele in GDF5 rs143383 C/T polymorphism was significantly higher than the CC and CT alleles in the case group, compared with the control group (P = .001). A significant difference was found between the TT allele and other alleles in female and male patients compared with the control group (P = .02).

CONCLUSIONS
The D14 allele of the ASPN gene and TT allele of the GDF5 gene (rs143383 + 104T/C) are associated with hand and knee OA in the Kurdish population, indicating that these alleles could be risk factors for OA, at least in our populations.

D020022:Genetic Predisposition to Disease

asporin
polymorphism
osteoarthritis
growth/differentiation factor-5


Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity.

Abstract:
BACKGROUND
Triple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs).

METHODS
We applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1-/- mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival.

RESULTS
The immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1.

CONCLUSION
Thermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.

TRIAL REGISTRATION NUMBERS
NCT03237572 and NCT04116320.

D057086:High-Intensity Focused Ultrasound Ablation

D064726:Triple Negative Breast Neoplasms

adaptive immunity
immunotherapy
breast neoplasms
combined modality therapy


Motivational Deficits in Schizophrenia and the Representation of Expected Value.

Abstract: Motivational deficits (avolition and anhedonia) have historically been considered important negative symptoms of schizophrenia (SZ). Numerous studies have attempted to identify the neural substrates of avolition and anhedonia in schizophrenia , but these studies have not produced much agreement. Deficits in various aspects of reinforcement processing have been observed in individuals with schizophrenia, but it is not exactly clear which of these deficits actually engender motivational impairments in SZ. The purpose of this chapter is to examine how various reinforcement-related behavioral and neural signals could contribute to motivational impairments in both schizophrenia and psychiatric illness, in general. In particular, we describe different aspects of the concept of expected value (EV), such as the distinction between the EV of stimuli and the expected value of actions, the acquisition of value versus the estimation of value, and the discounting of value as a consequence of time or effort required. We conclude that avolition and anhedonia in SZ are most commonly tied to aberrant signals for expected value, in the context of learning. We discuss implications for further research on the neural substrates of motivational impairments in psychiatric illness.

Avolition
Anhedonia
Reinforcement
Basal ganglia
Orbitofrontal


A liquid chromatography-tandem mass spectrometry method for pharmacokinetics and tissue distribution of a camptothecin quaternary derivative in rats.

Abstract: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to identify and quantify the camptothecin quaternary derivative CPT8 for application in pharmacokinetics and tissue distribution studies. Rat plasma and tissue samples were extracted with methanol by using camptothecin as the internal standard (IS). Chromatographic separation of CPT8 and the IS was achieved using a Hypersil GOLD C18 column, with a flow rate of 1.0 mL/min followed by quantification with tandem mass spectrometry, operating with electrospray ionization in the positive ion mode and by applying multiple reaction monitoring. The MS/MS ion transitions were monitored at m/z 484.3-361.2 for CPT8 and m/z 349.0-305.2 for the IS (CPT). A calibration curve was constructed using CPT8 concentrations ranging from 2.5 ng/mL to 2500 ng/mL (r>0.993). The efficiency of CPT8 extraction from plasma and tissue samples ranged from 91.23% to 105.4%. Intra- and inter-day precision (relative standard deviation) values were 0.21% and 7.25%, respectively. No matrix effects were observed. The freeze-thaw stability, post-extraction stability, and stability following short- and long-term storage at low temperatures ranged from 84.12% to 108.2%. The preclinical data obtained using this method is expected to facilitate future clinical investigations of CPT8.

Li|Qingyong|Q| Zhu|Qiaochu|Q| Zhang|Xueke|X| Hua|Changlong|C| Deng|Xiaoqiu|X| Zhao|Tengfei|T| Sun|Baihe|B|

D002851:Chromatography, High Pressure Liquid

Pharmacokinetics
Tissue distribution
Camptothecin derivative
LC–MS/MS


Characterization of the response to low pH of Lactobacillus casei ΔRR12, a mutant strain with low D-alanylation activity and sensitivity to low pH.

Abstract:
AIMS
To identify the differences that account for the acid sensitivity of Lactobacillus casei ΔRR12. RR12 controls the expression of the dlt operon, and its inactivation leads to a diminished teichoic acid D-alanylation activity. To this end, a comparison of its response of ΔRR12 to low pH with the parental strain Lact. casei BL23 was carried out.

METHODS AND RESULTS
The ability to induce an acid tolerance response (ATR), fatty acid (FA) composition and proteome changes induced in both strains in response to acid were investigated. Results obtained showed that both strains induce a growth-phase-dependent ATR. However, significant differences in the content of FAs and membrane-associated proteins were detected.

CONCLUSIONS
The greater abundance of cytoplasmic proteins in the membrane fraction of the mutant strain ΔRR12 suggests an increased permeability of the cell membrane in this strain.

SIGNIFICANCE AND IMPACT OF THE STUDY
The analysis of the response to low pH of strain ΔRR12 indicated that the inactivation of TCS12 affected the content of FAs and proteins associated to the cell envelope. Increased abundance of cytoplasmic proteins suggested that low alanylation of teichoic acids affected the permeability of the cell membrane and possibly accounts for the acid sensitivity of strain ΔRR12.

Revilla-Guarinos|A|A| Alcántara|C|C| Rozès|N|N| Voigt|B|B| Zúñiga|M|M|

D001426:Bacterial Proteins
D002462:Cell Membrane
D005227:Fatty Acids
D006863:Hydrogen-Ion Concentration
D007780:Lactobacillus casei
D008565:Membrane Proteins
D009154:Mutation
D020543:Proteome
D013682:Teichoic Acids

Lactobacillus casei
acid sensitivity
acid tolerance response
fatty acids
D-alanylation of teichoic acids


Traumatic Brain Injury Update.

Abstract: Traumatic brain injury is a devastating, life-changing event in most cases. After the primary brain insult, it is helpful to use evidence-based monitoring techniques to guide implementation of essential interventions to minimize secondary injury and thereby improve patient outcomes. An update on multimodal neuromonitoring is provided in this narrative review, with discussion of tools and techniques currently used in the treatment of patients with brain injury. Neuroprotective treatments, from the well-studied targeted temperature management to new potential therapeutics under investigation, such as glyburide, also are presented.

D000070642:Brain Injuries, Traumatic
D003422:Critical Care
D006801:Humans

traumatic brain injury
multimodal neuromonitoring
neuroprotection


Activation of aryl hydrocarbon receptor by 6-formylindolo[3,2-b]carbazole alleviated acute kidney injury by repressing inflammation and apoptosis.

Abstract: Acute kidney injury (AKI) is a multifactorial disease of various aetiologies. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that responds to ligands to induce or repress gene expressions, thereby regulating a diverse spectrum of biological or pathophysiologic effects. However, the effect of AhR on AKI remains unknown. A single intraperitoneal injection of 50% glycerol was performed to induce rhabdomyolysis in C57BL/6J mice. The bilateral renal pedicles were occluded for 30 minutes and then removed to stimulate renal I/R injury. 6-formylindolo[3,2-b]carbazole (FICZ), a photo-oxidation product of tryptophan with a high affinity for AhR, was used. The in vitro study was performed on HK-2 cells. Ferrous myoglobin and FICZ was dissolved in the medium in different cell groups. Treatment with AhR agonist FICZ significantly alleviated the elevation of serum creatinine and urea in AKI. AKI modelling-induced renal damage was attenuated by FICZ. AhR mainly expressed in proximal tubular cells and could be activated by FICZ administration. Meanwhile, AKI triggered the production of pro-inflammatory cytokines in injured kidneys, while FICZ inhibited their expressions. Furthermore, FICZ effectively reversed cell apoptosis in AKI models. Mechanistically, AKI stimulated the activation of NF-κB and JNK pathways in the kidneys, while FICZ significantly suppressed these corresponding protein expressions. For the in vitro study, FICZ also inhibited inflammation and apoptosis in myoglobin or H/R-stimulated HK-2 cells. In summary, agonism of AhR by FICZ alleviated rhabdomyolysis and I/R-induced AKI. FICZ inhibited inflammation and apoptosis via suppressing NF-κB and JNK pathways in proximal tubular cells.

Tao|Sibei|S| Guo|Fan|F| Ren|Qian|Q| Liu|Jing|J| Wei|Tiantian|T| Li|Lingzhi|L| Ma|Liang|L|0000-0001-8327-7969 Fu|Ping|P|

aryl hydrocarbon receptor
acute kidney injury
inflammation
apoptosis
renal tubular epithelial cell


Predictive value of tumor-infiltrating lymphocytes for response to neoadjuvant chemotherapy and breast cancer prognosis.

Abstract:
BACKGROUND
Tumor-infiltrating lymphocytes (TILs) are predictive for the response to neoadjuvant chemotherapy (NAC) of breast cancer. However, little is known about the predictive value of TILs for axillary lymph node involvement after NAC.

METHODS
We analyzed 282 breast cancer patients who were operated following NAC and curative surgery from 2008 to 2018. TILs were assessed in core needle biopsies before NAC, and the biopsies were divided into three groups: low (0%-10% immune cells in stromal tissue within the tumor), intermediate (11%-59%), and high (≥60%). The patients were followed for an average of 63 months (range, 2-116 months). We analyzed retrospectively the predictive value of TILs for the response to NAC, including pathological complete response (pCR) and axillary lymph node involvement (positive lymph node ratio (LNR; the ratio of the number of nodes involved to the total number of nodes dissected)). The prognostic values of TILs and LNR were assessed.

RESULTS
A pCR was achieved in 27 of 188 patients (14.4%) in the low-TIL group, in 14 of 57 patients (24.6%) in the intermediate-TIL group, and in 13 of 37 (35.1%) in the high-TIL group (p = .007). Among patients who underwent axillary lymph node dissection after NAC, patients with high TILs had lower LNR (p = 0021) compared with the other groups. Kaplan-Meier analysis showed that overall survival (OS; p < .001) and disease-free survival (p < .001) were significantly longer for patients with low LNR (≤0.2). TILs were positively correlated with disease-free survival (p = .028), but TILs did not correlate with OS (p = .171). Moreover, by multivariable analysis, LNR independently affected disease-free survival (p < .001).

CONCLUSIONS
TILs may be predictive for pCR rate, postoperative residual lymph node involvement, and disease-free survival of breast cancer patients. High TILs may suggest favorable outcomes.

D000971:Antineoplastic Combined Chemotherapy Protocols

positive lymph node ratio
disease-free survival
triple-negative breast cancer


Changes in Hemostasis System in Outbred Female Mice with Cisplatin-Induced Procoagulant Status.

Abstract: Procoagulant status was modeled in outbred female mice by single injection of cisplatin in a maximum tolerated dose and hemostasis parameters monitored over 30 days by methods of coagulogram and low-frequency piezothromboelastography (global test). Monitoring revealed waveform changes in the hemostatic potential: the structural and chronometric hypercoagulation recorded starting from the first day and attaining its maximum on days 5-7 was followed by hypocoagulation and returned to normocoagulation on day 30. This pattern reflects prolonged effect of cisplatin: formation of severe dysfunction of the endothelium providing the main anticoagulant pool of hemostasis (day 1) aggravated by disturbances of the plastic functions of the liver (days 15-20), and recovery (days 20-30).

Filonova|M V|MV|
Fedorova|E P|EP|
Churin|A A|AA|
Kotlovskaya|L Yu|LY|
Solov'ev|M A|MA|
Udut|V V|VV|

cisplatin
low-frequency piezothromboelastography
hemostatic potential
endothelial dysfunction
outbred mice


Ameliorative effects of oleanolic acid on fluoride induced metabolic and oxidative dysfunctions in rat brain: Experimental and biochemical studies.

Abstract: Beneficial effects of oleanolic acid on fluoride-induced oxidative stress and certain metabolic dysfunctions were studied in four regions of rat brain. Male Wistar rats were treated with sodium fluoride at a dose of 20 mg/kg b.w./day (orally) for 30 days. Results indicate marked reduction in acidic, basic and neutral protein contents due to fluoride toxicity in cerebrum, cerebellum, pons and medulla. DNA, RNA contents significantly decreased in those regions after fluoride exposure. Activities of proteolytic enzymes (such as cathepsin, trypsin and pronase) were inhibited by fluoride, whereas transaminase enzyme (GOT and GPT) activities increased significantly in brain tissue. Fluoride appreciably elevated brain malondialdehyde level, free amino acid nitrogen, NO content and free OH radical generation. Additionally, fluoride perturbed GSH content and markedly reduced SOD, GPx, GR and CAT activities in brain tissues. Oral supplementation of oleanolic acid (a plant triterpenoid), at a dose of 5mg/kgb.w./day for last 14 days of fluoride treatment appreciably ameliorated fluoride-induced alteration of brain metabolic functions. Appreciable counteractive effects of oleanolic acid against fluoride-induced changes in protein and nucleic acid contents, proteolytic enzyme activities and other oxidative stress parameters indicate that oleanolic acid has potential antioxidative effects against fluoride-induced oxidative brain damage.

Sarkar|Chaitali|C| Pal|Sudipta|S| Das|Niranjan|N| Dinda|Biswanath|B|

Oleanolic acid
Fluoride
Oxidative stress
Metabolic dysfunction
Nonenzymatic antioxidants


Physicians' experiences working in emergency medicine in a rural area in Northern Sweden: a qualitative study.

Abstract:
INTRODUCTION
Working in emergency medicine in rural areas may entail challenges due to absence of medical backup, difficulties in logistics, lack of healthcare system coordination, and, potentially, feelings of loneliness. The aim of this study was to elucidate the experiences of physicians working in an emergency medical setting in a rural area in Northern Sweden.

METHODS
A qualitative study was performed based on semi-structured interviews. Six physicians were interviewed. The interviews were transcribed and analysed using the systematic text condensation method.

RESULTS
Rural physicians described thriving in the rural environment. Four main themes were identified as important to their wellbeing and job satisfaction. They described close relations to the nearest referral centre, where they felt connected to the personnel in the centre. The participants described this as a crucial factor aiding their everyday work in emergency medicine. The rural physicians underlined educational and professional development individually, in teams training sessions, and through the locally created rural residency program for rural GPs as important. They expressed an adaptability to the rural environment and described having a problem-solving attitude. Additionally they found a functional transport system crucial as part of their workflow.

CONCLUSION
Overall, the rural physicians thrived in the rural environment where interpersonal relations and creative initiatives along with a customised rural residency program prepared the physicians to work in rural areas. Despite the long distances between hospitals and health clinics, the physicians rarely felt alone in the field and the general well-functioning transport system with possibility for improvisations aided them in medical emergencies.

Setrinen Hansen|Nina Magdalena|NM|
Mikkelsen|Søren|S|
Bruun|Henriette|H|
From|Erika|E|
Milling|Louise|L|

emergency medicine
Sweden
medical
education
general/family practice
qualitative research


APC/CFZR-1 regulates centrosomal ZYG-1 to limit centrosome number.

Abstract: Aberrant centrosome numbers are associated with human cancers. The levels of centrosome regulators positively correlate with centrosome number. Thus, tight control of centrosome protein levels is critical. In Caenorhabditis elegans, the anaphase-promoting complex/cyclosome and its co-activator FZR-1 (APC/CFZR-1), a ubiquitin ligase, negatively regulates centrosome assembly through SAS-5 degradation. In this study, we report the C. elegans ZYG-1 (Plk4 in humans) as a potential substrate of APC/CFZR-1. Inhibiting APC/CFZR-1 or mutating a ZYG-1 destruction (D)-box leads to elevated ZYG-1 levels at centrosomes, restoring bipolar spindles and embryonic viability to zyg-1 mutants, suggesting that APC/CFZR-1 influences centrosomal ZYG-1 via the D-box motif. We also show the Slimb/βTrCP-binding (SB) motif is critical for ZYG-1 degradation, substantiating a conserved mechanism by which ZYG-1/Plk4 stability is regulated by the SKP1-CUL1-F-box (Slimb/βTrCP)-protein complex (SCFSlimb/βTrCP)-dependent proteolysis via the conserved SB motif in C. elegans. Furthermore, we show that co-mutating ZYG-1 SB and D-box motifs stabilizes ZYG-1 in an additive manner, suggesting that the APC/CFZR-1 and SCFSlimb/βTrCP ubiquitin ligases function cooperatively for timely ZYG-1 destruction in C. elegans embryos where ZYG-1 activity remains at threshold level to ensure normal centrosome number.

Centrosome
ZYG-1
FZR-1
C. elegans
Proteolysis
APC/C


The 12-3-12 cationic gemini surfactant as a novel gastrointestinal bioadhesive material for improving the oral bioavailability of coenzyme Q10 naked nanocrystals.

Abstract: To improve the oral bioavailability of nanocrystalline drug preparations, the cationic 12-3-12 quaternary ammonium surfactant gemini was introduced into nanocrystals as a novel gastrointestinal bioadhesive material. Coenzyme Q10 (CoQ10), a typical Biopharmaceutics Classification System (BCS) class II drug, was used as a model drug. The 12-3-12 gemini surfactant was added to the preparation at a low concentration and imbued the particles with abundant positive charges. In vitro and in vivo gastrointestinal adhesion tests confirmed that the gemini-modified nanocrystals were prone to adhere to the upper gastrointestinal tract (GIT), thereby prolonging retention time in the GIT and enhancing absorption. In the distribution study in rats, the use of nanocrystals modified with gemini led to greater drug distribution to the heart and the liver than that achieved with the naked nanocrystals. A pharmacokinetic study in beagle dogs showed that the gemini-modified CoQ10 nanocrystals improved the oral bioavailability of CoQ10 in a dose-dependent manner, and the smaller size produced a much better effect with the same gemini modification. These results demonstrate that the cationic surfactant gemini is a promising oral bioadhesive material with applications in nanoscale drug delivery systems.

Song|Yanzhi|Y| Han|Jie|J| Feng|Rui|R| Wang|Mengjing|M| Tian|Qingjing|Q| Zhang|Ting|T| Liu|Xinrong|X| Cheng|Xiaobo|X| Deng|Yihui|Y|

gemini
Bioadhesive material
oral bioavailability
coenzyme Q10
nanocrystal
drug delivery system


A cis-acting bidirectional transcription switch controls sexual dimorphism in the liverwort.

Abstract: Plant life cycles alternate between haploid gametophytes and diploid sporophytes. While regulatory factors determining male and female sexual morphologies have been identified for sporophytic reproductive organs, such as stamens and pistils of angiosperms, those regulating sex-specific traits in the haploid gametophytes that produce male and female gametes and hence are central to plant sexual reproduction are poorly understood. Here, we identified a MYB-type transcription factor, MpFGMYB, as a key regulator of female sexual differentiation in the haploid-dominant dioicous liverwort, Marchantia polymorpha MpFGMYB is specifically expressed in females and its loss resulted in female-to-male sex conversion. Strikingly, MpFGMYB expression is suppressed in males by a cis-acting antisense gene SUF at the same locus, and loss-of-function suf mutations resulted in male-to-female sex conversion. Thus, the bidirectional transcription module at the MpFGMYB/SUF locus acts as a toggle between female and male sexual differentiation in M. polymorpha gametophytes. Arabidopsis thaliana MpFGMYB orthologs are known to be expressed in embryo sacs and promote their development. Thus, phylogenetically related MYB transcription factors regulate female gametophyte development across land plants.

D018506:Gene Expression Regulation, Plant

sexual differentiation
Marchantia polymorpha
R2R3 MYB‐type transcription factor
antisense transcription
lncRNA


Simultaneous Hip and Distal Radius Fractures-Does It Make a Difference with Respect to Rehabilitation?

Abstract:
INTRODUCTION
A minority of patients with hip fractures sustain concomitant wrist fractures. Little is known about the rehabilitation outcome in this group of patients.

AIM OF STUDY
Prospective investigation of functional outcome and survival in patients with combined hip and wrist fractures compared with patients who sustain an isolated hip fracture.

METHODS
341 patients who presented with an acute hip fracture during a 12 month period were included in the study. Outcome at discharge and 4 months follow-up was compared between patients with isolated hip fractures and those patients who sustained simultaneous distal wrist fractures.

RESULTS
The actual incidence of concurrent hip and wrist fractures in our cohort was 4.7%. Patients who sustained a concurrent hip and wrist fracture showed no differences regarding short- and long-term functional outcome and survival.

CONCLUSION
Our results imply that patients with simultaneous hip and wrist fractures have no difference in rehabilitative outcome. Future studies should further investigate the distinctive characteristics of this patient subgroup.

Dubljanin-Raspopović|Emilija|E|
Lj|Marković-Denić|MD|
Kadija|Marko|M|
Tomanović Vujadinović|Sanja|S|
Tulić|Goran|G|
Selaković|Ivan|I|
Aleksić|Milica|M|

rehabilitation
hip fracture
wrist fracture
functional outcome
mortality


Ensemble learning based automatic detection of tuberculosis in chest X-ray images using hybrid feature descriptors.

Abstract: Tuberculosis (TB) remains one of the major health problems in modern times with a high mortality rate. While efforts are being made to make early diagnosis accessible and more reliable in high burden TB countries, digital chest radiography has become a popular source for this purpose. However, the screening process requires expert radiologists which may be a potential barrier in developing countries. A fully automatic computer-aided diagnosis system can reduce the need of trained personnel for early diagnosis of TB using chest X-ray images. In this paper, we have proposed a novel TB detection technique that combines hand-crafted features with deep features (convolutional neural network-based) through Ensemble Learning. Handcrafted features were extracted via Gabor Filter and deep features were extracted via pre-trained deep learning models. Two publicly available datasets namely (i) Montgomery and (ii) Shenzhen were used to evaluate the proposed system. The proposed methodology was validated with a k-fold cross-validation scheme. The area under receiver operating characteristics curves of 0.99 and 0.97 were achieved for Shenzhen and Montgomery datasets respectively which shows the superiority of the proposed scheme.

Ensemble learning
Tuberculosis
Computer aided diagnosis
Convolutional neural network


Study on the Plasma Protein Binding Rate and Compatibility Regularity of the Constituents Migrating to Blood of Simiao Yong'an Decoction.

Abstract:
OBJECTIVE
To study the compatibility regularity of Simiao Yong'an decoction by determining the plasma protein binding rate with the constituents in Simiao Yong'an decoction and to preliminarily clarify the effects of the compatibility on the plasma protein binding rate of different components.

METHODS
Based on the equilibrium dialysis method, high-performance liquid chromatography was used to determine the contents of six constituents, which were divided into a single group and combination groups, in Simiao Yong'an decoction in the internal and external dialysis solutions. The obtained plasma protein binding rate through calculations was an index to evaluate the binding of the above components to plasma protein in different conditions.

RESULTS
Harpagide, harpagoside, sweroside and loganin showed low plasma protein binding rates, ferulic acid exhibited a moderate plasma protein binding rate, and glycyrrhizic acid showed a high plasma protein binding rate. The compatibility study showed that glycyrrhizic acid promoted the binding of ferulic acid to plasma protein. Glycyrrhizic acid and ferulic acid were the key compounds to promote the binding of harpagide to plasma protein. Glycyrrhizic acid, harpagide, harpagoside and loganin had a significant inhibitory effects on the binding of sweroside to plasma protein. The plasma protein binding capacities of harpagoside and loganin were reduced by the other five constituents. Glycyrrhizic acid had the strongest plasma protein binding effect, and the binding effect was not affected by other components.

CONCLUSION
This study explores the effects of compound compatibility on effective components from the perspective of plasma protein binding by high-performance liquid chromatography combined with the equilibrium dialysis method, and lays a foundation for clarifying the compatibility rule of Simiao Yong'an decoction and also provides a new idea for the study of the compatibility of traditional Chinese medicine formulas.

Yu|Xiao|X| Jiao|Qishu|Q| Jiang|Yanyan|Y| Guo|Shuzhen|S| Zhang|Wei|W| Liu|Bin|B|

Plasma protein binding rate
equilibrium dialysis
Simiao Yong’an decoction
drug interaction
pharmacokinetics
traditional Chinese medicine compound


Neonatal seizures are associated with redistribution and loss of GABAA α-subunits in the hypoxic-ischaemic pig.

Abstract: Seizures are a common manifestation of hypoxic-ischaemic brain injury in the neonate. In status epilepticus models alterations to GABAA R subunit expression have been suggested to contribute to (i) abnormal development of the GABAergic system, (ii) why seizures become self-sustaining and (iii) the development of pharmacoresistance. Detailed investigation of GABAA R subunit protein expression after neonatal hypoxia-ischaemia (HI) is currently insufficient. Using our pig model of HI and subsequent spontaneous neonatal seizures, we investigated changes in protein expression of the three predominant α-subunits of the GABAA R; α1 , α2 and α3 . Anaesthetized, ventilated newborn pigs (< 24 h old) were subjected to 30 min HI and subsequently recovered to 24 or 72 h. Amplitude-integrated electroencephalography was used to monitor brain activity and identify seizure activity. Brain tissue was collected post-mortem and GABAA R α-subunit protein expression was analysed using western blot and immunohistochemistry. GABAA R α1 and α3 protein expression was significantly reduced in animals that developed seizures after HI; HI animals that did not develop seizures did not exhibit the same reductions. Immunohistochemistry revealed decreased α1 and α3 expression, and α1 redistribution from the cell membrane to the cytosol, in the hippocampus of seizure animals. Multivariate analyses, controlling for HI severity and neuronal injury, revealed that seizures were independently associated with significant GABAA R α3 reduction. This is the first study to show loss and redistribution of GABAA R α-subunits in a neonatal brain experiencing seizures. Our findings are similar to those reported in models of SE and in chronic epilepsy.

brain injury
GABAA receptor subunits
anticonvulsants
hypoxia


Aortic Stiffness, Inflammation, and Incidence of Cardiovascular Events in Elderly Participants From the General Population.

Abstract: Low-grade inflammation and arterial stiffness are key factors in the development of vascular aging. However, the interplay between arterial stiffness and inflammation for cardiovascular (CV) disease is unclear. Aortic pulse wave velocity (aPWV) and the inflammatory markers, high-sensitivity C-reactive protein (CRP) and orosomucoid, were measured in 2710 participants (median age: 72 years). These participants were followed up for a mean of 7.6 years for a composite CV disease end point. Per 1 interquartile range increment of CRP and orosomucoid, respectively, aPWV increased by 0.19 m/s (95% CI: 0.07-0.32) and 0.19 m/s (0.11-0.27), after multifactorial adjustment. Mediation analysis showed that aPWV, after multifactorial adjustment, mediated 8% (-4, 20) of the CV disease risk associated with CRP and 8% (-4, 18) of orosomucoid risk. The associated risk increased with combinations of high aPWV and high CRP or orosomucoid. We found no evidence that arterial PWV acted as an important mediator of the relationship between systemic inflammation and CV disease risk in this elderly population. The results instead indicate an additive effect. Our study supports the view that arterial stiffness and chronic inflammation affects CV risk mainly through separate causal pathways.

inflammation
arterial stiffness
pulse wave velocity
C-reactive protein
orosomucoid
aorta
arteriosclerosis


Pharmacy Students' Ability to Identify Fall Risk-Increasing Drugs Using an Innovative Assessment Tool.

Abstract: Objective. To evaluate change in the ability of third-year pharmacy students to identify drugs that increase fall risk after training in and experience using the Medication Falls Risk Assessment Tool (MFRAT). Methods. An assessment was administered to students prior to MFRAT use and after MFRAT use. The assessment consisted of 10 medication regimens for various chronic conditions (50 distinct drug choices with 30 correct answers and 20 distractors), and students were to identify fall risk increasing drugs (FRIDs). Using a flipped-classroom approach, students viewed an online presentation on FRIDs and then participated in instructor guided, in-class application of the MFRAT using student-collected data from an actual patient case. Students completed medication therapy management (MTM) documentation. The assessment data for students who had previously used the MFRAT (experienced) were analyzed separately from first time users (inexperienced). Results. Three assessment scores were evaluated: number correct (maximum 30; higher score is better), number of distractors (maximum 20; lower score better), and a combined total score (maximum 50; higher score better). In inexperienced users (n=104), pre- and post-assessment means improved significantly for correct score (24.9 vs 29.5) and total score (39.4 vs 44.3). Among experienced users (n=10), pre- and post-assessment means improved significantly for correct responses (27.3 vs 29.7), distractors (7.0 vs 3.5), and total score (40.3 vs 46.2). Conclusion. The ability of both pharmacy students who had used the MFRAT previously and those who had not to correctly identify FRIDs increased on the post-assessment.

Wahler|Robert G|RG|
Piccione|Christine|C|
Maerten-Rivera|Jaime|J|

D064420:Drug-Related Side Effects and Adverse Reactions

risk assessment clinical decision support tool


Leukemic arthritis and severe hypercalcemia in a man with chronic myeloid leukemia: a case report and review of the literature.

Abstract:
BACKGROUND
Patients with chronic myeloid leukemia typically present with high white blood cell counts revealed during annual checkups. Leukemic arthritis and hypercalcemia are rare manifestations in patients with chronic myeloid leukemia.

CASE PRESENTATION
A 35-year-old Thai man who had been diagnosed with chronic myeloid leukemia in the chronic phase developed blast crisis while he was receiving ongoing treatment with imatinib at 400 mg/day. Initially, he presented with oligoarthritis in both knees and ankles. A bone scintigraphy showed a prominent bony uptake, with a symmetrical, increased uptake in many bone areas. Induction therapy with a 7 + 3 induction regimen was prescribed in conjunction with 600 mg of imatinib once daily before switching to 140 mg of dasatinib. He subsequently developed severe hypercalcemia (total serum calcium of 17.8 mg/dL), with generalized osteolytic lesions detected on a bone survey. His serum vitamin D level was 50.64 ng/mL, while the serum parathyroid hormone level was 9.82 pg/mL. Despite the administration of an aggressive intravenously administered hydration, intravenously administered calcitonin, and 600 mg/day of imatinib, the severe hypercalcemia was refractory. We therefore decided to prescribe 20 mg/day of intravenously administered dexamethasone; fortunately, his serum calcium level decreased dramatically to normal range within a few days.

CONCLUSIONS
Although leukemic arthritis and severe hypercalcemia are extraordinary presentations in patients with chronic myeloid leukemia, the advanced phase of the disease might bring on these symptoms. Apart from parathyroid hormone-related protein-related hypercalcemia, vitamin D is a mechanism of humoral-mediated hypercalcemia.

D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Leukemic arthritis
Hypercalcemia
Chronic myeloid leukemia
Osteolytic bone


The effect of serum vitamin D normalization in preventing recurrences of benign paroxysmal positional vertigo: A case-control study.

Abstract:
BACKGROUND
Benign paroxysmal positional vertigo (BPPV) is a condition with recurrent attacks in a significant proportion of patients. The present case- control study was conducted to assess the influence of serum vitamin D normalization on recurrent attacks of vitamin D deficient patients.

METHODS
Diagnosis of BPPV was made based on history and clinical examination and exclusion of other conditions. Serum 25-hydroxy vitamin D (25-OHD) was measured using ELISA method and a levels of < 20 ng/ml was considered a deficiency of vitamin D. Inclusion criteria were as follows: history of recurrent attacks and serum 25-OHD<20.ng/ml. While the patients with history of trauma, surgery and chronic systemic diseases were excluded. The patients were classified into two groups: treatment and control, intermittently. Both groups received Epley rehabilitation therapy one session per week for 4 weeks but the treatment group received an additional supplement of 50.000 IU of vitamin D (cholecalciferol) weekly for two months to achieve serum 25-OHD ≥ 30 ng/ml and the study patients were followed-up for 6 months.

RESULTS
Twenty-seven patients were allocated to each group. At baseline, serum 25-OHD was similar (10.7±2.3 vs 11.41±1.9, P=0.23). At month 2, serum 25-OHD in the treatment group increased significantly to ≥ 30 ng/ ml, whereas serum 25-OHD in the control group remained unchanged (34.2±3.3 vs 10.6 10.6±2.2 ng/ml, P=0.001). During the follow-up period, attacks of BPPV in the treatment group decreased significantly compared with the control group (14.8% vs 96.3% OR= 0.18, P=0.001).

CONCLUSION
The findings of this study indicate that the normalization of serum vitamin D significantly reduces BPPV recurrences.

Sheikhzadeh|Mahboobeh|M| Lotfi|Yones|Y| Mousavi|Abdollah|A| Heidari|Behzad|B| Bakhshi|Enyatollah|E|

BPPV
25-hydroxy vitamin D
Epley Therapy
Recurrent vertigo


Development and Characterization of an 18F-labeled Ghrelin Peptidomimetic for Imaging the Cardiac Growth Hormone Secretagogue Receptor.

Abstract: One-third of patients with heart disease develop heart failure, which is diagnosed through imaging and detection of circulating biomarkers. Imaging strategies reveal morphologic and functional changes but fall short of detecting molecular abnormalities that can lead to heart failure, and circulating biomarkers are not cardiac specific. Thus, there is critical need for biomarkers that are endogenous to myocardial tissues. The cardiac growth hormone secretagogue receptor 1a (GHSR1a), which binds the hormone ghrelin, is a potential biomarker for heart failure. We have synthesized and characterized a novel ghrelin peptidomimetic tracer, an 18F-labeled analogue of G-7039, for positron emission tomography (PET) imaging of cardiac GHSR1a. In vitro analysis showed enhanced serum stability compared to natural ghrelin and significantly increased cellular uptake in GHSR1a-expressing OVCAR cells. Biodistribution studies in mice showed that tissue uptake of the tracer was independent of circulating ghrelin levels, and there was negligible cardiac uptake and high uptake in the liver, intestines, and kidneys. Specificity of tracer uptake was assessed using ghsr -/- mice; both static and dynamic PET imaging revealed no difference in cardiac uptake, and there was no significant correlation between cardiac standardized uptake values and GHSR1a expression. Our study lays the groundwork for further refinement of peptidomimetic PET tracers targeting cardiac GHSR1a.

D000072078:Positron Emission Tomography Computed Tomography

ghrelin
imaging
cardiac
heart disease
heart failure
biomarkers
GHSR1a
PET


Protecting the health of responders: Team Health.

Abstract: The rise in humanitarian disasters has led to more volunteers responding to deploy with humanitarian organisations. Those organisations that use these volunteers have a responsibility for the health of these teams of workers. This personal view outlines the three phases of 'Team Health'-prepare, sustain and recover. This is a paper commissioned as a part of the Humanitarian and Disaster Relief Operations special issue of BMJ Military Health.

preventive medicine
public health
tropical medicine


Morning cortisol and fasting glucose are elevated in women with chronic widespread pain independent of comorbid restless legs syndrome.

Abstract:
BACKGROUND AND AIMS
Chronic widespread pain (CWP) is associated with poor quality of sleep, but the detailed underlying mechanisms are still not fully understood. In this study we investigated the influence of CWP on morning cortisol and fasting glucose concentrations as well as sleep disordered breathing.

METHODS
In this case-control study, subjects with CWP (n=31) and a control group without CWP (n=23) were randomly selected from a population-based cohort of women. Current pain intensity, sleep quality, excessive daytime sleepiness [Epworth sleepiness scale (ESS)], psychiatric comorbidity and occurrence of restless legs syndrome (RLS) were assessed. Overnight polygraphy was applied to quantify sleep apnoea, airflow limitation and attenuations of finger pulse wave amplitude (>50%) as a surrogate marker for increased skin sympathetic activity. Morning cortisol and fasting glucose concentrations were determined. Generalised linear models were used for multivariate analyses.

RESULTS
CWP was associated with higher cortisol (464±141 vs. 366±111 nmol/L, p=0.011) and fasting glucose (6.0±0.8 vs. 5.4±0.7 mmol/L, p=0.007) compared with controls. The significance remained after adjustment for age, body mass index, RLS and anxiety status (β=122±47 nmol/L and 0.89±0.28 mmol/L, p=0.009 and 0.001, respectively). The duration of flow limitation in sleep was longer (35±22 vs. 21±34 min, p=0.022), and pulse wave attenuation was more frequent (11±8 vs. 6±2 events/h, p=0.048) in CWP subjects compared with controls. RLS was associated with higher ESS independent of CWP (β=3.1±1.3, p=0.018).

CONCLUSIONS
Elevated morning cortisol, impaired fasting glucose concentration and increased skin sympathetic activity during sleep suggested an activated adrenal medullary system in subjects with CWP, which was not influenced by comorbid RLS.

IMPLICATIONS
CWP is associated with activated stress markers that may deteriorate sleep.

Stehlik|Romana|R| Ulfberg|Jan|J| Zou|Ding|D| Hedner|Jan|J| Grote|Ludger|L|

cortisol
glucose
restless legs syndrome
finger pulse wave
skin sympathetic activation
multi-site pain


Pelargonium sidoides extract EPs 7630: a review of its clinical efficacy and safety for treating acute respiratory tract infections in children.

Abstract:
Background
In numerous randomized controlled trials (RCTs) and systematic reviews such as those published by the Cochrane Collaboration, Pelargonium sidoides extract EPs® 7630 was shown to be effective in acute respiratory tract infections (aRTI) in all investigated age-groups. This narrative review focuses on recently published results from RCTs investigating the clinical efficacy and safety of EPs 7630 in children and adolescents with different manifestations of aRTI, in order to present a broader overview and to provide an update on the state of knowledge regarding the use of EPs 7630 in this age-group.

Methods
The Cochrane review on P. sidoides extract for aRTI published by the Cochrane Collaboration was searched for cited RCTs with EPs 7630 in children and adolescents suffering from aRTI. A PubMed and SCOPUS literature search was performed for publications issued before June 13, 2017 (search terms: children, Pelargonium sidoides, EPs 7630, respiratory). Reference lists of publications found were searched for relevant citations.

Results
Eight RCTs investigating the application of EPs 7630 in acute bronchitis, acute tonsil-lopharyngitis, and aRTI in the context of chronic preconditions were identified. Results showed a statistically significant improvement of aRTI symptom severity for EPs 7630 as compared to controls. The investigation of EPs 7630 in asthmatic children and adolescents with aRTI demonstrated a significant symptom-alleviating effect and a possibly associated reduction of asthma attacks. In immunocompromised children with acute upper RTI, an alleviating effect of EPs 7630 was shown. All RCTs reviewed reported good safety and tolerability of EPs 7630.

Conclusion
The P. sidoides extract EPs 7630 is effective and safe for those of pediatric age and may be regarded as an alternative option for the management of aRTI.

Pelargonium sidoides
EPs 7630
acute respiratory tract infections
children
acute bronchitis
asthma


Social engagement, self-efficacy, and posttraumatic stress symptoms across 6 months of psychotherapy.

Abstract:
OBJECTIVE
The current study was conducted in a naturalistic treatment setting to examine whether and how perceptions about social engagement, trauma coping self-efficacy, and posttraumatic stress symptoms (PTS) influence one another across 6 months of psychotherapy for trauma survivors.

METHOD
The sample included 183 clients who reported exposure to traumatic events and significant PTS (PCL-5 ≥ 33). Participants (Mage  = 37.8, 53.6% female) completed surveys at intake, 3 months, and 6 months into treatment. A cross-lagged panel analysis was used to test the relationships among perceived social engagement, coping self-efficacy, and PTS across three assessment points.

RESULTS
PTS at 3-months was a mediator in the relationship between intake perceived social engagement and 6-month coping self-efficacy and between intake perceived social engagement and 6-month perceived social engagement.

CONCLUSIONS
PTS several months into treatment may serve as a mechanism between intake perceived social engagement and functional outcomes such as coping self-efficacy.

social engagement
posttraumatic stress
treatment
coping self-efficacy
functional outcomes
social functioning


Ameliorative effect of polydatin on hyperglycemia and renal injury in streptozotocin-induced diabetic rats.

Abstract: To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1β, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin.  As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.

Wang|Lijuan|L| Huang|Liji|L| Li|Nan|N| Miao|Junjun|J| Liu|Wei|W| Yu|Jiangyi|J|

Polydatin
Diabetic nephropathy
Inflammatory factors
SGLT
Streptozotocin.


Presence of Renal Simple Cysts Is Associated With Increased Risk of Abdominal Aortic Aneurysms.

Abstract: We compared the incidence of renal simple cysts in 271 patients with abdominal aortic aneurysm (AAA) and 1387 patients without AAA (controls) using computed tomography (CT) angiography and abdominal CT, as a health screening program. The AAA group had significantly higher prevalence of renal simple cysts (55% vs 19%, P = .001) and chronic obstructive pulmonary disease (COPD; 12% vs 1%, P = .011) than the controls. After propensity score matching (n = 164), the prevalence of renal simple cysts was still significantly higher in the AAA group. In multivariate analysis, independent predictors of AAA were age, male gender, smoking history, hypertension, high-sensitivity C-reactive protein, creatinine, COPD, and renal simple cysts. The structural weakness predisposing for renal simple cysts may be associated with the initiation of AAA formation. More studies are needed to determine whether the presence of renal simple cysts can be considered as a risk factor for AAA.

D029424:Pulmonary Disease, Chronic Obstructive

renal simple cysts
abdominal aortic aneurysm
connective tissue disorder


High mass accuracy assay for trimethylamine N-oxide using stable-isotope dilution with liquid chromatography coupled to orthogonal acceleration time of flight mass spectrometry with multiple reaction monitoring.

Abstract: Trimethylamine N-oxide (TMAO) has attracted interest as circulating levels have reported prognostic value in patients with cardiovascular conditions, such as heart failure. With continual advances in accurate mass measurements, robust methods that can employ the capabilities of time of flight mass spectrometers would offer additional utility in the analysis of complex clinical samples. A Waters Acquity UPLC was coupled to a Waters Synapt G2-S high-resolution mass spectrometer. TMAO was measured in plasma by stable-isotope dilution-hydrophilic interaction liquid chromatography-time of flight mass spectrometry with multiple reaction monitoring (LC-ToF-MRM). Two transitions were monitored: m/z 76.1 to 58.066/59.073 and m/z 85.1 to 66.116/68.130. The method was assessed for linearity, lower limits of detection and quantitation, and reproducibility. A selected cohort of patients with systolic heart failure (SHF; n = 43) and healthy controls (n = 42) were measured to verify the assay is suitable for the analysis of clinical samples. Quantitative analysis of TMAO using LC-ToF-MRM enabled linearity to be established between 0.1 and 75 μmol/L, with a lower limit of detection of 0.05 μmol/L. Relative standard deviations reported an inter-day variation of ≤20.8% and an intra-day variation of ≤11.4% with an intra-study quality control variation of 2.7%. Run times were 2.5 min. Clinical application of the method reported that TMAO in SHF was elevated compared to that of healthy controls (p < 0.0005). LC-ToF-MRM offers a highly selective method for accurate mass measurement of TMAO with rapid and reproducible results. Applicability of the method was shown in a selected cohort of patient samples.

Heaney|Liam M|LM|
Jones|Donald J L|DJ|
Mbasu|Richard J|RJ|
Ng|Leong L|LL|
Suzuki|Toru|T|

D021241:Spectrometry, Mass, Electrospray Ionization

Time of flight
Multiple reaction monitoring
TMAO
Heart failure
High-resolution mass spectrometry
LC-MS/MS


Vocal Health Practices Among School Teachers: A Study From Chennai, India.

Abstract:
INTRODUCTION
A healthy vocal system is a prerequisite to produce a serviceable voice for any vocal profession. The concept of vocal health (VH) among teachers is worth exploring considering their known risk of developing voice disorders.

AIM
To provide socioculture-specific information on VH practices and nature of voice problems in teachers.

METHOD
A VH questionnaire was developed to elicit opinions toward one's own voice health and factors that indicated and contributed to impaired/poor VH from 384 school teachers.

RESULTS AND DISCUSSION
'Flexible voice' (23%), 'enduring voice' (22%), and 'good voice' (22%) were descriptions to indicate good VH by teachers. 'Vocal fatigue' (13%), 'dry throat' (9.4%), 'throat irritation' (4.7%), and 'pain while swallowing/speaking' (3.1%) were frequently reported throat sensations to indicate poor VH. For 30.2% of the teachers, voice mattered for professional needs. However, most of them managed to cope with voice problems through several home remedies and 'intentional/self-imposed neglect' despite their vocal difficulties. Sociocultural factors influencing these findings and scope to escalate voice problems in teachers as a public health issue are discussed.

CONCLUSION AND IMPLICATION
Insight and perception of VH based on self-reports and information on voice practices among teachers pertinent to this geographical location provide scope to develop models for counseling and preventive treatment for voice problems.

D000328:Adult
D000368:Aged
D005260:Female
D006304:Health Status
D006801:Humans
D007194:India
D008297:Male
D008875:Middle Aged
D009784:Occupational Diseases
D016272:Occupational Health
D065840:Protective Factors
D012307:Risk Factors
D000070777:School Teachers
D064890:Social Determinants of Health
D014832:Voice Disorders
D014833:Voice Quality
D014834:Voice Training
D055815:Young Adult

Vocal health
School teachers
Voice problems
Voice practices
Voice usage


Accuracy of Carpal Tunnel Injection: A Prospective Evaluation of 756 Patients.

Abstract: Background: Corticosteroid injection into the carpal tunnel is both a diagnostic test and a therapeutic modality in the treatment of carpal tunnel syndrome. Many injection techniques are described in the literature. Improper placement of injection may result in damage to neurovascular structures in the carpal canal or decrease efficacy of the test and/or therapy. The purpose of this study is to determine if carpal tunnel injection using anatomic landmarks is reproducible and safe. A review of the senior author's injection technique is presented. Methods: Over 8 years, there were 756 attempted placements of a 25-gauge needle into the carpal tunnel in a simulated carpal tunnel injection prior to open carpal tunnel release. The needle was inserted at the wrist crease, just ulnar to palmaris longus. Open carpal tunnel release was subsequently performed, and position of the needle was recorded. Results: In 572 patients (75.7%), the needle was found to be in the carpal tunnel without penetration of contents. The needle was in the carpal tunnel but piercing the median nerve in 66 attempts (8.7%). The carpal tunnel was missed in 118 attempts (15.6%). Conclusions: This is the largest study looking at accuracy of carpal tunnel injection using anatomic landmarks. Our injection accuracy (75.7%) is less than reported in previous studies, which note 82% to 100% accuracy using the same injection technique. This may indicate that carpal tunnel injection is less reliable than previously thought. Safety of carpal tunnel injection remains an important concern. The median nerve was penetrated in 8.7% of attempts.

Green|David P|DP|
MacKay|Brendan J|BJ|
Seiler|Steven J|SJ|
Fry|Michael T|MT|

carpal tunnel
carpal tunnel injection
carpal tunnel syndrome
injection technique
anatomic landmarks
median nerve
injection accuracy


Comparing science communication theory with practice: An assessment and critique using Australian data.

Abstract: Scholars have variously described different models of science communication over the past 20 years. However, there has been little assessment of theorised models against science communication practice. This article compares 515 science engagement activities recorded in a 2012 Australian audit against the theorised characteristics of the three dominant models of deficit, dialogue and participation. Most engagement activities had objectives that reflected a mix of deficit and dialogue activities. Despite increases in scientific controversies like climate change, there appears to be a paucity of participatory activities in Australia. Those that do exist are mostly about people being involved with science through activities like citizen science. These participatory activities appear to coexist with and perhaps even depend on deficit activities. Science communication scholars could develop their models by examining the full range of objectives for engagement found in practice and by recognising that any engagement will likely include a mix of approaches.

science communication theory
science communication practice
science engagement
science communication models


Angiotensin II Influences Pre-mRNA Splicing Regulation by Enhancing RBM20 Transcription Through Activation of the MAPK/ELK1 Signaling Pathway.

Abstract: RNA binding motif 20 (RBM20) is a key regulator of pre-mRNA splicing of titin and other genes that are associated with cardiac diseases. Hormones, like insulin, triiodothyronine (T3), and angiotensin II (Ang II), can regulate gene-splicing through RBM20, but the detailed mechanism remains unclear. This study was aimed at investigating the signaling mechanism by which hormones regulate pre-mRNA splicing through RBM20. We first examined the role of RBM20 in Z-, I-, and M-band titin splicing at different ages in wild type (WT) and RBM20 knockout (KO) rats using RT-PCR; we found that RBM20 is the predominant regulator of I-band titin splicing at all ages. Then we treated rats with propylthiouracil (PTU), T3, streptozotocin (STZ), and Ang II and evaluated the impact of these hormones on the splicing of titin, LIM domain binding 3 (Ldb3), calcium/calmodulin-dependent protein kinase II gamma (Camk2g), and triadin (Trdn). We determined the activation of mitogen-activated protein kinase (MAPK) signaling in primary cardiomyocytes treated with insulin, T3, and Ang II using western blotting; MAPK signaling was activated and RBM20 expression increased after treatment. Two downstream transcriptional factors c-jun and ETS Transcription Factor (ELK1) can bind the promoter of RBM20. A dual-luciferase activity assay revealed that Ang II, but not insulin and T3, can trigger ELK1 and thus promote transcription of RBM20. This study revealed that Ang II can trigger ELK1 through activation of MAPK signaling by enhancing RBM20 expression which regulates pre-mRNA splicing. Our study provides a potential therapeutic target for the treatment of cardiac diseases in RBM20-mediated pre-mRNA splicing.

Cai|Hanfang|H|
Zhu|Chaoqun|C|
Chen|Zhilong|Z|
Maimaiti|Rexiati|R|0000-0001-6751-2113
Sun|Mingming|M|
McCormick|Richard J|RJ|
Lan|Xianyong|X|
Chen|Hong|H|
Guo|Wei|W|

D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2

D047908:Intracellular Signaling Peptides and Proteins

angiotensin II
pre-mRNA splicing
RBM20
hormones
insulin
T3


Genomic and Resistance Epidemiology of Gram-Negative Bacteria in Africa: a Systematic Review and Phylogenomic Analyses from a One Health Perspective.

Abstract: Antibiotic resistance (AR) remains a major threat to public and animal health globally. However, AR ramifications in developing countries are worsened by limited molecular diagnostics, expensive therapeutics, inadequate numbers of skilled clinicians and scientists, and unsanitary environments. The epidemiology of Gram-negative bacteria, their AR genes, and geographical distribution in Africa are described here. Data were extracted and analyzed from English-language articles published between 2015 and December 2019. The genomes and AR genes of the various species, obtained from the Pathosystems Resource Integration Center (PATRIC) and NCBI were analyzed phylogenetically using Randomized Axelerated Maximum Likelihood (RAxML) and annotated with Figtree. The geographic location of resistant clones/clades was mapped manually. Thirty species from 31 countries and 24 genera from 41 countries were analyzed from 146 articles and 3,028 genomes, respectively. Genes mediating resistance to β-lactams (including bla TEM-1, bla CTX-M, bla NDM, bla IMP, bla VIM, and bla OXA-48/181), fluoroquinolones (oqxAB, qnrA/B/D/S, gyrA/B, and parCE mutations, etc.), aminoglycosides (including armA and rmtC/F), sulfonamides (sul1/2/3), trimethoprim (dfrA), tetracycline [tet(A/B/C/D/G/O/M/39)], colistin (mcr-1), phenicols (catA/B, cmlA), and fosfomycin (fosA) were mostly found in Enterobacter spp. and Klebsiella pneumoniae, and also in Serratia marcescens, Escherichia coli, Salmonella enterica, Pseudomonas, Acinetobacter baumannii, etc., on mostly IncF-type, IncX3/4, ColRNAI, and IncR plasmids, within IntI1 gene cassettes, insertion sequences, and transposons. Clonal and multiclonal outbreaks and dissemination of resistance genes across species and countries and between humans, animals, plants, and the environment were observed; Escherichia coli ST103, K. pneumoniae ST101, S. enterica ST1/2, and Vibrio cholerae ST69/515 were common strains. Most pathogens were of human origin, and zoonotic transmissions were relatively limited.IMPORTANCE Antibiotic resistance (AR) is one of the major public health threats and challenges to effective containment and treatment of infectious bacterial diseases worldwide. Here, we used different methods to map out the geographical hot spots, sources, and evolutionary epidemiology of AR. Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., Neisseria meningitis/gonorrhoeae, Vibrio cholerae, Campylobacter jejuni, etc., were common pathogens shuttling AR genes in Africa. Transmission of the same clones/strains across countries and between animals, humans, plants, and the environment was observed. We recommend Enterobacter spp. or K. pneumoniae as better sentinel species for AR surveillance.

genomics
Africa
One Health
antibiotic resistance
diagnostics
mobilome
molecular epidemiology
resistome