miRNA expression profiles of premalignant and malignant arsenic-induced skin lesions.
Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59-172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.


A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy.
Klotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Bioinformatics analyses of The Cancer Genome Atlas (TCGA) datasets revealed a correlation between the survival of PDAC patients, levels of klotho expression, and DNA methylation, and demonstrated a unique hypermethylation pattern of klotho in pancreatic tumors. The in vivo effects of klotho and KL1 were examined using three mouse models. Employing a novel genetic model, combining pancreatic klotho knockdown with a mutation in Kras, the lack of klotho contributed to PDAC generation and decreased mousece survival. In a xenograft model, administration of viral particles carrying sKL, a spliced klotho isoform containing the KL1 domain, inhibited pancreatic tumors. Lastly, treatment with soluble sKL prolonged survival of Pdx1-Cre; KrasG12D/+;Trp53R172H/+ (KPC) mice, a model known to recapitulate human PDAC. In conclusion, this study provides evidence that klotho is a tumor suppressor in PDAC. Furthermore, these data suggest that the levels of klotho expression and DNA methylation could have prognostic value in PDAC patients, and that administration of exogenous sKL may serve as a novel therapeutic strategy to treat PDAC.


The adsorption behavior of natural sand in contact with uranium contaminated seawater.
This study was undertaken to investigate the interaction between uranium contaminated seawater and the sand in contact with this seawater. Adsorption data have been evaluated from column experiments of seawater from Marmara, Black Sea and Mediterranean contaminated with 10(-7)M uranium. The uranium uptake on the fractionated and non-fractionated sand of these sea have been measured as a function of time. The adsorption proceeds via a rather fast stage followed by a slower one. Results could be correlated with particle size and porosity of the sand. Adsorption isotherms are also derived from amount of adsorbed uranium vs. time plots and the results have been analyzed by the Langmuir, Freundlich and Dubinin-Radushckevich (D R) isotherm equations over the entire range of uranium concentrations. By fitting the data to D-R isotherm, we have calculated the adsorption energy and decided to type of the adsorption.


Conversation Orientation Moderates the Relationship between Information Sharing of Medically Assisted Reproduction and Child Adjustment.
Parents who experienced infertility have increasingly used medically assisted reproduction (MAR) to add children to their families over the past few decades. These parents will need to decide if they will tell their children about being conceived using MAR. Although MAR information sharing operates within family contexts, little is known about the role of conversation orientation-one family contextual factor-in child outcomes associated with MAR information sharing in middle childhood. Derived from the Family Communication Patterns Theory, this study proposes that conversation orientation moderates the associations between MAR information sharing and children's psychosocial adjustment. This proposal was tested using a sample of 81 6- to 12-year-old MAR-conceived children from 55 families and a structured observational measure of conversation orientation. Multiple regression analyses showed that MAR information sharing interacted with conversation orientation to influence children's behavioral and attention problems but not emotional problems. In families with high conversation orientation, MAR information sharing was not significantly associated with children's behavioral and attention problems. In families with low conversation orientation, MAR information sharing was significantly associated with an increase in children's behavioral and attention problems. Results of this exploratory study demonstrate the potential significance of general communication orientation in understanding child outcomes of MAR information sharing and highlight the needed family context nuances in MAR research.


A quenched-flow system for measuring heterogeneous enzyme kinetics with sub-second time resolution.
Even though many enzyme processes occur at the interface of an insoluble substrate, these reactions are generally much less studied than homogenous enzyme reactions in the aqueous bulk. Interfacial (or heterogeneous) enzyme reactions involve several reaction steps, and the established experimental approach to elucidate multi-step reactions is transient (or pre steady-state) kinetics. A key requirement for pre steady-state measurements is good time resolution, and while this has been amply achieved in different commercial instruments, they are generally not applicable to precipitating suspensions of insoluble substrate. Perhaps for this reason, transient kinetics has rarely been reported for heterogeneous enzyme reactions. Here, we describe a quenched-flow system using peristaltic pumps and stirred substrate suspensions with a dead time below 100ms. The general performance was verified by alkali catalyzed hydrolysis of 2,4-dinitrophenyl acetate (DNPA), and the applicability to heterogeneous reactions was documented by two cellulases (Cel7A and Cel7B) acting on suspensions of microcrystalline cellulose (Avicel) at different loads up to 15g/l. The results showed distinctive differences between the two enzymes. In particular, we found that endo-lytic Cel7B combined very quickly with the substrate and reached the maximal activity within the dead-time of the instrument. Conversely, exo-lytic Cel7A showed a much slower initiation with maximal activity after 5-8s and a 10-fold lower turnover. We suggest that the instrument may provide an important tool in attempts to elucidate the mechanism of cellulases and other enzymes' action on insoluble substrate.


Comparison of clinical and biomechanical characteristics between individuals with lower limb amputation with and without lower back pain: A systematic review and meta-analysis.
Lower back pain is a debilitating condition common to individuals with lower limb amputation. It is unclear what risk factors contribute to the development of back pain. This study systematically reviewed and analyzed the available evidence regarding the clinical and biomechanical differences between individuals with amputation, with and without lower back pain. A literature search was conducted in PubMed, Web of Science, Scopus, and CINAHL databases in November 2020 and repeated in June 2021 and June 2022. Studies were included if they reported comparisons of demographic, anthropometric, biomechanical, and other clinical variables between participants with and without LBP. Study quality and potential for reporting bias were assessed. Meta-analyses were conducted to compare the two groups. Thirteen studies were included, with aggregated data from 436 participants (239 with LBP; 197 pain free). The median reporting quality score was 37.5%. The included studies enrolled participants who were predominantly male (mean = 91.4%, range = 77.8-100%) and with trauma-related amputation. Meta-analyses showed that individuals with LBP exhibited moderate (3.4 out of 10) but significantly greater pain than those without LBP. We found no between-group differences in age, height, weight, BMI, and time since amputation (p = 0.121-0.682). No significant differences in trunk/pelvic kinematics during gait were detected (p = 0.07-0.446) between the groups. Demographic, anthropometric, biomechanical, and simple clinical outcome variables may be insufficient for differentiating the risk of developing back pain after amputation. Investigators should be aware of the existing gender bias in sampling and methodological limitations, as well as to consider incorporating psychosocial measures when studying LBP in this clinical population.


Negative latent tuberculosis at time of incarceration: identifying a very high-risk group for infection.
The main aim was to measure the incidence of latent tuberculosis infection (LTBI) and identify risk factors associated with infection. In addition, we determined the number needed to screen (NNS) to identify LTBI and active tuberculosis. We followed 129 prisoners for 2 years following a negative two-step tuberculin skin test (TST). The cumulative incidence of TST conversion over 2 years was 29·5% (38/129), among the new TST converters, nine developed active TB. Among persons with no evidence of LTBI, the NNS to identify a LTBI case was 3·4 and an active TB case was 14·3. The adjusted risk factors for LTBI conversion were incarceration in prison number 1, being formerly incarcerated, and overweight. In conclusion, prisoners have higher risk of LTBI acquisition compared with high-risk groups, such as HIV-infected individuals and children for whom LTBI testing should be performed according to World Health Organization guidance. The high conversion rate is associated with high incidence of active TB disease, and therefore we recommend mandatory LTBI screening at the time of prison entry. Individuals with a negative TST at the time of entry to prison are at high risk of acquiring infection, and should therefore be followed in order to detect convertors and offer LTBI treatment. This approach has a very low NNS for each identified case, and it can be utilized to decrease development of active TB disease and transmission.


Fish consumption, insulin sensitivity and beta-cell function in the Insulin Resistance Atherosclerosis Study (IRAS).
Previous research on the association between fish consumption and incident type 2 diabetes has been inconclusive. In addition, few studies have investigated how fish consumption may be related to the metabolic abnormalities underlying diabetes. Therefore, we examined the association of fish consumption with measures of insulin sensitivity and beta-cell function in a multi-ethnic population. We examined the cross-sectional association between fish consumption and measures of insulin sensitivity and secretion in 951 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Fish consumption, categorized as <2 vs. ≥2 portions/week, was measured using a validated food frequency questionnaire. Insulin sensitivity (S(I)) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Higher fish consumption was independently associated with lower S(I)-adjusted AIR (β = -0.13 [-0.25, -0.016], p = 0.03, comparing ≥2 vs. <2 portions/week). Fish consumption was positively associated with intact and split proinsulin/C-peptide ratios, however, these associations were confounded by ethnicity (multivariable-adjusted β = 0.073 [-0.014, 0.16] for intact proinsulin/C-peptide ratio, β = 0.031 [-0.065, 0.13] for split proinsulin/C-peptide ratio). We also observed a significant positive association between fish consumption and fasting blood glucose (multivariable-adjusted β = 2.27 [0.68, 3.86], p = 0.005). We found no association between fish consumption and S(I) (multivariable-adjusted β = -0.015 [-0.083, 0.053]) or fasting insulin (multivariable-adjusted β = 0.016 [-0.066, 0.10]). Fish consumption was not associated with measures of insulin sensitivity in the multi-ethnic IRAS cohort. However, higher fish consumption may be associated with pancreatic beta-cell dysfunction.


Preparing for an aging Australia: The development of multidisciplinary core competencies for the Australian health and aged care workforce.
Appropriately skilled staff are required to meet the health and care needs of aging populations yet, shared competencies for the workforce are lacking. This study aimed to develop multidisciplinary core competencies for health and aged care workers in Australia through a scoping review and Delphi survey. The scoping review identified 28 records which were synthesized through thematic analysis into draft domains and measurable competencies. Consensus was sought from experts over two Delphi rounds (n = 111 invited; n = 59 round one; n = 42 round two). Ten domains with 66 core competencies, to be interpreted and applied according to the worker's scope of practice were finalized. Consensus on multidisciplinary core competencies which are inclusive of a broad range of registered health professionals and unregistered aged care workers was achieved. Shared knowledge, attitudes, and skills across the workforce may improve the standard and coordination of person-centered, integrated care for older Australians from diverse backgrounds.


Nasal Malignant Melanoma With an Inverted Papilloma in the Contralateral Nasal Cavity: A Case Report.
Background: We describe a patient with sinonasal mucosal melanoma (SNMM) and an inverted papilloma, which existed independently in both nasal cavities. Case presentation: We describe an unusual case of a 74-year-old male patient with SNMM and an inverted papilloma. He presented with symptoms of coughing up blood and pain in the left forehead. The patient underwent surgical resection of the lesion, and the SNMM and inverted papilloma were confirmed by histopathology. The patient refused further treatment after surgery, but was re-admitted 7 months later with local recurrence of the left tumor and systemic metastases. Conclusions: Nasal malignant melanoma with an inverted papilloma in the contralateral nasal cavity is rare and can easily be misdiagnosed as the same tumor by imaging. Simultaneous histopathology of bilateral nasal masses is very necessary. The recommended treatment is surgery for the inverted papilloma. An SNMM is a devastating tumor with poor outcomes.


Age, outcome, and rehabilitation costs after paraplegia caused by traumatic injury of the thoracic spinal cord, conus medullaris, and cauda equina.
The object of this study was to investigate the relationships of age on neurologic and functional outcome, hospitalization length of stay (LOS), and hospital charges after spinal cord injury (SCI). At 20 medical centers, 2,169 consecutive adult patients with paraplegia SCI were assessed in acute care and inpatient rehabilitation. Outcome and treatment measures included the ASIA motor index score, functional independence measure, discharge to community ratio, LOS, and hospital charges. Age differences were examined by separating the sample into 11 age categories and conducting one-way analyses of variance on treatment, medical expense, and outcome measures that included the Functional Independence Measure (FIM) and ASIA motor index scores. Cramer's statistic was used to derive a chi-square value that indicated whether variables differed significantly in terms of age. Post-hoc Tukey tests were also performed. Age-related differences were found with multiple demographic variables. Significant differences between age categories were found with regard to the following treatment measures: ASIA motor index scores at acute-care admission and at discharge, rehabilitation LOS, inpatient rehabilitation hospitalization charges, total LOS, total hospitalization charges, FIM scores at inpatient rehabilitation admission and discharge, FIM change, and FIM efficiency. In conclusion, in patients with paraplegia, age appears to adversely affect functional outcome, rehabilitation LOS, and hospital costs. However, neurologic recovery as defined by the ASIA motor scores does not appear to be related to age.


Tbx3 is required for outflow tract development.
Conotruncal and ventricular septal congenital heart anomalies result from defects in formation and division of the embryonic outflow tract. Cardiac remodeling during outflow tract and ventricular septation converts the tubular embryonic heart into a parallel circulatory system with an independent left ventricular outlet and right ventricular inlet. Tbx3 encodes a T-box-containing transcription factor expressed in the developing conduction system of the heart. Mutations in TBX3 cause ulnar-mammary syndrome. Here we show that mice lacking Tbx3 develop severe outflow tract defects, including connection of both the aorta and pulmonary trunk with the right ventricle, in addition to aortic arch artery anomalies and abnormal communication between the right atrium and left ventricle. Alignment defects are preceded by a delay in caudal displacement of the arterial pole of the heart during aortic arch artery formation. Embryonic anterior-posterior patterning and cardiac chamber development are unaffected in Tbx3 mutant embryos. However, the contribution of second heart field derived progenitor cells to the arterial pole of the heart is impaired. Tbx3 is expressed in pharyngeal epithelia and neural crest cells in the pharyngeal region, suggesting an indirect role in second heart field deployment. Loss of Tbx3 affects multiple signaling pathways regulating second heart field proliferation and outflow tract morphogenesis, including fibroblast growth factor signaling, leading to a failure of normal heart tube extension and consequent atrioventricular and ventriculoarterial alignment defects.


[The changing epidemiology of extended spectrum β-lactamase-producing Klebsiella pneumoniae].
In the last two decades, Klebsiella pneumoniae demonstrated some characteristics of acquisition of plasmids coding extended spectrum β-lactamases (ESBL). The review data showed an increase in worldwide prevalence of ESBL and a temporal shift in the prevalence of ESBL types in K. pneumoniae during this last decade. CTX-M-15 seems to be the predominant ESBL type in K. pneumoniae in some parts of the world. The dissemination of several nosocomial CTX-M-15-producing K. pneumoniae clones was reported unlike the worldwide dissemination of a single virulent ST131 CTX-M-15 producing Escherichia coli clone. The diversity of plasmids carrying the bla(CTX-M-15) gene in K. pneumoniae suggested the frequent transfer of this gene between different replicons. The acquisition of the bla(CTX-M-15) gene by K. pneumoniae was probably occurred via horizontal transfer from E. coli.


Plasma cell leukaemia and other aggressive plasma cell malignancies.
Extramedullary plasma cell cancers, such as plasma cell leukaemia (PCL) and multiple extramedullary plasmacytomas (MEP) are very aggressive malignancies. These can be primary (de-novo) or secondary due to progressive prior multiple myeloma (MM). Recent reports suggest an increase in incidence of these disorders. Compared to MM, organ invasion is common in PCL, while soft tissue tumors involving the head, neck or paraspinal area are common sites for MEP. Markers of poor prognosis are frequently observed in these extramedullary forms of plasma cell cancers, and survival is significantly inferior compared to patients with MM. Conventional chemotherapeutic and radiotherapy approaches have been employed with variable results. Even high dose chemotherapy with autologous stem cell rescue has not been able to demonstrate consistent improvement in survival outcome. Although not specifically evaluated, novel anti-plasma cell agents, such as the proteasome inhibitor bortezomib, and immunomodulatory drugs, such as lenalidomide, appear to be active against these aggressive cancers. Clinical and translational research directed at improved understanding of disease biology and development of novel therapeutics is urgently needed.


Development of an 18-Item Measure of Symptom Burden in Patients With Glaucoma From the Collaborative Initial Glaucoma Treatment Study's Symptom and Health Problem Checklist.
Administration of a brief questionnaire to evaluate glaucoma symptoms would lend useful information for patient care. To develop a shortened glaucoma symptom measure based on the Collaborative Initial Glaucoma Treatment Study (CIGTS) Symptom and Health Problem Checklist (SHPC) and evaluate its psychometric properties. This measure development study evaluated the factor structure of the 43-item SHPC that was obtained from CIGTS participants at baseline and every 6 months thereafter. These 607 participants were enrolled at 14 clinical centers in the United States and had newly diagnosed open-angle glaucoma. Their mean deviation (SD) from visual field testing was −5.5 (4.3) dB. Data were collected from October 1993 through April 1997. The factor structure of the SHPC, confirmatory factor analysis of the resulting 18-item questionnaire (SHPC-18), the reliability of the SHPC-18, and associations of the 2 symptom subscales (Local Eye and Visual Function) of the SHPC-18 with visual field severity and 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ25) subscales. Among the 607 participants (mean [SD] age at enrollment, 57.5 [10.9] years), 334 (55.0%) were men and 273 (45.0%) were women; 231 (38.1%) were African American. Exploratory factor analysis and longitudinal growth modeling documented Local Eye and Visual Function symptom subscales. Cronbach α values for mean weighted internal consistency were 0.83 and 0.89 for the Local Eye and Visual Function subscales, respectively, and remained stable over time. Scores on each subscale significantly correlated with the NEI-VFQ25 total score (r = −0.41 and r = −0.59, respectively) and with all subscale scores (P < .01). Participants with more severe glaucoma had higher (worse) mean (SD) scores than those with mild glaucoma at baseline on the Local Eye (4.68 [6.62] vs 3.07 [5.60]) and Visual Function (8.44 [11.45] vs 4.42 [8.94]; P < .05) SHPC-18 subscales. Participants who underwent trabeculectomy reported a higher frequency of any Local Eye symptoms than those treated with topical medications (eg, at 12 months, 153 of 269 [56.9%] vs 11 of 276 [40.9%]; P < .001). These results suggest that the SHPC-18 is a reliable, responsive, and psychometrically sound measure of patient-reported, glaucoma-related symptoms. The measure is responsive to treatment and discriminates the severity of glaucoma. This shorter version of the original SHPC measure may be useful in clinical and research settings to better understand the influence of glaucoma symptoms on patients' daily life.


Biology-based mapping of vector-borne parasites by geographic information systems and remote sensing.
Application of growing degree day-water budget analysis and satellite climatology to vector-borne parasites will be reviewed to demonstrate the value of using the unique thermal-hydrological preferences and limits of tolerance of individual parasite-vector systems to define the environmental niche of disease agents in the landscape by modern geospatial analysis methods. Applications of geospatial modeling will be illustrated by examples on fascioliasis, malaria, leprosy and leishmaniasis.


A physiological and morphological study of the horizontal cell types of the rabbit retina.
A perfused, isolated retina-eyecup preparation of the rabbit was utilized to correlate the physiology and morphology of horizontal cells. Neurons were physiologically characterized by intracellular recording techniques and subsequently stained with intracellular iontophoretically injected horseradish peroxidase for morphological identification. Three types of rabbit horizontal cell recordings have been differentiated, based on variations in response waveform, amplitude-intensity properties, and area summation characteristics. These three types have been unequivocally associated with the axonless A-type horizontal cells and the somatic and axon terminal endings (each displaying its own distinct physiology) of B-type horizontal cells first described in studies using Golgi-impregnation techniques (Fisher and Boycott, '74). In addition, the sizes of A-type horizontal cells were found to be directly related to their retinal eccentricities from the optic desk. However a unique subclass of A-type cells has been discovered (elongated or Ae type) which displayed the largest dendritic field of any cells studied here, yet had the smallest eccentricities--within 1.4 mm of the optic disk. Moreover, elongated A-type cells exhibited long asymmetrical dendritic fields which were oriented parallel with the visual streak. The unique asymmetry and orientation of these cells suggests that they may have orientation-biased receptive field properties. Physiological evidence for an orientation-biased horizontal cell is presented in support of this notion.


Computed tomography of the cervical lymph nodes: use of intravenous contrast enhancement.
Intravenous contrast administration increases the sensitivity of computed tomographic scanning for enlarged cervical lymph nodes but requires a detailed knowledge of neck anatomy, especially in order to distinguish certain normal vessels from involved nodal groups. Along the collar chain, relations between the parotid and submandibular salivary glands and the posterior and anterior facial veins and facial artery are analyzed. The digastric muscle is defined as a transitional landmark between collar and deep cervical nodes. Along the deep cervical chain, emphasis is on the internal jugular vein, its variability in size, and its relations to the anterior scalene and omohyoid muscles.


[The ultrasound-assisted method for the extraction of cellular elements from saliva traces left on cigarette butts].
Specimens for cytological studies prepared from the traces of saliva left on cigarette butts using an ultrasound bath contained 5-7 times more epithelial cells than samples obtained by the traditional method. The new technique requires much less material for the analysis. It was validated during forensic medical examination of saliva traces left on cigarette.


Individual differences in crossmodal brain activity predict arcuate fasciculus connectivity in developing readers.
Crossmodal integration of auditory and visual information, such as phonemes and graphemes, is a critical skill for fluent reading. Previous work has demonstrated that white matter connectivity along the arcuate fasciculus (AF) is predicted by reading skill and that crossmodal processing particularly activates the posterior STS (pSTS). However, the relationship between this crossmodal activation and white matter integrity has not been previously reported. We investigated the interrelationship of crossmodal integration, both in terms of behavioral performance and pSTS activity, with AF tract coherence using a rhyme judgment task in a group of 47 children with a range of reading abilities. We demonstrate that both response accuracy and pSTS activity for crossmodal (auditory-visual) rhyme judgments was predictive of fractional anisotropy along the left AF. Unimodal (auditory-only or visual-only) pSTS activity was not significantly related to AF connectivity. Furthermore, activity in other reading-related ROIs did not show the same AV-only AF coherence relationship, and AV pSTS activity was not related to connectivity along other language-related tracts. This study is the first to directly show that crossmodal brain activity is specifically related to connectivity in the AF, supporting its role in phoneme-grapheme integration ability. More generally, this study helps to define an interdependent neural network for reading-related integration.


Inactivation of Kv3.3 potassium channels in heterologous expression systems.
Kv3.3 K+ channels are believed to incorporate an NH2-terminal domain to produce an intermediate rate of inactivation relative to the fast inactivating K+ channels Kv3.4 and Kv1.4. The rate of Kv3.3 inactivation has, however, been difficult to establish given problems in obtaining consistent rates of inactivation in expression systems. This study characterized the properties of AptKv3.3, the teleost homologue of Kv3.3, when expressed in Chinese hamster ovary (CHO) or human embryonic kidney (HEK) cells. We show that the properties of AptKv3.3 differ significantly between CHO and HEK cells, with the largest difference occurring in the rate and voltage dependence of inactivation. While AptKv3.3 in CHO cells showed a fast and voltage-dependent rate of inactivation consistent with N-type inactivation, currents in HEK cells showed rates of inactivation that were voltage-independent and more consistent with a slower C-type inactivation. Examination of the mRNA sequence revealed that the first methionine start site had a weak Kozak consensus sequence, suggesting that the lack of inactivation in HEK cells could be due to translation at a second methionine start site downstream of the NH2-terminal coding region. Mutating the nucleotide sequence surrounding the first methionine start site to one more closely resembling a Kozak consensus sequence produced currents that inactivated with a fast and voltage-dependent rate of inactivation in both CHO and HEK cells. These results indicate that under the appropriate conditions Kv3.3 channels can exhibit fast and reliable inactivation that approaches that more typically expected of "A"-type K+ currents.


Laser resurfacing.
In a society desiring images of beauty and youthfulness, the world of cutaneous surgery offers the gifts of facial rejuvenation for those determined to combat the signs of aging. With the development of novel laser and plasma technology, pigmentary changes, scarring, and wrinkles can be conquered providing smoother, healthier, younger-looking skin. This review highlights five of the most popular resurfacing technologies in practice today including the carbon dioxide (CO(2)) laser, the erbium:yttrium-aluminum-garnet (Er:YAG) laser, combination resurfacing, fractional photothermolysis, and plasma resurfacing.


Microfluidic development and biological evaluation of targeted therapy-loaded biomimetic nano system to improve the metastatic melanoma treatment.
Optimizing current therapies is among next steps in metastatic melanoma (MM) treatment landscape. The innovation of this study is the design of production process by microfluidics of cell membrane (CM)-modified nanoparticles (NPs), as an emerging biomimetic platform that allows for reduced immune clearance, long blood circulation time and improved specific tumor targeting. To achieve melanoma selectivity, direct membrane fusion between synthetic liposomes and CMs extracted from MM cell line was performed by microfluidic sonication approach, then the hybrid liposomes were loaded with cobimetinib (Cob) or lenvatinib (Lenva) targeting agents and challenged against MM cell lines and liver cancer cell line to evaluate homotypic targeting and antitumor efficacy. Characterization studies demonstrated the effective fusion of CM with liposome and the high encapsulation efficiency of both drugs, showing the proficiency of microfluidic-based production. By studying the targeting of melanoma cells by hybrid liposomes versus liposomes, we found that both NPs entered cells through endocytosis, whereas the former showed higher selectivity for MM cells from which CM was extracted, with 8-fold higher cellular uptake than liposomes. Hybrid liposome formulation of Cob and Lenva reduced melanoma cells viability to a greater extent than liposomes and free drug and, notably, showed negligible toxicity as demonstrated by bona fide haemolysis test. The CM-modified NPs presented here have the potential to broaden the choice of therapeutic options in MM treatment.


Subdivision of the T1 size descriptor for stage I non-small cell lung cancer has prognostic value: a single institution experience.
Non-small cell lung cancer (NSCLC) staging is currently being revised by the International Association for the Study of Lung Cancer (IASLC). Among other changes, the revised staging system proposes the subdivision of the T1 tumor (<or= 3 cm) category into the following two subgroups: T1a (<or= 2 cm); and T1b (> 2 cm but <or= 3 cm). This study investigated the prognostic differences between patients in these two T1 tumor subgroups. A total of 291 patients with stage IA (T1N0M0) NSCLC who had undergone surgical resection between January 1, 1991, and December 31, 2004, were identified by the cancer registry. The mean and median follow-up times were 62 and 54 months, respectively. The patients were subdivided into T1a and T1b groups. Overall survival (OS) as well as disease-free survival (DFS) periods were determined by retrospective chart review and compared for statistical significance. Patient-specific and disease-specific information was recorded in order to identify possible confounding variables. When patients were subdivided into T1a (n = 193) and T1b (n = 98) groups, significant differences were observed in both OS (p = .023) and DFS (p = .014). No statistically significant difference was detected in the mean age, pack-year smoking history, or percent predicted FVC or FEV(1) between the T1a and T1b groups. In addition, there was no statistically significant difference in the type of surgery or nodal staging performed on the patients in the two groups. The T1 descriptor should be subdivided at 2 cm to reflect the observed prognostic differences. Our findings agree with the new staging system proposed by the IASLC, revealing its profound applicability to individual institutions.


Ultrastructure and function of isolated myocytes after calcium depletion and repletion.
We describe a system in which the contractile response of a single isolated Ca-tolerant rat myocyte can be monitored while stimulated in Ca-free (37 degrees C) and then Ca-containing medium. This same cell is then processed for ultrastructural analysis. We find unattached isolated Ca-tolerant myocytes can withstand Ca depletion and repletion. They respond to stimulation after Ca repletion with healthy twitches and are structurally intact. The cell surface of the isolated myocyte appears similar to that seen in the intact myocytes even after 15 min in Ca-free solution. This is in marked contrast to myocardial cells in tissue where Ca depletion causes separation of the layers of the glycocalyx. When the cell is attached to a fine pipette so that some of the sarcolemma is under stress, the sequence of Ca depletion and repletion drives the cell into hypercontracture and loss of structural integrity that is characteristic of the Ca paradox.


Interference of moonlight with the photoperiodic measurement of time by plants, and their adaptive reaction.
Threshold values of photoperiodic time-measurements correspond approximately to moonlight intensities. Experiments with Glycine and Euglena reveal that this is also the threshold value for synchronization of the circadian cycle. Saturation of this reaction is reached with 10 lx in 12:12 hr light-dark cycles. Thus, moonlight might disturb time measurement.In Glycine, Arachis, and Trifolium the intensity of the light coming from the moon to the upper surface of the leaf is reduced by circadian leaf movement to values between 5 and 20 per cent (or even less than 5 per cent) of full-moon light intensity. Such a reduction eliminates the disturbing effects of moonlight. This finding indicates that leaf movements have an adaptive value of the kind that Darwin sought to identify. It also indicates that the behavior of the upper leaf epidermis as a "sense organ for light"(13) has an adaptive value.In the short-day plants Perilla ocymoides and Chenopodium amaranticolor, a specific photoperiodic phenomenon was found that counteracts the disturbing effect of moonlight. Here light intensities similar to those of moonlight, introduced during the night, promote flowering instead of inhibiting it.


The gramicidin A transmembrane channel: a proposed pi(L,D) helix.
A lipophilic, left-handed helical structure is proposed for gramicidin A in which the C-O bonds alternately point toward the amino and carboxyl ends; it is a hybrid of the 4.3(14) and 4.4(16) helices. The C-O groups pointing toward the carboxyl end form part of 16-membered hydrogen-bonded rings, whereas the C-O moieties pointing toward the amino end form 14-membered hydrogenbonded rings. The proposed structure is based on conformational analysis combined with requirements for the gramicidin A transmembrane channel. Two helices combine to form the channel. The alternating C-O directions allow hydrogen-bonded dimerization by the unique possibilities of head-to-head and tail-to-tail attachment. The formyl group at the amino end allows for a favorable head-to-head attachment with no loss of structural continuity. Unpublished studies. by M. C. Goodall on the lipid bilayer conductance of deformyl gramicidin A strongly argue for head-to-head attachment. Such hydrogen-bonded association is not possible with previously described helices, as the C-O groups all point in the same direction. In relation to possible pi((L,D)) helices in mammalian systems, it should be noted that glycines would fill the role of D residues. The conformation can undergo ion-induced relaxations, which provide approximate tetrahedral coordination for the ion, with facile shifting of coordinations. The ready exchange of coordinations provides the mechanism for movement of the ion along the channel. Conceivably, such transmembrane channels could have application as models for ion transport across biological membranes-an application which may be as great as, or greater than, that of carriers such as valinomycin and nonactin. Specifically, biogenic amines and drugs containing aromatic groups could control access to the channel by interactions with the two tryptophan residues at the ethanolamine end and with the negative region provided by the three oxygens.


Assessment of polychlorinated biphenyls and polybrominated diphenyl ethers in Tibetan butter.
The Tibetan plateau is considered a potential cold trap for persistent organic pollutants (POPs) and plays an important role in the global long-range transport of these compounds. This present work surveyed the concentrations of polychlorinated biphenyl (PCBs) and polybrominated diphenyl ethers (PBDEs) in Tibetan butter samples collected from different prefectures in Tibet autonomous region (TAR). summation operator(25)PCB concentrations ranged from 137 to 2518 pg g(-1) with a mean value 519 pg g(-1), which were far lower than those in the butter from other regions in the world. The highest level was found in butter from Sichuan province, which is located to the east of the Tibetan plateau and the lowest value was in samples from southeast TAR. The average concentration of summation Sigma(12)PBDE was 125 pg g(-1). The sample with highest and lowest summation Sigma(12)PBDE concentration (955 and 18.0 pg g(-1)) was from the south and southeast part of the plateau, respectively. Back trajectory model implied that the sources of these two groups of POPs were by atmospheric deposition in south, whereas the western plateau was mainly influenced by the tropical monsoon from south Asia. Air currents from Sichuan and Gansu province are further responsible for the atmospheric transport of PCBs and PBDEs to the eastern and northern side of the plateau. Local air concentrations of summation Sigma(5)PCBs predicted using air-milk transfer factor were at the lower end of published global levels.


Aboriginal dental assistants can safely apply fluoride varnish in regional, rural and remote primary schools in New South Wales, Australia.
There are significant inequalities in oral health status between Aboriginal and non-Aboriginal children in Australia, particularly where the children have insufficient access to various forms of fluoride. There has been a growing interest in seeing fluoride varnish programs used more widely for Aboriginal children due to proven effectiveness. Despite this, there has been limited scale-up of these programs in Australia. This study investigates the feasibility of using Aboriginal dental assistants to provide regular fluoride varnish applications for Aboriginal children in the primary school setting. A mixed-methods approach including auditing the number of Aboriginal dental assistants were trained and then approved by the NSW Chief Health Officer to apply fluoride varnish, and collection and reporting of participant data on the each of the fluoride varnish days in the local patient management system. Six Aboriginal Community Controlled Health Services from regional NSW were invited to participate in the study. They also nominated a primary school and an Aboriginal dental assistant to participate in the study. Data were obtained from four 'fluoride varnish days' held at the schools over a 12-month period between December 2017 and December 2018. The number of Aboriginal dental assistants were trained and then approved by the NSW Chief Health Officer to apply fluoride varnish is also reported. In total, 8 Aboriginal dental assistants were trained to apply fluoride varnish during the study. Overall, students participating in the study received three or more fluoride varnish applications. Results showed that Aboriginal dental assistants are able to safely and effectively apply fluoride varnish in a school setting with remote supervision. This program can be scaled at the state level in NSW, and this could provide the basis for a nationally consistent program. Initial discussions have been held with several jurisdictions to lead this process via the Australian Health Ministers Advisory Council (AHMAC) based on the results of this study and the support of key stakeholders. The Poche Centre as part of its scale-up planning for the Fluoride Varnish Program is examining the feasibility of including the apply fluoride varnish skillset in its existing Aboriginal Dental Assistant Scholarship Program.


The Antioxidant Activities of Natural Polysaccharides.
The natural polysaccharides contain plant polysaccharides, animal polysaccharides and microbial polysaccharides. They are a kind of biological macromolecules with immune regulation, anti-tumor, anti-radiation, anti-inflammation, anti-fatigue and anti-aging effects. These effects are related to their antioxidant properties. The action mechanisms of antioxidation and scavenging free radicals for natural polysaccharides were reviewed. The recent research progresses and our work on antioxidant properties of polysaccharides and their derivatives were summarized. At last, the existing problems of antioxidant polysaccharides were analyzed, and the development prospects were also presented. It is important to study the antioxidant activities of polysaccharides and their derivatives for the development of natural antioxidants.


Childhood sexual abuse, HPA axis regulation, and mental health: an integrative review.
Adults who experienced childhood sexual abuse (CSA) are at increased risk for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Animal studies suggest that dysregulated biological stress systems are a potential mechanism, but there are multiple challenges involved in conducting translational studies in humans. The purpose of this integrative literature review was to determine the state of the science of hypothalamic-pituitary-adrenal (HPA) axis regulation in adults who experienced CSA, with a focus on the health outcomes of MDD and PTSD. A variety of methods for HPA axis measurement were used in the 10 reviewed studies. The results suggested that changes in HPA axis regulation are present in many adults who experienced CSA-with and without a current MDD or PTSD diagnosis. Further research is needed to verify these findings. The review results can help researchers determine research strategies that will optimize scarce subject and financial resources.


Accelerated landfill waste decomposition by external leachate recirculation from an old landfill cell.
This research is focused on the management of moisture regime for a young landfill site in terms of leachate recirculation which entails the containment, collection and reinjection of leachate back into the landfill to promote in situ anaerobic biological treatment. Moreover, an innovative leachate management strategy was developed by using leachate recirculation from a mature landfill site into a young landfill site to provide accelerated waste stabilization. For this purpose, two reactors simulating young and old landfills were used in the laboratory. These reactors were loaded with shredded and compacted municipal solid waste with a typical composition determined for Istanbul Region. Both reactors were operated in a constant temperature room at 32 degrees C to enhance the growth of anaerobic microorganisms. Moreover, water was added to the reactors in order to simulate the annual rainfall. The reactor having the properties of old landfills was used as a control reactor. The reactor which represented the characteristics of young landfill was operated under four operational stages to enhance the activity of methanogenic population and accelerate waste stabilization. Results of this study indicated that the utilization of leachate recirculation enhanced waste stabilization in the young landfill by increasing the uniformity, and providing additional substrate and nutrients. Additions of buffer solutions of KOH and Na2CO3 together with leachate recirculation enhanced further waste stabilization and prevented possible acid inhibition. The utilization of external leachate recycled from the old landfill having desired acclimated anaerobic microorganisms, low organic content and higher buffer capacity into a young landfill could be a promising leachate management strategy for faster and controlled waste stabilization.


[The effect of highly intensive irradiation on the functional status of the brain in monkeys].
In experiments with Macaca fascicularis a study was made of early manifestations of the central nervous system (CNS) disturbances caused by exposure to 24 MeV electrons (45 Gy). The results obtained permit us to distinguish two main ways (stereotypes) by which a clinical picture of early postirradiation period develops: "comatose" and "non-comatose". A general clinical characteristic of each stereotype and stages of their development are presented. The postirradiation disturbances of nervous and psychic activity of monkeys are considered within the framework of the concept concerning acute reactions of exogenous type. It is suggested that the course of the early postirradiation period is conditioned by the "involvement" of some phylogenetically determined, universal systemic mechanisms of the CNS response to external harmful effects.


Rift Valley fever, Sudan, 2007 and 2010.
To elucidate whether Rift Valley fever virus (RVFV) diversity in Sudan resulted from multiple introductions or from acquired changes over time from 1 introduction event, we generated complete genome sequences from RVFV strains detected during the 2007 and 2010 outbreaks. Phylogenetic analyses of small, medium, and large RNA segment sequences indicated several genetic RVFV variants were circulating in Sudan, which all grouped into Kenya-1 or Kenya-2 sublineages from the 2006-2008 eastern Africa epizootic. Bayesian analysis of sequence differences estimated that diversity among the 2007 and 2010 Sudan RVFV variants shared a most recent common ancestor circa 1996. The data suggest multiple introductions of RVFV into Sudan as part of sweeping epizootics from eastern Africa. The sequences indicate recent movement of RVFV and support the need for surveillance to recognize when and where RVFV circulates between epidemics, which can make data from prediction tools easier to interpret and preventive measures easier to direct toward high-risk areas.


Super-tough and thermo-healable hydrogel - promising for shape-memory absorbent fiber.
Recoverable hydrogels with high stretch and toughness have been synthesized by a one-step radical polymerization. They consist of covalently crosslinked polyacrylamide (PAAm) and ionically crosslinked carrageenan. Such double network (DN) hydrogels can be stretched beyond 20 times their initial length, and their fracture energy reached a high value of ∼9500 J m-2. By comparing hydrogel tensile properties at different temperatures, the contribution of ionic network to the toughness was quantitatively determined in percentage for the first time. The stretched hydrogels were completely healed by short treatment at a mild temperature. Through drying at stretch, they were also transformed into stiff absorbent fibers that still preserved their shape memory of wet state.


Linoleic acid: a natural feed compound against porcine epidemic diarrhea disease.
Porcine epidemic diarrhea virus (PEDV) is a pig coronavirus that causes severe diarrhea and high mortality in piglets, but as no effective drugs are available, this virus threatens the pig industry. Here, we found that the intestinal contents of specific pathogen-free pigs effectively blocked PEDV invasion. Through proteomic and metabolic analyses of the intestinal contents, we screened 10 metabolites to investigate their function and found that linoleic acid (LA) significantly inhibited PEDV replication. Further investigations revealed that LA inhibited viral replication and release mainly by binding with PEDV NSP5 to regulate the PI3K pathway and, in particular, inhibiting AKT phosphorylation. In vivo experiments illustrated that orally administered LA protected pigs from PEDV challenge and severe diarrhea. These findings provide strong support for exploring antiviral drugs for coronavirus treatment.


Putative neuroendocrine cells in the Aplysia cerebral ganglion.
We report on a special population of cells in the Aplysia cerebral ganglion that are characterized by several features compatible with neuroendocrine function. These cells can be recognized in living ganglia by their small size, white color and their typical distribution as a compact cluster in the central medial region of the dorsal ganglion surface. Upon intracellular recording, these cells generate action potentials of relatively long duration (about 25 ms), as compared with the faster action potentials of larger white cells or of non-white cells (about 4 ms). Intracellular injection of the small white cells with Lucifer yellow after recording revealed a dual projection area: single cells have one process which branches extensively into many varicose terminals as it courses through the neuropil, and then sends varicose terminals to the vascular sheath at the periphery of the ganglion. In cryostat sections, these cells were specifically characterized by their content of large granules, the staining characteristics of which distinguish them from lipochondria or lysosomes. Their ability to bind fluorochromes nonspecifically is of particular importance for the interpretation of histochemical localization studies based on immunofluorescence techniques.


Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension.
Decreased total compliance of the pulmonary vascular bed is associated with increased mortality in patients with pulmonary arterial hypertension (PAH). We investigated whether proximal pulmonary artery stiffness, in terms of area distensibility and noninvasively assessed relative area change (RAC), calculated as relative cross-sectional area change, predicts mortality in patients with PAH. Eighty-six subjects underwent right-heart catheterization and MRI to assess area distensibility and RAC. Patients were followed up to 48 months. Kaplan-Meier plot and Cox proportional hazards regression analyses assessed the predictive value of area distensibility and RAC. In 70 patients, the diagnosis PAH was confirmed, and 16 subjects served as control subjects. In comparison with control subjects, proximal pulmonary arteries of patients were distended (685 +/- 214 mm2 vs 411 +/- 153 mm2, p < 0.001), less distensible (area distensibility = 0.46 +/- 0.38.10(-2) mm Hg(-1) vs 3.69 +/- 1.96.10(-2) mm Hg(-1), p < 0.0001), and RAC was smaller (20 +/- 10% vs 58 +/- 21%, p < 0.0001) [mean +/- SD]. RAC showed an inverse curvilinear relation with mean pulmonary artery pressure (R2 = 0.47). Eighteen patients (26%) died because of cardiopulmonary causes. Patients with a pulmonary artery RAC <or= 16% had a worse prognosis than those with a value > 16% (log-rank p < 0.001). RAC predicted mortality better than area distensibility. Noninvasively measured pulmonary artery RAC predicts mortality in patients with PAH.


Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs.
The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.


A Comparison of Robotic Versus Laparoscopic Adrenalectomy in Patients With Primary Hyperaldosteronism.
Over the last decade, robotic approaches have been described for removing adrenal tumors. Although there are reports comparing robotic and laparoscopic techniques in general, there are limited data on outcomes in patients with primary hyperaldosteronism (PHA). The aim of this study is to compare the safety and efficacy of robotic adrenalectomy (RA) versus laparoscopic adrenalectomy (LA) for PHA. The records of 20 patients who underwent RA for PHA were compared with 16 patients who underwent LA between 2000 and 2014. Data were retrospectively reviewed from a prospectively maintained, IRB-approved adrenal database. Statistical analysis was performed using t test and the Fisher exact analysis. Continuous variables are reported as mean±SEM. Demographic and clinical parameters were similar between the groups. There were no conversions to open in either group. Estimated blood loss, length of stay, and complication rates were comparable. Operative time was shorter in the robotic versus laparoscopic group (130±8.94 vs. 159±11.1 min, P=0.0487). In follow-up, the improvement in patients' blood pressure after adrenalectomy, as assessed by the reduction in the number of antihypertensive medications, was similar between the 2 groups. However, 1 patient in the RA and 1 patient in the LA group were not cured, as determined by postoperative aldosterone:renin levels. The biochemical cure rate between the groups was similar (P=0.529). To our knowledge, this is the first study comparing robotic versus laparoscopic resection of PHA. Our results show that the robotic approach was similar to laparoscopic regarding safety and efficacy. Operative time was shorter with the robotic approach, which could be related to more efficient dissection with wristed instrumentation.


Palaeoecology of the Hiraiso Formation (Miyagi Prefecture, Japan) and implications for the recovery following the end-Permian mass extinction.
The Hiraiso Formation of northeast Japan represents an important and under-explored archive of Early Triassic marine ecosystems. Here, we present a palaeoecological analysis of its benthic faunas in order to explore the temporal and spatial variations of diversity, ecological structure and taxonomic composition. In addition, we utilise redox proxies to make inferences about the redox state of the depositional environments. We then use this data to explore the pace of recovery in the Early Triassic, and the habitable zone hypothesis, where wave aerated marine environments are thought to represent an oxygenated refuge. The age of the Hiraiso Formation is equivocal due to the lack of key biostratigraphical index fossils, but new ammonoid finds in this study support an early Spathian age. The ichnofossils from the Hiraiso Formation show an onshore-offshore trend with high diversity and relatively large faunas in offshore transition settings and a low diversity of small ichnofossils in basinal settings. The body fossils do not, however, record either spatial or temporal changes, because the shell beds represent allochthonous assemblages due to wave reworking. The dominance of small burrow sizes, presence of key taxa including Thalassinoides, Rhizocorallium and Holocrinus, presence of complex trace fossils, and both erect and deep infaunal tiering organisms suggests that the benthic fauna represents an advanced stage of ecological recovery for the Early Triassic, but not full recovery. The ecological state suggests a similar level of ecological complexity to late Griesbachian and Spathian communities elsewhere, with the Spathian marking a globally important stage of recovery following the mass extinction. The onshore-offshore distribution of the benthic faunas supports the habitable zone hypothesis. This gradient is, however, also consistent with onshore-offshore ecological gradients known to be controlled by oxygen gradients in modern tropical and subtropical settings. This suggests that the habitable zone is not an oxygenated refuge that is only restricted to anoxic events. The lack of observed full recovery is likely a consequence of a persistent oxygen-limitation (dysoxic conditions), hot Early Triassic temperatures and the lack of a steep temperature/water-depth gradient within the habitable zone.


Enzyme activity demonstrates multiple pathways of innate immunity in Indo-Pacific anthozoans.
Coral reefs are threatened by increasing levels of coral disease and the functional loss of obligate algal symbionts (bleaching). Levels of immunity relate directly to susceptibility to these threats; however, our understanding of fundamental aspects of coral immunology is lacking. We show that three melanin-synthesis pathway components (mono-phenoloxidase, ortho-diphenoloxidase (tyrosinase-type pathway) and para-diphenoloxidase (laccase-type pathway)) are present in both their active (phenoloxidase, PO) and inactive (prophenoloxidase, PPO) forms across a diverse range of 22 species of healthy Indo-Pacific anthozoans. We also demonstrate transglutaminase activity of the coagulation cascade for, to our knowledge, the first time in a coral. Melanin-synthesis enzyme activities varied among taxa, although they were generally lowest in the coral family Acroporidae and highest in the Poritidae and Oculinidae. Inactive tyrosinase-type activity (PPO) and active laccase-type activity (PO) correlate with taxonomic patterns in disease resistance, whereas the converse pattern in activity levels correlates with bleaching resistance. Overall, we demonstrate the presence of several melanin-synthesis pathways in Indo-Pacific corals, co-regulation among some pathway components, and highlight their potential roles in coral health.


Electron-Equivalent Valency through Molecularly Well-Defined Multivalent DNA.
Oligonucleotide-functionalized nanoparticles (NPs), also known as "programmable atom equivalents" (PAEs), have emerged as a class of versatile building blocks for generating colloidal crystals with tailorable structures and properties. Recent studies have shown that, at small size and low DNA grafting density, PAEs can also behave as "electron equivalents" (EEs), roaming through and stabilizing a complementary PAE sublattice. However, it has been challenging to obtain a detailed understanding of EE-PAE interactions and the underlying colloidal metallicity because there is inherent polydispersity in the number of DNA strands on the surfaces of these NPs; thus, the structural uniformity and tailorability of NP-based EEs are somewhat limited. Herein, we report a strategy for synthesizing colloidal crystals where the EEs are templated by small molecules, instead of NPs, and functionalized with a precise number of DNA strands. When these molecularly precise EEs are assembled with complementary NP-based PAEs, X-ray scattering and electron microscopy reveal the formation of three distinct "metallic" phases. Importantly, we show that the thermal stability of these crystals is dependent on the number of sticky ends per EE, while lattice symmetry is controlled by the number and orientation of EE sticky ends on the PAEs. Taken together, this work introduces the notion that, unlike conventional electrons, EEs that are molecular in origin can have a defined valency that can be used to influence and guide specific phase formation.


Human-induced pluripotent stem cells as a model for studying sporadic Alzheimer's disease.
The discovery of induced pluripotent stem cell (iPSC) technology has the potential to accelerate scientific research for Alzheimer's disease (AD). iPSCs are therefore increasingly considered for AD modeling and drug development. Nevertheless, most of the work conducted so far has mainly focused on iPSC models from patients with familial AD (fAD), while actually sporadic AD (sAD) is more prevalent and represents over 90% of the AD cases in the population. The development of more sAD models is therefore key for studying this multifactorial disorder. In fact, probing the unique genomes of sAD patients and their interaction with AD-associated environmental factors could contribute to a better understanding of this disease. However, initial iPSC-based models for sAD have shown a high degree of variability and inconsistencies in terms of AD hallmarks. In this review, we provide an overview of the studies that have been conducted for sAD so far. In addition, we critically assess important sources of variability related to the model in addition to those that might be explained by the heterogeneous nature of sAD. These considerations might aid in developing more consistent iPSC models of sAD, which could help in developing a better understanding of the molecular mechanisms underlying the disease.


Effects of oophorectomy and hormone replacement therapy on the pulsatility indices of hepatic and renal arteries.
To investigate the flow velocity waveform changes of the hepatic and renal arteries in women with surgical menopause who received hormone replacement therapy versus those who did not. Eighty women who had undergone surgical menopause were divided into 2 groups. The first group (n = 38) consisted of patients who did not receive estrogen treatments after surgery; patients in the second group (n = 42) did receive treatments. The hepatic and renal arteries of patients in both groups were examined by duplex Doppler ultrasonography before the commencement of hormone replacement therapy and after 2 years of treatment, and the pulsatility indices were calculated. No significant differences were detected in the renal and hepatic artery pulsatility indices of patients in the estrogen treatment group (group 2) before and after total abdominal hysterectomy and bilateral salpingo-oophorectomy (P > .05). No significant differences in preoperative and postoperative hepatic arterial pulsatility indices were detected among patients in group 1 (P > .05). Renal artery pulsatility indices measured before and after total abdominal hysterectomy and bilateral salpingooophorectomy did show a statistically significant difference in group 1 (P < .001). In addition, a statistically significant difference was detected before and after surgery in both groups when pulsatility indices were measured at the second-year control dose. Hepatic arterial pulsatility indices are not affected in postmenopausal women, but renal artery pulsatility indices rise to some extent in women not receiving hormone replacement therapy.


Immobilized imidazolium-based ionic liquids in C18 for solid-phase extraction.
In this work, two solid-phases based on imidazolium-based ionic liquids were obtained and characterized for solid-phase extraction of fluoroquinolones. The process of immobilization was performed replacing a toxic reagent by UV-irradiation to get a harmless process. The obtained solid-phases were characterized by nuclear magnetic resonance spectroscopy and elemental analysis. Each solid-phase was packed in a cartridge and was used in solid-phase extraction processes for norfloxacin and ciprofloxacin, after the optimization of some parameters such as the elution solvent, the eluent volume and, the sample volume to be used during the loading step. The developed solid-phases with immobilized ionic liquids were successfully implemented for the studied compounds and indicate high probabilities to be useful in solid-phase extractions of other fluoroquinolones.


[Preventable tuberculosis cases in Japan--a new approach to the assessment of tuberculosis control problems].
I defined cases of tuberculosis which could not be prevented from infection or development of disease among infected, or could not be detected in the early stages as "preventable cases" in order to evaluate tuberculosis control efforts in the community, Japan. Among 241 bacteriologically confirmed cases with pulmonary tuberculosis newly registered from 1988 through 1989 in Yamagata Prefecture, 80 (33%) were defined as preventable cases by observing their course and the process of diagnosis. That is to say, one-third of bacillary cases could have been prevented in Yamagata where the incidence of tuberculosis was lowest in Japan, if existing prevention and control methods had been effectively used. Causes of prevention failure were investigated in detail. The most common cause was tardy detection of cases, especially due to delayed confirmation of diagnosis (so called "doctor's delay"). The delayed confirmation of diagnosis resulted from neglecting chest X-ray and sputum examination and from ignoring high risk groups. In the younger age group, it was mainly attributed to insufficient family contact examinations. Tuberculin skin tests are necessary not only for those aged 15 years and younger but also for those aged 16-29, when they are found to be household contacts of smear-positive cases. An evaluation of tuberculosis control program defining preventable cases would be a beneficial approach to the surveillance of tuberculosis.


Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis.
Many important physiological and pathological processes are modulated by angiogenesis. It has been shown that initiation of this angiogenic process is an essential early step in the progression of malignant tumors. We report here that ablation of peripheral dopaminergic nerves markedly increased angiogenesis, microvessel density, microvascular permeability, and growth of malignant tumors in mice. Endogenous peripheral dopamine acted through D2 receptors as significantly more angiogenesis and tumor growth was observed in D2 dopamine receptor knockout mice in comparison with controls. The vascular endothelial growth factor receptor 2 phosphorylation, which is critical for promoting angiogenesis, was also significantly more in tumor endothelial cells collected from the dopamine-depleted and D2 dopamine receptor knockout animals. These results reveal that peripheral endogenous neurotransmitter dopamine might be an important physiological regulator of vascular endothelial growth factor-mediated tumor angiogenesis and growth and suggest a novel link between endogenous dopamine, angiogenesis, and tumor growth.


Screening for dementia: a review of self- and informant-assessment instruments.
The objective of this study was to review available dementia screening instruments that could be recommended for self-administration, particularly in electronic format. Owing to the gradual loss of insight associated with the progression of dementia, a broad definition of self-administration including self-administration by concerned informants (family, friends, carers) was used. A systematic search of PubMed, PsychINFO, and the Cochrane Library Database was conducted. Only available full-text articles about dementia screening instruments written in English were included. Articles reporting on instruments used in a non-English context were excluded unless a validated English version of the instrument was available. Included instruments were assessed against the precise criteria and characteristics of the Mini-mental State Examination (MMSE), the most widely used screening instrument. The Concord Informant Dementia Scale (CIDS) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were the only instruments meeting all selection criteria. The Memory Impairment Screen (MIS) also met the criteria, although it lacks validation for self-administration. No instrument has been validated for self-administration in electronic format. It is recommended that the MIS, the CIDS and the IQCODE be validated for self-administration in electronic format.


Correlation between improvement in visual acuity and QOL after Ranibizumab treatment for age-related macular degeneration patients: QUATRO study.
To evaluate the correlation between visual acuity improvement and vision-related QOL after ranibizumab treatment in Japanese patients with AMD. In this one-year prospective, interventional, open-label, multicenter study involving four sites, patients with neovascular AMD were enrolled and observed for 12 months. Treatment-naïve patients received 0.5 mg ranibizumab as needed after three initial monthly doses. The best corrected visual acuity (BCVA) and central macular thickness (CMT) were measured at every visit. Evaluations with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and patient satisfaction questionnaire were performed at baseline and 3 and 12 months after initial treatment. The primary endpoint was change in BCVA and QOL 3 months after ranibizumab treatment. QOL outcomes were also assessed in the better and poor BVCA subgroups. The study enrolled 100 patients. The mean logMAR BCVA after treatment improved significantly from 0.43 to 0.30 at 3 months (p< 0.0001), and 0.28 at 12 months (p< 0.0001). The mean NEI-VFQ-25 composite scores improved from 79.48 to 84.13 at 3 months (p< 0.0001), and 86.0 at 12 months (p< 0.0001). The 3 and 12-month changes in NEI-VFQ-25 score and BCVA showed significant correlation. In the poor baseline visual acuity group (decimal BCVA ≤0.5), there was a significant correlation between the changes in the NEI-VFQ-25 score and BCVA (p=0.02) but not in the better baseline visual acuity group (decimal BCVA > 0.6, p=0.1) at 3 months. There were no significant differences in the satisfaction questionnaire score from baseline to at 3 months (p=0.54) and 12 months (p=0.23). The average CMT improved significantly from 340 to 264 μm at 3 months (p< 0.0001) and to 268 μm at 12 months (p< 0.0001). Intravitreal ranibizumab treatment resulted in improvement in visual acuity, anatomical change, and visual function change in Japanese AMD patients. Significant improvement was seen in patient visual function, and this was correlated with changes in VA, except immediately after loading dose treatment in patients with higher baseline VA. The patients' satisfaction with the treatment remained unchanged during the study period. This study is registered at UMIN Clinical Trials Registry ( UMIN000012013 ). Registered October 10, 2013, as prospective study.


Endothelin ETA receptor regulates signaling and ANF gene expression via multiple G protein-linked pathways.
We have characterized the interaction of endothelin (ET) with cultured neonatal rat ventricular myocytes. Binding studies indicate a single population of ETA receptors [53,000 sites/cell, apparent dissociation constant (Kd) for ET-1 approximately 0.07 nM]. Analysis of mRNA levels for ET receptors using 35 cycles of reverse transcriptase-polymerase chain reaction demonstrates the presence of only ETA-receptor message. Studies with ET-1 and a variety of congeners and antagonists indicate that ETA receptors couple to both the stimulation of phosphoinositide turnover and the inhibition of adenylyl cyclase. In myocytes transfected with an atrial natriuretic factor (ANF) promoter linked to a luciferase reporter gene, ET-1 stimulates luciferase expression through an ETA receptor. These data indicate that the ETA receptor is the exclusive receptor on neonatal ventricular myocytes and that this receptor couples to both phosphoinositide hydrolysis and adenylyl cyclase. ET-1 also induces a threefold increase in mitogen-activated protein kinase (MAPK) activity, an effect that is not sensitive to pertussis toxin (PTx). By contrast, ET-stimulated ANF-luciferase expression is partially inhibited by treatment of cells with PTx, suggesting that both PTx-sensitive (Gi) and PTx-insensitive (Gq) pathways mediate the effects of ET-1 on ANF gene expression in neonatal myocytes and that hormonal regulation of ANF expression may utilize pathways in addition to the activation of MAPK.


Patient and Therapeutic Profiles of Pulmonary Hypertension in Chronic Lung Diseases in Japan: A Cohort Study Using a Claims Database.
Pulmonary hypertension (PH) is often complicated by chronic lung diseases (CLDs) such as chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Differentiating between PH associated with CLD (group 3 PH) and pulmonary arterial hypertension (PAH) in CLD is often difficult and reporting on the efficacy of PAH-specific therapies is inconsistent as a result of the lack of understanding of the heterogeneity of patients with PH. A retrospective observational cohort study was conducted to understand the baseline characteristics, comorbidities, and treatment profiles of patients with PH in CLD in a real-world setting using a large-scale claims database (Medical Data Vision). Administrative and clinical data for patients admitted to acute-care hospitals in Japan between April 2008 and January 2021 were analyzed. A total of 115,921 patients with CLD (109,578 with COPD and 6343 with ILD, of whom 569 and 176 had PH, respectively) were analyzed. This study found lower PH diagnosis rates among patients with COPD and patients with ILD than in previous studies. The majority of PH with CLD patients were elderly (mean age 75.7 years) and male (80.81%). Among patients with CLD prescribed PAH-specific therapies (105 patients with COPD; 64 patients with ILD), most received these as monotherapy (COPD, 84.76%; ILD, 75.56%); the most common were phosphodiesterase 5 inhibitors (COPD, 42.70%; ILD, 18.37%), prostacyclins (oral; COPD, 48.31%; ILD, 24.49%), and endothelin receptor antagonists (ERA) (COPD, 8.99%; ILD, 18.37%). Comorbidities (e.g., pulmonary, cardiac, kidney), home oxygen therapy (HOT), and echocardiography (ECHO) were factors associated with the diagnosis of PH. This is the first study using an administrative database that provides real-world data on patients with PH in CLD in Japan. Our results indicate that PH may be misdiagnosed or underdiagnosed in Japan which may lead to suboptimal treatment for patients, and supports the need for further evidence to guide appropriate treatment.


The excess light energy that is neither utilized in photosynthesis nor dissipated by photoprotective mechanisms determines the rate of photoinactivation in photosystem II.
Photoinactivation of PSII is thought to be caused by the excessive light energy that is neither used for photosynthetic electron transport nor dissipated as heat. However, the relationship between the photoinactivation rate and excess energy has not been quantitatively evaluated. Chenopodium album L. plants grown under high-light and high-nitrogen (HL-HN) conditions show higher tolerance to photoinactivation and have higher photosynthetic capacity than the high-light and low-nitrogen (HL-LN)- and low-light and high-nitrogen (LL-HN)-grown plants. The rate of photoinactivation in the LL-HN plants was faster than that in the HL-LN, which was similar to that in the HL-HN plants, while the LL-HN and HL-LN plants had similar photosynthetic capacities [Kato et al. (2002b) Funct. Plant Biol. 29: 787]. We quantified partitioning of light energy between the electron transport and heat dissipation at the light intensities ranging from 300 to 1,800 micromol m(-2) s(-1). The maximum electron transport rate was highest in the HL-HN plants, heat dissipation was greatest in the HL-LN plants, and the excess energy, which was neither consumed for electron transport nor dissipated as heat, was greatest in the LL-HN plants. The first-order rate constant of the PSII photoinactivation was proportional to the magnitude of excess energy, with a single proportional constant for all the plants, irrespective of their growth conditions. Thus the excess energy primarily determines the rate of PSII photoinactivation. A large photosynthetic capacity in the HL-HN plants and a large heat dissipation capacity in the HL-LN plants both contribute to the protection of PSII against photoinactivation.


The Effect of 2 Forms of Talocrural Joint Traction on Dorsiflexion Range of Motion and Postural Control in Those With Chronic Ankle Instability.
Talocrural joint mobilizations are commonly used to address deficits associated with chronic ankle instability (CAI). Examine the immediate effects of talocrural joint traction in those with CAI. Blinded, crossover. Laboratory. Twenty adults (14 females; age = 23.80 ± 4.02 y; height = 169.55 ± 12.38 cm; weight = 78.34 ± 16.32 kg) with self-reported CAI participated. Inclusion criteria consisted of a history of ≥1 ankle sprain, ≥2 episodes of giving way in the previous 3 mo, answering "yes" to ≥4 questions on the Ankle Instability Instrument, and ≤24 on the Cumberland Ankle Instability Tool. Subjects participated in 3 sessions in which they received a single treatment session of sustained traction (ST), oscillatory traction (OT), or a sham condition in a randomized order. Interventions consisted of four 30-s sets of traction with 1 min of rest between sets. During ST and OT, the talus was distracted distally from the ankle mortise to the end-range of accessory motion. ST consisted of continuous distraction and OT involved 1-s oscillations between the mid and end-range of accessory motion. The sham condition consisted of physical contact without force application. Preintervention and postintervention measurements of weight-bearing dorsiflexion, dynamic balance, and static single-limb balance were collected. The independent variable was treatment (ST, OT, sham). The dependent variables included pre-to-posttreatment change scores for the WBLT (cm), normalized SEBTAR (%), and time-to-boundary (TTB) variables(s). Separate 1-way ANOVAs examined differences between treatments for each dependent variable. Alpha was set a priori at P < .05. No significant treatment effects were identified for any variables. A single intervention of ST or OT did not produce significant changes in weight-bearing dorsiflexion range of motion or postural control in individuals with CAI. Future research should investigate the effects of repeated talocrural traction treatments and the effects of this technique when combined with other manual therapies.


Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.
Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).


Comparing conventional, biochemical and genotypic methods for accurate identification of Klebsiella pneumoniae in Sudan.
Klebsiella pneumoniae is recognized as one of the most important healthcare-associated pathogens worldwide due to its tendency to develop antibiotic resistance and cause fatal outcomes. Bacterial identification methods such as culture and biochemical tests are routinely used with limited accuracy in many low- and middle-income countries, including Sudan. The aim of this study was to test the accuracy of identification of K. pneumoniae in Khartoum, Sudan. Two hundred and fifty K. pneumoniae isolates were collected and identified using conventional phenotypic methods, biochemically using API 20E and genotypically by amplification of 16S-23S rDNA and sequencing of rpoB, gapA and pgi. Only 139 (55.6 %) of the isolates were confirmed as K. pneumoniae genotypically by PCR and 44.4 % were identified as non- K. pneumoniae . The results demonstrate that the identification panels used by the hospitals were inaccurately identifying K. pneumonia and led to overestimation of the prevalence of this organism. The current identification methods used in Khartoum hospitals are highly inaccurate, and therefore we recommend the use of a comprehensive biochemical panel or molecular methods, when possible, for accurate identification of K. pneumoniae .


Jerzego, a new hisponine jumping spider from Borneo (Araneae: Salticidae).
A new genus and species of hisponine jumping spider from Sarawak, Jerzego corticicola Maddison sp. nov. are described, representing one of the few hisponine jumping spiders known from Asia, and the only whose male is known. Although similar to the primarily-Madagascan genus Hispo in having an elongate and flat body, sequences of 28s and 16sND1 genes indicate that Jerzego is most closely related to Massagris and Tomomingi, a result consistent with morphology. Females of Jerzego and other genera of Hisponinae were found to have an unusual double copulatory duct, which appears to be a synapomorphy of the subfamily. Two species are transferred from Hispo, Jerzego bipartitus (Simon) comb. nov. and Jerzego alboguttatus (Simon) comb. nov. Diagnostic illustrations and photographs of living spiders are provided.


Yersinia enterocolitica exploits different pathways to accomplish adhesion and toxin injection into host cells.
The current paradigm suggests that Yersinia enterocolitica (Ye) adheres to host cells via the outer membrane proteins Yersinia adhesin A (YadA) or invasin (Inv) to facilitate injection of Yops by the type III secretion system. In this process Inv binds directly to β1 integrins of host cells while YadA may bind indirectly via extracellular matrix proteins to β1 integrins. Here we challenged this paradigm and investigated the requirements for Yop injection. We demonstrate that Inv- but not YadA-mediated adhesion depends on β1 integrin binding and activation, and that tight adhesion is a prerequisite for Yop injection. By means of novel transgenic cell lines, shRNA approaches and RGD peptides, we found that YadA, in contrast to Inv, may use a broad host cell receptor repertoire for host cell adhesion. In the absence of β1 integrins, YadA mediates Yop injection by interaction with αV integrins in cooperation with yet unknown cofactors expressed by epithelial cells, but not fibroblasts. Electron microscopic and flow chamber studies revealed that a defined intimate contact area between Ye and host cells resulting in adhesion forces resisting shear stress is required for Yop injection. Thus, the indirect binding of YadA to a broad extracellular matrix (ECM) binding host cell receptor repertoire of different cell types makes YadA a versatile tool to ensure Yop injection. In conclusion, given the differential expression of the outer membrane proteins Inv and YadA in the course of Ye infection and differential expression of integrins by various host cell populations, the data demonstrate that Ye is flexibly armed to accomplish Yop injection in different host cell types, a central event in its immune evasion strategy.


A longitudinal study of age- and gender-related annual rate of volume changes in regional gray matter in healthy adults.
The aim of this study was to analyze correlations among the annual rate of gray matter volume change, age, gender, and cerebrovascular risk factors in 381 healthy community-dwelling subjects with a large age range by applying a longitudinal design over 6 years using brain magnetic resonance images (MRIs). Brain MRI data were processed with voxel-based morphometry using a custom template by applying diffeomorphic anatomical registration using the exponentiated lie algebra procedure. The annual rate of regional gray matter volume change showed significant positive correlations with age in several regions, including the bilateral temporal pole, caudate nucleus, ventral and dorsolateral prefrontal cortices, insula, hippocampus, and temporoparietal cortex, whereas significant negative correlations with age were observed in several regions including the bilateral cingulate gyri and anterior lobe of the cerebellum. Additionally, a significant age-by-gender interaction was found for the annual rate of regional gray matter volume change in the bilateral hippocampus. No significant correlations were observed between the annual rate of regional gray matter volume change and body mass index or systolic blood pressure. A significant positive correlation between the annual rate of gray matter volume change and age indicates that the region shows not linear but accelerated gray matter loss with age. Therefore, evaluating the annual rate of the gray matter volume change with age in healthy subjects is important in understanding how gray matter volume changes with aging in each brain region and in anticipating what cognitive functions are likely to show accelerated decline with aging.


Theoretical insights into the mechanism of selective Peptide bond hydrolysis catalyzed by [Pd(H(2)O)(4)](2+).
In this study, mechanisms for the hydrolysis of the Gly-Pro bond in Gly-Pro-Met and Gly-Pro-His, the Gly-Sar bond in Gly-Sar-Met, and the Gly-Gly bond in the Gly-Gly-Met peptide catalyzed by [Pd(H(2)O)(4)](2+) (I) have been investigated at the DFT level. In all cases, the optimized structure of the active bidentate complex, formed by the reaction of I with the substrate [Pd(H(2)O)(2){(Gly)-(Pro)-(Met-kappaS,kappaN)}](1+) complex for the Gly-Pro-Met peptide, was found to exist in the trans conformation. This structure is in agreement with the experimentally measured TOCSY and ROESY (1)H NMR spectra. After the formation of this complex, the following two mechanisms have been proposed experimentally: (1) external attack mechanism and (2) internal delivery mechanism. The DFT calculations suggest that in the external attack mechanism the calculated barriers are prohibitively high (i.e., 50-70 kcal/mol) for the cleavage of all the peptide bonds, and therefore, this mechanism is ruled out. However, in the internal delivery mechanism, the bidentate complex is first transformed from the trans to the cis conformation. Here, the overall barriers for the hydrolysis of the Gly-Pro-Met, Gly-Pro-His, Gly-Sar-Met, and Gly-Gly-Met peptide bonds are 38.3, 41.4, 39.8, and 39.2 kcal/mol, respectively. These barriers are in much better agreement with the experimentally measured rate constants at pH 2.0 and at 60 degrees C. The substitution of Pd(II) with Pt(II) was found to make a negligibly small difference (0.53 kcal/mol) on the barrier for the cleavage of the Gly-Pro-His bond. These calculations indicate that after the creation of the active bidentate complex in the trans conformation the internal delivery mechanism is the most energetically feasible.


Emerging role of endovascular grafts in complex aortoiliac occlusive disease.
Aortobifemoral bypass is the standard therapy for complex aortoiliac occlusive disease. The purpose of this study was to examine the use of endovascular grafts as an alternative to aortobifemoral bypass in patients with advanced aortoiliac occlusive disease at high risk. Endovascular grafts were placed in 23 limbs in 22 patients with TransAtlantic Inter-Society Consensus document (TASC) type C and D lesions. All procedures were performed in the operating room, and images were obtained with portable digital fluoroscopy. Surgical exposure of the ipsilateral common femoral artery was performed to enable safe closure of 9F to 12F sheath sites and to facilitate ipsilateral interventions in the distal external iliac artery. Concomitant infrainguinal outflow procedures were performed in 6 patients. Twenty of 22 patients were men; mean patient age was 63.2 +/- 3.2 years. Indications for intervention were rest pain in 12 of 23 limbs and tissue loss in 9 of 22 limbs. Risk factors included hostile abdomen or pelvis in 8 patients, coronary artery disease in 11 patients, end-stage renal disease in 3 patients, and severe chronic obstructive pulmonary disease in 3 patients. Each patient received a mean of 1.6 grafts. Initial technical success was 95.2%, with one technical failure. There was no 30-day mortality. All patients experienced at least one grade improvement per Society for Vascular Surgery reporting standards. Primary patency at 24 months was 84.2% +/- 8.0%, with a limb salvage rate of 95.3% +/- 5.0%. Mean (+/- SD) ankle brachial index improved from 0.49 +/- 0.22 to 0.87 +/- 0.26 (P <.001). Endovascular grafting to treat advanced aortoiliac occlusive disease can be accomplished with good clinical outcome and acceptable short-term patency. This endovascular technique can be a viable alternative to conventional surgical revascularization in patients with advanced aortoiliac occlusive disease at high risk.


NAD(P)H:menadione oxidoreductase of the amitochondriate eukaryote Giardia lamblia: a simpler homologue of the vertebrate enzyme.
The amitochondriate eukaryote Giardia lamblia contains an NAD(P)H:menadione oxidoreductase (EC 22.214.171.124) (glQR) that catalyses the two-electron transfer oxidation of NAD(P)H with a quinone as acceptor. The gene encoding this protein in G. lamblia was expressed in Escherichia coli. The purified recombinant protein had an NAD(P)H oxidoreductase activity, with NADPH being a more efficient electron donor than NADH. Menadione, naphthoquinone and several artificial electron acceptors served as substrate for the enzyme. glQR shows high amino acid similarity to its homologues in vertebrates and also to a series of hypothetical proteins from bacteria. Although glQR is considerably smaller than the mammalian enzymes, three-dimensional modelling shows similar arrangement of the secondary structural elements. Most amino acid residues of the mammalian enzymes that participate in substrate binding or catalysis are conserved. Conservation of these features and the similarity in substrate specificity and in susceptibility to inhibitors establish glQR as an authentic member of this protein family.


Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling.
Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial-mesenchymal transition (EMT) driven by transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced microRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-β1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-β1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-β1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.


Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss.
Oral squamous cell carcinoma (OSCC), a subset of head and neck squamous cell carcinoma (HNSCC), is the eighth most common cancer in the U.S.. Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage-fusion-bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR-CHEK1 pathway, and that knocking down the ATR-CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR-CHEK1 pathway and flow cytometry showed G2 M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR-CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF-00477736) resulted in increased sensitivity of the tumor cells to IR. Our results suggest that distal 11q loss is a useful biomarker in OSCC for radioresistance that can be reversed by ATR-CHEK1 pathway inhibition.