mtDNA Heteroplasmy at the Core of Aging-Associated Heart Failure. An Integrative View of OXPHOS and Mitochondrial Life Cycle in Cardiac Mitochondrial Physiology.
The most common aging-associated diseases are cardiovascular diseases which affect 40% of elderly people. Elderly people are prone to suffer aging-associated diseases which are not only related to health and medical cost but also to labor, household productivity and mortality cost. Aging is becoming a world problem and it is estimated that 21.8% of global population will be older than 65 years old in 2050; and for the first time in human history, there will be more elderly people than children. It is well accepted that the origin of aging-associated cardiovascular diseases is mitochondrial dysfunction. Mitochondria have their own genome (mtDNA) that is circular, double-stranded, and 16,569 bp long in humans. There are between 500 to 6000 mtDNA copies per cell which are tissue-specific. As a by-product of ATP production, reactive oxygen species (ROS) are generated which damage proteins, lipids, and mtDNA. ROS-mutated mtDNA co-existing with wild type mtDNA is called mtDNA heteroplasmy. The progressive increase in mtDNA heteroplasmy causes progressive mitochondrial dysfunction leading to a loss in their bioenergetic capacity, disruption in the balance of mitochondrial fusion and fission events (mitochondrial dynamics, MtDy) and decreased mitophagy. This failure in mitochondrial physiology leads to the accumulation of depolarized and ROS-generating mitochondria. Thus, besides attenuated ATP production, dysfunctional mitochondria interfere with proper cellular metabolism and signaling pathways in cardiac cells, contributing to the development of aging-associated cardiovascular diseases. In this context, there is a growing interest to enhance mitochondrial function by decreasing mtDNA heteroplasmy. Reduction in mtDNA heteroplasmy is associated with increased mitophagy, proper MtDy balance and mitochondrial biogenesis; and those processes can delay the onset or progression of cardiovascular diseases. This has led to the development of mitochondrial therapies based on the application of nutritional, pharmacological and genetic treatments. Those seeking to have a positive impact on mtDNA integrity, mitochondrial biogenesis, dynamics and mitophagy in old and sick hearts. This review covers the current knowledge of mitochondrial physiopathology in aging, how disruption of OXPHOS or mitochondrial life cycle alter mtDNA and cardiac cell function; and novel mitochondrial therapies to protect and rescue our heart from cardiovascular diseases.


Hazardous chemicals: psychological dimensions of the health sequelae of a community exposure in Texas.
A chemical spill from an oil refinery exposed the local community to more than 40,000 lb of highly toxic and corrosive hydrofluoric acid. A community based symptom prevalence study found an association between exposure and physical symptoms: the psychological impact of the disaster and its potential effect on the reporting of physical symptoms is examined here. The study used a population based survey design consisting of two phases: phase I, the exposure phase, and, phase II, the symptom prevalence phase. In phase I, information indicative of exposure was collected on 10,811 individuals in a door to door survey of a geographically defined area. In phase II, symptom prevalence information was gathered through in-person interviews with 2509 subjects selected from the phase I census in a sampling scheme that balanced across the exposure categories with regard to age, gender, and predisposition. The refusal rate in both phases was < 5%. Stepwise logistic regression analyses were used to assess the relative predictive importance of psychological variables and hydrofluoric acid exposure in explaining the reported physical symptoms two years after the disaster. The findings show a linear relationship between the level of hydrofluoric acid exposure and the degree of psychological stress two years after the accident. High exposure had a long term (more than two years) impact on physical health for some self reported symptoms, even after controlling for the psychological impact. Some physical symptom reports, however, were better explained by psychological status than by exposure to hydrofluoric acid. The physical symptoms for which exposure was the major predictor were those for which the biological plausibility of a relationship with hydrofluoric acid exposure was direct. Measures of psychological status should be included in symptom studies of health sequelae to man-made disasters so that the physical effects of exposure can be more accurately assessed.


Clinicians' interpretations of point of care urine culture versus laboratory culture results: analysis from the four-country POETIC trial of diagnosis of uncomplicated urinary tract infection in primary care.
Urine culture at the point of care minimises delay between obtaining the sample and agar inoculation in a microbiology laboratory, and quantification and sensitivity results can be available more rapidly in primary care. To identify the degree to which clinicians' interpretations of a point-of-care-test (POCT) urine culture (Flexicult™ SSI-Urinary Kit) agrees with laboratory culture in women presenting to primary care with symptoms of uncomplicated urinary tract infections (UTI). Primary care clinicians used the Flexicult™-POCT, recorded their findings and took a photograph of the result, which was interpreted by microbiology laboratory technicians. Urine samples were additionally processed in routine care laboratories. Cross tabulations were used to identify important differences in organism identification, quantification and antibiotic susceptibility between these three sources of data. The influence of various laboratory definitions for UTI on culture were assessed. Primary care clinicians identified 202/289 urine samples (69.9%) as positive for UTI using the Flexicult™-POCT, whereas laboratory culture identified 94-190 (32.5-65.7%) as positive, depending on definition thresholds. 82.9% of samples identified positive for E. coli on laboratory culture were also considered positive for E. coli using the Flexicult™ -POCT, and susceptibilities were reasonably concordant. There were major discrepancies between laboratory staff interpretation of Flexicult™ photographs, clinicians' interpretation of the Flexicult™ test, and laboratory culture results. Flexicult™-POCT overestimated the positivity rate of urine samples for UTI when laboratory culture was used as the reference standard. However, it is unclear whether point-of-care or laboratory based urine culture provides the most valid diagnostic information.


Patient trends and outcomes of surgery for type A acute aortic dissection in Japan: an analysis of more than 10 000 patients from the Japan Cardiovascular Surgery Database.
To evaluate the background trends and surgical outcomes for more than 10 000 patients with acute type A dissection in Japan in a recent 8-year period. Data on replacement of the ascending aorta and/or aortic arch for acute type A dissection were collected from the Japan Cardiovascular Surgery Database from 2008 to 2015. Linear-by-linear association tests or Cuzick's test for trend was used to evaluate group trends over time. The results were calculated for ascending or hemiarch replacement and arch replacement. A multivariable logistic regression model was used to calculate the risk-adjusted operative mortality rate. A total of 11 843 patients were included. The overall 30-day mortality and operative mortality rates were 7.6% and 9.5%, respectively. The number of surgically treated cases increased from 2436 patients in 2008-2009 to 3533 in 2014-2015, a 45.0% increase. A trend analysis revealed significant changes in patient characteristics with time, including increasing age and rate of preoperative renal failure. Despite worsening risk factors, the unadjusted operative mortality rate with arch replacement showed a significant downward trend (P = 0.01; test of trend). The risk-adjusted mortality rate showed a downward trend both in ascending aorta or hemiarch replacement and arch replacement, although the trend was not statistically significant (P > 0.05). Unadjusted and adjusted operative deaths have shown a decreasing trend, although patients undergoing surgery for acute type A dissection have demonstrated worsening of risk factors, such as age and renal failure. The number of surgeries performed for acute type A dissection significantly increased throughout the study period in Japan.


Systemic Oxidative Stress, Aging and the Risk of Cardiovascular Events in the General Female Population.
Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stress plays a pivotal role. Systemic oxidative stress is reflected by decreased levels of free thiols (R-SH, sulfhydryl groups), which are key components of the extracellular antioxidant machinery. In this study, we investigated the relation between serum free thiols as marker of oxidative stress and the female cardiovascular phenotype, as well as potential associations with the risk of cardiovascular (CV) events in pre- and postmenopausal women from the general population. Methods: Female participants (n = 2,980) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study were included. Serum free thiol concentrations were analyzed for associations with demographic, clinical, biochemical, and gynecological parameters, as well as with menopausal status and, prospectively, with the risk of CV events. Results: Postmenopausal women had significantly reduced levels of serum free thiols (4.8 ± 1.0 vs. 5.2 ± 1.0 μmol/g, P < 0.001) compared to reproductive women. In multivariable analyses, serum free thiols were significantly associated with menopausal status (OR 0.70 [0.49-0.98], P = 0.039), even when adjusted for potential confounding factors, except for age (P = 0.550). Prospectively, serum free thiols were significantly associated with the risk of CV events (HR 0.52 [0.27-0.97], P = 0.040), even with covariate adjustment, although this disappeared when correcting for age. Conclusion: In this study, we revealed serum free thiols to be strongly associated with the female cardiovascular phenotype as well as with female risk of CV events, where the influence of age itself seemed to outweigh that of female menopause. Future studies are warranted to further unravel the clinical utility of serum free thiol levels in the context of female cardiovascular risk management.


Impairments on nonspatial self-ordered and externally ordered working memory tasks after lesions of the mid-dorsal part of the lateral frontal cortex in the monkey.
Monkeys with lesions of the mid-dorsal part of the lateral frontal cortex, which extends above the sulcus principalis as far as the midline (MDL lesions), were shown to exhibit severe and long-lasting impairments on certain nonspatial working memory tasks: the self-ordered and externally ordered tasks (experiments 1, 2, 3, 5, 6, and 8). These tasks, which were modeled on similar ones previously used with patients, measure the capacity to monitor, within working memory, self-generated choices and the occurrence of externally ordered stimuli. Monkeys with lesions of the adjacent posterior dorsolateral frontal cortex, which surrounds the arcuate sulcus (PA lesions), performed as well as the normal control animals on these tasks. Experiments 4 and 5 showed that the critical variable accounting for the impairment on the self-ordered and externally ordered working memory tasks by monkeys with MDL lesions is the size of the set of stimuli that must be monitored. Furthermore, the MDL lesions did not affect basic recognition memory (experiment 6), or primacy and recency mnemonic effects [i.e., the capacity to discriminate between the initial (or final) items and other items in a list of stimuli (experiments 4 and 7), or the capacity to select from a set of stimuli on the basis of a learned fixed sequence (experiment 9)]. Thus, lesions of the mid-dorsal part of the lateral frontal cortex give rise to an impairment in working memory that depends on the size of the set of the stimuli that have to be monitored.


Nonlinear chirp of dispersion-managed return-to-zero pulses.
Applying variational methods, we derive a reduced system of equations from the nonlocal equation that governs the average dynamics in dispersion-managed systems. These equations, which apply for any type of return-to-zero pulse, describe the stroboscopic evolution of the pulse parameters and bypass the fast variations inside each dispersion map. In the limit of large map strength we integrate the equations to obtain explicitly formulas for the parameters of a chirped return-to-zero pulse as well as the amount of post-transmission compensation needed to restore the initial pulse width.


Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10.
Inhalation of 9,10-phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust, exerts fatal damage against a variety of cells involved in respiratory function. Here, we show that treatment with high concentrations of 9,10-PQ evokes apoptosis of lung cancer A549 cells through production of reactive oxygen species (ROS). In contrast, 9,10-PQ at its concentrations of 2 and 5 μM elevated the potentials for proliferation, invasion, metastasis and tumorigenesis, all of which were almost completely inhibited by addition of an antioxidant N-acetyl-l-cysteine, inferring a crucial role of ROS in the overgrowth and malignant progression of lung cancer cells. Comparison of mRNA expression levels of six aldo-keto reductases (AKRs) in the 9,10-PQ-treated cells advocated up-regulation of AKR1B10 as a major cause contributing to the lung cancer malignancy. In support of this, the elevation of invasive, metastatic and tumorigenic activities in the 9,10-PQ-treated cells was significantly abolished by the addition of a selective AKR1B10 inhibitor oleanolic acid. Intriguingly, zymographic and real-time PCR analyses revealed remarkable increases in secretion and expression, respectively, of matrix metalloproteinase 2 during the 9,10-PQ treatment, and suggested that the AKR1B10 up-regulation and resultant activation of mitogen-activated protein kinase cascade are predominant mechanisms underlying the metalloproteinase induction. In addition, HPLC analysis and cytochrome c reduction assay in in vitro 9,10-PQ reduction by AKR1B10 demonstrated that the enzyme catalyzes redox-cycling of this quinone, by which ROS are produced. Collectively, these results suggest that AKR1B10 is a key regulator involved in overgrowth and malignant progression of the lung cancer cells through ROS production due to 9,10-PQ redox-cycling.


Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers.
The fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas is poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in high-grade serous ovarian carcinoma, we evaluated the functional role of cyclin E1 in serous carcinogenesis. Cyclin E1 was expressed in early- and late-stage human tumor samples. In primary human fallopian tube secretory epithelial cells, cyclin E1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together, our findings corroborate the hypothesis that cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of high-grade serous ovarian carcinomas.


Trabecular bone adaptation to loading in a rabbit model is not magnitude-dependent.
Although mechanical loading is known to influence trabecular bone adaptation, the role of specific loading parameters requires further investigation. Previous studies demonstrated that the number of loading cycles and loading duration modulate the adaptive response of trabecular bone in a rabbit model of applied loading. In the current study, we investigated the influence of load magnitude on the adaptive response of trabecular bone using the rabbit model. Cyclic compressive loads, producing peak pressures of either 0.5 or 1.0 MPa, were applied daily (5 days/week) at 1 Hz and 50 cycles/day for 4 weeks post-operatively to the trabecular bone on the lateral side of the distal right femur, while the left side served as an nonloaded control. The adaptive response was characterized by microcomputed tomography and histomorphometry. Bone volume fraction, bone mineral content, tissue mineral density, and mineral apposition rate (MAR) increased in loaded limbs compared to the contralateral control limbs. No load magnitude dependent difference was observed, which may reflect the critical role of loading compared to the operated, nonloaded contralateral limb. The increased MAR suggests that loading stimulated new bone formation rather than just maintaining bone volume. The absence of a dose-dependent response of trabecular bone observed in this study suggests that a range of load magnitudes should be examined for biophysical therapies aimed at augmenting current treatments to enhance long-term fixation of orthopedic devices.


Physical properties and erosion behavior of poly(trimethylene carbonate-co-ε-caprolactone) networks.
Form-stable resorbable networks are prepared by gamma irradiating trimethylene carbonate (TMC)- and ε-caprolactone (CL)-based (co)polymer films. To evaluate their suitability for biomedical applications, their physical properties and erosion behavior are investigated. Homopolymer and copolymer networks that are amorphous at room temperature are flexible and rubbery with elastic moduli ranging from 1.8 ± 0.3 to 5.2 ± 0.4 MPa and permanent set values as low as 0.9% strain. The elastic moduli of the semicrystalline networks are higher and range from 61 ± 3 to 484 ± 34 MPa. The erosion behavior of (co)polymer networks is investigated in vitro using macrophage cultures, and in vivo by subcutaneous implantation in rats. In macrophage cultures, as well as upon implantation, a surface erosion process is observed for the amorphous (co)polymer networks, while an abrupt decrease in the rate and a change in the nature of the erosion process are observed with increasing crystallinity. These resorbable and form-stable networks with tuneable properties may find application in a broad range of biomedical applications.


Environment and human friendly colored materials prepared using black and white components.
Our lives in the present age are full of colorful items. However, when many coloring materials cannot be used due to environmental concerns, this colorful life that has been constructed will be diminished. Maintaining our rich lifestyle necessitates the development of technologies that can make safe and secure color materials from materials with less burden on people and the environment. Herein, the author reveals that structural colored materials with little angle dependence can be prepared using various materials with short-range order in the refractive index, which is comparable to the wavelength of visible light, and with the aid of a black substance. This approach enables the preparation of colorful materials from materials that have a low environmental burden and are non-toxic to living things; examples of such materials include silica, carbon black, and iron oxide. If we can achieve mechanical stabilization and hue stabilization of these coloring materials, we can develop new green pigments with low toxicity, good color development, and high durability. The use of conventional angular-dependent structural colored materials has been limited. However, structural colored materials with no angle dependence, such as those prepared by the author, can be used in fields where pigments have traditionally been used. For example, they could be used in coating materials for automobiles and buildings, and in pigments used by artists. Environmentally friendly green color materials are expected to promote sustainable development. In this review, I will describe how to prepare structural colored materials with less angle dependency using white and black substances previously reported by the author.


Synthesis and evaluation of radioiodinated (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter.
Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT. (S,S)-(123/125)I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of (3)H-nisoxetine and (S,S)-(125)I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-(125)I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-(123)I-IPBM were carried out in the common marmoset. (S,S)-(125)I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-(125)I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-(125)I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-(123)I-IPBM allowed brain NET imaging in the common marmoset with SPECT. These results suggest that (S,S)-(123)I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.


MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
Professional antigen-presenting cells secrete major histocompatibility complex class II (MHC II) carrying exosomes with unclear physiological function(s). Exosomes are first generated as the intraluminal vesicles (ILVs) of a specific type of multivesicular body, and are then secreted by fusion of this compartment with the plasma membrane. We have previously shown that in contrast to the sorting of MHC II at lysosomally targeted multivesicular bodies, sorting of MHC II into exosomes does not rely on MHC II ubiquitination. In search for proteins that drive the incorporation of MHC II into exosomes or functionally discriminate exosomal from plasma membrane MHC II, we first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins, including known and not previously identified constituents. Using quantitative MS, we then identified a small subset of proteins that were specifically co-immunoprecipitated with MHC II from detergent-solubilized exosomes. These include HSC71, HSP90, 14-3-3ɛ, CD20 and pyruvate kinase type M2 (PKM2), and we speculate on the functionality of their interaction with exosomal MHC II.


Diabetes mellitus at the time of diagnosis of cirrhosis is associated with higher incidence of spontaneous bacterial peritonitis, but not with increased mortality.
DM (diabetes mellitus) is present in 20-40% of patients with liver cirrhosis, but its prognostic impact is unclear. Therefore, in the present study, we investigated whether the presence of DM in patients with cirrhosis was associated with increased mortality, and/or with increased incidence of SBP (spontaneous bacterial peritonitis). We reviewed medical and laboratory data of 230 patients with cirrhosis from the period 2001-2011, for whom data were complete in n=226. Follow-up for the outcomes mortality and SBP was performed until May 2012, with only 13 patients lost to follow-up. DM was present at baseline in 78 patients (35%). Median follow-up was 6.2 (interquartile range, 3.1-9.3) years, during which 118 patients died [47 out of 78 with DM (60%), and 71 out of 148 without DM (48%)]. The presence of DM at baseline was not associated with increased mortality after adjustment for age {HR (hazard ratio), 1.00 [95% CI (confidence interval), 0.67-1.50]}. Further adjustment for sex, aetiology of cirrhosis, platelet count and the Child-Pugh or MELD (model for end-stage liver disease) score did not change this finding. During follow-up, 37 patients developed incident SBP (19 with DM and 18 without DM). DM at baseline was associated with incident SBP, even after adjustment for age, sex, aetiology, platelet count and the Child-Pugh [HR, 2.39 (95% CI, 1.10-5.18)] or MELD score [HR, 2.50 (95% CI, 1.16-5.40)]. In conclusion, the presence of DM at baseline in patients with cirrhosis was associated with an increased risk of SBP, which may represent an increased susceptibility to infections. On the other hand, DM was not clearly associated with increased mortality in these patients.


Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia.
Persistent arterial hypotension is a hallmark of sepsis and is believed to be caused, at least in part, by excess nitric oxide (NO). NO can combine with superoxide to produce peroxynitrite, which activates matrix metalloproteinases (MMPs). Whether MMP inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia is unknown. Male Sprague-Dawley rats were administered either bacterial lipopolysaccharide (LPS, 4 mg/kg ip) or vehicle (pyrogen-free water). Later (30 min), animals received the MMP inhibitor doxycycline (4 mg/kg ip) or vehicle (pyrogen-free water). After LPS injection (6 h), animals were killed, and aortas were excised. Aortic rings were mounted in organ baths, and contractile responses to phenylephrine or KCl were measured. Aortas and plasma were examined for MMP activity by gelatin zymography. Aortic MMP and inducible nitric oxide synthase (iNOS) were examined by immunoblot and/or immunohistochemistry. Doxycycline prevented the LPS-induced development of ex vivo vascular hyporeactivity to phenylephrine and KCl. iNOS protein was significantly upregulated in aortic homogenates from endotoxemic rats; doxycycline did not alter its level. MMP-9 activity was undetectable in aortic homogenates from LPS-treated rats but significantly upregulated in the plasma; this was attenuated by doxycycline. Plasma MMP-2 activities were unchanged by LPS. Specific MMP-2 activity was increased in aortas from LPS-treated rats. This study demonstrates the in vivo protective effect of the MMP inhibitor doxycycline against the development of vascular hyporeactivity in endotoxemic rats.


Soil and stand structure explain shrub mortality patterns following global change-type drought and extreme precipitation.
The probability of extreme weather events is increasing, with the potential for widespread impacts to plants, plant communities, and ecosystems. Reports of drought-related tree mortality are becoming more frequent, and there is increasing evidence that drought accompanied by high temperatures is especially detrimental. Simultaneously, extreme large precipitation events have become more frequent over the past century. Water-limited ecosystems may be more vulnerable to these extreme events than other ecosystems, especially when pushed outside of their historical range of variability. However, drought-related mortality of shrubs-an important component of dryland vegetation-remains understudied relative to tree mortality. In 2014, a landscape-scale die-off of the widespread shrub, big sagebrush (Artemisia tridentata Nutt.), was reported in southwest Wyoming, following extreme hot and dry conditions in 2012 and extremely high precipitation in September of 2013. Here we examine how severe drought, extreme precipitation, soil texture and salinity, and shrub-stand characteristics contributed to this die-off event. At 98 plots within and around the die-off, we quantified big sagebrush mortality, characterized soil texture and salinity, and simulated soil-water conditions from 1916 to 2016 using an ecosystem water-balance model. We found that the extreme weather conditions alone did not explain patterns of big sagebrush mortality and did not result in extreme (historically unprecedented) soil-water conditions during the drought. Instead, plots with chronically dry soil conditions experienced greatest mortality following the global change-type (hot) drought in 2012. Furthermore, mortality was greater in locations with high potential run-on and low potential run-off where saturated soil conditions were simulated in September 2013, suggesting that extreme precipitation also played an important role in the die-off in these locations. In locations where drought alone contributed to mortality, stem density negatively impacted big sagebrush. In locations that may have been affected by both drought and saturation, however, mortality was greatest where stem density was lowest, suggesting that these locations may have already been less favorable to big sagebrush. Paradoxically, vulnerability to both extreme events (drought and saturation) was associated with finer-textured soils, and our results highlight the importance of soils in determining local variation of the vulnerability of dryland plants to extreme events.


The epidemiology of fragility fractures: is there a role for bone quality?
Fragility fractures, particularly those of the hip, vertebrae, and distal forearm, constitute a major public health problem. The two ultimate determinants of fracture are bone strength and propensity to trauma. Bone strength depends not only upon bone mass but also upon a variety of qualitative aspects of bone structure. These include its architecture, the amount of fatigue damage it has sustained, and changes in its bulk material properties, indices that are collectively subsumed into the term "bone quality." Fragility fractures show differences in their patterns of incidence by age, sex, ethnic group, geographic area, and season. Many of these differences are currently unexplained, and disorders of bone quality might contribute to them. There are two fracture sites at which evidence implicates bone quality more directly--the spine and proximal femur. Many vertebral compression fractures follow minimal trauma, and controlled studies suggest that vertebral microarchitecture contributes to fracture risk independently of vertebral bone mass. At the hip, observational studies have pointed to a role for disordered trabecular architecture, accumulation of microfractures (fatigue damage), and the accumulation of osteoid. The extent to which these phenomena act independently of bone mass, however, remains uncertain.


Successful and unsuccessful nonsurgical removal of ingested golf balls and an artificial egg in four rat snakes (Pantherophis alleghaniensis).
4 wild adult rat snakes (Pantherophis alleghaniensis) were evaluated after ingesting spherical or ovoid foreign bodies. Physical examination revealed a large, firm mass at the level of the stomach in each snake. Radiographic findings were consistent with ingestion of a golf ball (3 snakes) or an artificial egg (1 snake). Signs consistent with prolonged impaction included scale loss, dermal abrasions, and apparent loss of body condition in one snake and regional skin ulceration, dehydration, and generalized muscle atrophy in another. Nonsurgical removal of the foreign body was attempted in anesthetized or heavily sedated snakes by external manipulation in the orad direction. A golf ball was removed through the oral cavity without complications in 1 snake. In the other 3 snakes, tension caused by the advancing foreign body resulted in full-thickness skin rupture in the cervical region. The procedure was completed with the use of a balloon catheter to aid foreign body advancement for 1 of the 3 snakes, and the skin defect was closed. The procedure was converted to esophagotomy for the other 2 snakes. Three snakes recovered and were released; 1 died of complications from prolonged impaction and esophageal perforation. The described nonsurgical techniques for removal of ingested round or ovoid foreign bodies were associated with substantial complications in 3 of 4 treated rat snakes. Although a nonsurgical method for removal of ingested objects such as golf balls could benefit snakes, the methods used for these patients did not appear to be more beneficial than traditional gastrotomy.


Functionalised type-I collagen as a hydrogel building block for bio-orthogonal tissue engineering applications.
In this study, we derivatized type I collagen without altering its triple helical conformation to allow for facile hydrogel formation via the Michael addition of thiols to methacrylates without the addition of other crosslinking agents. This method provides the flexibility needed for the fabrication of injectable hydrogels or pre-fabricated implantable scaffolds, using the same components by tuning the modulus from Pa to kPa. Enzymatic degradability of the hydrogels can also be easily fine-tuned by variation of the ratio and the type of the cross-linking component. The structural morphology reveals a lamellar structure mimicking native collagen fibrils. The versatility of this material is demonstrated by its use as a pre-fabricated substrate for culturing human corneal epithelial cells and as an injectable hydrogel for 3-D encapsulation of cardiac progenitor cells.


Testing adaptive hypotheses of convergence with functional landscapes: a case study of bone-cracking hypercarnivores.
Morphological convergence is a well documented phenomenon in mammals, and adaptive explanations are commonly employed to infer similar functions for convergent characteristics. I present a study that adopts aspects of theoretical morphology and engineering optimization to test hypotheses about adaptive convergent evolution. Bone-cracking ecomorphologies in Carnivora were used as a case study. Previous research has shown that skull deepening and widening are major evolutionary patterns in convergent bone-cracking canids and hyaenids. A simple two-dimensional design space, with skull width-to-length and depth-to-length ratios as variables, was used to examine optimized shapes for two functional properties: mechanical advantage (MA) and strain energy (SE). Functionality of theoretical skull shapes was studied using finite element analysis (FEA) and visualized as functional landscapes. The distribution of actual skull shapes in the landscape showed a convergent trend of plesiomorphically low-MA and moderate-SE skulls evolving towards higher-MA and moderate-SE skulls; this is corroborated by FEA of 13 actual specimens. Nevertheless, regions exist in the landscape where high-MA and lower-SE shapes are not represented by existing species; their vacancy is observed even at higher taxonomic levels. Results highlight the interaction of biomechanical and non-biomechanical factors in constraining general skull dimensions to localized functional optima through evolution.


The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation.
Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Src-dependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR- or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response.


Fluorescent carbon nanomaterials: "quantum dots" or nanoclusters?
Despite many efforts, the mechanisms of light absorption and emission of small fluorescent carbon nanoparticles (C-dots) are still unresolved and are a subject of active discussion. In this work we address the question as to whether the fluorescence is a collective property of these nanoparticles or they are composed of assembled individual emitters. Selecting three types of C-dots with "violet", "blue" and "green" emissions and performing a detailed study of fluorescence intensity, lifetime and time-resolved anisotropy as a function of excitation and emission wavelengths together with the effect of viscogen and dynamic fluorescence quencher, we demonstrate that the C-dots represent assemblies of surface-exposed fluorophores. They behave as individual emitters, display electronic anisotropy, do not exchange their excited-state energies via homo-FRET and possibly display sub-nanosecond intra-particle mobility.


New nonlinear ultrasonic method for material characterization: Codirectional shear horizontal guided wave mixing in plate.
A nonlinear ultrasonic method is proposed based on a group of newly discovered wave triplets where two primary codirectional shear-horizontal SH0 waves mix in a weakly nonlinear plate and generate a cumulative S0 Lamb wave at the sum frequency. Theoretical analyses show that any combination of two primary SH0 waves whose frequencies sum to the frequency at which the SH0 mode intersects the S0 Lamb wave mode results in an internally resonant secondary S0 Lamb wave. Moreover, the relationship between the frequency combination and the nonlinear Lamb wave generation efficiency is revealed, which guides further engineering applications. Finite element validations are carried out with the aid of a subtraction method for the nonlinear feature extraction. The cumulative effect of the generated S0 Lamb wave at the sum frequency as well as the influence of the frequency combinations on the nonlinear Lamb wave generation efficiency is confirmed. Experiments are performed to validate the proposed method as well as demonstrate its use for material characterization. The experiments require a gel filter to mitigate the influence of the undesired nonlinear sources. With the gel filter, the cumulative effect of the secondary S0 Lamb wave is verified and the corresponding slope is extracted and further used to characterize the material status of the fatigue samples. Results demonstrate the proposed method provides high sensitivity to early fatigue damage, which makes it promising for the further early damage detection applications.


PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification.
The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function.


Recurrent Mycobacterium avium infection after seven years of latency in a HIV-infected patient receiving efficient antiretroviral therapy.
We report the first case of Mycobacterium avium reactivation, after prolonged latency, in a HIV-infected patient receiving highly active antiretroviral therapy with undetectable viral replication and normal CD4 cell count. The patient presented with a painful swollen shoulder seven years after initial M. avium bacteriaemia. Articular puncture grew M. avium. The isolates of the first and second infection were identical using repetitive-sequence-based Polymerase Chain Reaction analyses.


MicroRNA Targeted Therapeutic Approach for Pancreatic Cancer.
Pancreatic cancer remains the fourth leading cause of cancer-related death in the US and is expected to be the second leading cause of cancer-related death by 2030. Therefore, it is important to better understand the molecular pathogenesis, phenotypes and features of pancreatic cancer in order to design novel molecularly targeted therapies for achieving better therapeutic outcome of patients with pancreatic cancer. Recently, the roles of microRNAs (miRNAs) in the development and progression of pancreatic cancer became a hot topic in the scientific community of pancreatic cancer research. By conducting miRNA expression profiling, the aberrant expression of miRNAs was revealed in the serum and in cancer tissues from patients with pancreatic cancer. These aberrantly expressed miRNAs are critically correlated with the disease stage, drug resistance, and survival of pancreatic cancer patients. Hence, targeting these tiny molecules, the specific miRNAs, could provide an efficient and optimal approach in the therapy of pancreatic cancer. Indeed, the pre-clinical and in vivo experiments showed that nanoparticle delivery of synthetic oligonucleotides or treatment with natural agents could be useful to modulate the expression of miRNAs and thereby inhibit pancreatic cancer growth and progression, suggesting that targeting miRNAs combined with conventional anti-cancer therapeutics could be a novel therapeutic strategy for increasing drug sensitivity and achieving better therapeutic outcome of patients diagnosed with pancreatic cancer.


Expression of Cataract-linked γ-Crystallin Variants in Zebrafish Reveals a Proteostasis Network That Senses Protein Stability.
The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were γB- and γD-crystallin mutants linked to dominant cataracts in mouse models. Although thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone α-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different γD-crystallin mutants in the zebrafish lens and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins. Unlike mouse models, a strong correlation was observed between the severity and penetrance of the phenotype and the level of destabilization of the mutant. We interpret this result to reflect the presence of a proteostasis network that can "sense" protein stability. In the more destabilized mutants, the capacity of this network is overwhelmed, leading to the observed increase in phenotypic penetrance. Overexpression of αA-crystallin had no significant effects on the penetrance of lens defects, suggesting that its chaperone capacity is not limiting. Although consistent with the prevailing hypothesis that a chaperone network is required for lens transparency, our results suggest that αA-crystallin may not be efficient to inhibit aggregation of lens γ-crystallin. Furthermore, our work implicates additional inputs/factors in this underlying proteostasis network and demonstrates the utility of zebrafish as a platform to delineate mechanisms of cataract.


Asymmetric introgression in the horticultural living fossil cycas sect. Asiorientales using a genome-wide scanning approach.
The Asian cycads are mostly allopatric, distributed in small population sizes. Hybridization between allopatric species provides clues in determining the mechanism of species divergence. Horticultural introduction provides the chance of interspecific gene flow between allopatric species. Two allopatrically eastern Asian Cycas sect. Asiorientales species, C. revoluta and C. taitungensis, which are widely distributed in Ryukyus and Fujian Province and endemic to Taiwan, respectively, were planted in eastern Taiwan for horticultural reason. Higher degrees of genetic admixture in cultivated samples than wild populations in both cycad species were detected based on multilocus scans by neutral AFLP markers. Furthermore, bidirectional but asymmetric introgression by horticultural introduction of C. revoluta is evidenced by the reanalyses of species associated loci, which are assumed to be diverged after species divergence. Partial loci introgressed from native cycad to the invaders were also detected at the loci of strong species association. Consistent results tested by all neutral loci, and the species-associated loci, specify the recent introgression from the paradox of sharing of ancestral polymorphisms. Phenomenon of introgression of cultivated cycads implies niche conservation among two geographic-isolated cycads, even though the habitats of the extant wild populations of two species are distinct.


Laparoscopic ventral hernia repair with primary fascial closure versus bridged repair: a risk-adjusted comparative study.
Laparoscopy, specifically the bridged mesh technique, is a popular means used for ventral hernia repair. While laparoscopy has decreased the incidence of surgical site infection (SSI), hernia recurrence rates remain unchanged. Some surgeons advocate laparoscopic primary fascial closure (PFC) with placement of intraperitoneal mesh to decrease recurrence rates. We hypothesize that in patients undergoing laparoscopic ventral hernia repair (LVHR), PFC compared to a bridged mesh repair decreases hernia recurrence rates. A multicenter, retrospective database of all ventral hernia repairs performed from 2010-2012 was accessed. Patients who underwent LVHR with mesh were reviewed. Patients who had PFC were compared to bridged repair. Primary outcome was hernia recurrence determined by clinical examination or CT scan. Secondary outcomes included SSI and seroma formation. A total of 1594 patients were identified. Following exclusion, a total of 196 patients were left who underwent LVHR with a mean follow-up period of 17.5 months. Ninety-seven patients underwent PFC, while 99 underwent bridged repairs. Initial comparisons between both groups was negative for any significant statistical difference in terms of recurrence, seroma formation, SSI, deep/organ space SSI, reoperation, and readmission. The same initial findings held true during subgroup analysis. Propensity score analysis was then performed for recurrence, seroma, and SSI controlling for age, gender, immune status, ASA class, BMI, smoking status, and acute repair. No statistically significant differences were identified in either group. Primary fascial closure during laparoscopic hernia repairs did not result in reduced recurrence, seroma, and SSI as compared to bridge repairs in a retrospective, multi-institutional study. However, additional research is needed to further evaluate benefits to the patient in terms of pain, function, cosmesis, and overall satisfaction. Randomized, blinded, control trials should focus on these parameters in future investigations.


Disability, wages, and commuting in New York.
In the U.S., substantial employment and wage gaps persist between workers with and without disabilities. A lack of accessible transportation is often cited as a barrier to employment in higher wage jobs for people with disabilities, but little is known about the intraurban commuting patterns of employed people with disabilities in relation to their wage earnings. Our study compares wages and commute times between workers with and without disabilities in the New York metropolitan region and identifies the intraurban zones where residents experience higher inequities in wage earnings and commute times. We obtained our data from the Public Use Microdata Sample (PUMS) of the American Community Survey (ACS) for the 2008-2012 time period. We used linear mixed-effects models and generated separate models with log hourly wage or one-way commute time as the dependent variable. We find significant differences in wages and commute times between workers with and without disabilities at the scale of the metropolitan region as well as by intraurban zone. At the metropolitan scale, disabled workers earn 16.6% less and commute one minute longer on average than non-disabled workers. High commute and wage inequalities converge in the center, where workers with disabilities are more likely to use public transit, earn 17.1% less, and travel nearly four minutes longer on average than workers without disabilities. These results suggest that transport options are less accessible and slower for disabled workers than they are for non-disabled workers. Our findings indicate a need for more accessible and quicker forms of transportation in the center along with an increased availability of centrally located and affordable housing to reduce the disability gap in wages and commute times. We also find that workers with disabilities generally seek higher wages in exchange for longer commute times, but the results differ by race/ethnicity and gender. Compared to white men, minority workers earn much less, and white and Hispanic women have significantly shorter commute times. Our findings offer new geographic insights on how having a disability can influence wage earnings and commute times for workers in different intraurban zones in the New York metropolitan region.


Effect of a high-egg diet on cardiometabolic risk factors in people with type 2 diabetes: the Diabetes and Egg (DIABEGG) Study-randomized weight-loss and follow-up phase.
Some country guidelines recommend that people with type 2 diabetes (T2D) limit their consumption of eggs and cholesterol. Our previously published 3-mo weight-maintenance study showed that a high-egg (≥12 eggs/wk) diet compared with a low-egg diet (<2 eggs/wk) did not have adverse effects on cardiometabolic risk factors in adults with T2D. The current study follows the previously published 3-mo weight-maintenance study and assessed the effects of the high-egg compared with the low-egg diets as part of a 3-mo weight-loss period, followed by a 6-mo follow-up period for a total duration of 12 mo. Participants with prediabetes or T2D (n = 128) were prescribed a 3-mo daily energy restriction of 2.1 MJ and a macronutrient-matched diet and instructed on specific types and quantities of foods to be consumed, with an emphasis on replacing saturated fats with monounsaturated and polyunsaturated fats. Participants were followed up at the 9- and 12-mo visits. From 3 to 12 mo, the weight loss was similar (high-egg compared with low-egg diets: -3.1 ± 6.3 compared with -3.1 ± 5.2 kg; P = 0.48). There were no differences between groups in glycemia (plasma glucose, glycated hemoglobin, 1,5-anhydroglucitol), traditional serum lipids, markers of inflammation (high-sensitivity C-reactive protein, interleukin 6, soluble E-selectin), oxidative stress (F2-isoprostanes), or adiponectin from 3 to 12 mo or from 0 to 12 mo. People with prediabetes or T2D who consumed a 3-mo high-egg weight-loss diet with a 6-mo follow-up exhibited no adverse changes in cardiometabolic markers compared with those who consumed a low-egg weight-loss diet. A healthy diet based on population guidelines and including more eggs than currently recommended by some countries may be safely consumed. This trial is registered at http://www.anzctr.org.au/ as ACTRN12612001266853.


Woody plant phylogenetic diversity mediates bottom-up control of arthropod biomass in species-rich forests.
Global change is predicted to cause non-random species loss in plant communities, with consequences for ecosystem functioning. However, beyond the simple effects of plant species richness, little is known about how plant diversity and its loss influence higher trophic levels, which are crucial to the functioning of many species-rich ecosystems. We analyzed to what extent woody plant phylogenetic diversity and species richness contribute to explaining the biomass and abundance of herbivorous and predatory arthropods in a species-rich forest in subtropical China. The biomass and abundance of leaf-chewing herbivores, and the biomass dispersion of herbivores within plots, increased with woody plant phylogenetic diversity. Woody plant species richness had much weaker effects on arthropods, but interacted with plant phylogenetic diversity to negatively affect the ratio of predator to herbivore biomass. Overall, our results point to a strong bottom-up control of functionally important herbivores mediated particularly by plant phylogenetic diversity, but do not support the general expectation that top-down predator effects increase with plant diversity. The observed effects appear to be driven primarily by increasing resource diversity rather than diversity-dependent primary productivity, as the latter did not affect arthropods. The strong effects of plant phylogenetic diversity and the overall weaker effects of plant species richness show that the diversity-dependence of ecosystem processes and interactions across trophic levels can depend fundamentally on non-random species associations. This has important implications for the regulation of ecosystem functions via trophic interaction pathways and for the way species loss may impact these pathways in species-rich forests.


Sahamalaza Sportive Lemur, Lepilemur sahamalaza, Vocal Communication: Call Use, Context and Gradation.
Stereotypical vocalisations can facilitate long-distance communication in dense and, thus, sound-degrading forest habitats. Despite this, primate vocal repertoires often also include gradations between different call types that are used in social interactions. Because many nocturnal primates show a solitary social structure, it has been difficult to assess the role vocalisations play in mediating their social encounters. Here we aim to expand on the call types of Sahamalaza sportive lemurs, Lepilemur sahamalaza, as well as investigate their variability and use in social contexts. Through long-term behavioural observations with concurrent recording of vocalisations of known and unknown individuals between 2015 and 2016, we described three previously unrecorded calls and expanded the vocal repertoire to 12 different call types that were used in both targeted social and broadcast solitary contexts. Linear discriminant function and cluster analysis supported initial observations that vocalisations within call types were variable and that at least two call types can be classified as "graded," contrary to expectations. Despite variations in call-context connections, no clear patterns of call use could be established. However, measurable differences in vocal behaviour between the seasons and the sexes indicate that calling is used in a reproductive context, similar to other nocturnal and diurnal primates.


Schistosome egg antigens, including the glycoprotein IPSE/alpha-1, trigger the development of regulatory B cells.
Infection with the helminth Schistosoma (S.) mansoni drives the development of interleukin (IL)-10-producing regulatory B (Breg) cells in mice and man, which have the capacity to reduce experimental allergic airway inflammation and are thus of high therapeutic interest. However, both the involved antigen and cellular mechanisms that drive Breg cell development remain to be elucidated. Therefore, we investigated whether S. mansoni soluble egg antigens (SEA) directly interact with B cells to enhance their regulatory potential, or act indirectly on B cells via SEA-modulated macrophage subsets. Intraperitoneal injections of S. mansoni eggs or SEA significantly upregulated IL-10 and CD86 expression by marginal zone B cells. Both B cells as well as macrophages of the splenic marginal zone efficiently bound SEA in vivo, but macrophages were dispensable for Breg cell induction as shown by macrophage depletion with clodronate liposomes. SEA was internalized into acidic cell compartments of B cells and induced a 3-fold increase of IL-10, which was dependent on endosomal acidification and was further enhanced by CD40 ligation. IPSE/alpha-1, one of the major antigens in SEA, was also capable of inducing IL-10 in naïve B cells, which was reproduced by tobacco plant-derived recombinant IPSE. Other major schistosomal antigens, omega-1 and kappa-5, had no effect. SEA depleted of IPSE/alpha-1 was still able to induce Breg cells indicating that SEA contains more Breg cell-inducing components. Importantly, SEA- and IPSE-induced Breg cells triggered regulatory T cell development in vitro. SEA and recombinant IPSE/alpha-1 also induced IL-10 production in human CD1d+ B cells. In conclusion, the mechanism of S. mansoni-induced Breg cell development involves a direct targeting of B cells by SEA components such as the secretory glycoprotein IPSE/alpha-1.


Advancing cross-national planning and partnership: Proceedings from the International Multimorbidity Symposium 2019.
The International Multimorbidity Symposium was held in November 2019 at Western University to achieve three main objectives: to discuss progress and findings from various jurisdictions; to facilitate collaboration through group discussion to identify strategies to move multimorbidity research forward; and to create concrete plans to ensure advances in multimorbidity research and knowledge can be achieved through cross-national partnership. This event included keynote presentations, elevator pitch presentations and breakout sessions and there was a total of 35 attendees from eight countries, representing diverse disciplines and training levels. The overall themes arising from the event were: the importance of integrating the study and management of multimorbidity from both the primary care and public health perspectives; meaningful engagement and collaboration with patients and caregivers to understand key dimensions of multimorbidity; the considerable benefit of collaborative international partnerships; and the need to spread and scale innovations for health care systems that can better respond to the complex needs of patients and caregivers who are living with multimorbidity. Finally, it was well-acknowledged among the attendees that expanding the collaboration and discussion among international colleagues via in-person and virtual events will be important to move multimorbidity research forward.


Experimental congenital obstructive uropathy.
Continued experimental work in congenital obstructive uropathy is essential to support the rapidly advancing field of fetal medicine. It is possible to reproduce the clinically relevant obstructive lesions in an experimental model. On the basis of data from these models, the tentative conclusion is that in utero intervention is beneficial in severe congenital obstructive uropathy associated with oligohydramnios. The limited human experience provides insufficient data to confirm this hypothesis but has demonstrated the technical feasibility of prenatal interventions. There is a critical need for further refinement in understanding the complex pathophysiology of congenital obstructive uropathy, not only the renal consequences, but also the pulmonary and systemic effects. There remains the particular need to resolve the determinants and indicators of functional salvageability of the kidneys and lungs in congenital obstructive uropathy.


Regulation of Antitumor Immune Responses by Exosomes Derived from Tumor and Immune Cells.
Exosomes are lipid membrane-enclosed vesicles released by all cell types that act at the paracrine or endocrine level to favor cell differentiation, tissue homeostasis, organ remodeling and immune regulation. Their biosynthesis begins with a cell membrane invagination which generates an early endosome that matures to a late endosome. By inward budding of the late endosome membrane, a multivesicular body (MVB) with intraluminal vesicles (ILVs) is generated. The fusion of MVBs with the plasma membrane releases ILVs into the extracellular space as exosomes, ranging in size from 30 to 100 nm in diameter. The bilipid exosome membrane is rich in cholesterol, ceramides and phosphatidylserine and can be loaded with DNA, RNA, microRNAs, proteins and lipids. It has been demonstrated that exosome secretion is a common mechanism used by the tumor to generate an immunosuppressive microenvironment that favors cancer development and progression, allowing tumor escape from immune control. Due to their ability to transport proteins, lipids and nucleic acids from the cell that gave rise to them, exosomes can be used as a source of biomarkers with great potential for clinical applications in diagnostic, prognostic or therapeutic areas. This article will review the latest research findings on exosomes and their contribution to cancer development.


The immune system and the repair of skeletal muscle.
Skeletal muscle injury, despite the initial trigger, leads to a stereotypical cascade of events mediated by cells of the immune system. Acute damage recruits cells of the innate immune system (polymorphonuclear leukocytes and monocytes/macrophages) that initially release noxious molecules and clear the cellular debris. Macrophages in particular display two distinct differentiation patterns. At early times after acute damage inflammatory macrophages are predominant, and play a non-redundant role in the clearance of cellular debris. At later time points, when fibre regeneration occurs, macrophages acquire a de-activated phenotype, which has been associated to tissue remodelling. A role for cells of the acquired immune system, in particular antigen-specific T and B cells, in muscle regeneration has been envisaged, but still needs to be elucidated. Similar events possibly play a role during persistent muscle damage in which fibres never completely heal. As a consequence infiltrating leukocytes stay alive and are continuously activated. Their effector function in situ contributes to perpetuate the damage and results in the deposition of collagen with interstitial fibrosis and fat accumulation. In this review we will discuss the events characterising acute and persistent damage in stretch-induced injury, autoimmune polymyositis, inclusion bodies myositis and muscular dystrophies. We will focus on the molecular interactions involved in the positive and negative regulation of the inflammatory damage, with specific attention to their exploitation in the context of strategies to limit muscle wasting and supporting fibre regeneration.


Genetic clues to the molecular basis of tobacco addiction and progress towards personalized therapy.
The molecular processes that underlie addiction are beginning to unfold. Genetically determined variations in dopaminergic neurotransmission predispose to nicotine dependence. In addition, tobacco use is likely to be governed by the rate at which smokers metabolize nicotine. Functional polymorphisms in CYTOCHROME P450 monooxygenases that metabolize nicotine have now been defined and it should soon be possible to identify fast nicotine metabolizers by DNA analysis. Here, we review the key neurotransmitter receptors and metabolic enzymes implicated in tobacco dependence. We explore the potential benefits of classifying smokers according to the molecular aetiology of their habit. One major benefit will be in planning effective strategies for smoking cessation. Methods of typing for alleles related to smoking behavior that might be suitable for use in clinical practice in the future will also be discussed


Cognitive behavioural group therapy versus mindfulness-based stress reduction group therapy for intimate partner violence: a randomized controlled trial.
Violence in close relationships is a global public health problem and there is a need to implement therapeutic programs designed to help individuals who voluntarily seek help to reduce recurrent intimate partner violence. The effectiveness of such interventions in this population remains inconclusive. The aim of the present study was to compare the effectiveness of cognitive-behavioural group therapy (CBGT) vs mindfulness-based stress reduction (MBSR) group therapy in reducing violent behavior amongst individuals who are violent in intimate partnerships and who voluntarily seek help. One hundred forty four participants were randomized using an internet-based computer system. Nineteen withdrew after randomization and 125 participants were randomly assigned to the intervention condition (CBGT, n = 67) or the comparator condition (MBSR, n = 58). The intervention condition involved two individual sessions followed by 15 cognitive-behavioural group therapy sessions. The comparator condition included one individual session before and after 8 mindfulness-based group sessions. Participants (N = 125) and their relationship partners (n = 56) completed assessments at baseline, and at three, six, nine and twelve months' follow-up. The pre-defined primary outcome was reported physical, psychological or sexual violence and physical injury as measured by the revised Conflict Tactics Scale (CTS2). The intent-to-treat analyses were based on 125 male participants (intervention group n = 67; comparator group n = 58). Fifty-six female partners provided collateral information. Baseline risk estimate in the CBGT-group was .85 (.74-.92), and .88 (.76-.94) in the MBSR-group for physical violence. At 12-months' follow-up a substantial reduction was found in both groups (CBGT: .08 (.03-.18); MBSR: .19 (.11-.32)). Results provide support for the efficacy of both the cognitive-behavioural group therapy and the mindfulness-based stress reduction group therapy in reducing intimate partner violent behavior in men voluntarily seeking treatment. NCT01653860, registered July 2012.


Static point-spread function correction dominating higher-order speckle terms at high adaptive correction.
At high adaptive correction, the randomly shifting speckles familiar in conventional astronomical imaging become organized into patterns with distinct regularities that may permit partial suppression of the image noise they produce. Mathematically, the phase exponential in the Fourier-optical imaging expression may be expanded in a Taylor series in remnant phase phi, which is small at very high correction, leading to a perturbed point-spread function (PSF) that is a sum of algebraic terms, each of distinct spatial symmetry. At sufficiently high correction, one need deal with only a few of the lowest-order terms. A first-order expansion gives an ideal PSF plus two terms, linear and quadratic, describing the two brightest, physically most relevant kinds of speckle. A second-order expansion gives three new terms, the brightest of which is primarily a static correction to the PSF, with a much smaller true speckle component. When the correction is great enough to isolate individual speckle terms, the two terms from the first-order expansion alone determine the essential physics. A general observational strategy is outlined for reducing speckle noise in highly corrected companion searches, dominated by a few speckle terms of definite spatial symmetry.


The evolution of Bordetella pertussis has selected for mutations of acr that lead to sensitivity to hydrophobic molecules and fatty acids.
Whooping cough, or pertussis, is resurgent in numerous countries worldwide. This has renewed interest in Bordetella pertussis biology and vaccinology. The in vitro growth of B. pertussis has been a source of difficulty, both for the study of the organism and the production of pertussis vaccines. It is inhibited by fatty acids and other hydrophobic molecules. The AcrAB efflux system is present in many different bacteria and in combination with an outer membrane factor exports acriflavine and other small hydrophobic molecules from the cell. Here, we identify that the speciation of B. pertussis has selected for an Acr system that is naturally mutated and displays reduced activity compared to B. bronchiseptica, in which the system appears intact. Replacement of the B. pertussis locus with that of B. bronchiseptica conferred higher levels of resistance to growth inhibition by acriflavine and fatty acids. In addition, we identified that the transcription of the locus is repressed by a LysR-type transcriptional regulator. Palmitate de-represses the expression of the acr locus, dependent on the LysR regulator, strongly suggesting that it is a transcriptional repressor that is regulated by palmitate. It is intriguing that the speciation of B. pertussis has selected for a reduction in activity of the Acr efflux system that typically is regarded as protective to bacteria.


Systems Neuroscience of Natural Behaviors in Rodents.
Animals evolved in complex environments, producing a wide range of behaviors, including navigation, foraging, prey capture, and conspecific interactions, which vary over timescales ranging from milliseconds to days. Historically, these behaviors have been the focus of study for ecology and ethology, while systems neuroscience has largely focused on short timescale behaviors that can be repeated thousands of times and occur in highly artificial environments. Thanks to recent advances in machine learning, miniaturization, and computation, it is newly possible to study freely moving animals in more natural conditions while applying systems techniques: performing temporally specific perturbations, modeling behavioral strategies, and recording from large numbers of neurons while animals are freely moving. The authors of this review are a group of scientists with deep appreciation for the common aims of systems neuroscience, ecology, and ethology. We believe it is an extremely exciting time to be a neuroscientist, as we have an opportunity to grow as a field, to embrace interdisciplinary, open, collaborative research to provide new insights and allow researchers to link knowledge across disciplines, species, and scales. Here we discuss the origins of ethology, ecology, and systems neuroscience in the context of our own work and highlight how combining approaches across these fields has provided fresh insights into our research. We hope this review facilitates some of these interactions and alliances and helps us all do even better science, together.


Alcohol use, stigmatizing/discriminatory attitudes, and HIV high-risk sexual behaviors among men who have sex with men in China.
This research was conducted to assess the correlates of alcohol consumption and HIV/AIDS-related stigmatizing and discriminatory attitudes among men who have sex with men (MSM) in Shandong province, China. A cross-sectional survey provided demographics, sexual behaviors, illicit drug use, alcohol consumptions, and service utilization. Of 1,230 participants, 82.8% were single, 85.7% aged <35 years, 47.2% had college or higher education, and 11.7% drank alcohol >3 times per week in the past six months. The average total score of stigmatizing and discriminatory attitude was 37.4 ± 4.4. More frequent episodes of alcohol use were independently associated with higher levels of HIV/AIDS-related stigma and discrimination, unprotected anal sex, bisexual identity, multiple male sex partners, drug use, and lower levels of education. Expressing higher levels of HIV/AIDS-related stigmatizing and discriminatory attitudes was independently associated with alcohol use, unprotected male anal sex, bisexuals, more male sex partners, commercial sex with men, and non-receipt of peer education in the past year. HIV/AIDS-related stigmatizing and discriminatory attitudes are common and associated with alcohol use and unprotected sex among MSM. The finding highlights the needs to develop programs that would reduce HIV/AIDS-related stigmatizing and discriminatory attitudes and strengthen alcohol use prevention and risk reduction initiatives among MSM.


Recombinant adeno-associated virus serotype 2 vectors mediate stable interleukin 10 secretion from salivary glands into the bloodstream.
We have constructed a recombinant adeno-associated virus serotype 2 vector encoding human interleukin 10 (rAAVhIL10). IL-10 is a potent antiinflammatory/immune cytokine, which has received growing attention for its therapeutic potential. Human IL-10 (hIL-10) production was virus dose dependent after in vitro infection of HSG cells, a human submandibular gland cell line. The vector-derived hIL-10 produced was biologically active, as the medium from rAAVhIL10-infected HSG cells caused a dose-dependent blockade of IL-12 secretion from spleen cells of IL-10 knockout mice challenged with heat-killed Brucella abortus. Administration of rAAVhIL10 (10(10) genomes per gland) to both mouse submandibular glands led to hIL-10 secretion into the bloodstream (approximately 1-5 pg/ml), that is, in an endocrine manner, which was stable for approximately 2 months. Salivary gland administration of rAAVhIL10 under experimental conditions was more efficacious than intravenous administration (approximately 0.5-0.7 pg/ml). Also, hIL-10 was readily secreted in vitro from organ cultures of minced submandibular glands infected with rAAVhIL10, 6 or 8 weeks earlier. Consistent with these results, hIL-10 mRNA was detected by reverse transcription-polymerase chain reaction in submandibular glands of mice infected with rAAVhIL10 but not from control mice. At these doses, little to no hIL-10 was detected in mouse saliva. Using a rAAV serotype 2 vector encoding beta-galactosidase, we observed that the primary parenchymal target cells were ductal. These findings represent the first report of rAAV use to target exocrine glands for systemic secretion of a therapeutic protein, and support the notion that rAAV serotype 2 vectors may be useful in salivary glands for local (periglandular) and systemic gene-based protein therapeutics.


Cupriavidus malaysiensis sp. nov., a novel poly(3-hydroxybutyrate-co-4-hydroxybutyrate) accumulating bacterium isolated from the Malaysian environment.
Bacterial classification on the basis of a polyphasic approach was conducted on three poly(3 hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] accumulating bacterial strains that were isolated from samples collected from Malaysian environments; Kulim Lake, Sg. Pinang river and Sg. Manik paddy field. The Gram-negative, rod-shaped, motile, non-sporulating and non-fermenting bacteria were shown to belong to the genus Cupriavidus of the Betaproteobacteria on the basis of their 16S rRNA gene sequence analyses. The sequence similarity value with their near phylogenetic neighbour, Cupriavidus pauculus LMG3413T, was 98.5%. However, the DNA-DNA hybridization values (8-58%) and ribotyping analysis both enabled these strains to be differentiated from related Cupriavidus species with validly published names. The RiboPrint patterns of the three strains also revealed that the strains were genetically related even though they displayed a clonal diversity. The major cellular fatty acids detected in these strains included C15:0 ISO 2OH/C16:1 ω7c, hexadecanoic (16:0) and cis-11-octadecenoic (C18:1 ω7c). Their G+C contents ranged from 68.0 to 68.6 mol%, and their major isoprenoid quinone was Ubiquinone Q-8. Of these three strains, only strain USMAHM13 (= DSM 25816 = KCTC 32390) was discovered to exhibit yellow pigmentation that is characteristic of the carotenoid family. Their assembled genomes also showed that the three strains were not identical in terms of their genome sizes that were 7.82, 7.95 and 8.70 Mb for strains USMAHM13, USMAA1020 and USMAA2-4, respectively, which are slightly larger than that of Cupriavidus necator H16 (7.42 Mb). The average nucleotide identity (ANI) results indicated that the strains were genetically related and the genome pairs belong to the same species. On the basis of the results obtained in this study, the three strains are considered to represent a novel species for which the name Cupriavidus malaysiensis sp. nov. is proposed. The type strain of the species is USMAA1020T (= DSM 19416T = KCTC 32390T).


Photophysics of tryptophan in bacteriophage T4 lysozymes.
Bacteriophage T4 lysozyme contains three tryptophan residues in distinct environments. Lysozymes with one or two of these residues replaced by tyrosine are used to characterize the photophysics of tryptophan in these individual sites. The fluorescence spectra, average lifetimes, and quantum yields of these three single-tryptophan variants are understandable in terms of the neighboring residues. The emission spectra and radiative lifetimes are found to be the same for all three species while the quantum yield and decay kinetics are quite distinct. The variation of the average nonradiative rate constant is correlated with neighboring quenching groups. Quenching by I- correlates with exposure of the tryptophan residue based on the crystal structure. Complex behavior is observed for the time dependence of the fluorescence decay in all three cases, including that of the immobile tryptophan-138 residue. The complexity of the fluorescence decay is ascribed to heterogeneity in the nonradiative rate constant among microstates. Energy transfer between tryptophan residues is inferred to occur from comparison of the quantum yields of the two-tryptophan and single-tryptophan proteins and is discussed in terms of the Förster mechanism.


Prevalence and molecular characterization of Clostridium difficile isolated from feedlot beef cattle upon arrival and mid-feeding period.
The presence of indistinguishable strains of Clostridium difficile in humans, food animals and food, as well as the apparent emergence of the food-animal-associated ribotype 078/toxinotype V as a cause of community-associated C. difficile infection have created concerns about the potential for foodborne infection. While studies have reported C. difficile in calves, studies of cattle closer to the age of harvest are required. Four commercial feedlots in Alberta (Canada) were enrolled for this study. Fecal samples were collected at the time of arrival and after acclimation (< 62, 62-71 or > 71 days on feed). Selective culture for Clostridium difficile was performed, and isolates were characterized by ribotyping and pulsed-field gel electrophoresis. A logistic regression model was built to investigate the effect of exposure to antimicrobial drugs on the presence of C. difficile. Clostridium difficile was isolated from 18 of 539 animals at the time of feedlot arrival (CI = 2.3-6.1) and from 18 of 335 cattle at mid-feeding period (CI = 2.9-13.1). Overall, there was no significant difference in the prevalence of C. difficile shedding on arrival versus mid-feeding period (P = 0.47). No association between shedding of the bacterium and antimicrobial administration was found (P = 0.33). All the isolates recovered were ribotype 078, a toxinotype V strain with genes encoding toxins A, B and CDT. In addition, all strains were classified as NAP7 by pulsed field gel electrophoresis (PFGE) and had the characteristic 39 base pairs deletion and upstream truncating mutation on the tcdC gene. It is apparent that C. difficile is carried in the intestinal tracts of a small percentage of feedlot cattle arriving and later in the feeding period and that ribotype 078/NAP7 is the dominant strain in these animals. Herd management practices associated with C. difficile shedding were not identified, however further studies of the potential role of antimicrobials on C. difficile acquisition and shedding are required.


A collagen telopeptide binding peptide shows potential in aiding collagen bundle formation and fibril orientation.
Type I collagen, the main component of the extracellular matrix (ECM), assembles into bundles, which are then arranged in an orderly manner in many tissues. Various in vitro methods have been developed to mimic this native characteristic to create aligned, collagen-based materials for constructing tissue-engineered organs. In this study, we examined a new strategy to enhance collagen bundle formation and fibril orientation through administration of a collagen telopeptide binding peptide (CTBP). We found that CTBP, or a double-armed CTBP-PEG-CTBP derivative, could interact with both individual collagen molecules and fibrils. The CTBP interaction with collagen molecules inhibited fibril formation, whereas with reconstituted collagen fibrils, CTBP-PEG-CTBP promoted collagen bundle formation and fibril orientation. Finally, the addition of the CTBP derivative to the collagen matrix showed good cellular compatibility during in vitro cell culture. Taken together, our findings suggest that CTBP may have the potential for creating orderly, aligned, collagen-based matrices for tissue engineering.


Comparing different dosing regimens of bevacizumab in the treatment of neovascular macular degeneration: study protocol for a randomised controlled trial.
Bevacizumab (Avastin®) is as effective as ranibizumab (Lucentis®) in the treatment of neovascular age-related macular degeneration (nAMD). However it has two important structural differences. First, it has two active sites instead of one; second, it retains the Fc portion of the antibody which would be expected to confer a significantly longer half-life. These agents have been associated with systemic complications including strokes, so it is desirable to use the smallest effective dose. Furthermore, the standard dosing regimen requires monthly hospital visits, which present a significant challenge both to the hospital services and to the patients (who are elderly). Patients ≥50 years who are eligible for anti-vascular endothelial growth factor (VEGF) treatment of nAMD in the NHS, who are either newly referred for treatment or have reactivation of nAMD and who have not received treatment to either eye for the previous six months. We have designed a factorial multi-centre masked randomised controlled trial using bevacizumab as the intervention, with patients randomised to one of four arms: to standard or low dose and to monthly or two-monthly patient review. The aim is to recruit sufficient patients (around 1,000) to obtain 304 patients meeting the endpoint over a four-year period. The primary endpoint is time to treatment failure to be analysed using Cox regression. This randomised control trial will show if half dose and two monthly as required is as effective as full dose and monthly regimes. A two monthly as required regimen of Bevacizumab would significantly reduce both the cost and the service delivery burden for the treatment of nAMD while a reduced dose would be expected to enhance the safety profile of this treatment regime. International Standard Randomised Controlled Trial Number: ISRCTN95654194 , registered on 22 September 2009.


The cytoplasmic domain of chondrolectin interacts with the beta-subunit of Rab geranylgeranyl transferase.
Mouse chondrolectin (chodl) was isolated out of the tail tip of four-day old 129/SvJ mice as a by-product of a PCR-based subtractive cDNA library screening. The gene is predominantly expressed in adult skeletal muscle, heart, testes and lungs and in embryonic stadia. Chodl is the mouse homologue of human chondrolectin (CHODL), a gene that encodes for a type Ia transmembrane protein and that is expressed in human testis, prostate, heart and skeletal muscle tissue. CHODL-splice variants (CHODL ( f ), CHODL ( f Delta E ), CHODL ( Delta E )) are detected in human leukocytes. The proteins of the chondrolectin family belong to the family of C-type lectins. As the members of this protein family are important for a wide array of biological processes, the function of chodl was investigated by searching for its protein interaction partners. The beta-subunit of Rab geranylgeranyl transferase (Rabggtb) was isolated 8 times after a complete Sos recruitment system (SRS) screen with the cytoplasmic domain of chodl. The interaction was confirmed with in vitro transcription/translation and co-immunoprecipitation (co-IP) experiments.


On the relationship between fire regime and vegetation structure in the tropics.
We assessed data from 11 experiments examining the effects of the timing and/or frequency of fire on tropical forest and/or savanna vegetation structure over one decade or more. The initial 'control treatment' in many such cases consisted of previously cleared land. This is as opposed to natural vegetation subject to some sort of endogenous fire regime before the imposition of fire treatments. Effects of fire on fractional foliar cover are up to 10-fold greater when clearing pre-treatments are imposed. Moreover, because many of the 'classic' fire trials were initialised with applied management questions in mind, most have also used burning regimes much more frequent and/or severe than those occurring in the absence of human activity. Once these factors are taken into account, our modelling analysis shows that nonanthropogenic fire regimes serve to reduce canopy vegetative cover to a much lower extent than has previously been argued to be the case. These results call into question the notion that fire effects on tropical vegetation can be of a sufficient magnitude to maintain open-type savanna ecosystems under climatic/soil regimes otherwise sufficient to give rise to a more luxurious forest-type vegetation cover.


Identification of thyroid hormone receptor active compounds using a quantitative high-throughput screening platform.
To adapt the use of GH3.TRE-Luc reporter gene cell line for a quantitative high-throughput screening (qHTS) platform, we miniaturized the reporter gene assay to a 1536-well plate format. 1280 chemicals from the Library of Pharmacologically Active Compounds (LOPAC) and the National Toxicology Program (NTP) 1408 compound collection were analyzed to identify potential thyroid hormone receptor (TR) agonists and antagonists. Of the 2688 compounds tested, eight scored as potential TR agonists when the positive hit cut-off was defined at ≥10% efficacy, relative to maximal triiodothyronine (T3) induction, and with only one of those compounds reaching ≥20% efficacy. One common class of compounds positive in the agonist assays were retinoids such as all-trans retinoic acid, which are likely acting via the retinoid-X receptor, the heterodimer partner with the TR. Five potential TR antagonists were identified, including the antiallergy drug tranilast and the anxiolytic drug SB 205384 but also some cytotoxic compounds like 5-fluorouracil. None of the inactive compounds were structurally related to T3, nor had been reported elsewhere to be thyroid hormone disruptors, so false negatives were not detected. None of the low potency (>100µM) TR agonists resembled T3 or T4, thus these may not bind directly in the ligand-binding pocket of the receptor. For TR agonists, in the qHTS, a hit cut-off of ≥20% efficacy at 100 µM may avoid identification of positives with low or no physiological relevance. The miniaturized GH3.TRE-Luc assay offers a promising addition to the in vitro test battery for endocrine disruption, and given the low percentage of compounds testing positive, its high-throughput nature is an important advantage for future toxicological screening.


Effect of IRS4 levels on PI 3-kinase signalling.
Insulin receptor substrate 1 (IRS1) and IRS2 are well-characterized adapter proteins that relay signals from receptor tyrosine kinases to downstream components of signalling pathways. In contrast, the function of IRS4 is not well understood. IRS4 overexpression has been associated with acute lymphoblastic leukaemia and subungual exostosis, while point mutations of IRS4 have been found in melanomas. Here, we show that while IRS4 expression is low in most cancer cell lines, IRS4 mRNA and protein levels are markedly elevated in certain cells including the NCI-H720, DMS114, HEK293T and HEK293AAV lines. Surprisingly, IRS4 expression was also strongly induced when HEK293 cells were infected with retroviral particles and selected under puromycin, making IRS4 expression a potential off-target effect of retroviral expression vectors. Cells with high expression of IRS4 displayed high phosphatidylinositol (3,4,5)-trisphosphate (PIP3) levels, as well as elevated Akt and p70 S6 kinase activities, even in the absence of growth factors. PI 3-kinase (PI3K) signalling in these cells depends on IRS4, even though these cells also express IRS1/2. Knockdown of IRS4 also inhibited cell proliferation in cells with high levels of IRS4. Together, these findings suggest IRS4 as a potential therapeutic target for cancers with high expression of this protein.


Rigidity in routines and the development of resistance to change in individuals with Prader-Willi syndrome.
Individuals with Prader-Willi syndrome (PWS) commonly show debilitating resistance to change, which has been linked to cognitive deficits in task switching. Anecdotal reports suggest that exposure to flexibility in routines during development may be beneficial for limiting subsequent resistance to change in people with PWS, which is consistent with a beneficial role of such exposure on the development of task switching, highlighted in typical children. Here, we aim to investigate the development of resistance to change in individuals with PWS and hypothesise that exposure to increased rigidity in routines will be associated with increased subsequent resistance to change. An author-compiled informant report interview and two previously validated questionnaires were administered to the caregivers of 10 individuals with PWS (5-23 years). The interview examined rigidity in routines and resistance to change across life stages defined by easily distinguishable events (before school, during primary school, during secondary school, after school, currently), using open-ended and structured yes/no and 5-point Likert questions. Open-ended data were coded using an author-compiled system. Responses from two additional informants and data from the questionnaires were used to assess inter-informant reliability and concurrent validity of the structured questions. The validity of the interview was supported by acceptable inter-rater reliability of the open-ended coding system and inter-informant reliability, internal consistency and concurrent validity of structured questions. Descriptive analyses of ratings of behaviour change showed a pattern of increasing resistance to change over the life course for the four oldest individuals, who had all been exposed to substantial rigidity in routines before and during primary school. Furthermore, only one individual - currently in primary school - was exposed to very little rigidity in routines before and during primary school, and he had showed a decrease in resistance to change after entering primary school. Open-ended data showed that more individuals currently evidencing little resistance to change had been exposed to parent or self-imposed flexibility in routines, than those currently evidencing substantial resistance to change. However, correlational analyses on rigidity and resistance to change ratings highlighted the possibility that rigidity during primary school is most relevant for developing resistance to change. Finally, open-ended data emphasised an important beneficial role of rigidity in routines for limiting the current challenging behaviour of individuals with high resistance to change. Because task switching appears to evidence a period of high developmental sensitivity during early primary school years, we propose that this period may represent a critical time when increasing flexibility in the routines of children with PWS could limit the development of resistance to change. However, a careful balance would need to be struck, given the apparent benefit of rigid routines on current behaviour. Further work in this area is much needed.


Structure of the ribosomal interacting GTPase YjeQ from the enterobacterial species Salmonella typhimurium.
The YjeQ class of P-loop GTPases assist in ribosome biogenesis and also bind to the 30S subunit of mature ribosomes. YjeQ ribosomal binding is GTP-dependent and thought to specifically direct protein synthesis, although the nature of the upstream signal causing this event in vivo is as yet unknown. The attenuating effect of YjeQ mutants on bacterial growth in Escherichia coli makes it a potential target for novel antimicrobial agents. In order to further explore the structure and function of YjeQ, the isolation, crystallization and structure determination of YjeQ from the enterobacterial species Salmonella typhimurium (StYjeQ) is reported. Whilst the overall StYjeQ fold is similar to those of the previously reported Thematoga maritima and Bacillus subtilis orthologues, particularly the GTPase domain, there are larger differences in the three OB folds. Although the zinc-finger secondary structure is conserved, significant sequence differences alter the nature of the external surface in each case and may reflect varying signalling pathways. Therefore, it may be easier to develop YjeQ-specific inhibitors that target the N- and C-terminal regions, disrupting the metabolic connectivity rather than the GTPase activity. The availability of coordinates for StYjeQ will provide a significantly improved basis for threading Gram-negative orthologue sequences and in silico compound-screening studies, with the potential for the development of species-selective drugs.


Changes in GABAB modulation during a theta cycle may be analogous to the fall of temperature during annealing.
Changes in GABA modulation may underlie experimentally observed changes in the strength of synaptic transmission at different phases of the theta rhythm (Wyble, Linster, & Hasselmo, 1997). Analysis demonstrates that these changes improve sequence disambiguation by a neural network model of CA3. We show that in the framework of Hopfield and Tank (1985), changes in GABA suppression correspond to changes in the effective temperature and the relative energy of data terms and constraints of an analog network. These results suggest that phasic changes in the activity of inhibitory interneurons during a theta cycle may produce dynamics that resemble annealing. These dynamics may underlie a role for the theta cycle in improving sequence retrieval for spatial navigation.


Beating Nyquist with light: a compressively sampled photonic link.
We report the successful demonstration of a compressively sampled photonic link. The system takes advantage of recent theoretical developments in compressive sampling to enable signal recovery beyond the Nyquist limit of the digitizer. This rather remarkable result requires that (1) the signal being recovered has a sparse (low-dimensional) representation and (2) the digitized samples be incoherent with this representation. We describe an all-photonic system architecture that meets these requirements and then show that 1 GHz harmonic signals can be faithfully reconstructed even when digitizing at 500 MS/s, well below the Nyquist rate.


Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation.
Characterization and biological roles of the peroxisome proliferator-activated receptor (PPAR) isotypes are well known in monogastrics, but not in ruminants. However, a wealth of information has accumulated in little more than a decade on ruminant PPARs including isotype tissue distribution, response to synthetic and natural agonists, gene targets, and factors affecting their expression. Functional characterization demonstrated that, as in monogastrics, the PPAR isotypes control expression of genes involved in lipid metabolism, anti-inflammatory response, development, and growth. Contrary to mouse, however, the PPARγ gene network appears to controls milk fat synthesis in lactating ruminants. As in monogastrics, PPAR isotypes in ruminants are activated by long-chain fatty acids, therefore, making them ideal candidates for fine-tuning metabolism in this species via nutrients. In this regard, using information accumulated in ruminants and monogastrics, we propose a model of PPAR isotype-driven biological functions encompassing key tissues during the peripartal period in dairy cattle.