Immunocytochemical and morphometric study of prolactin cells during amphibian morphogenesis.
The peroxidase-antiperoxidase (PAP) immunocytochemical technique and rabbit antihuman prolactin (PRL) antiserum were used to localize and identify PRL-producing cells in the pars distalis of Bufo calamita, Hyla meridionalis, Alytes cisternasii, Pelobates cultripes, and Rana perezi tadpoles at different stages of development as well as in 1-year-old post-metamorphic animals. This cell type was located throughout the gland in P. cultripes and R. perezi and in the caudal two-thirds in B. calamita, H. meridionalis, and A. cisternasii in premetamorphic animals. These distribution patterns do not show changes throughout development. Morphometry was used to evaluate the changes observed in pars distalis volume and stereological parameters of PRL immunoreactive cells during development. Pars distalis volume increased during the larval growth period and decreased throughout the metamorphic climax. PRL volume density and cellular area showed different patterns in the different species, although the correlation between these parameters suggests a period of great proliferative rate followed by changes in cellular size. The changes observed in PRL total volume suggest the existence of two phases in amphibian development: (i) a period of PRL storage during pre- and prometamorphosis and (ii) a period of release at the metamorphic climax.


The evolution of the environment and its influence on the evolution of life.
Thermodynamic data and known paleogeological data were used to deduce when and what elements (compounds) were readily available during the whole history of the earth. On the basic assumption that available compounds would dictate the type of organisms to emerge, we attempted to derive a kind of evolutionary tree. This was then compared with the existing evolutionary trees derived from the sequences of proteins and polynucleotides.


Effect of X-ray irradiation on pharmacokinetics of irinotecan hydrochloride and expression of CES1 and CYP3A1 in rats.
Concurrent chemoradiation with irinotecan hydrochloride (CPT-11) is accepted for cancer treatment. However, the effects of X-ray irradiation on chemotherapeutics in the plasma remain unclear. We evaluated the pharmacokinetics of CPT-11 in rats after exposure to X-ray irradiation and examined the changes of protein and mRNA expression of CES1 and CYP3A1. The X-ray irradiation with 1 Gy and 5 Gy was delivered to the whole body of rats. CPT-11 at 30 and 60 mg/kg, respectively, was intravenously infused 24 h after irradiation. CPT-11 was determined by RP-HPLC in plasma. ELISA and PCR were used to analyze the protein and mRNA expression of CES1 and CYP3A1, respectively. Compared with control rats, the X-ray irradiation decreased the AUC of CPT-11 (30 mg/kg) by 15.6% at 1 Gy and 39.0% at 5 Gy and increased the CL by 60.0% at 5 Gy. The X-ray irradiation could also decrease the AUC of CPT-11 (60 mg/kg) and increase the CL. In addition, the protein and mRNA expression of CES1 and CYP3A1 were increased significantly in rats after irradiation. This study found significant changes in the pharmacokinetics of CPT-11 in rats after exposure to X-ray irradiation, and they might be due to significant increases in the expressions of CYP3A1 and CES1. The pharmacokinetics of CPT-11 should be rechecked, and the optimal CPT-11 dose should be reevaluated during concurrent chemoradiation therapy.


Ulcerative colitis-specific delivery of keratinocyte growth factor by neutrophils-simulated liposomes facilitates the morphologic and functional recovery of the damaged colon through alleviating the inflammation.
Keratinocyte growth factor (KGF) was effective to treat ulcerative colitis. However, its poor stability and unspecific distribution toward inflamed bowel were two important obstacles hindering its consistent efficacy. Herein, KGF was firstly encapsulated into the liposomes (KGF-Lips) to improve its stability. Thereafter, the neutrophil membrane vesicle (NEM) was extracted from the activated neutrophil which was isolated from the healthy mice and then activated by lipopolysaccharide. Subsequently, NEM was inlaid in KGF-Lips to construct a neutrophil-like liposome (KGF-Neus). KGF was easily encapsulated into KGF-Neus with a high encapsulation efficiency of 95.3 ± 0.72%. Controlling NEM/lipid ratio at 1:50, KGF-Neus displayed the spherical morphology with Dh of 154.8 ± 2.7 nm, PDI of 0.18, and zeta potential of -2.37 ± 0.14 mV. Moreover, KGF-Neus exhibited good stability of Dh and significantly improved the chemical stability of KGF. Owing to NEM-associated proteins, KGF-Neus were specifically internalized by the inflammatory HUVECs. Moreover, KGF-Neus were specifically homed to the inflamed bowel in dextran sulfate sodium-induced mice after intravenous injection, resulting in the effective recovery of the morphology and function of the bowel. The therapeutic mechanisms of KGF-Neus were highly associated with alleviation of inflammation in colitis. Overall, the neutrophil-like liposome may be an excellent carrier for the colitis-targeted delivery of KGF.


[Systematic review and meta-analysis of diagnostic accuracy of 18F-FDG PET in suspected recurrent head and neck cancer].
A meta-analysis of the literature was performed in this article in order to evaluate the diagnostic accuracy of 18F-FDG PET in suspected recurrent head and neck cancer. A systematic review of the literature was performed using 1987 to 2007 MEDLINE and CANCERLIT databases, applying selection criteria to the studies found. Sensitivity, specificity, positive and negative likelihood ratios, and odds ratio were calculated. The diagnostic accuracy was evaluated with ROC (receive-operating-characteristics) curves. Nineteen articles were included in the meta-analysis. Sensitivity of 18F-FDG PET was 94 %, specificity 80 %, and the summary ROC curve showed a good trade-off between sensitivity and specificity. 18F-FDG PET was useful in patients with suspected recurrence of head and neck cancer, showing a high sensitivity and intermediate-high specificity.


Persistence of endometriosis after correction of an obstructed reproductive tract anomaly.
Endometriosis is commonly found in adolescents with an obstructed reproductive tract and has been reported to always regress after correction. This study highlights 5 patients who had persistent pain and a diagnosis of endometriosis following correction of their anomaly. The cases include patients with agenesis of the lower vagina or an obstructed hemivagina. All had recurrence of pain 6 months to 5 years after their corrective surgery. Laparoscopy revealed Stage I, II, and IV endometriosis. This case series reveals that endometriosis does not always resolve following repair of an obstructive anomaly. This may result from prior/ongoing peritoneal seeding or other factors. Given possible disease progression and potential adverse effect on fertility, it important to consider laparoscopy and medical therapy if these patients have persistent pain.


Introduction of a national program for HbA1c testing in Guyana South America and initial results.
Diabetes is an increasing challenge for low- and middle-income countries (LMIC) and access to HbA1c testing is limited. HbA1c, a measure of glycaemic control averaged over 3 months, provides both clinicians and policymakers with a tool to identify the risk of long-term diabetes comorbidity. We describe the steps used to implement standardised testing in Guyana South America and the initial results according to a locally developed protocol as part of a country-wide project to improve the care of people with all forms of diabetes The steps identified include: a standardised method traceable to a recognized international reference standard, participation in a quality control cycle with an international reference laboratory, a clinical pathway for testing to reduce inappropriate use and minimize resource wastage, training of technicians in operation and maintenance of equipment, identification of a suitable space with constant power supply, a reliable procurement system, education of healthcare professionals on interpretation and follow-up of results and feedback of programme results to improve clinical practice. Some steps for implementation of the national HbA1c testing program were initiated better than others. Initial unreliability of the service undermined confidence in the system. Failure to follow the testing protocol led to some patients being tested too soon and others too late. Cost of reagents was about 5.60 USD/test. We trained 340 people in diabetes care and knowledge was improved but were unable to assess whether it was appropriately applied. Over one third of people tested in the 30-70 age group had an HbA1c over 9% (75 mmol/mol) and this did not improve over the 5 years of testing. Despite the difficulties we think our unique experience of implementation of a nationwide HbA1c testing programme has important lessons for other LMICs.


Strategies for managing perioperative hypertension.
Hypertension is a pervasive and growing health concern. The occurrence of hypertension due to systemic vasoconstriction in patients before, during, and after surgery is not uncommon and can have serious consequences with regard to outcomes. Careful evaluation prior to surgery to identify the underlying cause of hypertension is important in selecting the best treatment option. Preoperative treatment options include oral beta-adrenergic receptor blockers, alpha2-adrenergic receptor antagonists, and in the case of hypertensive emergencies, the fast-acting parenteral agents sodium nitroprusside, the intravenous beta-adrenergic receptor blocker esmolol, and nicardipine. Therapeutic options during and after surgery include sodium nitroprusside, esmolol, and nicardipine, among others.


Gas-phase thermochemistry of noncovalent ligand-alkali metal ion clusters: An impact of low frequencies.
The experimental gas-phase thermochemistry of reactions: M+ (S)n-1 + S → M+ (S)n and M+ + nS→ M+ (S)n , where M is an alkali metal and S is acetonitrile/ammonia, is reproduced. Three approximations are tested: (1) scaled rigid-rotor-harmonic-oscillator (sRRHO); (2) the sRRHO(100) identical to (1), but with all vibrational frequencies smaller than 100 cm-1 replaced with 100 cm-1 ; (3) Grimme's modified scaled RRHO (msRRHO) (Grimme, Chem. Eur. J., 2012, 18, 9955-9964). The msRRHO approach provides the most accurate reaction entropies with the mean unsigned error (MUE) below 5.5 cal mol-1 K-1 followed by sRRHO(100) and sRRHO with MUEs of 7.2 and 16.9 cal mol-1 K-1 . For the first time, we propose using the msRRHO scheme to calculate the enthalpy contribution that is further utilized to arrive at reaction Gibbs free energies (∆Gr ) ensuring the internal consistency. The final ∆Gr MUEs for msRRHO, sRRHO(100) and sRRHO schemes are 1.2, 3.6 and 3.1 kcal mol-1 .


Microsurgical anatomical vascular study of the PICA-PICA bypass.
To assess the posterior inferior cerebellar artery (PICA)-PICA bypass possibility. Fifteen adult cadaver heads were used for surgical simulation, and the far-lateral approach was used to expose the surgical field. The bilateral PICA course, diameter, and perforators were observed and measured to evaluate the possibility of a PICA-PICA bypass. The PICA-PICA bypass was performed in seven (46.7 %) of the 15 specimens; the procedure was performed easily in three specimens, a little difficult in two, and was difficult in two specimens because of the relationship between the tonsil and the short parallel length of the bilateral tonsillomedullary (p3) segment. In eight (53.3 %) of the 15 specimens, PICA-PICA bypass was not feasible for reasons including 1) the caliber of the bilateral p3 was unmatched for bypass, 2) the distance of bilateral p3 in the midline was > 7 mm, 3) the middle segment of p3 perforating direct arteries limited the buffer length, and 4) single caudal loops. The possibility of PICA-PICA bypass was determined by the proximity of the bilateral p3, caliber match, and mobilization of the bilateral caudal loop due to the perforators. The difficulty of the PICA-PICA bypass mainly depends on the relationship between the cerebellar tonsil and the parallel length of the bilateral PICA in the midline.


Design and characterization of a ferromagnetic, air gapped magneto-optic Faraday rotator.
A method has been developed to modulate the plane of polarized light through the use of a high permeability ferrite core design. A proof-of-principal, optical Faraday effect device has been constructed and tested. Magnetic fields were generated to provide up to 1 deg of rotation at frequencies of direct current up to 10 kHz using a terbium gallium garnet crystal rod.


Efficient and selective recovery of iron phosphate from the leachate of incinerated sewage sludge ash by thermally induced precipitation.
Phosphorus recovery from incinerated sewage sludge ash (ISSA) is important but hindered by low selectivity. Here, a novel strategy of acid leaching followed by thermally induced precipitation was proposed for the efficient and selective recovery of FePO4 from ISSA samples. A high phosphorus leaching efficiency of ∼ 99.6% was achieved with 0.2 mol/L H2SO4 and liquid to solid (L/S) ratio of 50 mL/g. Without removing various co-existing ions (Al3+, Ca2+, SO42-, etc.), high-purity FePO4 of ∼ 92.9% could be facilely produced from this highly acidic H2SO4 leachate (pH = 1.2) by simple addition of Fe(III) at a molar ratio of 1:1 to the phosphorus and reacted at 80 °C for thermally induced precipitation. The remained acid leachate could be further reused for five times to continue leaching phosphorus from the ISSA samples and produce the FePO4 precipitates with a high phosphorus recovery efficiency of 81.1 ± 1.8%. The selective recovery of FePO4 from the acid leachate was demonstrated more thermodynamically favorable compared to other precipitates at this acidic pH of 1.2, and elevated temperature of 80 °C towards thermally induced precipitation. The estimated cost of this strategy was ∼$26.9/kg-P and lower than that of other existing technologies. The recovered FePO4 precipitates could be used as a phosphate fertilizer to promote the growth of ryegrass, and also as a precursor to synthesize high-value LiFePO4 battery material, demonstrating the high-value application potential of the phosphorus from the ISSA.


Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states.
Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.


Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6.
5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented. A set of 589 sequential patients from a clinical database receiving 5-FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600-3,600 mg/m2 of continuous infusion 5-FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose. A simple regression model with R(2) = 0.51 developed over n = 307 cycle-pair observations characterizes the AUC-Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145-727 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients. 5-FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20-30 mg · h/L are recommended.


Novel framework of GIS based automated monitoring process on environmental biodegradability and risk analysis using Internet of Things.
A proper method on real-time monitoring of organic biomass degradation and its evaluation for safeguarding the ecosystem is the need of the hour. The work process designed in this study is to demarcate the anaerobic digestion potential using kinetic modelling and web GIS application methods. Wastewater source that causes pollution are identified through satellite maps such as solid earth, drain system, surface of earth structure, land filling and land use. The grabbed data are utilized for identifying the concentration of sludge availability. Based on literature resource multi influencing factor techniques are introduced along with overlay method to differentiate digestion potential of sludge source. This study optimizes the biodegradation potential of domestic sewage at different sludge concentrations in a pilot model operated with the samples identified through topographical drainage survey. The materialization of devices is using the Internet of Things (IoTs), that is pragmatic to be the promising tendency. Kinetic study, methanogenic assay test are performed with three different cation binding agents to find its solubilization potential and methane evolution, which is further subjected to digestion potential in anaerobic conditions for possible application in the field of environmental science. Risk analysis reveals that land filling method will have highest impact on maintaining sustainable environment. The results outcome on natural biodegradation may be used for individual house hold wastewater management for the locality.


Emergence of ST39 carbapenem-resistant Klebsiella pneumoniae producing VIM-1 and KPC-2.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes life-threatening hospital-acquired infections. KPC and VIM carbapenemase production is the main molecular mechanism for carbapenem resistance. The aim of the current study was the genetic characterization of four ST39 CRKP isolates simultaneously producing VIM-1 and KPC-2, obtained in a Greek tertiary hospital. Identification and antimicrobial susceptibility testing were performed through VITEK 2. Multiplex PCR, multiplex lateral flow immunoassay, phenotypic tests and next generation sequencing were applied. The sequence reads were de novo assembled and annotated, while antimicrobial resistance genes and plasmids were identified using bioinformatics software. Genomic comparison and core genome single-nucleotide polymorphism-based phylogenetic analysis were also performed. Three isolates were pandrug-resistant, and one was extensively drug-resistant; they all carried blaVIM-1 and blaKPC-2 genes and were assigned to ST39. BlaVIM-1 was integrated in a class 1 integron. They all harboured many antimicrobial resistance genes and various plasmids. The mgrB gene of all isolates was disrupted by an insertion sequence (ISKpn14). Genome comparison and phylogenetic analysis revealed that the isolates were closely related. To our knowledge this is the first report on detection of CRKP ST39 isolates simultaneously producing VIM-1 and KPC-2 in addition to colistin resistance. The knowledge of the clonal relatedness of the isolates can lead to the implementation of strict infection control measures absolutely needed to eliminate their spread.


Life's Simple 7 and Incident Hypertension: The REGARDS Study.
Background The Life's Simple 7 (LS7) metric incorporates health behaviors (body mass index, diet, smoking, physical activity) and health factors (blood pressure, cholesterol, glucose) to estimate an individual's level of cardiovascular health. The association between cardiovascular health and incident hypertension is unresolved. Hypertension's threshold was recently lowered and it is unclear if better cardiovascular health is associated with lower risk of incident hypertension with the updated threshold or in a multirace cohort. We sought to assess the association between better LS7 score and risk of incident hypertension among Black and White adults using a 130/80 mm Hg hypertension threshold. Methods and Results We determined the association between LS7 metric and incident hypertension in the REGARDS (Reasons for Geographic and Racial Disparities in Stroke) study, including participants free of baseline hypertension (2003-2007) who completed a second visit between 2013 and 2016. Hypertension was defined as systolic/diastolic blood pressure ≥130/80 mm Hg or antihypertensive medication use. Each LS7 component was assigned 0 (poor), 1 (intermediate), or 2 (ideal) points. We generated a 14-point score by summing points. Among 2930 normotensive participants (20% Black, 80% White), the median (25th-75th percentiles) LS7 total score was 9 (8-10) points. Over a median follow-up of 9 years, 42% developed hypertension. In the fully adjusted model, each 1-point higher LS7 score had a 6% lower risk of incident hypertension (risk ratio, 0.94 per 1 point; 95% CI, 0.92-0.96). Conclusions Better cardiovascular health was associated with lower risk of incident hypertension using a 130/80 mm Hg hypertension threshold among Black and White adults.


The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis.
MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911.


Influence of dentures on SAR in the visible Chinese human head voxel phantom exposed to a mobile phone at 900 and 1800 MHz.
To investigate the influence of dentures on electromagnetic energy absorption during the daily use of a mobile phone, a high-resolution head phantom based on the Visible Chinese Human dataset was reconstructed. Simulations on phantoms with various dentures were performed by using the finite-difference time-domain method with a 0.47 wavelength dipole antenna and a mobile phone model as radiation sources at 900 and 1800 MHz. The Specific energy Absorption Rate (SAR) values including 1 and 10 g average SAR values were assessed. When the metallic dental crowns with resonance lengths of approximately one-third to one-half wavelength in the tissue nearby are parallel to the radiation source, up to 121.6% relative enhancement for 1 g average SAR and 17.1% relative enhancement for 10 g average SAR are observed due to the resonance effect in energy absorption. When the radiation sources operate in the normal configuration, the 10 g average SAR values are still in compliance with the basic restrictions established by the Institute of Electrical and Electronic Engineers (IEEE) and the International Commission on Non-Ionizing Radiation Protection (ICNIRP), indicating that the safety limits will not be challenged by the usage of dentures.


Influence of hay making on in situ nitrogen degradability of forages in cows.
The influence of hay making on in situ N degradability of forages was assessed by comparing the degradability of nine hays with that of standing forages at the time of harvest. Three ryegrass, two cocksfoot, and three alfalfa forages were used. The N degradability of hays was related closely to that of the corresponding standing forages (R = .91) and was, on average, lower (-2.5 points). This decrease in degradability after hay making was not constant; it increased when the degradability of the standing forage was high and when harvesting conditions were poor.


Genetic analysis of seed coat development in Arabidopsis.
In the angiosperms, fertilization initiates the formation of the seed from the ovule, including the differentiation of the seed coat from the ovule integuments. Seed coat differentiation includes some of the most dramatic cellular changes of seed development and culminates in the death of the seed coat cells. Recently, genetic analyses in Arabidopsis have contributed substantially to our understanding of many aspects of seed coat biology and it might not be long before the entire differentiation pathway is understood. Such an advance would contribute substantially to our understanding of many important cellular events, including secondary cell wall synthesis, cell morphogenesis, vacuolar targeting and cell death, and would provide tools for the manipulation of seed dormancy and germination.


Relationships among type A behavior, employment experiences, and gender: the Minnesota Heart Survey.
Previous studies indicate that Type A behavior is more prevalent among men than women. This sex difference may reflect variations in men's and women's job experiences, some of which may act as catalysts for Type A behavior. This study examines the relationship of Type A behavior (measured by the Jenkins Activity Survey) to men's and women's work hours, occupational mobility, and job-related interactions, using data from a population-based survey of 2512 employed men and women conducted in Minneapolis-St. Paul, Minnesota, between 1980 and 1982. Among both sexes, Type A behavior is related to long work hours, high occupational mobility, and nonsupportive interactions with co-workers, all job experiences more common for men than for women. No sex differences are found in the relationships between Type A behavior and these job experiences. Also, no sex difference is observed in the unadjusted Type A scores or in these scores when either age, education, or marital status is taken into account. The expected direction of the sex difference in Type A behavior is reversed when work hours are controlled: women have a higher Type A score than men when work hours are considered.


Trigger-activated autonomous DNA machine for amplified liver cancer biomarker microRNA21 imaging.
MicroRNA-21 (miRNA-21) is a kind of RNA that exists in biological fluids such as blood, urine and saliva. It has over expression in liver cancer and has different expression in different stages of cancer. However, due to the characteristics of small base number, short length, low abundance and easy degradation of miRNA-21, the detection of miRNA-21 is a challenging subject. Visualization, sensitive, specific and stable detection of tumor suppressor or oncogene microRNAs (miRNAs) remains challenging and is highly significant for clinical diagnostics. To solve this problem, we have developed a target-triggered hybridization assembly DNA machine for intracellular miRNA imaging based on strand displacement amplification (SDA) and branched hybridization chain reaction (B-HCR). In this approach, the target miRNA could hybridize with the template probe to trigger the SDA, resulting in the formation of nicked fragments (NFs) that hybridized with hairpin probe1 (HP1). The opened HP1 could hybridize with hairpin probe2 (HP2), leading to the self-assembly of hyperbranched DNA nanostructures through B-HCR. As expected, the newly developed method exhibits a detection limit down to 11.3 pM miRNA-21 and achieves high selectivity toward miRNA-21 against other interfering miRNAs. Due to its superior sensitivity and selectivity, our method can be further used to detect miRNA-21 in human serum samples. By taking advantage of intelligent design, the proposed method was also used for image miRNA-21 expression levels in different cell lines. This method shows a broad application in clinical diagnosis.


Deficiency of neuropeptide Y attenuates neointima formation after vascular injury in mice.
Restenosis after percutaneous coronary intervention (PCI) limits therapeutic revascularization. Neuropeptide Y (NPY), co-stored and co-released with the sympathetic nervous system, is involved in this process, but its exact role and underlying mechanisms remain to be fully understood. This study aimed to investigate the role of NPY in neointima formation after vascular injury. Using the left carotid arteries of wild-type (WT, NPY-intact) and NPY-deficient (NPY-/-) mice, ferric chloride-mediated carotid artery injury induced neointima formation. Three weeks after injury, the left injured carotid artery and contralateral uninjured carotid artery were collected for histological analysis and immunohistochemical staining. RT-qPCR was used to detect the mRNA expression of several key inflammatory markers and cell adhesion molecules in vascular samples. Raw264.7 cells were treated with NPY, lipopolysaccharide (LPS), and lipopolysaccharide-free, respectively, and RT-qPCR was used to detect the expression of these inflammatory mediators. Compared with WT mice, NPY-/- mice had significantly reduced neointimal formation three weeks after injury. Mechanistically, immunohistochemical analysis showed there were fewer macrophages and more vascular smooth muscle cells in the neointima of NPY-/- mice. Moreover, the mRNA expression of key inflammatory markers such as interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1), and intercellular adhesion molecule-1 (ICAM-1) was significantly lower in the injured carotid arteries of NPY-/- mice, compared to that in the injured carotid arteries of WT mice. In RAW264.7 macrophages, NPY significantly promoted TGF-β1 mRNA expression under unactivated but not LPS-stimulated condition. Deletion of NPY attenuated neointima formation after artery injury, at least partly, through reducing the local inflammatory response, suggesting that NPY pathway may provide new insights into the mechanism of restenosis.


Child survival: the role of a mother's education.
In developing countries, children are considered as social and human capital needed for growth and development. However, the ability of uneducated parents to provide basic services to keep a child alive has always been in doubt. This has resulted in the avoidable deaths of children. This study seeks to examine the role of a mother's education in keeping a child alive. This is achieved by using the Ghana Demographic and Health Survey (DHS) Dataset (1988-2014) with 33,896 observations. This study uses the negative binomial model and finds an inverse and statistically highly significant relationship between a mother's education and the survival of her child in Ghana. Further robustness checks confirm that the result is consistent across gender of child and years of data collection. In line with the finding, this study recommends women's education from the basic education level as it drives the probability of saving a life. Globally, we suggest that education, especially at the basic level, should include health education to address numerous health concerns.


Prevention of local tumor growth with paclitaxel-loaded microspheres.
Lung cancer is associated with a significant rate of locoregional recurrence after surgical resection, particularly when nonanatomic wedge resections are performed. The primary aim of this study was to assess the feasibility of a microsphere drug delivery system to locally deliver chemotherapy and prevent the establishment and growth of lung cancer cells and establish proof of concept for a potential future approach to target occult microscopic disease remaining at the surgical resection margin. Poly-(D,L-lactic-co-glycolic acid) (PLGA) microspheres loaded with the antineoplastic agent paclitaxel were prepared and tested for antitumor efficacy in an in vitro cell proliferation assay for tumor inhibition and induction of apoptosis. The in vivo prevention of Lewis lung carcinoma cell establishment and growth in subcutaneous tissues of mice was also assessed by comparing 4 treatment groups: Lewis lung carcinoma cells alone, Lewis lung carcinoma cells combined with 100 x 10(6) unloaded (carrier alone) PLGA microspheres, and Lewis lung carcinoma cells combined with 50 x 10(6) or 100 x 10(6) paclitaxel-loaded PLGA microspheres. After the coinjection of Lewis lung carcinoma cells with or without microspheres, in vivo tumor growth was monitored, and tumor weight was recorded on death. Paclitaxel-loaded PLGA microspheres were found to effectively prevent growth of tumor cells in culture through the induction of apoptosis. Similarly, paclitaxel-loaded PLGA microspheres significantly inhibited tumor growth in vivo at both the 50 x 10(6) and 100 x 10(6) microsphere dose (0.497 +/- 0.183 and 0.187 +/- 0.083 g total tumor weight, respectively) compared with 2.91 +/- 0.411 g for Lewis lung carcinoma cells with unloaded microspheres and 3.37 +/- 0.433 g for untreated tumor (P < .001). Toxicity was not clinically apparent in any animal treated with paclitaxel-loaded PLGA microspheres. Paclitaxel-loaded PLGA microspheres induce tumor apoptosis and inhibit the establishment and growth of lung cancer cells both in vitro and in vivo without obvious systemic toxicity. By using models consistent with localized microscopic tumor burdens, these results suggest that local delivery of paclitaxel through a microsphere system might lead to an effective future method of decreasing local tumor recurrence in non-small cell lung cancer when applied to the surgical margins at risk for microscopic tumor foci. Such an approach might be particularly efficacious after wedge resection in the setting of poor pulmonary reserve or significant comorbidity, where local recurrence rates are increased and acceptable alternative treatment options are limited.


Direct sunlight enabled photo-biochemical synthesis of silver nanoparticles and their Bactericidal Efficacy: Photon energy as key for size and distribution control.
It is highly desirable to discover novel green synthesis methods for cheap and scalable synthesis of nanoparticles (NPs) to reduce the negative impact on the environment. But these approaches generally impose great challenge in controlling size, shape, and homogeneity of product NPs. Here in the present study, we report a novel approach enabling direct sunlight and oyster mushroom (Pleurotus citrinopileatus) extract for the photo-biochemical synthesis of Ag NPs. Sunlight of different wavelength was used to control the size and distribution of photo-biochemically produced NPs. Interestingly, it is observed that a smaller wavelength of sunlight produces smaller sized of NPs with a narrow size distribution. For examples; blue sunlight produces colloidal silver NPs with an average diameter of ~ 3.28 nm and 0.72 nm size distribution, while full sunlight produces comparatively larger sized (7.08 nm) NPs with wider (2.92 nm) size distribution. Since present approach uses only direct sunlight, freely available renewable energy source, a cheap biological extract as reducing and capping agent and cheap silver precursor, therefore it is an environment-friendly approach and can be used for the synthesis of NPs at industrial scale. Moreover, the size-dependent bactericidal effect has also been studied against pathogenic, Escherichia coli, bacteria. The minimum inhibitory concentration (MIC) 25 ppm and MBC 30 ppm have been observed for silver NPs of 3.28 nm average diameter.


The crystal structures of 3-TAPAP in complexes with the urokinase-type plasminogen activator and picrate.
The urokinase-type plasminogen activator (uPA) is a protein involved in tissue remodeling and other biological processes. The inhibitors of uPA have been shown to prevent the spread of metastasis and tumor growth, and accordingly this enzyme is widely accepted as a promising anticancer target. In this work, we have investigated the conformation of the uPA inhibitor 3-TAPAP in two different crystalline environments of a picrate and a uPA complex. These structures were compared to the known structure of the 3-TAPAP in the complex with trypsin. In the complexes with the proteins, trypsin, and uPA, the binding mode of 3-TAPAP is similar. A larger difference in the conformation, in the comparison to these structures, has been observed by us in the 3-TAPAP picrate crystal. This observation contradicts the hypothesis that 3-TAPAP derivatives inhibit serine proteinases in preformed stable conformations.


2022 American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) Indications for Metabolic and Bariatric Surgery.
MAJOR UPDATES TO 1991 NATIONAL INSTITUTES OF HEALTH GUIDELINES FOR BARIATRIC SURGERY: Metabolic and bariatric surgery (MBS) is recommended for individuals with a body mass index (BMI) >35 kg/m2, regardless of presence, absence, or severity of co-morbidities.MBS should be considered for individuals with metabolic disease and BMI of 30-34.9 kg/m2.BMI thresholds should be adjusted in the Asian population such that a BMI >25 kg/m2 suggests clinical obesity, and individuals with BMI >27.5 kg/m2 should be offered MBS.Long-term results of MBS consistently demonstrate safety and efficacy.Appropriately selected children and adolescents should be considered for MBS.(Surg Obes Relat Dis 2022; https://doi.org/10.1016/j.soard.2022.08.013 ) © 2022 American Society for Metabolic and Bariatric Surgery. All rights reserved.


Effect of Nanoclay on Thermal Conductivity and Flexural Strength of Polymethyl Methacrylate Acrylic Resin.
The mechanical and thermal properties of polymethyl methacrylate (PMMA) acrylic resin should be improved to counterweigh its structural deficiencies. The aim of this study was to compare the flexural strength and thermal conductivity of conventional acrylic resin and acrylic resin loaded with nanoclay. The methacrylate monomer containing the 0.5, 1 and 2 wt% of nanoclay was placed in an ultrasonic probe and mixed with the PMMA powder. Scanning electron microscopy was used to verify homogeneous distribution of particles. Twenty-four 20×20×200-mm cubic samples were prepared for flexural strength test; 18 samples containing nanoclay and 6 samples for the control group. Another 24 cylindrical samples of 38×25 mm were prepared for thermal conductivity test. One-way ANOVA was used for statistical analysis, followed by multiple-comparison test (Scheffé's test). Statistical significance was set at p< 0.05. Increasing the concentration of nanoclay incorporated into the acrylic resin samples increased thermal conductivity but decreased flexural strength (p< 0.05). Based on the results of this study, adding nanoclay particles to PMMA improved its thermal conductivity, while it had a negative effect on the flexural strength.


Land use and habitat quality change in the Yellow River Basin: A perspective with different CMIP6-based scenarios and multiple scales.
Studying the spatial distribution of land use/land cover (LULC) and habitat quality (HQ), influenced by both climate change and socio-economic factors, holds immense importance for fostering ecological sustainability. The previous scale setting was based on changes in granularity and division of spatial ranges, without considering the differences in land quantity structure and spatial expansion under different spatial ranges. Therefore, this study is based on climate and economic data at different spatial scales to determine the various land demands of provinces (YRB-P) and integration of provinces (YRB-I) in the Yellow River Basin, and to limit the expansion of LULC in corresponding regions. At the same time, we have also established three future scenarios representing different development speeds based on the latest path of shared socio-economic development in CMIP6. We found exhibit significant characteristics in ecological responses under combinations of different scales and scenarios. Shandong and Henan Provinces are the main gathering (38.7-41.7%, 24.1-26.5%) and expansion (68.54-85.99 × 102km2, 18.89-34.12 × 102km2) provinces of built-up land under the YRB-P scale, and their HQ (0.260-0.397) are significantly lower than the average HQ (0.619-0.654). Forest land, grassland, and high value regions of HQ show "45°" distribution at two scales, with high and low values clearly clustered (Moran's I is 0.5440-0.580). The HQ evolution region is larger and more dispersed at the YRB-P scale, but accumulates in local areas at the YRB-I scale. In addition, the highest and lowest HQ mean values appear under the low speed development scenario at the YRB-P scale (0.721) and the rapid development scenario at the YRB-I scale (0.689), respectively. This study helps decision-makers control different scales and development scenarios to improve the ecological level of the study area.


Non-selective orexin-receptor antagonist attenuates stress-re-stress-induced core PTSD-like symptoms in rats: Behavioural and neurochemical analyses.
Post-traumatic stress disorder (PTSD) is a psychological disorder affecting many around the world. Growing evidence suggests that orexin-A is involved in the pathophysiology of depression and panic anxiety disorder. However, the role of orexin-A in PTSD remains unclear. Therefore, pharmacological manipulation of orexin-A can be a potential approach for the treatment of PTSD. Male Wistar rats were subjected to stress re-stress (SRS) by restraining them for 2 h followed by foot shock (FS) and halothane exposure on day-2 (D-2). Then the rats were weekly exposed to FS as re-stress cue . Suvorexant, an orexin antagonist (10, 20 and 30 mg/kg p.o.) and paroxetine (10 mg/kg p.o.) were administered from D-8 to D-32. Plasma and cerebrospinal fluid (CSF) were collected for corticosterone and orexin-A measurement. The analysis of serotonin and corticotropin-releasing factor receptor-1 (CRF-R1) were performed in the amygdalar tissue. SRS-induced PTSD-like symptoms like fear response, anxiety-like behaviour and hypocorticosteronism were attenuated by suvorexant and paroxetine. Interestingly, SRS exposed rats showed activation of orexin-A and serotonergic systems, which were also attenuated by suvorexant. Additionally, suvorexant ameliorated the extrahypothalamic induced upregulation of CRH-R1 in SRS-exposed rats. Therefore, orexin-A may be considered as a neurochemical-marker for PTSD and suvorexant alleviated PTSD-like symptoms through modulating orexinergic, serotonergic and neuroendocrine systems.


Plasma proteins from several components of the immune system differentiate chronic widespread pain patients from healthy controls - an exploratory case-control study combining targeted and non-targeted protein identification.
Chronic widespread pain (CWP), including fibromyalgia (FM), is characterized by generalized musculoskeletal pain and hyperalgesia. Plasma proteins from proteomics (non-targeted) and from targeted inflammatory panels (cytokines/chemokines) differentiate CWP/FM from controls. The importance of proteins obtained from these two sources, the protein-protein association network, and the biological processes involved were investigated. Plasma proteins from women with CWP (n = 15) and CON (n = 23) were analyzed using two-dimensional gel electrophoresis analysis and a multiplex proximity extension assay for analysis of cytokines/chemokines. Associations between the proteins and group were multivarietly analyzed. The protein-protein association network and the biological processes according to the Gene Ontology were investigated. Proteins from both sources were important for group differentiation; the majority from the two-dimensional gel electrophoresis analysis. 58 proteins significantly differentiated the two groups (R2 = 0.83). A significantly enriched network was found; biological processes were acute phase response, complement activation, and innate immune response. As with other studies, this study shows that plasma proteins can differentiate CWP from healthy subjects. Focusing on cytokines/chemokines is not sufficient to grasp the peripheral biological processes that maintain CWP/FM since our results show that other components of the immune and inflammation systems are also highly significant.


Crystal structure of sodium isosaccharate, NaC6H11O6 x H2O.
Sodium isosaccharate, NaC(6)H(11)O(6).H(2)O (Na-ISA), has been synthesized, and its crystal structure solved by single-crystal X-ray diffraction methods. Na-ISA crystallizes in the monoclinic space group P2(1) (#4) with cell parameters a = 9.2267(11) A, b = 5.0765(6) A, c = 9.7435(11) A, beta = 103.304(2) degrees, V = 444.13(9) A(3), Z = 2. The structure was refined by full-matrix least-squares on F2 yielding final R-values (all data) R1 = 0.0361 and Rw2 = 0.0935. The structure of Na-ISA consists of (C(6)H(11)O(6))(-) anions arranged in layers parallel to the bc plane. An extended network of O-H...O hydrogen bonds links the (ISA)(-) anions and the crystal water molecules. Each sodium atom is coordinated by four oxygen atoms belonging to four different (ISA)(-) anions and by one water molecule. The resulting NaO(5) polyhedra are linked by sharing common corners in zig-zag chains running parallel to the b-axis.


Cross-cultural adaptation and psychometric assessment of the statement format Decisional Conflict Scale for Mandarin version.
The statement format of the Decisional Conflict Scale (sf-DCS) is designed and widely used to assess patients' state of uncertainty during health related decision making. As yet no Mandarin version of the sf-DCS has been produced. This study aims to produce the first Mandarin version of the sf-DCS and test its validity and reliability in mainland China. The translation and cross-cultural adaptation of the original English version of the sf-DCS into Mandarin was carried out in accordance with previously published guidelines. The psychometric properties of sf-DCS were assessed in two hypothesized decision-making contexts through online surveys. In the online survey designed to test scale validity and reliability, 437 people responded to the influenza immunization survey and 238 responded to the breast cancer screening survey. The results confirm that the Mandarin version of sf-DCS has good criteria validity and the exploratory factor analysis suggested a fitted revised five factors model by removing three items. Respondents who were "unsure" about their decisions/intentions, had read less information, and reported lower self-perceived prior knowledge level scored higher on sf-DCS. The Cronbach's alpha for the sf-DCS total score was 0.963 and that for each subscale ranged from 0.784 to 0.937 in both decision making contexts, and the test-retest correlation coefficient was 0.528. The Mandarin version of sf-DCS has good criteria validity and its internal consistency is satisfactory. Our analysis suggests a refinement of the original sf-DCS's factor structure is needed.


Recent crosse designs increase ball velocity: implications for injury in women's lacrosse.
The aim of this preliminary investigation was to describe the kinematics of ball release from 24 different lacrosse stick models during the performance of an overhand pass. Multiple trials (N=120) of an overhand lacrosse pass, performed by an elite female lacrosse athlete, were captured in the sagittal plane using two-dimensional videography and analysed using motion analysis software. On average, there was a tendency for balls to release earlier from wood crosses (180.8+/-16.0 degrees ) than from synthetic crosses (183.6+/-6.0 degrees ) (p>0.15) and earlier from non-planar linear (179.7+/-6.7 degrees ) and non-planar curvilinear (182.5+/-9.5 degrees ) crosse heads than from traditional, planar-headed sticks (185.6+/-11.7 degrees ). Peak angular velocities of the stick shaft were lower for the wood as compared to the synthetic crosses (p<0.001) with mean values of 15.4+/-0.6rads(-1) and 16.6+/-0.7rads(-1), respectively. Similarly, the resultant velocity of the ball at release was significantly lower (p<0.001) for the wood crosses (13.9+/-0.8ms(-1)) as compared to the synthetic crosses (14.8+/-0.6ms(-1)). These results indicate that changes in the material composition and design of lacrosse sticks are changing the timing and rate at which balls release from the crosse pocket. Strict rule enforcement, good coaching, the mandatory use of protective equipment and continuous monitoring of changes in stick technology will be required if the frequency and severity of ocular, head and facial injuries are to be controlled.


Treatment of recurrent spontaneous abortions by immunization with paternal lymphocytes induces immunosuppression by placental isoferritin.
The immunological mechanism leading to an effective vaccination of unexplained habitual aborters with paternal lymphocytes is not yet elucidated. Since previous studies revealed that immunosuppression by placental isoferritin (PLF) may play an important role in the down regulation of the immune system during pregnancy, it was of interest to investigate whether alloimmunization activates immunosuppression by PLF. The immunosuppressive effect of PLF or anti-PLF CM-H-9 monoclonal antibody (MAb) was studied by a one-way mixed lymphocyte reaction (MLF) of alloimmunized women and their husbands. It was found that vaccination of the women with paternal lymphocytes resulted in in vitro immunosuppression by PLF as well as by CM-H-9 MAb, reaching the highest effect after three vaccinations (38 +/- 8 and 42 +/- 10%, respectively). The increase in PLF immunosuppressive effect was accompanied by the appearance of serum antipaternal human leukocyte antigen cytotoxic antibodies. However, there was no correlation between the degree of suppression and titer of antibodies. The study group was too small to reach a significant correlation between degree of immunosuppression and pregnancy outcome. Although it may be of value to measure the inhibitory effect of PLF in one-way MLR as an index of immunosuppression, further studies are needed to establish whether it is a relevant predictor of a successful pregnancy.


Suppression of repetitive self-injurious behavior by contingent inhalation of aromatic ammonia.
Two institutionalized children who exhibited high rates of severely self-injurious behaviors were punished with aromatic ammonia inhalation on a response-contingent basis. This contingency was applied throughout all aspects of each child's institutional program which focused on teaching of self-help skills. Suppression of the self-injurious responses was both rapid and general. The contingency was maintained for 2 months, although there was no responding after the first 5 days. Follow-up sessions, conducted 4 months after the punishment contingency was removed, revealed that suppression effects were highly durable. Aromatic ammonia inhalation appears to be an effective alternative for decelerating extremely maladaptive behaviors that do not yield to more conventional nonaversive forms of therapy. However, the procedure should be used with great caution, for it may involve risk to the subject.


The area function method for assessing the drug absorption rate in linear systems with zero-order input.
A noncompartmental approach for determination of the apparent zero-order absorption rate constant (k0) has been developed. The procedure evolves from the convolution integral and requires individual oral-dose plasma concentrations values and calculation of area intervals under the plasma concentration-time curves after intravenous administration. The proposed method was evaluated and compared with the Wagner-Nelson, Loo-Riegelman, deconvolution, nonlinear regression, and moment methods using errorless and errant simulation data from one- or two-compartment models. The area function method is generally equal to the best of these techniques (nonlinear regression) and superior to the weaker methods (moment, deconvolution, Loo-Riegelman), especially for errant two-compartment data. Coupled with a companion procedure for constructing fraction absorbed versus time plots and assessing first-order absorption rate constants, the area function methods offer direct and accurate means of discerning drug absorption kinetics without the need for assignment of a disposition model for drugs with linear elimination kinetics.


TG1019/OXE, a Galpha(i/o)-protein-coupled receptor, mediates 5-oxo-eicosatetraenoic acid-induced chemotaxis.
We have previously identified a Galpha(i/o)-protein-coupled receptor (TG1019/OXE) using 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) as its ligand. We investigated signal transduction from TG1019 following stimulation with 5-oxo-ETE and role of TG1019 in 5-oxo-ETE-induced chemotaxis, using Chinese hamster ovary cells expressing TG1019 (CHO/TG1019 cells). 5-Oxo-ETE induced intracellular calcium mobilization and rapid activation of MEK/ERK and PI3K/Akt pathways in CHO/TG1019 cells. CHO/TG1019 cells stimulated with 5-oxo-ETE and other eicosanoids exhibited chemotaxis with efficacies related to agonistic activity of each eicosanoid for TG1019. Pretreatment of the cells with pertussis toxin, a phospholipase C (PLC) inhibitor (U73122) or a PI3K inhibitor (LY294002), markedly suppressed 5-oxo-ETE-induced chemotaxis, whereas pretreatment with a MEK inhibitor (PD98059) had no significant effect on the chemotaxis. Our results show that TG1019 mediates 5-oxo-ETE-induced chemotaxis and that signals from TG1019 are transduced via Galpha(i/o) protein to PLC/calcium mobilization, MEK/ERK, and PI3K/Akt, among which PLC and PI3K would play important roles in the chemotaxis.


The human embryo selection arena is associated with transposable element activity.
Our current understanding of early human development is limited. A study in PLOS Biology found a previously undefined group of cells that diverges from the main lineages and undergo apoptosis through the activity of young transposable elements.


Maternal corneal thickness during pregnancy.
We measured central corneal thickness in 89 pregnant women. It was increased 16 micron (P = .01) compared to the control eyes of 18 nongravid and 17 postpartum women. There was no significant difference (P = .79) in corneal thickness between the nongravid and postpartum groups. When comparing subjects by week of gestation, there was no trend over time in corneal thickness (analysis by linear regression). Intraocular pressure was lowered during pregnancy, but it did not correlate with corneal thickness for either the pregnant or nonpregnant group.


Genetic Testing Among Patients with High-Risk Breast, Ovarian, Pancreatic, and Prostate Cancers.
The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment. A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area. Guideline-concordant testing (GCT) was assessed annually according to guideline updates. Frequency of testing according to patient/cancer characteristics was evaluated using chi-squared tests, and factors associated with receipt of genetic testing were identified using multivariable logistic regression. Testing occurred in 17% of HBOPP patients, increasing from 9% in 2013 to 21% in 2019 (p < 0.001). Ovarian cancer had the highest testing (40%) and prostate cancer the lowest (4%). Age < 50, female sex, non-Hispanic White race, commercial insurance, urban location, family history of HBOPP, and triple negative breast cancer (TNBC) were associated with increased testing (all p < 0.05). GCT increased from 38% in 2013 to 44% in 2019, and was highest for early age at breast cancer diagnosis, TNBC, male breast cancer, and breast cancer with family history of HBOPP (all > 70% in 2019), and lowest for metastatic prostate cancer (6%). The frequency of genetic testing for HBOPP cancer has increased over time. Though GCT is high for breast cancer, there are gaps in concordance among patients with other cancers. Increasing provider and patient education, genetic counseling, and insurance coverage for testing among HBOPP patients may improve guideline adherence.


Evidence for a crucial role of paneth cells in mediating the intestinal response to injury.
The identification of the intestinal stem cell (ISC) markers Lgr5 and Bmi-1 has furthered our understanding of how they accomplish homeostasis in this rapidly self-renewing tissue. Recent work indicates that these markers identify a cycling Lgr5(+) ISC which can be replaced by a quiescent Bmi-1(+) ISC. Currently, there is little data on how these cells interact to control intestinal crypt homeostasis and regeneration. This interaction likely involves other differentiated cells within the niche as it has previously been demonstrated that the "stemness" of the Lgr5 ISC is closely tied to the presence of their neighboring Paneth cells. To investigate this, we used two conditional mouse models to delete the transcription factor β-catenin within the intestinal crypt. Critically these differ in their ability to drive recombination within Paneth cells and therefore allow us to compare the effect of deleting the majority of active ISCs in the presence or absence of the Paneth cells. After gene deletion, the intestines in the model in which Paneth cells were retained showed a rapid recovery and repopulation of the crypt-villus axis presumably from either a spared ISC or the hypothetical quiescent ISCs. However, in the absence of Paneth cells the recovery ability was compromised resulting in complete loss of intestinal epithelial integrity. This data indicates that the Paneth cells play a crucial role within the in vivo ISC niche in aiding recovery following substantial insult.


Statin therapy for young adults: A long-term investment worth considering.
HMG coenzyme A reductase inhibitors (statins) significantly decrease low-density lipoprotein-cholesterol, resulting in stabilization, and in some cases regression, of atherosclerotic plaque with subsequent reduction in atherosclerotic cardiovascular disease (ASCVD) events. To date, there remains a paucity of data to guide the use of statins in young adults (20-49 years old). We herein aim to summarize the potential benefits and risks for statin therapy in younger adults, outlining a possible approach to statin use in young adults. Early identification and treatment of young individuals at risk for ASCVD offers the potential to significantly reduce the lifetime risk of ASCVD. However, there is a paucity of data on the potential side effects of long-term statin use over many decades. Comprehensive risk assessment, including calculation of life-time ASCVD risk, as well as incorporating non-traditional risk factors including lipoprotein (a), strong family history of premature ASCVD, familial hypercholesterolemia, LDL-C level and presence of underlying systemic inflammatory disorders can be helpful in identifying young adults who stand to benefit the most from statin therapy. Selective use of coronary artery calcium (CAC) assessment, as well as potentially polygenic risk scores, can be considered in situations where there remains uncertainty regarding risk assessment. Importantly, the decision for statin treatment should occur in the context of a patient centered shared decision-making process.


Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells.
Resveratrol, a natural polyphenolic phytoalexine present in grapes and wines, has been reported to exert a variety of important pharmacological effects. We investigated the effects of resveratrol on the growth and polyamine metabolism of CaCo-2 human colon cancer cells. Treatment of the CaCo-2 cells with 25 microM resveratrol caused a 70% growth inhibition. The cells accumulated at the S/G2 phase transition of the cell cycle. No signs of cytotoxicity or apoptosis were detected. Resveratrol caused a significant decrease of ornithine decarboxylase (ODC) activity, a key enzyme of polyamine biosynthesis, which is enhanced in cancer growth. ODC inhibition resulted in the reduction of the intracellular putrescine content, indicating that polyamines might represent one of several targets involved in the anti-proliferative effects of resveratrol.


Human papillomavirus 16 detected in nasopharyngeal carcinomas in white Americans but not in endemic Southern Chinese patients.
We evaluated the relationship of human papillomavirus (HPV) and Epstein-Barr virus (EBV) with race in endemic and nonendemic cohorts of patients with nasopharyngeal carcinoma (NPC), and with smoking status in the nonendemic cohort. Tissue microarrays (TMAs) were constructed using samples from 86 patients treated in southern China and 108 patients from Stanford, California. TMAs were stained with p16, HPV in situ hybridization (ISH), and EBV ISH. Polymerase chain reaction (PCR) was used to confirm EBV(-) cases and HPV status in p16(+) cases. Survival data was available for the Stanford cohort only. No HPV(+) cases were detected in the Chinese cohort. In the Stanford cohort, 5 of 11 EBV(-) cases harbored HPV-16, 10 of 10 occurred in whites, and 8 of 11 were smokers. Patients with EBV(-) NPC also showed a trend toward worse survival. EBV(-) NPC shows an association with the presence of HPV, white race, and smoking. In contrast, EBV(-) NPC shows no association with HPV in the endemic cohort.


Investigation of Potential Paraoxonase-I Inhibitors by Kinetic and Molecular Docking Studies: Chemotherapeutic Drugs.
Metabolic processes in living organisms are closely related to the catalytic activity of enzymes. Changes in enzyme activity cause various diseases e.g., neurological, cancer, metabolic and cardiovascular. Most of the current therapeutic drugs available in clinical utilization function as enzyme inhibitors. The main goal of the current study to contribute to this growing drug design area (such as medication discovery and development) by investigating protein-drug interactions. The paraoxonase-I (PON1) enzyme was purified from human serum by using different and simple chromatographic techniques. Additionally, it was investigated inhibition effects of some chemotherapeutic drugs on the PON1. The purification results for PON1 depicted a 3880.83 EU/mg proteins specific activity and the molecular weight was calculated as 43 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These drugs found to strongly inhibit PON1, with IC50 values ranging from 0.222±0.002 to 688.300±0.897 µM. Ki constants for vincristine sulfate, epirubicin hydrochloride, and doxorubicin hydrochloride were determined to be 0.235±0.032 µM, 221.400±29.270 µM, and 913.300±201.000 µM, respectively. These drugs showed in competitive inhibition. Also, the molecular docking poses of these agents inside the catalytic sites of 1V04 and 3SRE were analysis.


IL-17 producing T cells in mouse models of multiple sclerosis and rheumatoid arthritis.
Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) are amongst the most common autoimmune diseases in the northern hemisphere. There is mounting evidence that in both afflictions, not only environmental and genetic factors influence disease, but cellular components such as autoreactive T cells also contribute to pathology. Animal models are key in the study and subsequent therapeutic development for human autoimmune diseases. As patient material is often difficult to obtain and in some cases--as in MS, where the central nervous system (CNS) is concerned--even not accessible, animal models provide a multifaceted tool to explore disease-underlying mechanisms. The pro-inflammatory T cell cytokine IL-17 has recently moved to center stage due to its crucial role in autoimmune diseases including MS and RA. A plethora of studies in animal models has sustained the relevance of this cytokine pathway for the development of autoimmunity and shed light on its cellular sources and patho-mechanisms. This review addresses the role of IL-17 producing T lymphocytes, in particular CD4(+) and γδ T cells, in three commonly used mouse models for MS and RA, namely experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), and antigen-induced arthritis (AIA). Comparing and combining knowledge gained from different animal models will broaden our understanding of the IL-17 biology and facilitate the translation to the human diseases.


An approach for immunodiagnosis of clinical cases of filariasis.
In this communication an immunodiagnostic approach has been adopted for detection of antigen and antibody in amicrofilaeamic Mf(-) patients by countercurrent immuno electrophoresis (CCIE) and immunodiffusion (ID). Using Setaria cervi and Immune Complex (IC) antigens, out of fifteen clinical cases the number of positive patients in CCIE were twelve and ten respectively. Sixty percent of the Mf(-) cases were positive in antigen detection against both the homologous and heterologous antibody. In ID nine Mf(-) cases gave precipitin bands against S. cervi antigen while with IC antigens ten patients were positive. In similar experiments, it was found that out of fifteen Mf(-) cases nine and eleven patients were positive in antigen detection against microfilaraemic Mf(+) sera and S. cervi antibody respectively. All the Mf(+) cases were positive in both antibody and antigen detection. From the standpoint of immunodiagnosis the data were analysed by two-way analysis of variance study and a newly developed system using Binomial distribution. The sera from the control group were negative in all the immunodiagnostic tests.


Signaling pathways to neuronal damage and apoptosis in human immunodeficiency virus type 1-associated dementia: Chemokine receptors, excitotoxicity, and beyond.
Dementia can occur as a debilitating consequence of human immunodeficiency virus-1 (HIV-1) infection. The neuropathology incited by HIV infection involves activation of chemokine receptors, inflammatory factors, and N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity, all of which can activate several downstream mechanisms. This article discusses recently identified pathways to neuronal damage triggered by HIV-1 and efforts aimed at development of applicable therapeutic intervention.


Clinical evaluation of the Vitek automated system with cards GNS 122 and 127 and VTK-R07.01 software for antimicrobial susceptibility testing of Pseudomonas aeruginosa.
The performance of the Vitek Automated Susceptibility Testing System software version VTKR07.01 (bioMerieux Vitek, Hazelwood, MO), for testing Pseudomonas aeruginosa was evaluated by comparing results for 200 clinical isolates with those of disk diffusion and manual broth microtiter dilution testing. For cefepime, the restricted major error rate was 0.53% and the minor error rate was 12.5%. For piperacillin, the restricted major error rate was 2.15%. For ticarcillin/clavulanic acid, restricted very major and major error rates of 6.5% and 3.2%, respectively, occurred. The results of our study indicate that the Vitek system performs within acceptable limits when testing piperacillin, but remains problematic for testing cefepime and ticarcillin-clavulanic acid.


Risk-guided maternity care to enhance maternal empowerment postpartum: A cluster randomized controlled trial.
To investigate whether a structured inquiry during pregnancy of medical factors and social factors associated with low socioeconomic status, and subsequent patient-centred maternity care could increase maternal empowerment. Cluster-randomised controlled trial. This study was conducted among pregnant women in selected urban areas in the Netherlands. This study was part of the nationwide Healthy Pregnancy 4 All-2 programme. Pregnant women listed at one of the sixteen participating maternity care organisations between July 1, 2015, and Dec 31, 2016. All practices were instructed to provide a systematic risk assessment during pregnancy. Practices were randomly allocated to continue usual care (seven practices), or to provide a patient-centred, risk-guided approach to addressing any risks (nine practices) identified via the risk assessment during pregnancy. Low postpartum maternal empowerment score. We recruited 1579 participants; 879 participants in the intervention arm, and 700 participants in the control arm. The prevalence of one or more risk factors during pregnancy was similar between the two arms: 40% and 39%, respectively. In our intention-to-treat analysis, the intervention resulted in a significant reduction in the odds of having a low empowerment score [i.e. the primary outcome; adjusted OR 0.69 ((95% CI 0.47; 0.99), P 0.046)]. Implementation of additional risk assessment addressing both medical and social factors and subsequent tailored preventive strategies into maternity care reduced the incidence of low maternal empowerment during the postpartum period. Introducing this approach in routine maternity care may help reduce early adversity during the postpartum period.


Characterization of conserved circular RNA in polyploid Gossypium species and their ancestors.
Circular RNA (circRNA) is a regulatory class of long, noncoding RNA found in both plant and animal kingdoms. The profile and characterization of circRNA in cotton species remains to be explored. Here, using 24 rRNA-depleted RNA-seq libraries of putative diploid progenitors of Gossypium spp., Gossypium arboreum and Gossypium raimondii, their interspecies hybrid (F1 ) and allotetraploid Gossypium hirsutum, 1041, 1478, 1311, and 499 circRNAs were identified in each cotton species, respectively. A prevalence of 23 exon-circRNAs contain noncanonical GT/AG signals, and only ~ 10% of exon-circRNA is associated with reverse complementary intronic sequences. This result implies that plants employ a method of circRNA splicing distinct from that of animals. In addition, 432 circRNAs are stably expressed in multiple cotton species.


Systematic Review and Meta-Analysis of Studies Comparing the Rate of Post-operative Periprosthetic Fracture Following Hip Arthroplasty With a Polished Taper Slip versus Composite Beam Stem.
We compared the incidence of postoperative periprosthetic femoral fractures (POPFF) following hip arthroplasty with either a cemented polished taper slip (PTS) stem or a cemented composite beam (CB) stem in comparative studies. A systematic review of comparative studies, written in English and published in peer-reviewed journals since the year 2000, was conducted. Study quality was assessed using the Newcastle-Ottawa scale.The overall study qualities were good. There were 913,021 patients from 18 cohorts included in the meta-analysis. There were 294,540 patients who received a CB stem and 618,481 received a PTS stem. Cohorts were classified as high- or low-risk for POPFF based on patient risk factors. A metanalysis was performed using a random effects model, and the relative incidence with 95% confidence intervals (CIs) was reported. The patients at low risk of POPFF had an incidence rate ratio of 3.14 (CI: 2.48, 3.98) for the PTS group versus the CB group. Whereas, the patients at high risk of POPFF had an incidence rate ratio of 9.87 (CI: 3.63, 26.80) for the PTS group versus the CB group. The risk of POPFF is lower when hip arthroplasty was performed using a CB stem versus a PTS stem. This protective effect was greatest in patients who had a higher risk of POPFF. Surgeons should consider the effect of cemented stem choice on the risk of subsequent periprosthetic femur fracture, particularly in frail or elderly patients who are at a higher risk of postoperative periprosthetic femoral fracture.


Vitamin D is Positively Associated with Bone Mineral Density Muscle Mass and Negatively with Insulin Resistance in Senile Diabetes Mellitus.
To explore the correlations between vitamin D level and bone mineral density (BMD), insulin resistance (HOMA-IR), and muscle mass in patients with senile type 2 diabetes mellitus (T2DM). Totally, 80 patients with senile T2DM admitted to China-Japan Friendship Hospital from Jan 2020 to Oct 2021 were enrolled and assigned to the 25 (OH)D-deficiency group (n = 35) or 25(OH)D-normal group (n = 45) according to serum 25(OH)D level. BMD and HOMA-IR in the femur neck and muscle masses of upper and lower limbs were compared between the two groups, and Pearson's correlation analysis was performed to determine the relations between 25(OH)D and BMD, HOMA-IR, and muscle masses of upper and lower limbs. No notable difference was found between the two groups in general data including age, gender, diabetes duration, BMI, HBA 1c, and fasting insulin (all P > 0.05). Compared with the 25(OH)D-normal group, the 25 (OH)D-deficiency group showed a notably lower BMD in the femur neck, notably lower muscle masses of upper and lower limbs, and a notably higher HOMA-IR level (all P < 0.05). The Pearson's correlation analysis revealed positive associations between 25(OH)D and BMD and muscle masses of upper and lower limbs in patients with senile T2DM and a negative correlation between 25(OH)D and HOMA-IR (all P < 0.05). The serum 25(OH)D decreases notably in patients with senile T2DM, and higher serum 25(OH)D level may improve insulin resistance, limb muscle masses, and bone density and thus maintain bone health.


Long-term human breast carcinoma cell lines of metastatic origin: preliminary characterization.
Nineteen human breast carcinoma cell lines have been established as continuous cultures during the past 6 years in our laboratory. This preliminary report is designed to list the lines by their designated code numbers (MDA-MB) and present a brief summary of their morphological, cytogenetic and biochemical characteristics. Sixteen of our lines were obtained from pleural effusions, two from brain metastases, and one from pericardial fluid. All lines have been shown to be distinct entities and are uncontaminated by HeLa cells or each other. A lq marker chromosome is present in all but one of the lines examined.


Genotoxicity of two fecal steroids in murine colonic epithelium assessed by the sister chromatid exchange technique.
Two components of human feces are known to induce nuclear anomalies in mice when applied intrarectally, but to be nonmutagenic in Salmonella. We have tested these two compounds for their ability to induce sister chromatid exchanges in the colonic epithelium of mice, the same tissue in which they induce nuclear anomalies when administered by the same route. One, 4-cholesten-3-one, induced sister chromatid exchanges whereas the other, 5-alpha-cholestan-3-one did not, even at the maximum feasible dose. The results suggest that 4-cholesten-3-one is more likely to be a significant factor in human colon cancer than the 5-alpha analog.


Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice.
Group 2 innate lymphoid cells (ILC2s) expressing IL-5 and IL-13 are localized at various mucosal tissues and play critical roles in the induction of type 2 inflammation, response to helminth infection, and tissue repair. Here, we reveal a unique ILC2 subset in the mouse intestine that constitutively expresses IL-4 together with GATA3, ST2, KLRG1, IL-17RB, and IL-5. In this subset, IL-4 expression is regulated by mechanisms similar to but distinct from those observed in T cells and is partly affected by IL-25 signaling. Although the absence of the microbiota had marginal effects, feeding mice with a vitamin B1-deficient diet compromised the number of intestinal IL-4+ ILC2s. The decrease in the number of IL-4+ ILC2s caused by the vitamin B1 deficiency was accompanied by a reduction in IL-25-producing tuft cells. Our findings reveal that dietary vitamin B1 plays a critical role in maintaining interaction between tuft cells and IL-4+ ILC2s, a previously uncharacterized immune cell population that may contribute to maintaining intestinal homeostasis.


Multicenter Validation of the max-ICH Score in Intracerebral Hemorrhage.
Outcome prognostication unbiased by early care limitations (ECL) is essential for guiding treatment in patients presenting with intracerebral hemorrhage (ICH). The aim of this study was to determine whether the max-ICH (maximally treated ICH) Score provides improved and clinically useful prognostic estimation of functional long-term outcomes after ICH. This multicenter validation study compared the prognostication of the max-ICH Score versus the ICH Score regarding diagnostic accuracy (discrimination and calibration) and clinical utility using decision curve analysis. We performed a joint investigation of individual participant data of consecutive spontaneous ICH patients (n = 4,677) from 2 retrospective German-wide studies (RETRACE I + II; anticoagulation-associated ICH only) conducted at 22 participating centers, one German prospective single-center study (UKER-ICH; nonanticoagulation-associated ICH only), and 1 US-based prospective longitudinal single-center study (MGH; both anticoagulation- and nonanticoagulation-associated ICH), treated between January 2006 and December 2015. Of 4,677 included ICH patients, 1,017 (21.7%) were affected by ECL (German cohort: 15.6% [440 of 2,377]; MGH: 31.0% [577 of 1,283]). Validation of long-term functional outcome prognostication by the max-ICH Score provided good and superior discrimination in patients without ECL compared with the ICH Score (area under the receiver operating curve [AUROC], German cohort: 0.81 [0.78-0.83] vs 0.74 [0.72-0.77], p < 0.01; MGH: 0.85 [0.81-0.89] vs 0.78 [0.74-0.82], p < 0.01), and for the entire cohort (AUROC, German cohort: 0.84 [0.82-0.86] vs 0.80 [0.77-0.82], p < 0.01; MGH: 0.83 [0.81-0.85] vs 0.77 [0.75-0.79], p < 0.01). Both scores showed no evidence of poor calibration. The clinical utility investigated by decision curve analysis showed, at high threshold probabilities (0.8, aiming to avoid false-positive poor outcome attribution), that the max-ICH Score provided a clinical net benefit compared with the ICH Score (14.1 vs 2.1 net predicted poor outcomes per 100 patients). The max-ICH Score provides valid and improved prognostication of functional outcome after ICH. The associated clinical net benefit in minimizing false poor outcome attribution might potentially prevent unwarranted care limitations in patients with ICH. ANN NEUROL 2021;89:474-484.


Changes of mesenchymal stromal cells mobilization and bone turnover in an experimental bone fracture model in ovariectomized mice.
The aim of this study was to characterize the mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) mobilization, and bone turnover in osteoporotic fracture healing in ovariectomized mice. In total, 112 female C57/BL mice were divided into two groups. The first group was sham-operated (SO), and the other group was ovariectomized (OVX). After three weeks, the right femora of the mice were fractured under anesthesia and internally fixed with steel pin. Peripheral blood and bone marrow were was collected for flow cytometry analysis, at 0 hours (h), 12 h, 24 h, 72 h and 168 h after fracture. MSCs and EPCs levels were assessed using cell surface antigens in different combinations (CD44+ CD34-CD45-, and CD34+ KDR+CD45-) by flow cytometry. At 0, 14, 28 and 42 days after fracture, sera were assayed for circulating levels of procollagen type I-N-terminal propeptide (P1NP) and C-terminal telopeptide of type I-collagen (CTX) by ELISA. Femurs were harvested at 2 weeks and 6 weeks after fracture for X-ray radiography, micro-computed tomography (micro-CT) and histology. Our results showed that bone marrow and peripheral blood MSCs numbers of the OVX mice were significantly lower than the SO mice, at 12 h, 24 h and 72 h after fracture. In addition, circulating P1NP and CTX levels of the OVX mice were significantly higher than the SO mice, at 2 and 4 weeks. Results of the present study revealed disorders of bone marrow MSCs mobilization and bone turnover may partially account for the delay of osteoporotic fracture healing.


Many ways to telomere dysfunction: in vivo studies using mouse models.
The existence of a capping structure at the extremities of chromosomes was first deduced in the 1930s by Herman Müller (Müller, 1938), who showed that X-irradiation of Drosophila rarely resulted in terminal deletions or inversions of chromosomes, suggesting that chromosome ends have protective structures that distinguish them from broken chromosomes, which he named telomeres. In this review, we will focus on mammalian telomeres and, in particular, on the analysis of different mouse models for proteins that are important for telomere function, such as telomerase and various telomere-binding proteins. These murine models are helping us to understand the consequences of telomere dysfunction for cancer, aging and DNA repair, as well as, the molecular mechanisms by which telomeres exert their protective function.


Treatment of vesicoureteral reflux in children using stabilized non-animal hyaluronic acid/dextranomer gel (NASHA/DX): a long-term observational study.
Vesicoureteral reflux (VUR) can be treated with open surgery, antibiotic therapy or endoscopic injection. A goal in children is to reduce the incidence of febrile urinary tract infections (UTIs). The present long-term observational study investigated outcomes and experiences of endoscopic treatment with stabilized non-animal hyaluronic acid/dextranomer, NASHA/Dx. Children treated with NASHA/Dx between 1993 and 1998 were sent a questionnaire by mail in 2005. Patients included in the study (n=231) had VUR grade III-V before treatment and grade 0-II afterwards. Patients completed 21 questions, with parental assistance if required. The questionnaire assessed clinical outcome, and the attitudes of both patients and their parents to their experiences of treatment with NASHA/Dx gel. Patients reporting UTI after treatment were contacted and their records analyzed. Questionnaires were completed by 179 eligible patients. Most (72%) received a single injection of NASHA/Dx gel, and all experienced febrile UTI before treatment. After treatment, 45 patients (25%) experienced UTI; 25 of these reported fever. Patient records and telephone interviews revealed no evidence of febrile UTI in 19 cases; febrile UTI was confirmed in six cases, an incidence of 3.4%. When asked about the worst aspect of VUR treatment, 9% indicated treatment with NASHA/Dx compared to 19% for medication and 72% for voiding cystourethrogram (VCUG); parent-rated responses were 19%, 24% and 57%, respectively. Endoscopic treatment with NASHA/Dx gel was associated with a low number of febrile UTIs following treatment, viewed positively and considered less bothersome than medication or VCUG. These findings support this treatment as a primary intervention for VUR.


Midcingulate somatomotor and autonomic functions.
The midcingulate cortex (MCC) is viewed as a central node within a large-scale system devoted to adjusting behavior in the face of changing environments. Whereas the role of the MCC in interfacing action and cognition is well established, its role in regulating the autonomic nervous system is poorly understood. Yet, adaptive reactions to novel or threatening situations induce coordinated changes in the sympathetic and the parasympathetic systems. The somatomotor maps in the MCC are organized dorsoventrally. A meta-analysis of the literature reveals that the dorsoventral organization might also concern connections with the autonomic nervous system. Activation of the dorsal and ventral parts of the MCC correlate with recruitments of the sympathetic and the parasympathetic systems, respectively. Data also suggest that, in the MCC, projections toward the sympathetic system are mapped along the sensory-motor system following the same cervico-sacral organization as projections on the spinal cord for skeletal motor control.


Human and machine drivers: Sharing control, sharing responsibility.
Machines are empowered with ever-increasing agency and decision-making authority to augment or even replace humans in various settings, making responsibility attribution less straightforward when they cause harm. Focusing on their applications in transportation, we consider human judgments of responsibility for automated vehicle crashes through a cross-national survey (N = 1657) and design hypothetical crashes after the 2018 Uber automated vehicle crash reportedly caused by a distracted human driver and an inaccurate machine driver. We examine the association between automation level-the human and machine drivers have different levels of agency (i.e., the human as a supervisor, backup driver, and mere passenger, respectively)-and human responsibility through the lens of perceived human controllability. We show the negative association between automation level and human responsibility, partly mediated by perceived human controllability, regardless of the involved responsibility metric (rating and allocation), the nationality of the involved participant (China and South Korea), and crash severity (injury and fatality). When the human and machine drivers in a conditionally automated vehicle jointly cause a crash (e.g., the 2018 Uber crash), the human driver and car manufacturer are asked to share responsibility. Our findings imply that the driver-centric tort law needs to be control-centric. They offer insights for attributing human responsibility for crashes involving automated vehicles.


LAPTM4B-35 promotes cancer cell migration via stimulating integrin beta1 recycling and focal adhesion dynamics.
Metastasis is the main cause of cancer patients' death despite tremendous efforts invested in developing the related molecular mechanisms. During cancer cell migration, cells undergo dynamic regulation of filopodia, focal adhesion, and endosome trafficking. Cdc42 is imperative for maintaining cell morphology and filopodia, regulating cell movement. Integrin beta1 activates on the endosome, the majority of which distributes itself on the plasma membrane, indicating that endocytic trafficking is essential for this activity. In cancers, high expression of lysosome-associated protein transmembrane 4B (LAPTM4B) is associated with poor prognosis. LAPTM4B-35 has been reported as displaying plasma membrane distribution and being associated with cancer cell migration. However, the detailed mechanism of its isoform-specific distribution and whether it relates to cell migration remain unknown. Here, we first report and quantify the filopodia localization of LAPTM4B-35: mechanically, that specific interaction with Cdc42 promoted its localization to the filopodia. Furthermore, our data show that LAPTM4B-35 stabilized filopodia and regulated integrin beta1 recycling via interaction and cotrafficking on the endosome. In our zebrafish xenograft model, LAPTM4B-35 stimulated the formation and dynamics of focal adhesion, further promoting cancer cell dissemination, whereas in skin cancer patients, LAPTM4B level correlated with poor prognosis. In short, this study establishes an insight into the mechanism of LAPTM4B-35 filopodia distribution, as well as into its biological effects and its clinical significance, providing a novel target for cancer therapeutics development.


Examining an underlying mechanism between perceived stress and smoking cessation-related outcomes.
The mediational role of negative reinforcement smoking outcome expectancies in the relation between perceived stress and (1) perceived barriers to cessation, (2) severity of problematic symptoms during past quit attempts, and (3) smoking-specific experiential avoidance (AIS) was examined. Data were drawn from a baseline assessment of a larger clinical trial. Participants included 332 adult treatment-seeking smokers (47.3% female; Mage=38.45; SD=.50; age range: 18-65 years). Results indicated that perceived stress was indirectly related to perceived barriers to smoking cessation, severity of problematic symptoms during past quit attempts, and AIS through negative reinforcement outcome expectancies. These results were evident after accounting for the variance explained by gender, negative affectivity, and alternative outcome expectancies for smoking. The present findings suggest that smokers with greater perceived stress experience greater negative reinforcement smoking expectancies, which in turn, may be related to numerous processes involved in the maintenance of smoking.


Compound effects of bisulphite ion on frog skeletal muscle.
To characterize the structures of the nicotinic cholinoceptors in the frog rectus abdominis muscle, group-selective reagents have been used. Possible modifications of the excitation-contraction coupling have also been studied. The effect of the bisulphite ion on skeletal muscle has been demonstrated earlier at presynaptic and postsynaptic levels. Another report questioned whether these effects were significant to the contractile process in general. The present study shows that bisulphite induced qualitative and quantitative changes in the muscular response to acetylcholine and electrical stimulation. The intervention is likely at the level of excitation-contraction coupling as well as at the previously proposed sites.


Comparative EXAFS investigation of uranium(VI) and -(IV) aquo chloro complexes in solution using a newly developed spectroelectrochemical cell.
The coordination of the U(IV) and U(VI) ions as a function of the chloride concentration in aqueous solution has been studied by U L(III)-edge extended X-ray absorption fine structure (EXAFS) spectroscopy. The oxidation state of uranium was changed in situ using a gastight spectroelectrochemical cell, specifically designed for the safe use with radioactive solutions. For U(VI) we observed the complexes UO2(H2O)5(2+), UO2(H2O)4Cl+, UO2(H2O)3Cl2(0), and UO2(H2O)2Cl3- with [Cl-] increasing from 0 to 9 M, and for U(IV) we observed the complexes U(H2O)9(4+), U(H2O)8Cl3+, U(H2O)(6-7)Cl2(2+), and U(H2O)5Cl3+. The distances in the U(VI) coordination sphere are U-Oax = 1.76+/-0.02 A, Oeq = 2.41 +/- 0.02 A, and U-Cl = 2.71 +/- 0.02 A; the distances in the U(IV) coordination sphere are U-O = 2.41 +/- 0.02 A and U-Cl = 2.71 +/- 0.02 A.


Single-cell transcriptomics identifies a distinct luminal progenitor cell type in distal prostate invagination tips.
The identification of prostate stem/progenitor cells and characterization of the prostate epithelial cell lineage hierarchy are critical for understanding prostate cancer initiation. Here, we characterized 35,129 cells from mouse prostates, and identified a unique luminal cell type (termed type C luminal cell (Luminal-C)) marked by Tacstd2, Ck4 and Psca expression. Luminal-C cells located at the distal prostate invagination tips (termed Dist-Luminal-C) exhibited greater capacity for organoid formation in vitro and prostate epithelial duct regeneration in vivo. Lineage tracing of Luminal-C cells indicated that Dist-Luminal-C cells reconstituted distal prostate luminal lineages through self-renewal and differentiation. Deletion of Pten in Dist-Luminal-C cells resulted in prostatic intraepithelial neoplasia. We further characterized 11,374 human prostate cells and confirmed the existence of h-Luminal-C cells. Our study provides insights into the prostate lineage hierarchy, identifies Dist-Luminal-C cells as the luminal progenitor cell population in invagination tips and suggests one of the potential cellular origins of prostate cancer.


Visual and vestibular projections to tongue motoneurons.
The rabbit hypoglossal neurons, localized in the mediocaudal part of the XIIth nucleus, receive visual and vestibular inputs able to induce reflex responses functionally driven both to prepare the oral cavity for food reception and to ensure a correct postural arrangement of the tongue. The aim of the present research was to show a possible convergence of visual input on the hypoglossal neurons modulated by the vestibular system and, thus, demonstrate that visual input plays a part in the control of the tongue posture. It was found that 78% of tested neurons responded to both photic stimulation of the retinae, performed by a conventional strobe unit, and electrical stimulation of the labyrinth, with different patterns of response. Moreover, visual input significantly modified both the hypoglossal neuron response and the electromyographic genioglossal response to caloric stimulation of the labyrinth. Because a significant visual influence on the hypoglossal nucleus response and the genioglossal muscle response to labyrinthine stimulation was observed, it can be concluded that vision does integrate the spatial information of the labyrinth to modulate the postural tone of the tongue muscles.


Sedation and Anesthesia in Exotic Animal Critical Care.
Sedation and anesthesia of exotic animals in inherently challenging, but often facilitates the best care for patients. Critical illness or injury adds on another layer of complexity to their management for obtaining diagnostics and providing treatments. This article serves to review some of the more recent literature of sedation and anesthesia within exotics practice, bringing to light some nuances and considerations for when those patients are critically ill or injured.


Familial oligodontia and regional odontodysplasia associated with a PAX9 initiation codon mutation.
Tooth agenesis is one of the most common craniofacial developmental anomalies. In hypodontia, one to five teeth are missing, whereas oligodontia refers to the absence of at least six teeth, excluding the third molars. Mutations in several genes including MSX1, PAX9, AXIN2, and WNT10A have been shown to cause non-syndromic tooth agenesis. Regional odontodysplasia (RO), also known as "ghost teeth," is a rare developmental anomaly of tooth formation affecting both dentitions. Some possible causes of RO have been suggested, yet the etiology remains unknown. Because the phenotypes of both oligodontia and RO co-occur in one Finnish family, the aim here was to investigate the genetic etiology of the two conditions. A mutation screening of the genes MSX1, PAX9, AXIN2, and WNT10A was performed for the family members of a RO patient and family history of oligodontia. An initiation codon mutation of the PAX9 gene was found in the proband and segregating with oligodontia in the family. The etiology of regional odontodysplasia (RO) may be genetic and the same genes can be involved both in RO and tooth agenesis. Our results give new insights into the etiology of regional odontodysplasia, yet further results are needed.


Interleukin-8 promotes integrin β3 upregulation and cell invasion through PI3K/Akt pathway in hepatocellular carcinoma.
Interleukin-8 (IL-8) plays a vital role in the invasion and metastasis of hepatocellular carcinoma (HCC), and is closely associated with poor prognosis of HCC patients. Integrin αvβ3, a member of the integrin family, has been reported to be overexpressed in cancer tissues and mediate the invasion and metastasis of HCC cells. However, the relationship between IL-8 and integrin αvβ3 in HCC and the underlying mechanism of IL-8 and integrin αvβ3 in the invasion of HCC remains unclear. The expression of IL-8, integrin αv and integrin β3 in HCC cells and tissues was detected by quantitative real-time PCR, Western blot and immunohistochemistry. Transwell assay and Western blot was used to detect the invasiveness, the expression of integrin β3 and the activation of PI3K/Akt pathway of HCC cells pretreated with IL-8 knockdown or exogenous IL-8. IL-8, integrin αv and integrin β3 were overexpressed in highly metastatic HCC cell lines compared with low metastatic cell lines. There was a positive correlation between integrin β3 and IL-8 expression in HCC tissues. IL-8 siRNA transfection reduced HCC cell invasion and the levels of integrin β3, p-PI3K and p-Akt. IL-8 induced HCC cell invasion and integrin β3 expression was significantly inhibited by transfection with CXCR1 siRNA or CXCR2 siRNA. When we stimulated HCC cells with exogenous IL-8, cell invasion and the levels of integrin β3, p-PI3K, and p-Akt increased, which could be effectively reversed by adding PI3K inhibitor LY294002. Our results suggest that IL-8 promotes integrin β3 upregulation and the invasion of HCC cells through activation of the PI3K/Akt pathway. The IL-8/CXCR1/CXCR2/PI3K/Akt/integrin β3 axis may serve as a potential treatment target for patients with HCC.