bluuebunny/crossref_metadata_2025 huggingface dataset:
A note on the rationale for estimating genealogical coancestry from molecular markers
Authors: Toro Miguel Ángel , García-Cortés Luis Alberto , Legarra Andrés
Published: July 2011

Background

Genetic relatedness or similarity between individuals is a key concept in population, quantitative and conservation genetics. When the pedigree of a population is available and assuming a founder population from which the genealogical records start, genetic relatedness between individuals can be estimated by the coancestry coefficient. If pedigree data is lacking or incomplete, estimation of the genetic similarity between individuals relies on molecular markers, using either molecular coancestry or molecular covariance. Some relationships between genealogical and molecular coancestries and covariances have already been described in the literature.

Methods

We show how the expected values of the empirical measures of similarity based on molecular marker data are functions of the genealogical coancestry. From these formulas, it is easy to derive estimators of genealogical coancestry from molecular data. We include variation of allelic frequencies in the estimators.

Results

The estimators are illustrated with simulated examples and with a real dataset from dairy cattle. In general, estimators are accurate and only slightly biased. From the real data set, estimators based on covariances are more compatible with genealogical coancestries than those based on molecular coancestries. A frequently used estimator based on the average of estimated coancestries produced inflated coancestries and numerical instability. The consequences of unknown gene frequencies in the founder population are briefly discussed, along with alternatives to overcome this limitation.

Conclusions

Estimators of genealogical coancestry based on molecular data are easy to derive. Estimators based on molecular covariance are more accurate than those based on identity by state. A correction considering the random distribution of allelic frequencies improves accuracy of these estimators, especially for populations with very strong drift.
Topical haemostatic agents for skin wounds: a systematic review
Authors: Groenewold Marieke D , Gribnau Astrid J , Ubbink Dirk T
Published: July 2011

Background

Various agents and techniques have been introduced to limit intra-operative blood loss from skin lesions. No uniformity regarding the type of haemostasis exists and this is generally based on the surgeon's preference. To study the effectiveness of haemostatic agents, standardized wounds like donor site wounds after split skin grafting (SSG) appear particularly suitable. Thus, we performed a systematic review to assess the effectiveness of haemostatic agents in donor site wounds.

Methods

We searched all randomized clinical trials (RCTs) on haemostasis after SSG in Medline, Embase and the Cochrane Library until January 2011. Two reviewers independently assessed trial relevance and quality and performed data analysis. Primary endpoint was effectiveness regarding haemostasis. Secondary endpoints were wound healing, adverse effects, and costs.

Results

Nine relevant RCTs with a fair methodological quality were found, comparing epinephrine, thrombin, fibrin sealant, alginate dressings, saline, and mineral oil. Epinephrine achieved haemostasis significantly faster than thrombin (difference up to 2.5 minutes), saline or mineral oil (up to 6.5 minutes). Fibrin sealant also resulted in an up to 1 minute quicker haemostasis than thrombin and up to 3 minutes quicker than placebo, but was not directly challenged against epinephrine. Adverse effects appeared negligible. Due to lack of clinical homogeneity, meta-analysis was impossible.

Conclusion

According to best available evidence, epinephrine and fibrin sealant appear superior to achieve haemostasis when substantial topical blood loss is anticipated, particularly in case of (larger) SSGs and burn debridement.
Plasmodium falciparum isolates from southern Ghana exhibit polymorphisms in the SERCA-type PfATPase6 though sensitive to artesunate in vitro
Authors: Kwansa-Bentum Bethel , Ayi Irene , Suzuki Takashi , Otchere Joseph , Kumagai Takashi , Anyan William K , Osei Joseph HN , Asahi Hiroko , Ofori Michael F , Akao Nobuaki , Wilson Michael D , Boakye Daniel A , Ohta Nobuo
Published: July 2011

Background

In 2005, Ghana replaced chloroquine with artemisinin-based combination therapy as the first-line treatment for uncomplicated malaria. The aim of this work was to determine for the first time, polymorphisms in the putative pfATPase6 and pftctp, pfmdr1, pfcrt genes in Ghanaian isolates, particularly at a time when there is no report on artemisinin resistance in malaria parasites from Ghana. The sensitivity of parasite isolates to anti-malaria drugs were also evaluated for a possible association with polymorphisms in these genes.

Methods

The prevalence of point mutations in the above Plasmodium falciparum genes were assessed from filter-paper blood blot samples by DNA sequencing. In vitro drug sensitivity test was carried out on some of the blood samples from volunteers visiting hospitals/clinics in southern Ghana using a modified version of the standard WHO Mark III micro-test.

Results

All successfully tested parasite isolates were sensitive to artesunate; while 19.4%, 29.0% and 51.6% were resistant to quinine, amodiaquine and chloroquine respectively. The geometric mean of IC50 value for artesunate was 0.73 nM (95% CI, 0.38-1.08), amodiaquine 30.69 nM (95% CI, 14.18-47.20) and chloroquine 58.73 nM (95% CI, 38.08-79.38). Twenty point mutations were observed in pfATPase6 gene, with no L263E and S769N. All mutations found were low in frequency, except D639G which was observed in about half of the isolates but was not associated with artesunate response (p = 0.42). The pftctp gene is highly conserved as no mutation was observed, while CVIET which is chloroquine-resistant genotype at codon 72-76 of the pfcrt gene was identified in about half of the isolates; this was consistent with chloroquine IC50 values (p = 0.001). Mutations were present in pfmdr1 gene but were not associated with artemisinin response (p = 1.00).

Conclusion

The pfATPase6 gene is highly polymorphic with D639G appearing to be fixed in Ghanaian isolates. These may just be spontaneous mutations as all parasite isolates that were tested displayed satisfactory in vitro response to artesunate. However, there is no improvement in susceptibility of the parasites to chloroquine five years after its proscription.
Antiobesity and lipid-lowering effects of Bifidobacterium spp. in high fat diet-induced obese rats
Authors: An Hyang Mi , Park Shin Young , Lee Do Kyung , Kim Jung Rae , Cha Min Kyeong , Lee Si Won , Lim Hyung Taeck , Kim Kyung Jae , Ha Nam Joo
Published: July 2011

Background

Recent studies have reported the preventive effects of probiotics on obesity. Among commensal bacteria, bifidobacteria is one of the most numerous probiotics in the mammalian gut and are a type of lactic acid bacteria. The aim of this study was to assess the antiobesity and lipid-lowering effects of Bifidobacterium spp. isolated from healthy Korean on high fat diet-induced obese rats.

Methods

Thirty-six male Sprague-Dawley rats were divided into three groups as follows: (1) SD group, fed standard diet; (2) HFD group, fed high fat diet; and (3) HFD-LAB group, fed high fat diet supplemented with LAB supplement (B. pseudocatenulatum SPM 1204, B. longum SPM 1205, and B. longum SPM 1207; 108 ~ 109 CFU). After 7 weeks, the body, organ, and fat weights, food intake, blood serum levels, fecal LAB counts, and harmful enzyme activities were measured.

Results

Administration of LAB reduced body and fat weights, blood serum levels (TC, HDL-C, LDL-C, triglyceride, glucose, leptin, AST, ALT, and lipase levels), and harmful enzyme activities (β-glucosidase, β-glucuronidase, and tryptophanase), and significantly increased fecal LAB counts.

Conclusion

These data suggest that Bifidobacterium spp. used in this study may have beneficial antiobesity effects.
Beyond platinum: synthesis, characterization, and in vitro toxicity of Cu(II)-releasing polymer nanoparticles for potential use as a drug delivery vector
Authors: Harris Alesha N , Hinojosa Barbara R , Chavious Montaleé D , Petros Robby A
Published: July 2011

The field of drug delivery focuses primarily on delivering small organic molecules or DNA/RNA as therapeutics and has largely ignored the potential for delivering catalytically active transition metal ions and complexes. The delivery of a variety of transition metals has potential for inducing apoptosis in targeted cells. The chief aims of this work were the development of a suitable delivery vector for a prototypical transition metal, Cu2+, and demonstration of the ability to impact cancer cell viability via exposure to such a Cu-loaded vector. Carboxylate-functionalized nanoparticles were synthesized by free radical polymerization and were subsequently loaded with Cu2+ via binding to particle-bound carboxylate functional groups. Cu loading and release were characterized via ICP MS, EDX, XPS, and elemental analysis. Results demonstrated that Cu could be loaded in high weight percent (up to 16 wt.%) and that Cu was released from the particles in a pH-dependent manner. Metal release was a function of both pH and the presence of competing ligands. The toxicity of the particles was measured in HeLa cells where reductions in cell viability greater than 95% were observed at high Cu loading. The combined pH sensitivity and significant toxicity make this copper delivery vector an excellent candidate for the targeted killing of disease cells when combined with an effective cellular targeting strategy.
Polystyrene negative resist for high-resolution electron beam lithography
Authors: Ma Siqi , Con Celal , Yavuz Mustafa , Cui Bo
Published: July 2011

We studied the exposure behavior of low molecular weight polystyrene as a negative tone electron beam lithography (EBL) resist, with the goal of finding the ultimate achievable resolution. It demonstrated fairly well-defined patterning of a 20-nm period line array and a 15-nm period dot array, which are the densest patterns ever achieved using organic EBL resists. Such dense patterns can be achieved both at 20 and 5 keV beam energies using different developers. In addition to its ultra-high resolution capability, polystyrene is a simple and low-cost resist with easy process control and practically unlimited shelf life. It is also considerably more resistant to dry etching than PMMA. With a low sensitivity, it would find applications where negative resist is desired and throughput is not a major concern.
System outage probability analysis in uplink multi-hop cellular systems over composite channels
Authors: Zhao Xibin , Wang Jun-Bo , Wang Jin-Yuan , Chen Ming , Feng Min , Sheng Ming
Published: July 2011

Owing to its superior performances, the multi-hop cellular system has drawn much attention in recent years. This paper aims to study the uplink system outage probability of the multi-hop cellular system over composite channels. Initially, we consider a composite channel model, which takes path loss, lognormal shadowing and Nakagami-m fading into account. Then, based on the amplify-and-forward relaying, the signal-to-noise ratio of each link is investigated. Further, an expression of the outage probability for a mobile station (MS) over a given position is derived after employing selective transmission scheme. After that, considering the distribution of MSs in the cellular systems, a numerical expression of the system outage probability is further obtained. Numerical results prove that the derived expression of the system outage probability can provide very good approximation to the realistic outage performance without time-intensive simulations. Moreover, it's also shown that the muilti-hop cellular system in this paper outperforms the conventional cellular system in terms of outage probability.
The expression of the receptor for advanced glycation end-products (RAGE) in RA-FLS is induced by IL-17 via Act-1
Authors: Heo Yu-Jung , Oh Hye-Jwa , Jung Young Ok , Cho Mi-La , Lee Seon-Yeong , Yu Jun-Geol , Park Mi-Kyung , Kim Hae-Rim , Lee Sang-Heon , Park Sung-Hwan , Kim Ho-Youn
Published: July 2011

Introduction

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathogenesis of arthritis. We conducted this study to determine the effect of interleukin (IL)-17 on the expression and production of RAGE in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). The role of nuclear factor-κB (NF-κB) activator 1 (Act1) in IL-17-induced RAGE expression in RA-FLS was also evaluated.

Methods

RAGE expression in synovial tissues was assessed by immunohistochemical staining. RAGE mRNA production was determined by real-time polymerase chain reaction. Act-1 short hairpin RNA (shRNA) was produced and treated to evaluate the role of Act-1 on RAGE production.

Results

RAGE, IL-17, and Act-1 expression increased in RA synovium compared to osteoarthritis synovium. RAGE expression and production increased by IL-17 and IL-1β (*P <0.05 vs. untreated cells) treatment but not by tumor necrosis factor (TNF)-α in RA-FLS. The combined stimuli of both IL-17 and IL-1β significantly increased RAGE production compared to a single stimulus with IL-17 or IL-1β alone (P <0.05 vs. 10 ng/ml IL-17). Act-1 shRNA added to the RA-FLS culture supernatant completely suppressed the enhanced production of RAGE induced by IL-17.

Conclusions

RAGE was overexpressed in RA synovial tissues, and RAGE production was stimulated by IL-17 and IL-1β. Act-1 contributed to the stimulatory effect of IL-17 on RAGE production, suggesting a possible inhibitory target for RA treatment.
Levosimendan inhibits release of reactive oxygen species in polymorphonuclear leukocytes in vitro and in patients with acute heart failure and septic shock: a prospective observational study
Authors: Hasslacher Julia , Bijuklic Klaudija , Bertocchi Cristina , Kountchev Jordan , Bellmann Romuald , Dunzendorfer Stefan , Joannidis Michael
Published: July 2011

Introduction

Levosimendan is an extensively investigated inodilator showing also cardioprotective and antiinflammatory effects. The aim of our study was to explore the influence of levosimendan on polymorphonuclear leucocytes (PMN), a main source of reactive oxygen species, in vitro and in patients with acute heart failure or septic myocardial depression.

Methods

PMN isolated from healthy volunteers were incubated with levosimendan in vitro. After stimulation with N-formyl-Met-Leu-Phe (fMLP) or phorbol 12-myristate 13-acetate (PMA) respiratory burst was quantified using a fluorescent dye. Apoptosis and expression of cell adhesion molecules of PMN were measured by flow cytometry. For determination of in vivo effects patients with acute heart failure (n = 16) or septic cardiac failure (n = 9) receiving levosimendan treatment were enrolled consecutively. PMN were isolated to measure respiratory burst activity before treatment as well as one and two hours after initiation of levosimendan administration. Furthermore inflammatory, hemodynamic and renal function parameters were obtained.

Results

In vitro, levosimendan suppressed respiratory burst activity in fMLP or PMA stimulated PMN in a dose dependent manner by 30 ± 11% (P < 0.001) at 100 ng/mL and by 27 ± 17% (P < 0.001) at 1000 ng/mL respectively. Markers of apoptosis and PMN cell adhesion molecule expression remained unaffected by levosimendan treatment.

In vivo, levosimendan treatment for two hours resulted in a significant reduction of PMA stimulated oxidative burst by 45% (P < 0.01) and fMLP stimulated oxidative burst by 49% (P < 0.05) in patients with acute heart failure. In patients suffering from septic shock levosimendan treatment decreased oxidative burst activity in unstimulated, fMLP and PMA stimulated PMN by 48% (P < 0.05), 46% (P < 0.01) and 43% (P < 0.01) respectively.

Conclusions

Levosimendan appears to exert distinct immunomodulatory effects by decreasing oxidative burst activity of PMN. This property might contribute to the previously described cardioprotective effects of the drug.
Automatic detection of patient-ventilator asynchrony by spectral analysis of airway flow
Authors: Gutierrez Guillermo , Ballarino Guillermo J , Turkan Hulya , Abril Juan , De La Cruz Lucy , Edsall Connor , George Binu , Gutierrez Susan , Jha Vinayak , Ahari Jalil
Published: July 2011

Introduction

Adequate ventilatory support of critically ill patients depends on prompt recognition of ventilator asynchrony, as asynchrony is associated with worse outcomes.

We compared an automatic method of patient-ventilator asynchrony monitoring, based on airway flow frequency analysis, to the asynchrony index (AI) determined visually from airway tracings.

Methods

This was a prospective, sequential observational study of 110 mechanically ventilated adults. All eligible ventilated patients were enrolled. No clinical interventions were performed. Airway flow and pressure signals were sampled digitally for two hours. The frequency spectrum of the airway flow signal, processed to include only its expiratory phase, was calculated with the Cooley-Tukey Fast Fourier Transform method at 2.5 minute intervals. The amplitude ratio of the first harmonic peak (H1) to that of zero frequency (DC), or H1/DC, was taken as a measure of spectral organization. AI values were obtained at 30-minute intervals and compared to corresponding measures of H1/DC.

Results

The frequency spectrum of synchronized patients was characterized by sharply defined peaks spaced at multiples of mean respiratory rate. The spectrum of asynchronous patients was less organized, showing lower and wider H1 peaks and disappearance of higher frequency harmonics. H1/DC was inversely related to AI (n = 110; r2 = 0.57; P < 0.0001). Asynchrony, defined by AI > 10%, was associated H1/DC < 43% with 83% sensitivity and specificity.

Conclusions

Spectral analysis of airway flow provides an automatic, non-invasive assessment of ventilator asynchrony at fixed short intervals. This method can be adapted to ventilator systems as a clinical monitor of asynchrony.
Long-period, long-duration seismic events during hydraulic fracture stimulation of a shale gas reservoir
Authors: Das Indrajit , Zoback Mark D.
Published: July 2011

We report here a series of long-period and long-duration (LPLD) seismic events observed during hydraulic fracturing in a shale gas reservoir. These unusual events, 10–100 s in duration, are observed most clearly in the frequency band of 10–80 Hz and are remarkably similar in appearance to tectonic tremor sequences first observed in subduction zones. These complex but coherent wave trains have finite moveouts obtained from cross-correlation. The moveout direction of the events confirms that they originate in the reservoir from the area where the fracturing is going on. Clear P- and S-wave arrivals cannot be resolved within the LPLD episodes but, in some cases, small micro-earthquakes occur in the sequences. Whether these micro-earthquakes are causal or coincidental is not known. It has also been observed that in three contiguous frac-stages, all LPLD events appear to come from two distinct places along one of two hypothetical fracture planes. Interestingly, the stages which have the largest number of LPLD events also have the highest observed pumping pressures during fracturing, the highest density of natural fractures, and the greatest number of micro-earthquakes. One possible explanation of these LPLD events is that the high pore fluid pressure during hydraulic fracturing stimulates slow slip on pre-existing fault planes. In the absence of elevated pressure, slip would not be expected on these planes as they are poorly oriented to the stress field. Slip on these fault planes may be occurring because the fluid pressure is close to the magnitude of the least principal stress. We observe a few events between pumping cycles perhaps indicating that, once triggered, these planes continue to slip due to the high transient pressure within the fault planes after pumping has stopped.
Documenting the Natural History of Patients With Resected Stage II Adenocarcinoma of the Colon After Random Assignment to Adjuvant Treatment With Edrecolomab or Observation: Results From CALGB 9581
Authors: Niedzwiecki Donna , Bertagnolli Monica M. , Warren Robert S. , Compton Carolyn C. , Kemeny Nancy E. , Benson Al Bowen , Eckhardt S. Gail , Alberts Steven , Porjosh Gity N. , Kerr David J. , Fields Anthony , Rougier Philippe , Pipas J. Marc , Schwartz Joel H. , Atkins James , O'Rourke Mark , Perry Michael C. , Goldberg Richard M. , Mayer Robert J. , Colacchio Thomas A.
Published: July 2011

Purpose

We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study also prospectively studied patient- and tumor-specific markers of treatment outcome.

Patients and Methods

After surgical resection, patients with stage II colon cancer were randomly assigned to either five infusions of edrecolomab at 28-day intervals or observation without adjuvant therapy.

Results

Final accrual included 1,738 patients; 865 patients received edrecolomab, and 873 patients were observed without adjuvant treatment. Median follow-up time was 7.9 years. There were no significant outcome differences between study arms (overall survival [OS], P = .71; disease-free survival, P = .64). The combined 5-year all-cause OS was 0.86 (95% CI, 0.84 to 0.88), and the combined 5-year disease-specific OS was 0.93 (95% CI, 0.91 to 0.94). The relationships between demographic and histopathologic factors and survival differed for all-cause and disease-specific survival outcomes, but no combined prognostic factor model was found to adequately classify patients at higher risk of recurrence or death as a result of colon cancer.

Conclusion

Edrecolomab did not prolong survival. Consequently, this large study with a long duration of follow-up provided unique data concerning the natural history of resected stage II colon cancer. Prognostic factors identified in previous retrospective and pooled analyses were associated with survival outcomes in this stage II patient cohort. Results from ongoing molecular marker studies may enhance our ability to determine the risk profile of these patients.
Survival and Disease Progression in Essential Thrombocythemia Are Significantly Influenced by Accurate Morphologic Diagnosis: An International Study
Authors: Barbui Tiziano , Thiele Juergen , Passamonti Francesco , Rumi Elisa , Boveri Emanuela , Ruggeri Marco , Rodeghiero Francesco , d'Amore Emanuele S.G. , Randi Maria Luigia , Bertozzi Irene , Marino Filippo , Vannucchi Alessandro M. , Antonioli Elisabetta , Carrai Valentina , Gisslinger Heinz , Buxhofer-Ausch Veronika , Müllauer Leonhard , Carobbio Alessandra , Gianatti Andrea , Gangat Naseema , Hanson Curtis A. , Tefferi Ayalew
Published: July 2011

Purpose

The WHO diagnostic criteria underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early/prefibrotic primary myelofibrosis (PMF). This study examined the clinical relevance of such a distinction.

Methods

Representatives from seven international centers of excellence for myeloproliferative neoplasms convened to create a clinicopathologic database of patients previously diagnosed as having ET (N = 1,104). Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis. All bone marrows subsequently underwent a central re-review.

Results

Diagnosis was confirmed as ET in 891 patients (81%) and was revised to early/prefibrotic PMF in 180 (16%); 33 patients were not evaluable. In early/prefibrotic PMF compared with ET, the 10-year survival rates (76% and 89%, respectively) and 15-year survival rates (59% and 80%, respectively), leukemic transformation rates at 10 years (5.8% and 0.7%, respectively) and 15 years (11.7% and 2.1%, respectively), and rates of progression to overt myelofibrosis at 10 years (12.3% and 0.8%, respectively) and 15 years (16.9% and 9.3%) were significantly worse. The respective death, leukemia, and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7% and 1.3% (relative risk [RR], 2.1; P < .001), 0.6% and 0.1% (RR, 5.2; P = .001), and 1% and 0.5% (RR, 2.0; P = .04). Multivariable analysis confirmed these findings and also identified age older than 60 years (hazard ratio [HR], 6.7), leukocyte count greater than 11 × 109/L (HR, 2.01), anemia (HR, 2.95), and thrombosis history (HR, 2.81) as additional risk factors for survival. Thrombosis and JAK2V617F incidence rates were similar between the two groups. Survival in ET was similar to the sex- and age-standardized European population.

Conclusion

This study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides important information on survival, disease complication rates, and prognostic factors in strictly WHO-defined ET and early/prefibrotic PMF.
Bone morphogenetic proteins regulate neural tube closure by interacting with the apicobasal polarity pathway
Authors: Eom Dae Seok , Amarnath Smita , Fogel Jennifer L. , Agarwala Seema
Published: July 2011

During neural tube closure, specialized regions called hinge points (HPs) display dynamic and polarized cell behaviors necessary for converting the neural plate into a neural tube. The molecular bases of such cell behaviors (e.g. apical constriction, basal nuclear migration) are poorly understood. We have identified a two-dimensional canonical BMP activity gradient in the chick neural plate that results in low and temporally pulsed BMP activity at the ventral midline/median hinge point (MHP). Using in vivo manipulations, high-resolution imaging and biochemical analyses, we show that BMP attenuation is necessary and sufficient for MHP formation. Conversely, BMP overexpression abolishes MHP formation and prevents neural tube closure. We provide evidence that BMP modulation directs neural tube closure via the regulation of apicobasal polarity. First, BMP blockade produces partially polarized neural cells, which retain contact with the apical and basal surfaces but where basolateral proteins (LGL) become apically localized and apical junctional proteins (PAR3, ZO1) become targeted to endosomes. Second, direct LGL misexpression induces ectopic HPs identical to those produced by noggin or dominant-negative BMPR1A. Third, BMP-dependent biochemical interactions occur between the PAR3-PAR6-aPKC polarity complex and phosphorylated SMAD5 at apical junctions. Finally, partially polarized cells normally occur at the MHP, their frequencies inversely correlated with the BMP activity gradient in the neural plate. We propose that spatiotemporal modulation of the two-dimensional BMP gradient transiently alters cell polarity in targeted neuronal cells. This ensures that the neural plate is flexible enough to be focally bent and shaped into a neural tube, while retaining overall epithelial integrity.
Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis
Authors: Sharir Amnon , Stern Tomer , Rot Chagai , Shahar Ron , Zelzer Elazar
Published: July 2011

The vertebrate skeleton consists of over 200 individual bones, each with its own unique shape, size and function. We study the role of intrauterine muscle-induced mechanical loads in determining the three-dimensional morphology of developing bones. Analysis of the force-generating capacity of intrauterine muscles in mice revealed that developing bones are subjected to significant and progressively increasing mechanical challenges. To evaluate the effect of intrauterine loads on bone morphogenesis and the contribution of the emerging shape to the ability of bones to withstand these loads, we monitored structural and mineral changes during development. Using daily micro-CT scans of appendicular long bones we identify a developmental program, which we term preferential bone growth, that determines the specific circumferential shape of each bone by employing asymmetric mineral deposition and transient cortical thickening. Finite element analysis demonstrates that the resulting bone structure has optimal load-bearing capacity. To test the hypothesis that muscle forces regulate preferential bone growth in utero, we examine this process in a mouse strain (mdg) that lacks muscle contractions. In the absence of mechanical loads, the stereotypical circumferential outline of each bone is lost, leading to the development of mechanically inferior bones. This study identifies muscle force regulation of preferential bone growth as the module that shapes the circumferential outline of bones and, consequently, optimizes their load-bearing capacity during development. Our findings invoke a common mechanism that permits the formation of different circumferential outlines in different bones.
FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium
Authors: Vega-Hernández Mónica , Kovacs Attila , De Langhe Stijn , Ornitz David M.
Published: July 2011

The epicardium serves as a source of growth factors that regulate myocardial proliferation and as a source of epicardial-derived cells (EPDC), which give rise to interstitial cardiac fibroblasts and perivascular cells. These progenitors populate the compact myocardium to become part of the mature coronary vasculature and fibrous skeleton of the heart. Little is known about the mechanisms that regulate EPDC migration into the myocardium or the functions carried out by these cells once they enter the myocardium. However, it has been proposed that cardiac fibroblasts are important for growth of the heart during late gestation and are a source of homeostatic factors in the adult. Here, we identify a myocardial to epicardial fibroblast growth factor (FGF) signal, mediated by FGF10 and FGFR2b, that is essential for movement of cardiac fibroblasts into the compact myocardium. Inactivation of this signaling pathway results in fewer epicardial derived cells within the compact myocardium, decreased myocardial proliferation and a resulting smaller thin-walled heart.
Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development
Authors: Yin Yongjun , Wang Fen , Ornitz David M.
Published: July 2011

Fibroblast growth factor (FGF) 9 is a secreted signaling molecule that is expressed in lung mesothelium and epithelium and is required for lung development. Embryos lacking FGF9 show mesenchymal hypoplasia, decreased epithelial branching and, by the end of gestation, hypoplastic lungs that cannot support life. Mesenchymal FGF signaling interacts with β-catenin-mediated WNT signaling in a feed-forward loop that functions to sustain mesenchymal FGF responsiveness and mesenchymal WNT/β-catenin signaling. During pseudoglandular stages of lung development, Wnt2a and Wnt7b are the canonical WNT ligands that activate mesenchymal WNT/β-catenin signaling, whereas FGF9 is the only known ligand that signals to mesenchymal FGF receptors (FGFRs). Here, we demonstrate that mesothelial- and epithelial-derived FGF9, mesenchymal Wnt2a and epithelial Wnt7b have unique functions in lung development in mouse. Mesothelial FGF9 and mesenchymal WNT2A are principally responsible for maintaining mesenchymal FGF-WNT/β-catenin signaling, whereas epithelial FGF9 primarily affects epithelial branching. We show that FGF signaling is primarily responsible for regulating mesenchymal proliferation, whereas β-catenin signaling is a required permissive factor for mesenchymal FGF signaling.
Crimpy inhibits the BMP homolog Gbb in motoneurons to enable proper growth control at theDrosophilaneuromuscular junction
Authors: James Rebecca E. , Broihier Heather T.
Published: July 2011

The BMP pathway is essential for scaling of the presynaptic motoneuron arbor to the postsynaptic muscle cell at the Drosophila neuromuscular junction (NMJ). Genetic analyses indicate that the muscle is the BMP-sending cell and the motoneuron is the BMP-receiving cell. Nevertheless, it is unclear how this directionality is established as Glass bottom boat (Gbb), the known BMP ligand, is active in motoneurons. We demonstrate that crimpy (cmpy) limits neuronal Gbb activity to permit appropriate regulation of NMJ growth. cmpy was identified in a screen for motoneuron-expressed genes and encodes a single-pass transmembrane protein with sequence homology to vertebrate Cysteine-rich transmembrane BMP regulator 1 (Crim1). We generated a targeted deletion of the cmpy locus and find that loss-of-function mutants exhibit excessive NMJ growth. In accordance with its expression profile, tissue-specific rescue experiments indicate that cmpy functions neuronally. The overgrowth in cmpy mutants depends on the activity of the BMP type II receptor Wishful thinking, arguing that Cmpy acts in the BMP pathway upstream of receptor activation and raising the possibility that it inhibits Gbb activity in motoneurons. Indeed, the cmpy mutant phenotype is strongly suppressed by RNAi-mediated knockdown of Gbb in motoneurons. Furthermore, Cmpy physically interacts with the Gbb precursor protein, arguing that Cmpy binds Gbb prior to the secretion of mature ligand. These studies demonstrate that Cmpy restrains Gbb activity in motoneurons. We present a model whereby this inhibition permits the muscle-derived Gbb pool to predominate at the NMJ, thus establishing the retrograde directionality of the pro-growth BMP pathway.
TECHNICAL NOTE—Optimizing Strategic Safety Stock Placement in General Acyclic Networks
Authors: Humair Salal , Willems Sean P.
Published: July 2011

We present two significant enhancements to the guaranteed-service (GS) model for multiechelon safety stock placement. First, we let each stage's expected inventory cost be a generalized nonconcave non-closed-form function of its incoming and outgoing service time. This allows the GS model to incorporate important phenomena such as variable stage times and nonnested review periods, which previous GS literature has not allowed. Second, we optimize the generalized cost GS model for directed acyclic networks, rather than assembly/distribution networks or trees. For the resulting NP-hard optimization problem, we present a provably optimal algorithm that runs within minutes for 29 chains from a data set of 38 real-world supply chains ranging from 8 to 2,025 stages. We also present two significantly faster yet near-optimal heuristics. One heuristic is motivated by the structure of the formulation's dual space, whereas the other heuristic simply terminates the optimization algorithm after a fixed number of iterations. As a performance benchmark, on the 38 chains, the first heuristic has an average optimality gap of approximately 1.1% and average run time of 88 seconds, whereas the second heuristic has an average optimality gap of 2.8% and an average run time of 5.9 seconds.
Heavy-Traffic Analysis of a Multiple-Phase Network with Discriminatory Processor Sharing
Authors: Verloop I. M. , Ayesta U. , Núñez-Queija R.
Published: July 2011

We analyze a generalization of the discriminatory processor-sharing (DPS) queue in a heavy-traffic setting. Customers present in the system are served simultaneously at rates controlled by a vector of weights. We assume that customers have phase-type distributed service requirements and allow that customers have different weights in various phases of their service.

In our main result we establish a state-space collapse for the queue-length vector in heavy traffic. The result shows that in the limit, the queue-length vector is the product of an exponentially distributed random variable and a deterministic vector. This generalizes a previous result by Rege and Sengupta [Rege, K. M., B. Sengupta. 1996. Queue length distribution for the discriminatory processor-sharing queue. Oper. Res. 44(4) 653–657], who considered a DPS queue with exponentially distributed service requirements. Their analysis was based on obtaining all moments of the queue-length distributions by solving systems of linear equations. We undertake a more direct approach by showing that the probability-generating function satisfies a partial differential equation that allows a closed-form solution after passing to the heavy-traffic limit.

Making use of the state-space collapse result, we derive interesting properties in heavy traffic: (i) For the DPS queue, we obtain that, conditioned on the number of customers in the system, the residual service requirements are asymptotically independent and distributed according to the forward recurrence times. (ii) We then investigate how the choice for the weights influences the asymptotic performance of the system. In particular, for the DPS queue we show that the scaled holding cost reduces as classes with a higher value for dk/E(Bkfwd) obtain a larger share of the capacity, where dk is the cost associated to class k, and E(Bkfwd) is the forward recurrence time of the class-k service requirement. The applicability of this result for a moderately loaded system is investigated by numerical experiments.
A Geometric Perspective on Lifting
Authors: Conforti Michele , Cornuéjols Gérard , Zambelli Giacomo
Published: July 2011

Recently it has been shown that minimal inequalities for a continuous relaxation of mixed-integer linear programs are associated with maximal lattice-free convex sets. In this paper, we show how to lift these inequalities for integral nonbasic variables by considering maximal lattice-free convex sets in a higher dimensional space. We apply this approach to several examples. In particular, we identify cases in which the lifting is unique.
Efficient Resource Allocation via Efficiency Bootstraps: An Application to R&D Project Budgeting
Authors: Chen Chien-Ming , Zhu Joe
Published: July 2011

Resource allocation decisions are crucial for the success of an organization. This paper proposes an integrated approach to resource allocation problems, in which decision makers have one observation of the multiple input-output criteria of candidates. We offer important improvements over existing approaches based on the widely used data envelopment analysis (DEA), which has two major limitations in its application to resource allocation. First, traditional DEA models compute efficiency scores by optimizing firm-specific shadow prices of inputs and outputs. This could be problematic, because in practice stakeholders would usually require unanimously agreed-upon trade-offs among evaluation criteria. Second, previous allocation approaches based on DEA do not allow for controlling the risk exposure of allocation portfolios. To tackle these problems, we propose an efficiency measure based on equilibrium shadow prices of different criteria, and we use the bootstrap efficiency distributions to gather information regarding efficiency variations and correlations. Through our methodology, decision makers can obtain the risk-minimizing allocation portfolio. We illustrate the proposed approach through an empirical R&D project budgeting problem in which we allocate funding according to the projects efficiency distributions.
A Periodic-Review Base-Stock Inventory System with Sales Rejection
Authors: Xu Yanyi , Bisi Arnab , Dada Maqbool
Published: July 2011

We consider a system in which an order is placed every T periods to bring the inventory position up to the base stock S. We accept demand until the inventory position reaches a sales rejection threshold M. Our objective is to find the optimal values of S and M that minimize the long-run average cost per period. We establish the stationary distribution of our system and develop structural properties of the optimal solution that facilitate computation. In particular, we show that in an optimal solution, the optimal value of M is nonnegative under some reasonable conditions. Hence, in our model a mixture of backorders and lost sales may occur. Additionally, we compare our system against traditional systems in which demand during stockouts is either fully backordered or lost.
TECHNICAL NOTE—Queueing Systems with Synergistic Servers
Authors: Andradóttir Sigrún , Ayhan Hayriye , Down Douglas G.
Published: July 2011

We consider tandem lines with finite buffers and flexible, heterogeneous servers that are synergistic in that they work more effectively in teams than on their own. Our objective is to determine how the servers should be assigned dynamically to tasks in order to maximize the long-run average throughput. In particular, we investigate when it is better to take advantage of synergy among servers, rather than exploiting the servers' special skills, to achieve the best possible system throughput. We show that when there is no trade-off between server synergy and servers' special skills (because the servers are generalists who are equally skilled at all tasks), the optimal policy has servers working in teams of two or more at all times. Moreover, for Markovian systems with two stations and two servers, we provide a complete characterization of the optimal policy and show that, depending on how well the servers work together, the optimal policy either takes full advantage of servers' special skills, or full advantage of server synergy (and hence there is no middle ground in this case). Finally, for a class of larger Markovian systems, we provide sufficient conditions that guarantee that the optimal policy should take full advantage of server synergy at all times.
Cellular and topochemical characteristics of secondary changes in bark tissues of beech (Fagus sylvatica)
Authors: Prislan Peter , Koch Gerald , Schmitt Uwe , Gričar Jožica , Čufar Katarina
Published: July 2011

Anatomical and histometrical investigations were carried out on bark tissues (non-collapsed and collapsed phloem, and periderm) of beech (Fagus sylvatica L.) trees growing at a forest site near Ljubljana, Slovenia (400 m a.s.l.). Secondary changes in bark, especially sclereid formation and lignification, were followed at cellular and sub-cellular levels by light microscopy (LM), UV microspectrophotometry (UMSP), and transmission electron microscopy (TEM). The average width of the whole bark was 5960 μm; non-collapsed phloem on average occupied 4%, collapsed phloem 89%, and periderm 7% of the bark. Secondary changes in mature phloem were characterized by a collapse of sieve tubes, inflation of axial parenchyma, and development of sclereids. The percentage of sclereid areas and the stage of their development elevated with increasing distance from the cambium. The most pronounced increment in the sclereid proportion was observed in the second- and third-fifth of the bark. Sclereid cell walls were thick and poly-lamellated and had similar spectral characteristics but distinctly higher UV absorbance values than xylem fibers. By means of a combination of LM, TEM and UMSP techniques, the structure and secondary changes in the bark could be precisely identified.
Influence of Precorrosion on Fatigue Properties of Shot-Peened Aluminium 7075-T651
Authors: Zupanc U. , Grum J.
Published: July 2011

Pitting corrosion has a major influence on aging of structural elements made of high-strength aluminium alloys as corrosion pits lead to much earlier fatigue crack initiation under tensile dynamic loading. In order to improve material resistance to corrosion fatigue, it is necessary to reduce pit-tip stresses in the corroded pits areas. Shot peening (SP) is an important and well-known cold working process, having been used in industrial applications for a long time. Shot peening as intense plastic deformation in the thin surface layer affects cold surface hardening by primary inducing favorable residual compressive stresses. It is used in order to increase fatigue strength in operation and to improve fatigue resistance of precorroded material. The paper deals with the surface integrity of shot-peened high-strength 7075-T651 aluminium alloy. The paper describes the effects of SP treatment by presenting analyses of surface roughness measurement, residual stresses, material bending fatigue resistance, fractographic analysis of fatigued specimens, and electrochemical potentiodynamic testing.
Intensive insulin treatment induces insulin resistance in diabetic rats by impairing glucose metabolism-related mechanisms in muscle and liver
Authors: Okamoto Maristela Mitiko , Anhê Gabriel Forato , Sabino-Silva Robinson , Ferreira Marques Milano Felipe dos Santos , Freitas Helayne Soares , Mori Rosana Cristina Tieko , Melo Karla Fabiana S , Machado Ubiratan Fabres
Published: July 2011

Insulin replacement is the only effective therapy to manage hyperglycemia in type 1 diabetes mellitus (T1DM). Nevertheless, intensive insulin therapy has inadvertently led to insulin resistance. This study investigates mechanisms involved in the insulin resistance induced by hyperinsulinization. Wistar rats were rendered diabetic by alloxan injection, and 2 weeks later received saline or different doses of neutral protamine Hagedorn insulin (1.5, 3, 6, and 9 U/day) over 7 days. Insulinopenic-untreated rats and 6U- and 9U-treated rats developed insulin resistance, whereas 3U-treated rats revealed the highest grade of insulin sensitivity, but did not achieve good glycemic control as 6U- and 9U-treated rats did. This insulin sensitivity profile was in agreement with glucose transporter 4 expression and translocation in skeletal muscle, and insulin signaling, phosphoenolpyruvate carboxykinase/glucose-6-phosphatase expression and glycogen storage in the liver. Under the expectation that insulin resistance develops in hyperinsulinized diabetic patients, we believe insulin sensitizer approaches should be considered in treating T1DM.
The transformation of hormonal stress responses throughout puberty and adolescence
Authors: Foilb Allison R , Lui Patina , Romeo Russell D
Published: July 2011

Prepubertal rats display heightened hormonal stress reactivity compared with adults in that levels of ACTH and corticosterone take twice as long (i.e. 40–60 min) to return to baseline following an acute stressor. Despite this substantial change in stress responsiveness, and the critical nature of the adolescence period of development, the maturation of the hormonal stress response from the time of pubertal onset to adulthood has not been thoroughly investigated. To examine this, we measured ACTH, corticosterone, and testosterone in 30-, 40-, 50-, 60-, and 70-day-old (i.e. spanning pubertal and adolescent development) male rats before and after a 30 min session of restraint stress. We found that the adult-like ACTH stress response develops between 50 and 60 days of age, while the corticosterone response changes between 30 and 40 days of age. We also found that adrenal corticosterone concentrations paralleled the plasma corticosterone response following restraint, suggesting that stress-induced adrenal corticosterone synthesis decreases during adolescent development and may, at least in part, contribute to the differential stress response observed before and after puberty. Finally, stress leads to increases in testosterone secretion, but only after 50 days of age. Collectively, these results indicate that shifts in hormonal stress responses occur throughout adolescent maturation and that these responses show distinct developmental profiles.
A Long-term Competent Chimeric Immune System in a Dizygotic Dichorionic Twin
Authors: Biran Valerie , Bornes Marie , Aboura Azzedine , Masmoudi Sonia , Drunat Séverine , Baumann Clarisse , Osimani Sara , Dalle Jean-Hugues , Sterkers Ghislaine , Verloes Alain , Farnoux Caroline , Maury Laure , Schmitz Thomas , Khung Suonavy , Baud Olivier
Published: July 2011

We present here a rare case that involved the long-term coexistence of 2 mature, functional, and equilibrated immune systems in a single child after fetofetal transfusion between dizygotic twins. A dichorionic diamniotic pregnancy complicated by twin anemia-polycythemia sequence resulted in the demise of 1 twin. The detection of abnormal vessels on the dichorionic plate strongly suggested the existence of functional vascular anastomoses leading to blood chimerism in the survivor. Genetic, phenotypic, and immunologic analyses at 2 years revealed chimeric lymphoid and myeloid cells in the surviving twin, although no tissue mosaicism was detected, which indicates that early transfusion led to mutual immune tolerance.