A Real Time Coincidence System for High Count-Rate TOF or Non-TOF PET Cameras Using Hybrid Method Combining AND-Logic and Time-Mark Technology.
A fully digital FPGA-based high count-rate coincidence system has been developed for TOF (Time of Flight) and non-TOF PET cameras. Using a hybrid of AND-logic and Time-mark technology produced both excellent timing resolution and high processing speed. In this hybrid architecture, every gamma event was synchronized by a 125 MHz system clock and generating a trigger associated with a time-mark given by an 8-bit high-resolution TDC (68.3 ps/bin). AND-logic was applied to the synchronized triggers for the real-time raw sorting of coincident events. An efficient FPGA based Time-mark fine-sort algorithm is used to select all the possible coincidence events within the preset coincidence time window. This FPGA-based coincidence system for a modular PET camera offers reprogrammable flexibility and expandability, so the coincidence system is easily employed, regardless of differences in the scale of the PET camera detector setup. A distributed processing method and pipeline technology were adopted in the design to obtain very high processing speed. In this design, both prompt and time-delayed accidental coincidences are simultaneously processed in real time. The real-time digital coincidence system supports coincidence in 2 to 12 detector module setups, capable of processing 72 million single events per second with no digital data loss and captures multiple-event coincidence for better imaging performance evaluation. The coincidence time window-size and time-offset of each coincidence event pair can be programmed independently in 68.3 ps increments (TDC LSB) during the data acquisition in different applications to optimize the signal-to-noise ratio. The complex coincidence system is integrated in one circuit board with 1.5 Gbps fiber optic interface. We demonstrated the system performance using the actual circuit and Monte Carlo simulations.


The future of genetics in psychology and psychiatry: microarrays, genome-wide association, and non-coding RNA.
Much of what we thought we knew about genetics needs to be modified in light of recent discoveries. What are the implications of these advances for identifying genes responsible for the high heritability of many behavioural disorders and dimensions in childhood? Although quantitative genetics such as twin studies will continue to yield important findings, nothing will advance the field as much as identifying the specific genes responsible for heritability. Advances in molecular genetics have been driven by technology, especially DNA microarrays the size of a postage stamp that can genotype a million DNA markers simultaneously. DNA microarrays have led to a dramatic shift in research towards genome-wide association (GWA) studies. The ultimate goal of GWA is to sequence each individual's entire genome, which has begun to happen. GWA studies suggest that for most complex traits and common disorders genetic effects are much smaller than previously considered: The largest effects account for only 1% of the variance of quantitative traits. This finding implies that hundreds of genes are responsible for the heritability of behavioural problems in childhood, and that it will be difficult to identify reliably these genes of small effect. Another discovery with far-reaching implications for future genetic research is the importance of non-coding RNA (DNA transcribed into RNA but not translated into amino acid sequences), which redefines what the word gene means. Non-coding RNA underlines the need for a genome-wide approach that is not limited to the 2% of DNA responsible for specifying the amino acid sequences of proteins. The only safe prediction is that the fast pace of genetic discoveries will continue and will increasingly affect research in child psychology and psychiatry. DNA microarrays will make it possible to use hundreds of genes to predict genetic risk and to use these sets of genes in top-down behavioural genomic research that explores developmental change and continuity, multivariate heterogeneity and co-morbidity, and gene-environment interaction and correlation. A crucial question is whether the prediction of genetic risk will be sufficiently robust to translate into genetically based diagnoses, personalized treatments, and prevention programmes.


ATPase Activity of the Subcellular Fractions of Colorectal Cancer Samples under the Action of Nicotinic Acid Adenine Dinucleotide Phosphate.
In tumor cells with defects in apoptosis, autophagy allows prolonged survival. Autophagy leads to an accumulation of damaged mitochondria by autophagosomes. An acidic environment is maintained in compartments of cells, such as autophagosomes, late endosomes, and lysosomes; these organelles belong to the "acid store" of the cells. Nicotinic acid adenine dinucleotide phosphate (NAADP) may affect the release of Ca2+ from these organelles and affect the activity of Ca2+ ATPases and other ion transport proteins. Recently, a growing amount of evidence has shown that the variations in the expression of calcium channels or pumps are associated with the occurrence, disease-presentation, and the prognosis of colorectal cancer. We hypothesized that activity of ATPases in cancer tissue is higher because of intensive energy metabolism of tumor cells. The aim of our study was to ascertain the effect of NAADP on ATPase activity on tissue samples of colorectal cancer patients' and healthy individuals. We tested the effect of NAADP on the activity of Na+/K+ ATPase; Ca2+ ATPase of endoplasmic reticulum (EPR) and plasma membrane (PM) and basal ATPase activity. Patients' colon mucus cancer samples were obtained during endoscopy from cancer and healthy areas (control) of colorectal mucosa of the same patients. Results. The mean activity of Na+/K+ pump in samples of colorectal cancer patients (n = 5) was 4.66 ± 1.20 μmol Pi/mg of protein per hour, while in control samples from healthy tissues of the same patient (n = 5) this value was 3.88 ± 2.03 μmol Pi/mg of protein per hour. The activity of Ca2+ ATPase PM in control samples was 6.42 ± 0.63 μmol Pi/mg of protein per hour and in cancer -8.50 ± 1.40 μmol Pi/mg of protein per hour (n = 5 pts). The mean activity of Ca2+ ATPase of EPR in control samples was 7.59 ± 1.21 μmol Pi/mg versus 7.76 ± 0.24 μmol Pi/mg in cancer (n = 5 pts). Basal ATPase activity was 3.19 ± 0.87 in control samples versus 4.79 ± 1.86 μmol Pi/mg in cancer (n = 5 pts). In cancer samples, NAADP reduced the activity of Na+/K+ ATPase by 9-times (p < 0.01) and the activity of Ca2+ ATPase EPR about 2-times (p < 0.05). NAADP caused a tendency to decrease the activity of Ca2+ ATPase of PM, but increased basal ATPase activity by 2-fold vs. the mean of this index in cancer samples without the addition of NAADP. In control samples NAADP caused only a tendency to decrease the activities of Na+/K+ ATPase and Ca2+ ATPase EPR, but statistically decreased the activity of Ca2+ ATPase of PM (p < 0.05). In addition, NAADP caused a strong increase in basal ATPase activity in control samples (p < 0.01). Conclusions: We found that the activity of Na+/K+ pump, Ca2+ ATPase of PM and basal ATPase activity in cancer tissues had a strong tendency to be higher than in the controls. NAADP caused a decrease in the activities of Na+/K+ ATPase and Ca2+ ATPase EPR in cancer samples and increased basal ATPase activity. In control samples, NAADP decreased Ca2+ ATPase of PM and increased basal ATPase activity. These data confirmed different roles of NAADP-sensitive "acidic store" (autophagosomes, late endosomes, and lysosomes) in control and cancer tissue, which hypothetically may be connected with autophagy role in cancer development. The effect of NAADP on decreasing the activity of Na+/K+ pump in cancer samples was the most pronounced, both numerically and statistically. Our data shows promising possibilities for the modulation of ion-transport through the membrane of cancer cells by influence on the "acidic store" (autophagosomes, late endosomes and lysosomes) as a new approach to the treatment of colorectal cancer.


Enhancing the imagined contact effect.
Recent research has found that mentally simulating positive out-group contact experiences can promote tolerance and more positive intergroup perceptions. We investigated two ways of enhancing this imagined contact effect. In Study 1 we found that asking participants to generate more detail in their imagined encounter led to expectations of their having a greater number of out-group acquaintances in the future. In Study 2 we found that instructing participants to close their eyes during an imagined encounter led to heightened intentions to engage in future actual contact. These findings add further support to the notion that imagining intergroup contact may be a valuable addition to existing interventions aimed at improving intergroup relations.


[Possibilities and limits of a cytologic early detection program for endometrial cancer].
In a review of the most important examination methods for diagnosis of endometrial carcinoma so far published the efficacy of each of the individual methods is assessed according to uniform criteria. Only the specimens diagnosed as positive were taken as a basis for the rate of correct diagnosis, in order to facilitate comparison of the efficacy of the methods with one another. The validity of the methods is briefly outlined. Cytological diagnosis of endometrial carcinoma is appreciably less reliable than that of cervical carcinoma, regardless of the method used. The cytodiagnostic problems are different, depending whether exfoliative cytology or endouterine biopsy techniques have been used. Cancers of highly differentiated tumor cells are most seldom identified by the conventional smear techniques. Taking the endometrial carcinoma and endometrial hyperplasia patients at Erlangen University Gynecological Clinic between 1963 and 1981 as a basis, and limiting the scope of the study to high-risk adipose patients aged over 45, one-fifth of the carcinomas and one-fourth of the precancerous patients would not be included in a program based on risk factors. Of the Erlangen patients, a 5-year survival probability of 95% and more was calculated for women with tumors from cytologically highly differentiated cancer cells in histological stage I. It is particularly difficult to identify these patients cytologically, and the prognosis for them can hardly be improved further. Cytological nucleus grading proved a reliable prognosis factor, in particular for histologically undifferentiated tumors.(ABSTRACT TRUNCATED AT 250 WORDS)


Impacts of overgrazing in a long term traditional grazing ecosystem on vegetation around watering points in a semi-arid rangeland of North-Eastern Iran.
In this study, the effects of livestock overgrazing on vegetation of the critical area around livestock watering points in a traditional grazing ecosystem was investigated on a semi-arid rangeland in North-East of Iran. Transects were placed in 8 geographical directions around watering points and samples were taken systematically. In each experimental plot, 4 m2, percentage of canopy cover, abundance, density and species richness of vegetation were calculated. The results of this study showed that the percentage of canopy cover, density and species richness were changed with distance from watering points. Critical area immediately adjacent to watering points was dominated by unpalatable Peganum harmala and contained of ruderal species such as Sophora sp. Adjacent to this was a zone dominated by species of low palatability such as Acantholimon sp. and Hulthemia persica. In areas most distant from watering points relative importance of moderately palatable species such as Artemisia herba-alba increased. These results show the negative impacts of overgrazing on vegetation and palatability in a traditional grazing ecosystem, which may indicate the necessity of a monitoring programme, to manage livestock grazing and watering points in North-East of Iran.


Professionalism--a required CLS/CLT curricular component.
Determine the impact of requiring Clinical Laboratory Science (CLS) students to participate in approved professionalism activities as part of a mandatory management course. Quasi-experimental, case study reporting qualitative results of 25 CLS students. During the admission interview, students complete a written response to questions about their perceptions related to professionalism. During the clinical educational year, students are required to complete approved professionalism activities as part of a management course. At the end of the course, students write a reflective paper focusing on their professional activities and how these experiences will influence their future professional practice. Overall themes of student reflections are provided. University of Nebraska Medical Center (UNMC) CLS Program in Omaha. After participating in a mandatory professionalism curricular component requiring active student participation in professional activities, student reflective writings provide evidence this is one successful approach to nurture professional identity within future Clinical Laboratory Science/Clinical Laboratory Technician (CLS/CLT) practitioners.


Implications of mortality transition for primary health care in rural South Africa: a population-based surveillance study.
In southern Africa, a substantial health transition is underway, with the heavy burden of chronic infectious illness (HIV/AIDS and tuberculosis) paralleled by the growing threat of non-communicable diseases. We investigated the extent and nature of this health transition and considered the implications for primary health care. Health and sociodemographic surveillance started in the Agincourt subdistrict, rural South Africa, in 1992. In a population of 70 000, deaths (n=6153) were rigorously monitored with a validated verbal autopsy instrument to establish probable cause. We used age-standardised analyses to investigate the dynamics of the mortality transition by comparing the period 2002-05 with 1992-94. Mortality from chronic non-communicable disease ranked highest in adults aged 50 years and older in 1992-94 (41% of deaths [123/298]), whereas acute diarrhoea and malnutrition accounted for 37% of deaths (59/158) in children younger than 5 years. Since then, all-cause mortality increased substantially (risk ratio 1.87 [95% CI 1.73-2.03]; p<0.0001) because of a six-fold rise in deaths from infectious disease affecting most age and sex groups (5.98 [4.85-7.38]; p<0.0001), and a modest increase in deaths from non-communicable disease (1.15 [0.99-1.33]; p=0.066). The change in female risk of death from HIV and tuberculosis (15.06 [8.88-27.76]; p<0.0001) was almost double that of the change in male risk (8.13 [5.55-12.36]; p<0.0001). The burden of disorders requiring chronic care increased disproportionately compared with that requiring acute care (2.63 [2.30-3.01]; p<0.0001 vs 1.31 [1.12-1.55]; p=0.0003). Mortality from non-communicable disease remains prominent despite the sustained increase in deaths from chronic infectious disease. The implications for primary health-care systems are substantial, with integrated chronic care based on scaled-up delivery of antiretroviral therapy needed to address this expanding burden.


Direct cauterization of the nasal septal artery for epistaxis.
Emergency management of epistaxis may include the use of local pressure and vasoconstrictors, chemical or electric cautery, hemostatic agents, nasal packing, embolization, and surgical arterial ligation. There is no definitive protocol for the management of epistaxis, although various protocols have been proposed in the literature. As approaches to surgical ligation of the arterial supply of the nasal cavity have evolved from external carotid ligation to minimally invasive approaches, surgical management of epistaxis has become more effective than embolization and may be less risky. In the surgical management of epistaxis, arterial ligation immediately proximal to the bleeding site is preferred. We propose a simple variation of the endoscopic sphenopalatine artery ligation that may be used to manage epistaxis arising from the nasal septum and floor.


Comparative study on the distribution of ovalbumin glycoforms by capillary electrophoresis.
Two commercial turkey egg ovalbumins (TEOs) with different quantities of mannose, were further purified by reversed-phase high-performance liquid chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis for either of the purified glycoproteins showed one big wide band and one close small band. Capillary electrophoresis was used for the investigation of the separation of glycoforms of both glycoproteins. The best resolution of the glycoforms was obtained, reproducibly, with 100 mM borate, 1.8 mM 1,4-diaminobutane and pH 8.6 electrophoretic buffer. At least 13 glycoform peaks could be separated for either of the two glycoproteins. Their glycoform patterns were highly similar except for the conspicuous decrease in quantity of four glycoforms in the ovalbumin containing less mannose, compared to that of the other with more mannose. Coinjection electrophoresis of the two glycoproteins indicated that almost every glycoform peak of the former exactly overlapped with its corresponding glycoform peak of the latter. These results clearly indicated that the two TEOs possessed the same glycoform patterns but differed in quantity at least four glycoforms. It was found that the glycoform patterns were remarkably different between TEO and chicken egg ovalbumin.


Human Skin Allograft for Patients With Diabetic Foot Ulcers, Venous Leg Ulcers, or Surgical/Traumatic Wounds Retrospective, Descriptive Study.
Chronic wounds such as diabetic foot ulcers (DFU) and venous leg ulcers (VLU) may take a long time to heal and increase the risk of complications. Previous studies have suggested human skin allograft may facilitate healing of these chronic wounds. A retrospective, descriptive study was conducted among outpatients with nonhealing DFU, VLU, surgical, or traumatic wounds managed with a meshed, partial-thickness, cryopreserved human skin allograft. Charts of all patients who received an allograft from 2011 to 2013 were abstracted if the wound was >1 cm2, had a duration>30 days, was adequately debrided, and was free of infection before the first allograft application. Primary outcome was percentage of wounds healed (ie, 100% epithelialized) at 12 and 20 weeks. Secondary outcome was the number of recorded adverse events. Wound measurements (area--calculated as width x length in cm2), wound type and duration, number of allograft applications, number of adverse events, and race, smoking status, and body mass index were abstracted. Of the 49 patients (average age 64.3 [SD 15.0]; 64% male) who met the inclusion criteria, 13 did not have medical follow-up through the primary outcomes at 12 and 20 weeks, leaving 36 patients (average age 65.1 [SD 15.4]; 67% male) available for analysis. The most common diagnoses were VLU (18 patients, 50%) and traumatic wounds (9 patients, 25%). Average wound size was 19.4 cm2 (SD 29.3, range 1.2-156, median 9.5), and average wound duration at initial treatment was 17.2 (SD 17.0, range 4-72, excluding outlier) weeks. Seventeen (17) wounds (47%) healed by 12 weeks, and 21 (58%) were healed by week 20 with an average of 3.3 (SD 2.0) allograft applications. No serious adverse events occurred. The results of this study are encouraging and add to the currently available literature on the use of allograft skin for chronic wounds, but the study design and sample size limit the ability to interpret the observations. Prospective, controlled clinical studies are needed to compare the efficacy, effectiveness, and cost-effectiveness of human skin allograft to standard care and to other advanced care modalities.


Nursing home care quality: a multidimensional theoretical model.
This exploratory study was undertaken to discover the defining dimensions of nursing home care quality and to propose a conceptual model to guide nursing home quality research and the development of instruments to measure nursing home care quality. Three focus groups were conducted in three central Missouri communities. A naturalistic inductive analysis of the transcribed content was completed. Two core variables (interaction and odor) and several related concepts emerged from the data. Using the core variables, related concepts, and detailed descriptions from participants, three models of nursing home care quality emerged from the analysis: (1) a model of a nursing home with good quality care; (2) a model of a nursing home with poor quality care; and (3) a multidimensional model of nursing home care quality. The seven dimensions of the multidimensional model of nursing home care quality are: central focus, interaction, milieu, environment, individualized care, staff, and safety. To pursue quality, the many dimensions must be of primary concern to nursing homes. We are testing an instrument based on the model to observe and score the dimensions of nursing home care quality.


Topical steroids and UV radiation in psoriasis.
This study evaluates the benefits of a potent and midstrength topical steroid compared with simple lubricating agents when used in combination with erythemagenic doses of sunlamp fluorescent UV irradiation in psoriasis. Twenty-six patients were studied in a bilateral symmetrical comparison. No significant differences were observed between topical corticosteroids and lubricants in the number of patients achieving a 75% or greater resolution of psoriasis. Topical corticosteroids did not reduce the number of treatments required for clearing. We did not observe faster recurrences in sites treated with topical corticosteroids. More severe burns and slightly less effectiveness were noted in patients irradiated five times weekly compared with three.


Detection of paracrine factors in oxidant lung injury.
It is well recognized that the oxidant gases ozone and nitrogen dioxide cause lung injury at high concentrations and, as such, are considered to be "hazardous" air pollutants. What is not known is the upper limit of their concentration in ambient air that can be tolerated without causing lung injury. This uncertainty is due, in major part, to a lack of sensitive and noninvasive tests that can identify the presence of early lung injury after exposure to oxidant gases. The hypothesis underlying the studies reported in this document was that the changes in cell populations that occur in the lung after oxidant lung injury are due to the local generation of lung-cell-specific growth factors, and that these factors should leak into the blood stream in sufficient quantities to allow their identification. Once identified, such factors could be used as early markers of oxidant injury. The question asked in the design of these studies was: "Is oxidant lung injury associated with the appearance in blood of factors that enhance lung cell growth, as tested in a cultured lung cell bioassay?" Groups of rats were exposed to either 1 ppm ozone, 85 percent oxygen, or air, and samples of plasma, lung washings, and lung tissue were collected at intervals over a two-week period. These samples were tested for their effect on the DNA synthesis of purified populations of three major lung cell types (pneumocyte, fibroblast, and endothelial cell) in culture. The concentrations of the two oxidant gases used in these studies were selected on the basis of their known effect on these cell types in the intact animal. The collected samples were tested either whole or after separation into various fractions, determined by the preference of the sample's constituents for an alkaline or acidic environment. This fractionation procedure was included because simple testing of crude samples may not always reveal the presence of biologically active material because both growth stimulators and growth inhibitors may be present in the same sample. The results from testing whole samples confirm that factors that enhance DNA synthesis by all three lung cell types do appear in blood and lavage after exposure to 1 ppm ozone or 85 percent oxygen. These factors appear to be distinct for each lung cell type, in that the timing of maximal activity in the collected samples differs for each cell type. The time at which they appear in blood bears a close temporal relationship with cellular changes reported to occur in the whole lung of similarly exposed animals.(ABSTRACT TRUNCATED AT 400 WORDS)


Outsourcing veterans for long-term care: comparison of community and state veterans' nursing homes.
This study compares the characteristics of state veterans' nursing homes and community nursing homes with VA per-diem residentes between 1999 - 2002. A structure, process, and outcome model was used to examine whether there was any difference in the multi-dimensional quality measures among the three types of community nursing homes (for profit, not-for-profit, and government) and state veterans' nursing homes. For profit community nursing homes were less likely to achieve nurse staffing standards while government facilities were more likely to achieve CNA staffing standards when compared to the state veterans' homes. All community nursing homes had a lower prevelance of tube feeds and catheterization when compared to state veterans' nursing homes. Only government community nursing homes had significantly lower quality of life deficiencies and pressure sore prevelance when compared to state veterans' nursing homes. Vigilant monitoring of all long-term care facilities utilized by veterans is needed.


Calpain: a molecule to induce AIF-mediated necroptosis in RGC-5 following elevated hydrostatic pressure.
RIP3 (Receptor-interacting protein 3) pathway was mainly described as the molecular mechanism of necroptosis (programmed necrosis). But recently, non-RIP3 pathways were found to mediate necroptosis. We deliberate to investigate the effect of calpain, a molecule to induce necroptosis as reported (Cell Death Differ 19:245-256, 2012), in RGC-5 following elevated hydrostatic pressure. First, we identified the existence of necroptosis of RGC-5 after insult by using necrostatin-1 (Nec-1, necroptosis inhibitor) detected by flow cytometry. Immunofluorescence staining and western blot were used to detect the expression of calpain. Western blot analysis was carried out to describe the truncated AIF (tAIF) expression with or without pretreatment of ALLN (calpain activity inhibitor). Following elevated hydrostatic pressure, necroptotic cells pretreated with or without ALLN was stained by Annexin V/PI, The activity of calpain was also examined to confirm the inhibition effect of ALLN. The results showed that after cell injury there was an upregulation of calpain expression. Upon adding ALLN, the calpain activity was inhibited, and tAIF production was reduced upon injury along with the decreased number of necroptosis cells. Our study found that calpain may induce necroptosis via tAIF-modulation in RGC-5 following elevated hydrostatic pressure.


Responsiveness of emulsions stabilized by lactoferrin nano-particles to simulated intestinal conditions.
There is an upsurge of interest in the use of nano-particles to fabricate emulsions and modulate their functionality, with particular emphasis on modulating emulsion digestive fate. Food grade nano-particles formed through controlled processing and electrostatic biopolymer interactions are yet to be systematically studied for their ability to stabilize emulsions and modulate emulsion digestibility. This study focused on the responsiveness of emulsions stabilized by lactoferrin (LF) nano-particles (NPs) and dietary fibers to key digestive parameters. Compared to native LF, LF-NPs comprised emulsion exhibited elevated creaming rates as evident from accelerated stability tests performed by analytical centrifugation. The electrostatic deposition of alginate or carrageenan onto the LF-NPs significantly improved the stability of the corresponding emulsions. Further, the use of various nano-particles showed to have both beneficial and deleterious effects on emulsion responsiveness to pH (2.0 < pH < 10.0), CaCl2 (0-40 mM) and bile (0-25 mg mL(-1)). Simulated pH-stat lipolysis experiments show that the use of LF or LF-NPs had no marked effect on lipolysis. Intriguingly, the use of LF-NPs and alginate reduced emulsion lipolysis by 14% while the use of LF-NPs and carrageenan increased lipolysis by 10%. Microscopy images as well as droplet characterization in terms of size and charge indicate that the altered emulsion responsiveness may be due to physical differences in emulsion properties (e.g. droplet size) and overall organization during digestion (e.g. aggregation vs. coalescence). Overall, this study's insights could prospectively be used to harness protein nano-particles to tweak emulsion behavior during digestion.


MiR-29a inhibited intestinal epithelial cells autophagy partly by decreasing ATG9A in ulcerative colitis.
Ulcerative colitis (UC), with high morbidity has become one of the fastest-growing severe illnesses in the world. Although MiR-29a is highly expressed in the tissues of UC patients, the mechanism of miR-29a involved in the specific pathogenesis of UC is not known. In this study, a GFP-light chain 3 (LC3) immunofluorescence assay was used to observe the formation of the autophagic spot; qRT-PCR and western blotting analyses were carried out to detect the expression of autophagy-related proteins, including BECN1, Autophagy-related gene (ATG)5, ATG16L, and transcription factor EB. The dual-fluorescence reporter assay was used to analyze the direct effect of miR-29a on ATG9A; experimental dextran sulfate sodium-induced colitis in mice was used to establish the UC model. Our studies showed that the overexpression of miR-29a not only suppressed the production of GFP-LC3 autophagy spots but also inhibited the level of LC3II/LC3I and upregulated the expression of P62 in HT29 and HCT116 cells. Moreover, the results showed that miR-29a directly targeted the 3'UTR region of ATG9A mRNA to suppress the activation of HT29 and HCT116 cells' autophagy. Also, overexpression of ATG9A rescued rapamycin-induced autophagy that was inhibited by overexpression of miR-29a. In addition, miR-29a also affected the expression of autophagy-related proteins (BECN1, ATG5, ATG16L1, and transcription factor EB). Notably, miR-29a was upregulated, whereas ATG9A was downregulated in the experimental dextran sulfate sodium-induced colitis in mice. In effect, this study showed that miR-29a inhibits rapamycin-induced intestinal epithelial cells' autophagy partly by decreasing ATG9A in UC. These findings may provide new insights that may help control the inflammation in UC.


Treatment of estrogen deficiency symptoms in women surviving breast cancer. Part 2: Hormone replacement therapy and breast cancer.
There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 59 breast cancer experts and patient advocates participated. The proceedings of the conference will be published in six installments in successive issues of ONCOLOGY. The first part, published last month, defined the problem and explored its magnitude and ramifications for patient management. This second part focuses on the benefits and risks of hormone replacement therapy (HRT) in patients with breast cancer.


Myelin water imaging at 0.55 T using a multigradient-echo sequence.
To investigate the prospects of a multigradient-echo (mGRE) acquisition for in vivo myelin water imaging at 0.55 T. Scans were performed on the brain of four healthy volunteers at 0.55 and 3 T, using a 3D mGRE sequence. The myelin water fraction (MWF) was calculated for both field strengths using a nonnegative least squares (NNLS) algorithm, implemented in the qMRLab suite. The quality of these maps as well as single-voxel fits were compared visually for 0.55 and 3 T. The obtained MWF values at 0.55 T are consistent with previously reported ones at higher field strengths. The MWF maps are a considerable improvement over the ones at 3 T. Example fits show that 0.55 T data is better described by an exponential model than 3 T data, making the assumed multi-exponential model of the NNLS algorithm more accurate. This first assessment shows that mGRE myelin water imaging at 0.55 T is feasible and has the potential to yield better results than at higher fields.


Effect of chronotype on academic achievement in a sample of Italian University students.
Circadian rhythms play an important role in biological function; their expression differs across individuals; three chronotypes are distinguished: Morning- [MT], Evening- [ET], and Neither- [NT] type. MT achieve peak activation in the first part of the day and are generally more conscientious and achievement-oriented than ET, which reach their best during the second half of the day and express a higher intelligence. University class schedules can sometimes conflict with ET circadian preferences, compromising their academic performance compared with their MT classmates. Conversely, MT students, being more aligned with their daily schedule, might be more advantaged in their mental performance. The attitudes and performance of NT students are little considered. No studies to date have investigated academic achievement in relation to chronotype in an Italian student population. To fill this gap, this study examined the relationship between chronotype and academic performance in a population of Motor Science Faculty in Milan, differentiating achievement in theoretical and practical subjects by chronotype. The study population was 423 university students (290 males and 133 females) and categorized by chronotype according to Morningness-Eveningness Questionnaire (MEQ) scores. Student transcripts were reviewed to obtain exam grades on three practical and three theoretical subjects. The interaction between MEQ score or chronotypes and mean exam grade was evaluated using one-way ANOVA. The mean grades on the theoretical and practical exams were higher for the MT than for either the ET or the NT students. The NT students (24.8 ± 0.1) had lower mean grades for the theoretical subjects than either the MT (26.3 ± 0.4) or the ET (25.3 ± 0.2) students, while the ET (26.6 ± 0.2) performed worse than either the MT (27.8 ± 0.2) or the NT students (26.9 ± 0.1) on the practical exams. The same trend was observed for the total sample and when subdivided by sex. In the total sample, significant differences in theoretical and practical exam grades were noted between chronotypes: MT vs ET (p < .002, p < .0006) and MT vs NT (p < .04, p < .003). The differences between the males were significant for the theoretical (p < .006, MT vs NT, p < .002) and the practical subjects (MT vs ET p < .004, MT vs NT, p < .01), but no significant differences were noted between the females. Our findings indicate overall better academic achievement by the MT students, whereas the NT had lower exam grades for the theoretical subjects and the ET performed worse on the practical exams. We speculate that the higher intelligence expressed by the ET students might have helped them compensate the disadvantage on the theoretical but not on practical exams, in which the effect of misalignment between circadian preferences and university class schedule was more evident.


Antibody markers of basal cells in complex epithelia.
In the course of immunohistochemical studies it has become apparent that there is a distinct phenotype of keratin expression that is shared by basal epithelial cells in a variety of different tissues. A basal cell can be defined as a cell in contact with a basal lamina but with no free luminal surface; this distinguishes it from a simple epithelial cell, which has a free luminal surface as well as basal lamina contact, and from stratifying suprabasal keratinocytes, which have neither basal lamina contact nor free luminal surface. All basal cells, whether they are in glandular ductal or secretory epithelia, or in stratified squamous epithelia, express the keratin pair K5 and K14. In this paper we describe monoclonal and polyclonal antibodies that are monospecific for both keratins 14 and 5 or are specific for denaturation-sensitive epitopes unique to basal cells, including five new monoclonal antibodies: LL001 and LL002 (to keratin 14), 2.1.D7 (to keratins 5, 6 and 8), and LH6 and LH8 (conformation-specific basal cell markers). These antibodies have been used to monitor the distribution of the basal cell phenotype and to demonstrate the expression of keratins 5 and 14 in this cell type, in both stratified epithelia and mixed epithelial glands. The consistent association of this keratin pair with basal cells suggests a possible specific function for these keratin in reinforcing epithelia under physical stress, whilst expression of these keratins may conflict with the differentiated functions of most simple epithelial cells.


IRDye78 conjugates for near-infrared fluorescence imaging.
The detection of human malignancies by near-infrared (NIR) fluorescence will require the conjugation of cancer-specific ligands to NIR fluorophores that have optimal photoproperties and pharmacokinetics. IRDye78, a tetra-sulfonated heptamethine indocyanine NIR fluorophore, meets most of the criteria for an in vivo imaging agent, and is available as an N-hydroxysuccinimide ester for conjugation to low-molecular-weight ligands. However, IRDye78 has a high charge-to-mass ratio, complicating purification of conjugates. It also has a potentially labile linkage between fluorophore and ligand. We have developed an ion-pairing purification strategy for IRDye78 that can be performed with a standard C18 column under neutral conditions, thus preserving the stability of fluorophore, ligand, and conjugate. By employing parallel evaporative light scatter and absorbance detectors, all reactants and products are identified, and conjugate purity is maximized. We describe reversible and irreversible conversions of IRDye78 that can occur during sample purification, and describe methods for preserving conjugate stability. Using seven ligands, spanning several classes of small molecules and peptides (neutral, charged, and/or hydrophobic), we illustrate the robustness of these methods, and confirm that IRDye78 conjugates so purified retain bioactivity and permit NIR fluorescence imaging of specific targets.


Gonadotropin independent sexual precocity in a Pakistani male infant from an activating mutation in LHCGR gene.
A male child, aged seven months, visited the out patients clinic of the National Institute of Child Health, Karachi, in May 2020 with the features of iso-sexual puberty. After ruling out the more common causes of early puberty, like congenital adrenal hyperplasia and tumours secreting chorionic gonadotropin hormone, hormonal assessment indicated raised testosterone independent of gonadotropin. The volume of the testicles was symmetric and testicular ultrasonography revealed no mass. Genetic analysis for the LHCGR gene was performed for confirmation which revealed activating heterozygous missense pathogenic mutation in c.1732G>T (p.Asp578Tyr). This is the first reported case of testotoxicosis (FMPP) from Pakistan which was genetically confirmed.


Lujan-Fryns Syndrome Phenotype with Autism-Like Behavior and Atypical Psychotic Symptoms: Case Report.
Lujan-Fryns Syndrome (LFS) is defined as a set of symptoms including mild-moderate mental retardation, marfanoid appearance, hypotonia at birth, hypernasal speech, characteristic craniofacial appearance and normal testis size. The frequency of the syndrome is not known thus the information obtained is solely based on case reports. Hereby, we present a patient with LFS diagnosis. The 29-year old male patient had mental retardation, aggression, and persecutory delusions, characteristic craniofacial and marfanoid features. During his speech pronominal reversal was observed ('the hurt him, he is so upset' when talking abour himself). After examination and genetic analysis, fragile X, Klinefelter, Marfan and Down syndromes and homocystinuria were eliminated as causes of mental retardation. A preliminary diagnoses of LFS done. No mutation was detected in exon 22 of the MED12 gene; but. Whole Exome Sequencing (WES) is ongoing. The patient was started on risperidone (4 mg/day) for psychotic symptoms and carbamazepine (200 mg/day) for impulse control and as an antiepileptic. After a follow up of 8 months, impulse control, psychotic symptoms and aggression improved significantly. Since the specific gene mutation of LFS was not determined in our case, we solely had to depend on clinical evaluation and genetic analysis. Although it is not easy to fully define or classify these syndromes, we believe every reported case will be a step in overcoming these difficulties.


Protein repellant silicone surfaces by covalent immobilization of poly(ethylene oxide).
Polydimethylsiloxane elastomers were surface modified with passivating polyethylene oxide (PEO) polymers of different molecular weights, both monofunctional and bifunctional. Following the introduction of Si-H groups on the surfaces by acid-catalyzed equilibration in the presence of polymethylhydrosiloxane, the PEO was linked by platinum-catalyzed hydrosilylation. ATR-FTIR, X-ray photoelectron spectroscopy (XPS) and water contact angle results confirmed that the PEO was successfully grafted to the silicone rubber. Atomic force microscopy and XPS suggested that surface coverage with PEO was very high on the modified surfaces but not complete. The protein-resistant properties of the PEO-modified surfaces were demonstrated by measuring the adsorption of fibrinogen from both buffer and plasma. Fibrinogen adsorption from buffer to the PEO-modified surfaces was reduced by more than 90% compared with controls.


Imaging Trapped Ion Structures via Fluorescence Cross-Correlation Detection.
Cross-correlation signals are recorded from fluorescence photons scattered in free space off a trapped ion structure. The analysis of the signal allows for unambiguously revealing the spatial frequency, thus the distance, as well as the spatial alignment of the ions. For the case of two ions we obtain from the cross-correlations a spatial frequency f_{spatial}=1490±2_{stat}±8_{syst} rad^{-1}, where the statistical uncertainty improves with the integrated number of correlation events as N^{-0.51±0.06}. We independently determine the spatial frequency to be 1494±11 rad^{-1}, proving excellent agreement. Expanding our method to the case of three ions, we demonstrate its functionality for two-dimensional arrays of emitters of indistinguishable photons, serving as a model system to yield structural information where direct imaging techniques fail.


Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes.
The inactive full-length form of GLP-1(1-37) stimulates conversion of both rat and human intestinal epithelial cells into insulin-secreting cells. We investigated whether oral administration of human commensal bacteria engineered to secrete GLP-1(1-37) could ameliorate hyperglycemia in a rat model of diabetes by reprogramming intestinal cells into glucose-responsive insulin-secreting cells. Diabetic rats were fed daily with human lactobacilli engineered to secrete GLP-1(1-37). Diabetic rats fed GLP-1-secreting bacteria showed significant increases in insulin levels and, additionally, were significantly more glucose tolerant than those fed the parent bacterial strain. These rats developed insulin-producing cells within the upper intestine in numbers sufficient to replace ∼25-33% of the insulin capacity of nondiabetic healthy rats. Intestinal tissues in rats with reprogrammed cells expressed MafA, PDX-1, and FoxA2. HNF-6 expression was observed only in crypt epithelia expressing insulin and not in epithelia located higher on the villous axis. Staining for other cell markers in rats treated with GLP-1(1-37)-secreting bacteria suggested that normal function was not inhibited by the close physical proximity of reprogrammed cells. These results provide evidence of the potential for a safe and effective nonabsorbed oral treatment for diabetes and support the concept of engineered commensal bacterial signaling to mediate enteric cell function in vivo.


Predicting nicotine dependence profiles among adolescent smokers: the roles of personal and social-environmental factors in a longitudinal framework.
Although several studies have reported that symptoms of nicotine dependence can occur after limited exposure to smoking, the majority of research on nicotine dependence has focused on adult smokers. Insufficient knowledge exists regarding the epidemiology and aetiology of nicotine dependence among adolescent smokers. The objective of the present study is to identify the effects of theoretically driven social and individual predictors of nicotine dependence symptom profiles in a population-based sample of adolescent smokers. A longitudinal study among 6,783 adolescents (12 to 14 years old at baseline) was conducted. In the first and second year of secondary education, personality traits and exposure to smoking in the social environment were assessed. Two and a half years later, adolescents' smoking status and nicotine dependence symptom profiles were assessed. A total of 796 adolescents were identified as smokers and included in the analyses. At follow-up, four distinct dependence symptom profiles were identified: low cravings only, high cravings and withdrawal, high cravings and behavioural dependence, and overall highly dependent. Personality traits of neuroticism and extraversion did not independently predict nicotine dependence profiles, whereas exposure to smoking in the social environment posed a risk for the initial development of nicotine dependence symptoms. However, in combination with environmental exposure to smoking, extraversion and neuroticism increased the risk of developing more severe dependence symptom profiles. Nicotine dependence profiles are predicted by interactions between personal and environmental factors. These insights offer important directions for tailoring interventions to prevent the onset and escalation of nicotine dependence. Opportunities for intervention programs that target individuals with a high risk of developing more severe dependence symptom profiles are discussed.


Optical Coherence Tomography Parameters as Predictors of Treatment Response to Eplerenone in Central Serous Chorioretinopathy.
Purpose: To present data on clinical response to eplerenone over a 1-year period in patients with central serous chorioretinopathy (CSC), and to evaluate optical coherence tomography (OCT) variables as predictors of treatment response at 3- and 12-month follow-up visits. Methods: Patients with acute or chronic CSC treated with eplerenone were retrospectively included. Clinical and imaging characteristics were recorded at baseline and at the 3-month and 12-month follow-up visits. Changes from baseline in quantitative measurements were calculated at each follow-up. Logistic regression analysis was computed to correlate clinical and OCT parameters at baseline with response to treatment at 3 and 12 months of follow-up. Results: A total of 50 eyes of 50 patients were included in the study. Mean ± SD best corrected visual acuity (BCVA) was 0.20 ± 0.14 Logarithm of the Minimum Angle of Resolution (LogMAR) at baseline and significantly improved at both the 3-month (0.12 ± 0.13 LogMAR, p < 0.0001) and 12-month (0.10 ± 0.12 LogMAR, p < 0.0001) follow-up visits. At the 3-month follow-up visit, 25 out of 50 eyes (50.0%) demonstrated macular complete subretinal fluid (SRF) resolution, while 13 eyes (26.0%) showed macular partial SRF resolution, and 12 eyes (24%) had neither partial nor complete macular SRF resolution. Among those patients with macular partial or complete SRF resolution at 3 months and thus not shifted to photodynamic therapy, 36 out of 38 cases had macular complete SRF resolution at the 12-month follow-up visit. There was a significant change from baseline at both follow-up visits in all anatomical OCT parameters (except for reduction in choroidal thickness that did not reach the statistical significance at the 12-month follow-up visit). Several OCT parameters at baseline were independently significant predictors for macular subretinal fluid complete resolution at 3 months, including (i) a thicker subfoveal choroidal thickness; (ii) a smaller subretinal fluid maximum diameter; (iii) a lower number of serous pigment epithelium detachments; and (iv) a lower number of intraretinal hyperreflective foci. Conclusion: Treatment with eplerenone in CSC patients is confirmed to be beneficial for both anatomical and functional outcomes. We identified attractive OCT metrics that could potentially be used as a tool to select patients who might mainly benefit from this treatment.


Comparison of MR-less PiB SUVR quantification methods.
(11)C-Pittsburgh compound B (PiB) is a positron emission tomography (PET) tracer designed to bind to amyloid-β (Aβ) plaques, one of the hallmarks of Alzheimer's disease (AD). The potential of PiB as an early marker of AD led to the increasing use of PiB in clinical research studies and development of several F-18-labeled Aβ radiotracers. Automatic quantification of PiB images requires an accurate parcellation of the brain's gray matter (GM). Typically, this relies on a coregistered magnetic resonance imaging (MRI) to extract the cerebellar GM, compute the standardized uptake value ratio (SUVR), and provide parcellation and segmentation for quantification of regional and global SUVR. However, not all subjects can undergo MRI, in which case, an MR-less method is desirable. In this study, we assess 3 PET-only quantification methods: a mean atlas, an adaptive atlas, and a multi-atlas approaches on a database of 237 subjects having been imaged with both PiB PET and MRI. The PET-only methods were compared against MR-based SUVR quantification and evaluated in terms of correlation, average error, and performance in classifying subjects with low and high Aβ deposition. The mean atlas method suffered from a significant bias between the estimated neocortical SUVR and the PiB status, resulting in an overall error of 5.6% (R(2) = 0.98), compared with the adaptive and multi-atlas approaches that had errors of 3.06% and 2.74%, respectively (R(2) = 0.98), and no significant bias. In classifying PiB-negative from PiB-positive subjects, the mean atlas had 10 misclassified subjects compared with 0 for the adaptive and 1 for the multi-atlas approach. Overall, the adaptive and the multi-atlas approaches performed similarly well against the MR-based quantification and would be a suitable replacements for PiB quantification when no MRI is available.


Mental Health Service Use Among Young Adults: A Communication Framework for Program Development.
Research on mental health service engagement has been dominated by attempts to identify determinants of engagement. Such knowledge is important but incomplete. Once identified, program designers need to use evidence-based principles to design programs to bring about changes in the empirically identified determinants. Research is relatively silent on such principles. This article develops a framework to guide program designers' as they address factors that constrain and/or facilitate engagement. The framework is grounded in communication theory and evidence from related behavioral science research. The literature is summarized and used to generate a check-list of questions to consider when structuring engagement programs.


Geochemical and isotopic evidences from groundwater and surface water for understanding of natural contamination in chronic kidney disease of unknown etiology (CKDu) endemic zones in Sri Lanka.
Chronic kidney disease of unknown etiology (CKDu) is the main health issue in the dry zone of Sri Lanka. Despite many studies carried out, causative factors have not been identified yet clearly. According to the multidisciplinary researches carried out so far, potable water is considered as the main causative factor for CKDu. Hence, the present study was carried out with combined isotopic and chemical methods to understand possible relationships between groundwater; the main drinking water source, and CKDu in four endemic areas in the dry zone. Different water sources were evaluated isotopically (2H, 3H and 18O) and chemically from 2013 to 2015. Results revealed that prevalence of CKDu is significantly low with the groundwater replenished by surface water inputs. It is significantly high with the groundwater stagnated as well as groundwater recharged from regional flow paths. Thus, the origin, recharge mechanism and flow pattern of groundwater, as well as geological conditions which would be responsible for natural contamination of groundwater appear as the main causative factors for CKDu. Therefore, detailed investigations should be made in order to identify the element(s) in groundwater contributing to CKDu. The study recommends providing drinking water to the affected zones using water sources associated with surface waters.


A systematic review and meta-analysis of victimisation and mental health prevalence among LGBTQ+ young people with experiences of self-harm and suicide.
LGBTQ+ youth have higher rates of self-harm and suicide than cisgender, heterosexual peers. Less is known about prevalence of risks within these populations. The first systematic review and meta-analysis to investigate the prevalence of risks among young people throughout the LGBTQ+ umbrella with experiences across the dimension of self-harm, suicidal ideation and suicide behaviour; and how they may differ between LGBTQ+ umbrella groups. MEDLINE, Scopus, EMBASE, PsycINFO, and Web of Science searches were run to identify quantitative research papers (database inception to 31st January, 2020). Articles included were empirical quantitative studies, which examined risks associated with self-harm, suicidal ideation or suicidal behaviour in LGBTQ+ young people (12-25 years). 2457 articles were identified for screening which was completed by two independent reviewers. 104 studies met inclusion criteria of which 40 had data which could be meta-analysed in a meaningful way. This analysis represents victimisation and mental health difficulties as risks among LGBTQ+ youth with self-harm and suicide experiences. Random-effects modelling was used for the main analyses with planned subgroup analyses. Victimisation and mental health were key risk factors across the dimension self-harm and suicide identified through all analyses. A pooled prevalence of 0.36 was indicated for victimisation and 0.39 for mental health difficulties within LGBTQ+ young people with experiences of self-harm or suicide. Odds ratios were calculated which demonstrated particularly high levels of victimisation (3.74) and mental health difficulties (2.67) when compared to cisgender, heterosexual counterparts who also had these experiences. Victimisation and mental health difficulties are highly prevalent among LGBTQ+ youth with experiences of self-harm and suicide. Due to inconsistency of reporting, further risk synthesis is limited. Given the global inclusion of studies, these results can be considered across countries and inform policy and suicide prevention initiatives. CRD42019130037.


Efficient generation of megakaryocytes from human induced pluripotent stem cells using food and drug administration-approved pharmacological reagents.
Megakaryocytes (MKs) are rare hematopoietic cells in the adult bone marrow and produce platelets that are critical to vascular hemostasis and wound healing. Ex vivo generation of MKs from human induced pluripotent stem cells (hiPSCs) provides a renewable cell source of platelets for treating thrombocytopenic patients and allows a better understanding of MK/platelet biology. The key requirements in this approach include developing a robust and consistent method to produce functional progeny cells, such as MKs from hiPSCs, and minimizing the risk and variation from the animal-derived products in cell cultures. In this study, we developed an efficient system to generate MKs from hiPSCs under a feeder-free and xeno-free condition, in which all animal-derived products were eliminated. Several crucial reagents were evaluated and replaced with Food and Drug Administration-approved pharmacological reagents, including romiplostim (Nplate, a thrombopoietin analog), oprelvekin (recombinant interleukin-11), and Plasbumin (human albumin). We used this method to induce MK generation from hiPSCs derived from 23 individuals in two steps: generation of CD34(+)CD45(+) hematopoietic progenitor cells (HPCs) for 14 days; and generation and expansion of CD41(+)CD42a(+) MKs from HPCs for an additional 5 days. After 19 days, we observed abundant CD41(+)CD42a(+) MKs that also expressed the MK markers CD42b and CD61 and displayed polyploidy (≥16% of derived cells with DNA contents >4N). Transcriptome analysis by RNA sequencing revealed that megakaryocytic-related genes were highly expressed. Additional maturation and investigation of hiPSC-derived MKs should provide insights into MK biology and lead to the generation of large numbers of platelets ex vivo.


A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders.
Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R-NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R-NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.


Control of proteolysis: hormones, nutrients, and the changing role of the proteasome.
The maintenance of protein balance is essential for the proper functioning of a cell. Protein degradation must be controlled to account for the availability of nutrients and hormone signals from the body as a whole. The proteasome is the major cytosolic protein degrading machinery, and is responsible for a considerable proportion of cellular protein degradation. It is thus a prime site for the integration of these various signals. We will examine some recent data regarding the mechanisms for control of the peptidolytic activities of the proteasome, and possible implications for signal transduction and integration. Nutrients, such as amino acids and fatty acids, have been shown to have effects on proteasome-mediated protein degradation. The ubiquitinylating process is important for the control of protein degradation by the 26S proteasome. Amino acids and hormones control the expression of the necessary components, and can control protein degradation on a relatively longer-term basis. The 20S proteasome has been shown to be capable of degrading proteins without activating subunits. Furthermore, the 20S proteasome is allosterically affected by a number of smaller peptides, suggesting a more immediate mechanism for control. Amino acids and fatty acids have been shown to exert such control in vitro. As more is learned about the functioning of the proteasome, the greater appreciation we have of its vital role in the control of cellular metabolism. Recent evidence shows that the proteasome is central to the integration of various nutrient and hormonal signals that the cell receives that may impact on protein metabolism.


Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells.
Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism of these actions is not clear. We have shown that GLA acts via peroxisome proliferator activated receptors (PPARs), by stimulating their phosphorylation and translocation to the nucleus. Removing PPAR gamma with antisense oligos abolished the effect of GLA on the expression of adhesion molecules and tumour suppressor genes, whereas removal of PPAR alpha had no effect. Tissues from patients with breast cancer showed a reduction of expression of both PPARs in cancer tissues, as compared with normal. Thus, PPAR gamma serves as the receptor for GLA in the regulation of gene expression in breast cancer cells.


Remarkable substituent effects on the oxidizing ability of triarylbismuth dichlorides in alcohol oxidation.
Substituent effects on the oxidizing ability of triarylbismuth dichlorides were examined by intermolecular and intramolecular competition experiments on geraniol oxidation in the presence of DBU. It was found that the oxidizing ability of the dichlorides increases with increasing electron-withdrawing ability of the para substituents, and by introduction of a methyl group at the ortho position of the aryl ligands attached to the bismuth. The intermolecular and intramolecular H/D kinetic isotope effects observed for the competitive oxidation of p-bromobenzyl alcohols indicate that the rate-determining step involves C-H bond cleavage. Several primary and secondary alcohols were oxidized efficiently under mild conditions by the combined use of newly developed organobismuth(V) oxidants and DBU.


Using Salivary Biomarkers for Stress Assessment in Offshore Saturation Diving: A Pilot Study.
Health monitoring during offshore saturation diving is complicated due to restricted access to the divers, the desire to keep invasive procedures to a minimum, and limited opportunity for laboratory work onboard dive support vessels (DSV). In this pilot study, we examined whether measuring salivary biomarkrers in samples collected by the divers themselves might be a feasible approach to environmental stress assessment. Nine saturation divers were trained in the passive drool method for saliva collection and proceeded to collect samples at nine time points before, during, and after an offshore commercial saturation diving campaign. Samples collected within the hyperbaric living chambers were decompressed and stored frozen at -20°C onboard the DSV until they were shipped to land for analysis. Passive drool samples were collected without loss and assayed for a selection of salivary biomarkers: secretory immunoglobulin A (SIgA), C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukins IL-6, IL-8, IL-1β, as well as cortisol and alpha-amylase. During the bottom phase of the hyperbaric saturation, SIgA, CRP, TNF-α, IL-8 and IL-1β increased significantly, whereas IL-6, cortisol and alpha-amylase were unchanged. All markers returned to pre-dive levels after the divers were decompressed back to surface pressure. We conclude that salivary biomarker analysis may be a feasible approach to stress assessment in offshore saturation diving. The results of our pilot test are consonant with an activation of the sympathetic nervous system related to systemic inflammation during hyperbaric and hyperoxic saturation.


Genetic relationship between measures of HDL phenotypes and insulin concentrations.
We used data from the San Antonio Family Heart Study to determine the HDL correlates of the insulin resistance syndrome (IRS), as reflected by insulin concentrations in nondiabetic subjects. We measured insulin concentrations both in the fasting state and 2 hours after a glucose challenge (2-hour insulin) and we assessed seven aspects of HDL phenotype, including size and concentration of both lipid and protein components. Measurements were obtained from 1202 nondiabetic members of 42 families. Initial quantitative genetic analyses revealed that a substantial portion of phenotypic variation in the nine variables was due to genes (heritabilities, h2, ranged from 0.32 to 0.47). We then conducted a series of bivariate genetic analyses, which indicated that there were significant additive genetic correlations (ie, pleiotropy) between the two measures of insulin and five of seven HDL measures tested, including concentrations of HDL cholesterol (fasting insulin only) and triglyceride, and HDL size distributions of apoAI, apoAII, and cholesterol; concentrations of apoAI and apoAII were not genetically related to either insulin measure. Increased insulin levels were associated with relatively smaller HDL phenotypes, and considering a similar association with small, dense LDLs, this finding suggests a common effect of insulin resistance on particle size distributions for these lipoproteins. Thus, these results suggest the existence of genes that pleiotropically influence variation in both HDLs and insulin levels and therefore contribute to the clustering of proatherogenic traits in the IRS.


SWI/SNF chromatin remodeling complex and glucose metabolism are deregulated in advanced bladder cancer.
Bladder cancer (BC) is a frequently diagnosed malignancy affecting predominantly adult and elderly populations. It is expected that due to the longer life time, BC will become even more frequent in the future; thus in consequence, it will represent serious health problem of older society part. The treatment of advanced BC is mostly ineffective due to its very aggressive behavior. So far, no effective targeted therapy is used for BC treatment. Here, we found that BC is characterized by lower protein levels of BRM, INI1, and BAF155 main subunits of SWI/SNF chromatin remodeling complex (CRC) which is involved in global control of gene expression and influences various important cellular processes like: cell cycle control, apoptosis, DNA repair, etc. Moreover, the expression of SMARCA2, a BRM encoding gene, strongly correlated with BC metastasis and expression of such metabolic genes as PKM2 and PRKAA1. Furthermore, the analysis of T24 and 5637 commonly used BC cell lines revealed different expression levels of metabolic genes including FBP1 gene encoding Frutose-1,6-Bisphosphatase, an enzyme controlling glycolysis flux and gluconeogenesis. The tested BC cell lines exhibited various molecular and metabolic alterations as well as differential glucose uptake, growth rate, and migration potential. We have shown that BRM subunit is involved in the transcriptional control of genes encoding metabolic enzymes. Moreover, we found that the FBP1 expression level and the SWI/SNF CRCs may serve as markers of molecular subtypes of BC. Collectively, this study may provide a new knowledge about the molecular and metabolic BC subtypes which likely will be of high importance for the clinic in the future.


[A contemporary model of environmental health sciences: its application in the recruitment of faculty and in academic development].
The authors describe the development and application of an intellectual model fitted to the environmental health sciences. The model became the basis for the design of a new study plan in addition to providing the strategy for recruitment of the faculty for the new School of Public Health of the San Diego State University in San Diego, California. They give an account of the circumstances leading up to the establishment of this institution, the gradual consolidation of the different health science programs into a single school with graduate studies leading to masters degrees in six main fields: environmental health, occupational health, epidemiology, maternal and child health, health services administration, and health development. The authors see the beginning of a redefinition of the function of the basic sciences represented in environmental health in the light of new knowledge and technology, and believe that all fields of knowledge (microbiology, parasitology and health development) will contribute as a unified whole to increase the capacity of public health to place both biological and environmental health problems in a context that society can control.


Expansive Quantum Mechanical Exploration of Chemical Reaction Paths.
Quantum mechanical methods have been well-established for the elucidation of reaction paths of chemical processes and for the explicit dynamics of molecular systems. While they are usually deployed in routine manual calculations on reactions for which some insights are already available (typically from experiment), new algorithms and continuously increasing capabilities of modern computer hardware allow for exploratory open-ended computational campaigns that are unbiased and therefore enable unexpected discoveries. Highly efficient and even automated procedures facilitate systematic approaches toward the exploration of uncharted territory in molecular transformations and dynamics. In this work, we elaborate on such explorative approaches that range from reaction network explorations with (stationary) quantum chemical methods to explorative molecular dynamics and migrant wave packet dynamics. The focus is on recent developments that cover the following strategies. (i) Pruning search options for elementary reaction steps by heuristic rules based on the first-principles of quantum mechanics: Rules are required for reducing the combinatorial explosion of potentially reactive atom pairings, and rooting them in concepts derived from the electronic wave function makes them applicable to any molecular system. (ii) Enforcing reactive events by external biases: Inducing a reaction requires constraints that steer and direct elementary-step searches, which can be formulated in terms of forces, velocities, or supplementary potentials. (iii) Manual steering facilitated by interactive quantum mechanics: As ultrafast quantum chemical methods allow for real-time manual interactions with molecular systems, human-intuition-guided paths can be easily explored with suitable human-machine interfaces. (iv) New approaches for transition-state optimization with continuous curve representations can provide stable schemes to be driven in an automated way by allowing for an efficient tuning of the curve's parameters (instead of a manipulation of a collection of structures along the path), and (v) reactive molecular dynamics and direct wave packet propagation exploit the equations of motion of an underlying mechanical theory (usually, classical Newtonian mechanics or Schrödinger quantum mechanics). Explorative approaches are likely to replace the current state of the art in computational chemistry, because they reduce the human effort to be invested in reaction path elucidations, they are less prone to errors and bias-free, and they cover more extensive regions of the relevant configuration space. As a result, computational investigations that rely on these techniques are more likely to deliver surprising discoveries.


Detection of Pseudomonas aeruginosa Metabolite Pyocyanin in Water and Saliva by Employing the SERS Technique.
Pyocyanin (PYO) is a metabolite specific for Pseudomonas aeruginosa. In the case of immunocompromised patients, it is currently considered a biomarker for life-threating Pseudomonas infections. In the frame of this study it is shown, that PYO can be detected in aqueous solution by employing surface-enhanced Raman spectroscopy (SERS) combined with a microfluidic platform. The achieved limit of detection is 0.5 μM. This is ~2 orders of magnitude below the concentration of PYO found in clinical samples. Furthermore, as proof of principle, the SERS detection of PYO in the saliva of three volunteers was also investigated. This body fluid can be collected in a non-invasive manner and is highly chemically complex, making the detection of the target molecule challenging. Nevertheless, PYO was successfully detected in two saliva samples down to 10 μM and in one sample at a concentration of 25 μM. This indicates that the molecules present in saliva do not inhibit the efficient adsorption of PYO on the surface of the employed SERS active substrates.


Protracted cognitive effects produced by clonidine in Macaca nemestrina performing a delayed matching task.
The alpha(2)-adrenergic receptor agonist clonidine was examined for its ability to improve working memory in monkeys. Clonidine (0.116-34.8 microg/kg) was administered to six pigtail macaques in their performance of a computer-assisted delayed matching-to-sample (DMTS) task. During DMTS sessions initiated 1 hour after dosing, there was a slight improvement in mean task accuracy (long delay trials; 0.116-microg/kg). On the following day, there was continued and added improvement in accuracies associated with the long delay trials. On the day following 1.16-microg/kg, the entire memory retention curve was shifted to the right of vehicle. When the animals were again tested 48 hours after dosing (no pretreatment), these two patterns of task enhancement were continued and enhanced. Mean task accuracy associated with long delay trials was significantly increased by 14.2% trials correct when animals were originally treated with 0.116-microg/kg of clonidine. Mean task accuracy associated with medium delay trials was significantly increased by 11.8% trials correct when animals were treated with 1.16-microg/kg. On the sixth day after clonidine, task accuracies were still significantly improved during medium delay trials after 0.116-microg/kg. Median sample and choice latencies were not significantly influenced by clonidine treatment. These findings are consistent with the ability of clonidine to induce a protracted improvement in aspects of working memory. Early (attentional) and late (retention) components of memory appeared to be differentially sensitive to the dose of clonidine. Central alpha(2)-adrenergic receptors should be considered legitimate drug targets for future compound development for cognition enhancement.


Succession planning. A strategy for taking charge.
This article on succession planning includes a definition of succession planning, the reasons for and components of succession planning, and why succession planning is important to the leadership of an organization, unit, division or department. Each component of succession planning, that is, vision, networking, and mentorship, is described, with examples that are intended to guide the reader to initiate and evaluate succession planning.


Modeling of the Coral Microbiome: the Influence of Temperature and Microbial Network.
Host-associated microbial communities are shaped by extrinsic and intrinsic factors to the holobiont organism. Environmental factors and microbe-microbe interactions act simultaneously on the microbial community structure, making the microbiome dynamics challenging to predict. The coral microbiome is essential to the health of coral reefs and sensitive to environmental changes. Here, we develop a dynamic model to determine the microbial community structure associated with the surface mucus layer (SML) of corals using temperature as an extrinsic factor and microbial network as an intrinsic factor. The model was validated by comparing the predicted relative abundances of microbial taxa to the relative abundances of microbial taxa from the sample data. The SML microbiome from Pseudodiploria strigosa was collected across reef zones in Bermuda, where inner and outer reefs are exposed to distinct thermal profiles. A shotgun metagenomics approach was used to describe the taxonomic composition and the microbial network of the coral SML microbiome. By simulating the annual temperature fluctuations at each reef zone, the model output is statistically identical to the observed data. The model was further applied to six scenarios that combined different profiles of temperature and microbial network to investigate the influence of each of these two factors on the model accuracy. The SML microbiome was best predicted by model scenarios with the temperature profile that was closest to the local thermal environment, regardless of the microbial network profile. Our model shows that the SML microbiome of P. strigosa in Bermuda is primarily structured by seasonal fluctuations in temperature at a reef scale, while the microbial network is a secondary driver.IMPORTANCE Coral microbiome dysbiosis (i.e., shifts in the microbial community structure or complete loss of microbial symbionts) caused by environmental changes is a key player in the decline of coral health worldwide. Multiple factors in the water column and the surrounding biological community influence the dynamics of the coral microbiome. However, by including only temperature as an external factor, our model proved to be successful in describing the microbial community associated with the surface mucus layer (SML) of the coral P. strigosa The dynamic model developed and validated in this study is a potential tool to predict the coral microbiome under different temperature conditions.


Using decision analysis to assess comparative clinical efficacy of surgical treatment of unstable ankle fractures.
The development of a robust treatment algorithm for ankle fractures based on well-established stability criteria has been shown to be prognostic with respect to treatment and outcomes. In parallel with the development of improved understanding of the biomechanical rationale of ankle fracture treatment has been an increased emphasis on assessing the effectiveness of medical and surgical interventions. The purpose of this study was to investigate the use of using decision analysis in the assessment of the cost effectiveness of operative treatment of ankle fractures based on the existing clinical data in the literature. Using the data obtained from a previous structured review of the ankle fracture literature, decision analysis trees were constructed using standard software. The decision nodes for the trees were based on ankle fracture stability criteria previously published. The outcomes were assessed by calculated Quality-Adjusted Life Years (QALYs) assigned to achieving normal ankle function, developing posttraumatic arthritis, or sustaining a postoperative infection. Sensitivity analysis was undertaken by varying the patient's age, incidence of arthritis, and incidence or infection. Decision analysis trees captured the essential aspects of clinical decision making in ankle fracture treatment in a clinically useful manner. In general, stable fractures yielded better outcomes with nonoperative treatment, whereas unstable fractures had better outcomes with surgery. These were consistent results over a wide range of postoperative infection rates. Varying the age of the patient did not qualitatively change the results. Between the ages of 30 and 80 years, surgery yielded higher expected QALYs than nonoperative care for unstable fractures, and generated lower QALYs than nonoperative care for stable fractures. Using local cost estimates for operative and nonoperative treatment, the incremental cost of surgery for unstable fractures was less than $40,000 per QALY (the usual cutoff for the determination of cost effectiveness) for patients aged up to 90 years. Decision analysis is a useful methodology in developing treatment guidelines. Numerous previous studies have indicated superior clinical outcomes when unstable ankle fractures underwent operative reduction and stabilization. What has been lacking was an examination of the cost effectiveness of such an approach, particularly in older patients who have fewer expected years of life. In light of the evidence for satisfactory outcomes for surgery of severe ankle fractures in older people, the justification for operative intervention is an obvious question that can be asked in the current increasingly cost-conscious environment. Using a decision-tree decision analysis structured around the stability-based ankle fracture classification system, in conjunction with a relatively simple cost effectiveness analysis, this study was able to demonstrate that surgical treatment of unstable ankle fractures in elderly patients is in fact cost effective. The clinical implication of the present analysis is that these existing treatment protocols for ankle fracture treatment are also cost effective when quality of life outcome measures are taken into account. Economic Level II. See Instructions for Authors for a complete description of levels of evidence.


Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves.
Congenital anomalies of the aortic valve are common and are associated with progressive valvular insufficiency and/or stenosis. In addition, aneurysm, coarctation, and dissection of the ascending aorta and aortic arch are often associated conditions that complicate patient management and increase morbidity and mortality. These associated aortopathies are commonly attributed to turbulent hemodynamic flow through the malformed valve leading to focal defects in the vessel wall. However, numerous surgical and pathological studies have identified widespread cystic medial necrosis and smooth muscle apoptosis throughout the aortic arch in affected patients. Here, we provide experimental evidence for an alternative model to explain the association of aortic vessel and valvular disease. Using mice with primary and secondary cardiac neural crest deficiencies, we have shown that neural crest contribution to the outflow endocardial cushions (the precursors of the semilunar valves) is required for late gestation valvular remodeling, mesenchymal apoptosis, and proper valve architecture. Neural crest was also shown to contribute to the smooth muscle layer of the wall of the ascending aorta and aortic arch. Hence, defects of cardiac neural crest can result in functionally abnormal semilunar valves and concomitant aortic arch artery abnormalities.


Prognosis of acute myocardial infarction using systolic time intervals recorded on the carotidogram.
The prognostic value of systolic time intervals and of other clinical and laboratory parameters was investigated in 68 patients with acute myocardial infarction (AMI) (55 males and 13 females; mean age 61 years) over a period of one month after onset of the disease. The statistical analysis of data was made by the STR stepwise regression method, using an IBM-360 computer. Finally the study resulted in a stepwise multiple regression equation with 4 factors of maximum statistical significance in the prognosis of AMI: peak SGOT level, age of patients, uncorrected left ventricular ejection time and index of preejection period. This new prognostic index allows a classification of patients with acute myocardial infarction (starting with the second day after onset) into groups of various severity, thus helping the practitioners in the choice of therapy.


MYCN-dependent expression of sulfatase-2 regulates neuroblastoma cell survival.
Heparan sulfate proteoglycans (HSPG) play a critical role in the interaction of tumor cells and their microenvironment. HSPG activity is dictated by sulfation patterns controlled by sulfotransferases, which add sulfate groups, and sulfatases (Sulf), which remove 6-O-sulfates. Here, we report altered expression of these enzymes in human neuroblastoma cells with higher levels of Sulf-2 expression, a specific feature of MYCN-amplified cells (MYCN-A cells) that represent a particularly aggressive subclass. Sulf-2 overexpression in neuroblastoma cells lacking MYCN amplification (MYCN-NA cells) increased their in vitro survival. Mechanistic investigations revealed evidence of a link between Sulf-2 expression and MYCN pathogenicity in vitro and in vivo. Analysis of Sulf-2 protein expression in 65 human neuroblastoma tumors demonstrated a higher level of Sulf-2 expression in MYCN-A tumors than in MYCN-NA tumors. In two different patient cohorts, we confirmed the association in expression patterns of Sulf-2 and MYCN and determined that Sulf-2 overexpression predicted poor outcomes in a nonindependent manner with MYCN. Our findings define Sulf-2 as a novel positive regulator of neuroblastoma pathogenicity that contributes to MYCN oncogenicity. Cancer Res; 74(21); 5999-6009. ©2014 AACR.


Crystallization and X-ray diffraction of 5'-fluoro-5'-deoxyadenosine synthase, a fluorination enzyme from Streptomyces cattleya.
Organofluorine compounds are widely prepared throughout the chemicals industry, but their prepararion generally requires harsh fluorinating reagents and non-aqueous solvents. On the other hand, biology has hardly exploited organofluorine compounds. A very few organisms synthesize organofluorine metabolites, suggesting they have evolved a mechanism to overcome the kinetic desolvation barrier to utilizing F(-)(aq). Here, the purification and crystallization of an enzyme from Streptomyces cattleya which is responsible for the synthesis of the C-F bond during fluoroacetate and 4-fluorothreonine biosynthesis is reported. The protein crystallizes in space group C222(1), with unit-cell parameters a = 75.9, b = 130.3, c = 183.4 A, alpha = beta = gamma = 90 degrees. Data were recorded to 1.9 A at the ESRF. The structure of the protein should provide important insights into the biochemical process of C-F bond formation.


Physical characterization of Arabica ground coffee with different roasting degrees.
Roasting is a determinative operation on the final quality of coffee. Roasting process causes physical, chemical and sensory changes on coffee. In this study roasting degree effect on physical properties of Arabica fine ground coffee was examined. The bulk properties, particle property, reconstitution properties, moisture content, water activities and color properties were investigated in different roasting degrees of coffee. The results showed that the physical characteristics of coffee samples were influenced by the degree of roast. To have longer shelf life, lower cost and better physical attributes of Arabica fine ground coffee, the roasting process should be kept at a lower degree. At the same time the requests and expectations of customer should also be considered.


Aberrant Pregnancy Adaptations in the Peripheral Immune Response in Type 1 Diabetes: A Rat Model.
Despite tight glycemic control, pregnancy complication rate in type 1 diabetes patients is higher than in normal pregnancy. Other etiological factors may be responsible for the development of adverse pregnancy outcome. Acceptance of the semi-allogeneic fetus is accompanied by adaptations in the maternal immune-response. Maladaptations of the immune-response has been shown to contribute to pregnancy complications. We hypothesized that type 1 diabetes, as an autoimmune disease, may be associated with maladaptations of the immune-response to pregnancy, possibly resulting in pregnancy complications. We studied pregnancy outcome and pregnancy-induced immunological adaptations in a normoglycemic rat-model of type 1 diabetes, i.e. biobreeding diabetes-prone rats (BBDP; 5 non-pregnant rats, 7 pregnant day 10 rats and 6 pregnant day 18 rats) , versus non-diabetic control rats (i.e. congenic non-diabetic biobreeding diabetes-resistant (BBDR; 6 non-pregnant rats, 6 pregnant day 10 rats and 6 pregnant day 18 rats) and Wistar-rats (6 non-pregnant, 6 pregnant day 10 rats and 5 pregnant day 18 rats)). We observed reduced litter size, lower fetal weight of viable fetuses and increased numbers of resorptions versus control rats. These complications are accompanied by various differences in the immune-response between BBDP and control rats in both pregnant and non-pregnant animals. The immune-response in non-pregnant BBDP-rats was characterized by decreased percentages of lymphocytes, increased percentages of effector T-cells, regulatory T-cells and natural killer cells, an increased Th1/Th2-ratio and activated monocytes versus Wistar and BBDR-rats. Furthermore, pregnancy-induced adaptations in BBDP-rats coincided with an increased Th1/Th2-ratio, a decreased mean fluorescence intensity CD161a/NKR-P1b ratio and no further activation of monocytes versus non-diabetic control rats. This study suggests that even in the face of strict normoglycemia, pregnancy complications still occur in type 1 diabetic pregnancies. This adverse pregnancy outcome may be related to the aberrant immunological adaptations to pregnancy in diabetic rats.


Sensory attributes and texture profile of beef burgers with gari.
Beef burgers were produced using gari to substitute beef in the product formulations at 0% (control), 10%, 15% and 20% respectively. Cooking yield increased significantly (p<0.05) with increasing use of gari. Sensory evaluation of the products revealed significant (p<0.05) differences for acceptability and texture attributes. The acceptability score for burgers produced with 15% gari was not significantly different (p>0.05) from the control without gari. Using gari had no significant (p>0.05) effect on flavor and odor attributes of beef burgers. Texture profile analysis of burgers showed significant (p<0.05) reductions in hardness, springiness, gumminess and chewiness at all levels of substituting beef with gari. Production cost of burgers reduced by 9%, 14% and 18% respectively using 10%, 15% and 20% gari in burgers. The results suggest that gari has promising potential for use in comminuted meat products.


Energetic Charged Particles in Saturn's Magnetosphere: Voyager 2 Results.
Results from the cosmic-ray system on Voyager 2 in Saturn's magnetosphere are presented. During the inbound pass through the outer magnetosphere, the >/= 0.43-million-electron-volt proton flux was more intense, and both the proton and electron fluxes were more variable, than previously observed. These changes are attributed to the influence on the magnetosphere of variations in the solar wind conditions. Outbound, beyond 18 Saturn radii, impulsive bursts of 0.14- to > 1.0- million-electron-volt electrons were observed. In the inner magnetosphere, the charged particle absorption signatures of Mimas, Enceladus, and Tethys are used to constrain the possible tilt and offset of Saturn's internal magnetic dipole. At approximately 3 Saturn radii, a transient decrease was observed in the electron flux which was not due to Mimas. Characteristics of this decrease suggest the existence of additional material, perhaps another satellite, in the orbit of Mimas.


The SystHERs registry: an observational cohort study of treatment patterns and outcomes in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.
Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in approximately 20% of invasive breast cancer cases and is associated with a more aggressive disease course than HER2-negative breast cancer. HER2-targeted therapies have altered the natural history of HER2-positive breast cancer, a trend that will likely further improve with the recent approval of new agents. A prospective, observational cohort study was designed and initiated to provide real-world insights into current treatment patterns, long-term survival, and patients' experiences with initial and subsequent treatments for HER2-positive metastatic breast cancer (MBC). The Systematic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) is a US-based prospective observational cohort study enrolling patients ≥18 years of age with recently diagnosed HER2-positive MBC not previously treated with systemic therapy in the metastatic setting. The primary objective of the study is to identify treatment patterns and clinical outcomes in recently diagnosed patients in a variety of practice settings. Secondary objectives include comparative efficacy, safety, and patient-reported outcomes (PROs). Healthcare resource utilization is an exploratory end point. Tumor tissue and blood sample collection is optional.The SystHERs registry will enroll approximately 1000 patients over a 3-year period, after which the study will continue for ≥5 years, allowing for a maximum follow-up of 8 years. The treating physician will determine all care and the frequency of visits. PRO measures will be completed at study enrollment and every 90 days. Clinical data will be abstracted quarterly from patient records. The first patient was enrolled in June 2012, and preliminary descriptive data based on 25% to 30% of the final study population are expected at the end of 2013, and as of April 25, 2014, 386 patients are enrolled. SystHERs is expected to provide in-depth data on demographic, clinicopathological, and treatment patterns and their associations with clinical outcomes, PROs, and healthcare resource utilization. Tumor tissue and DNA repositories will also be established for use in future translational research. NCT01615068 (ClinicalTrials.gov identifier).


The site-frequency spectrum associated with Ξ-coalescents.
We give recursions for the expected site-frequency spectrum associated with so-called Xi-coalescents, that is exchangeable coalescents which admit simultaneous multiple mergers of ancestral lineages. Xi-coalescents arise, for example, in association with population models of skewed offspring distributions with diploidy, recurrent advantageous mutations, or strong bottlenecks. In contrast, the simpler Lambda-coalescents admit multiple mergers of lineages, but at most one such merger each time. Xi-coalescents, as well as Lambda-coalescents, can predict an excess of singletons, compared to the Kingman coalescent. We compare estimates of coalescent parameters when Xi-coalescents are applied to data generated by Lambda-coalescents, and vice versa. In general, Xi-coalescents predict fewer singletons than corresponding Lambda-coalescents, but a higher count of mutations of size larger than singletons. We fit examples of Xi-coalescents to unfolded site-frequency spectra obtained for autosomal loci of the diploid Atlantic cod, and obtain different coalescent parameter estimates than obtained with corresponding Lambda-coalescents. Our results provide new inference tools, and suggest that for autosomal population genetic data from diploid or polyploid highly fecund populations who may have skewed offspring distributions, one should not apply Lambda-coalescents, but Xi-coalescents.


Spontaneous histologic lesions of the adult naked mole rat (Heterocephalus glaber): a retrospective survey of lesions in a zoo population.
Naked mole rats (NMRs; Heterocephalus glaber) are highly adapted, subterranean, eusocial rodents from semiarid regions of the eastern horn of Africa and the longest-living rodent known with a maximum life span of up to 30 years. They are a unique model for aging research due to their physiology, extreme longevity, and, when compared to mice and rats, resistance to cancer. Published surveys of disease in NMRs are sparse. Captive colonies in zoological collections provide an opportunity to monitor spontaneous disease over time in a seminatural environment. This retrospective study describes common lesions of a zoo population over a 15-year period during which 138 adult NMRs were submitted for gross and histologic evaluation. Of these, 61 (44.2%) were male, 77 (55.8%) female, 45 (32.6%) died, and 93 (67.4%) were euthanized. The most frequent cause of death or reason for euthanasia was conspecific trauma (bite wounds) and secondary complications. Some common histologic lesions and their prevalence were renal tubular mineralization (82.6%), hepatic hemosiderosis (64.5%), bite wounds (63.8%), chronic progressive nephropathy (52.9%), and calcinosis cutis (10.1%). In sum, 104 (75.4%) NMRs had more than one of the most prevalent histologic lesions. No malignant neoplasms were noted; however, there was a case of renal tubular adenomatous hyperplasia with nuclear atypia and compression that in rats is considered a preneoplastic lesion. This retrospective study confirms the NMR's relative resistance to cancer in spite of development of other degenerative diseases and highlights the utility of zoological databases for baseline pathological data on nontraditional animal models.


How does the metabolism of tumour cells differ from that of normal cells.
Tumour cells thrive in environments that would be hostile to their normal cell counterparts. Survival depends on the selection of cell lines that harbour modifications of both, gene regulation that shifts the balance between the cell cycle and apoptosis and those that involve the plasticity of the metabolic machinery. With regards to metabolism, the selected phenotypes usually display enhanced anaerobic glycolysis even in the presence of oxygen, the so-called Warburg effect, and anabolic pathways that provide precursors for the synthesis of lipids, proteins and DNA. The review will discuss the original ideas of Otto Warburg and how they initially led to the notion that mitochondria of tumour cells were dysfunctional. Data will be presented to show that not only the organelles are viable and respiring, but that they are key players in tumorigenesis and metastasis. Likewise, interconnecting pathways that stand out in the tumour phenotype and that require intact mitochondria such as glutaminolysis will be addressed. Furthermore, comments will be made as to how the peculiarities of the biochemistry of tumour cells renders them amenable to new forms of treatment by highlighting possible targets for inhibitors. In this respect, a case study describing the effect of a metabolite analogue, the alkylating agent 3BP (3-bromopyruvate), on glycolytic enzyme targets will be presented.