bluuebunny/crossref_metadata_2025 huggingface dataset:
Femoral anteversion and tibial torsion only explain 25% of variance in regression analysis of foot progression angle in children with diplegic cerebral palsy
Authors: Lee Kyoung Min , Chung Chin Youb , Sung Ki Hyuk , Kim Tae Won , Lee Seung Yeol , Park Moon Seok
Published: June 2013

Background

The relationship between torsional bony deformities and rotational gait parameters has not been sufficiently investigated. This study was to investigate the degree of contribution of torsional bony deformities to rotational gait parameters in patients with diplegic cerebral palsy (CP).

Methods

Thirty three legs from 33 consecutive ambulatory patients (average age 9.5 years, SD 6.9 years; 20 males and 13 females) with diplegic CP who underwent preoperative three dimensional gait analysis, foot radiographs, and computed tomography (CT) were included. Adjusted foot progression angle (FPA) was retrieved from gait analysis by correcting pelvic rotation from conventional FPA, which represented the rotational gait deviation of the lower extremity from the tip of the femoral head to the foot. Correlations between rotational gait parameters (FPA, adjusted FPA, average pelvic rotation, average hip rotation, and average knee rotation) and radiologic measurements (acetabular version, femoral anteversion, knee torsion, tibial torsion, and anteroposteriortalo-first metatarsal angle) were analyzed. Multiple regression analysis was performed to identify significant contributing radiographic measurements to adjusted FPA.

Results

Adjusted FPA was significantly correlated with FPA (r=0.837, p<0.001), contralateral FPA (r=0.492, p=0.004), pelvic rotation during gait (r=−0.489, p=0.004), knee rotation during gait (r=0.376, p=0.031), and femoral anteversion (r=0.350, p=0.046). In multiple regression analysis, femoral anteversion (p=0.026) and tibial torsion (p=0.034) were found to be the significant contributing structural deformities to the adjusted FPA (R2=0.247).

Conclusions

Femoral anteversion and tibial torsion were found to be the significant structural deformities that could affect adjusted FPA in patients with diplegic CP. Femoral anteversion and tibial torsion could explain only 24.7% of adjusted FPA.
Operant Behavioral Responses to Orofacial Cold Stimuli in Rats with Chronic Constrictive Trigeminal Nerve Injury: Effects of Menthol and Capsazepine
Authors: Zuo Xiaozhuo , Ling Jennifer X , Xu Guang-Yin , Gu Jianguo G
Published: June 2013

Both spinal and trigeminal somatosensory systems use the TRPM8 channel as a principal transducer for detecting cold stimuli. It is currently unclear whether this cold transducer may play a role in trigeminal neuropathic pain manifesting cold allodynia and hyperalgesia. In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI). Behavioral responses to cold stimuli in orofacial regions were assessed by the newly developed orofacial operant test in the ION-CCI rats. We tested menthol and capsazepine, two compounds that can activate and inhibit TRPM8 respectively, on orofacial operant responses to cold stimuli in ION-CCI rats. Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded. Total contact time was significantly reduced at the cooling temperatures of 17°C and 12°C in ION-CCI group in comparison with sham group, indicating the presence of cold allodynia and hyperalgesia in ION-CCI rats. When menthol was administered to ION-CCI rats, total contact time was further reduced and total contact number increased at the cooling temperatures. In contrast, after administration of capsazepine to ION-CCI rats, total contact time was significantly increased at the cooling temperatures. The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury.
An in-silico comparison of proton beam and IMRT for postoperative radiotherapy in completely resected stage IIIA non-small cell lung cancer
Authors: Berman Abigail T , Teo Boon-Keng Kevin , Dolney Derek , Swisher-McClure Samuel , Shahnazi Kambiz , Both Stefan , Rengan Ramesh
Published: June 2013

Introduction

Post-operative radiotherapy (PORT) for stage IIIA completely-resected non-small cell lung cancer (CR-NSCLC) has been shown to improve local control; however, it is unclear that this translates into a survival benefit. One explanation is that the detrimental effect of PORT on critical organs at risk (OARs) negates its benefit. This study reports an in-silico comparative analysis of passive scattering proton therapy (PSPT)- and intensity modulated proton therapy (IMPT) with intensity modulated photon beam radiotherapy (IMRT) PORT.

Methods

The computed tomography treatment planning scans of ten patients with pathologic stage IIIA CR-NSCLC treated with IMRT were used. IMRT, PSPT, and IMPT plans were generated and analyzed for dosimetric endpoints. The proton plans were constructed with two or three beams. All plans were optimized to deliver 50.4 Gy(RBE) in 1.8 Gy(RBE) fractions to the target volume.

Results

IMPT leads to statistically significant reductions in maximum spinal cord, mean lung dose, lung volumes treated to 5, 10, 20, and 30 Gy (V5, V10, V20, V30), mean heart dose, and heart volume treated to 40 Gy (V40), when compared with IMRT or PSPT. PSPT reduced lung V5 but increased lung V20, V30, and heart and esophagus V40.

Conclusions

IMPT demonstrates a large decrease in dose to all OARs. PSPT, while reducing the low-dose lung bath, increases the volume of lung receiving high dose. Reductions are seen in dosimetric parameters predictive of radiation pneumonitis and cardiac morbidity and mortality. This reduction may correlate with a decrease in dose-limiting toxicity and improve the therapeutic ratio.
High prevalence of HIV/AIDS risky sexual behaviors among street youth in gondar town: a community based cross sectional study
Authors: Tadesse Negash , Awoke Ayele Tadesse , Birhanu Mengesha Zelalem , Addis Alene Kefyalew
Published: June 2013

Background

Street youth are vulnerable to HIV/AIDS and all kinds of health risks. This study assessed HIV/AIDS risky sexual behaviors and its predictors among street youth in Gondar town, Northwest Ethiopia.

Methods

A community based cross sectional study was conducted on 467 street youth living in Gondar town. A pre tested and structured questionnaire via interview was used to collect data. Logistic regression analysis was used to identify predictors. Odds ratio with 95% CI was computed to assess the strength of associations.

Results

A total of 288 (61.7%) respondents had sexual intercourse in their life time. Among these 264 (91.7%) had more than one lifetime sexual partners. In addition, 80.5% of them used condom inconsistently in the last 12 months. Khat chewing was found to be predictor of having multiple sexual partners. Rural former residence and longer duration of stay on the street are also identified as predictors of inconsistent condom use.

Conclusion

High prevalence of HIV/AIDS risky sexual behaviors were observed among street youth in Gondar town. Interventions aimed at reducing sexual risky behaviors among street youth should focus on reducing the duration of stay on the street and chat chewing.
Polymorphisms in the SOCS7 gene and glucose homeostasis traits
Authors: Capuano Melissa M , Sorkin John D , Chang Yen-Pei C , Ling Hua , O’Connell Jeffrey R , Rothman Paul B , Mitchell Braxton D , Silver Kristi D
Published: June 2013

Background

SOCS7 is a member of the suppressor of cytokine signaling family of proteins and is expressed in skeletal muscle and islets. SOCS7 deficient mice develop islet hyperplasia in the setting of increased insulin sensitivity and normal glucose tolerance. The objective of this study was to determine if variants in SOCS7 play a role in variation of glucose and insulin levels and the development of type 2 diabetes (T2DM).

Results

Five SOCS7 tagging SNPs were genotyped in diabetic and nondiabetic Old Order Amish. A case–control study was performed in T2DM (n = 145) and normal glucose tolerant (n = 358) subjects. Nominal associations were observed with T2DM and the minor alleles for rs8068600 (P = 0.01) and rs8074124 (P = 0.04); however, only rs8068600 remained significant after Bonferroni adjustment for multiple comparisons (P = 0.01). Among nondiabetic Amish (n = 765), no significant associations with glucose or insulin traits including fasting or 2 hour glucose and insulin from the oral glucose tolerance test, insulin or glucose area under the curve, Matsuda Index or HOMA-IR were found for any of the SNPs.

Conclusion

In conclusion, genetic variants in the SOCS7 gene do not impact variation in glucose homeostasis traits and only minimally impact risk of T2DM in the Old Order Amish. Our study was not able to address whether rare variants that potentially impact gene function might influence T2DM risk.
Susceptibility of Anopheles sinensis to Plasmodium vivax in malarial outbreak areas of central China
Authors: Zhu Guoding , Xia Hui , Zhou Huayun , Li Julin , Lu Feng , Liu Yaobao , Cao Jun , Gao Qi , Sattabongkot Jetsumon
Published: June 2013

Background

Anopheles sinensis,Anopheles anthropophagus,Anopheles minimusandAnopheles dirusare the major vectors of malaria transmission in China.Anopheles sinensisis considered a secondary vector due to its relatively low malaria-transmission ability. However, in 2005, an outbreak of over 40,000Plasmodium vivaxmalaria cases was reported in areas whereAnopheles sinensiswas the only major vector. Therefore, it is necessary to reassess the malaria transmission ability of this vector species in China.

Methods

Laboratory colonies ofAn. sinensisandAn. anthropophagus, and first-generation progeny (F1) ofAn. sinensisthat had been collected in central China, were infected by direct membrane feeding assay with mono-vivaxgametocyte-containing blood collected fromvivax-infected patients. The mosquitoes were kept for 7 to 14 days post-blood feeding to allow parasites to develop into oocysts and sporozoites. Infectivity was measured by dissecting midguts and salivary glands. The presence of oocysts and sporozoites was determined by microscopy at 7 and 14 days post-blood feeding, and the numbers of gametocytes and asexual parasites, as well as mosquito parasite infections, were determined.

Results

The positive oocyst and sporozoite feed rates of the 142 pairs of lab-colonyAn. sinensisandAn. anthropophaguswere not significantly different, and the same results were found with the 10 pairs of laboratory and F1An. sinensis.An. sinensishad more oocysts/midgut at 7 days post-feeding thanAn. anthropophagus, but the gametocytemia, asexual parasitemia, and ratio of macrogametocytes to microgametocytes, did not correlate with either oocyst or sporozoite infection. However, in the oocyst-positive mosquitoes, there was a correlation between gametocytemia and the average oocyst number/midgut.

Conclusions

The susceptibility ofAn. sinensis(both laboratory and F1) toP. vivax-infected blood is similar toAnopheles anthropophagus, when evaluated by membrane feeding assay under laboratory conditions. In recent years, in central China, thevivaxmalaria transmission ability ofAn. sinensishas probably been underestimated. Further studies of this species in other regions are needed.An. sinensiscould also be a good candidate vector for evaluating candidate malaria transmission-blocking vaccines (TBV).
Carcinogenesis of PIK3CA
Authors: German Sidra , Aslam Hafiz Muhammad , Saleem Shafaq , Raees Aisha , Anum Tooba , Alvi Arsalan Ahmad , Haseeb Abdul
Published: June 2013

PIK3CA is the most frequently mutated oncogene in human cancers. PIK3CA is phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha. It controls cell growth, proliferation, motility, survival, differentiation and intracellular trafficking. In most of human cancer alteration occurred frequently in the alpha isoform of phosphatidylinositol 3 kinase. PIK3CA mutations were most frequent in endometrial, ovarian, colorectal, breast, cervical, squamous cell cancer of the head and neck, chondroma, thyroid carcinoma and in cancer family syndrome. Inhibition of PI3K signaling can diminish cell proliferation, and in some circumstances, promote cell death. Consequently, components of this pathway present attractive targets for cancer therapeutics. A number of PI3K pathway inhibitors have been developed and used. PI3K inhibitors (both pan-PI3K and isoform-specific PI3K inhibitors), dual PI3K-mTOR inhibitors that are catalytic site inhibitors of the p110 isoforms and mTOR (the kinase component of both mTORC1 and mTORC2), mTOR catalytic site inhibitors, and AKT inhibitors are the most advanced in the clinic. They are approved for the treatment of several carcinomas.
Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations
Authors: Bragadottir Gudrun , Redfors Bengt , Ricksten Sven-Erik
Published: June 2013

Introduction

Estimation of kidney function in critically ill patients with acute kidney injury (AKI), is important for appropriate dosing of drugs and adjustment of therapeutic strategies, but challenging due to fluctuations in kidney function, creatinine metabolism and fluid balance. Data on the agreement between estimating and gold standard methods to assess glomerular filtration rate (GFR) in early AKI are lacking. We evaluated the agreement of urinary creatinine clearance (CrCl) and three commonly used estimating equations, the Cockcroft Gault (CG), the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, in comparison to GFR measured by the infusion clearance of chromium-ethylenediaminetetraacetic acid (51Cr-EDTA), in critically ill patients with early AKI after complicated cardiac surgery.

Methods

Thirty patients with early AKI were studied in the intensive care unit, 2 to 12 days after complicated cardiac surgery. The infusion clearance for 51Cr-EDTA obtained as a measure of GFR (GFR51Cr-EDTA) was calculated from the formula: GFR (mL/min/1.73m2) = (51Cr-EDTA infusion rate × 1.73)/(arterial 51Cr-EDTA × body surface area) and compared with the urinary CrCl and the estimated GFR (eGFR) from the three estimating equations. Urine was collected in two 30-minute periods to measure urine flow and urine creatinine. Urinary CrCl was calculated from the formula: CrCl (mL/min/1.73m2) = (urine volume × urine creatinine × 1.73)/(serum creatinine × 30 min × body surface area).

Results

The within-group error was lower for GFR51Cr-EDTA than the urinary CrCl method, 7.2% versus 55.0%. The between-method bias was 2.6, 11.6, 11.1 and 7.39 ml/min for eGFRCrCl, eGFRMDRD, eGFRCKD-EPI and eGFRCG, respectively, when compared to GFR51Cr-EDTA. The error was 103%, 68.7%, 67.7% and 68.0% for eGFRCrCl, eGFRMDRD, eGFRCKD-EPI and eGFRCG, respectively, when compared to GFR51Cr-EDTA.

Conclusions

The study demonstrated poor precision of the commonly utilized urinary CrCl method for assessment of GFR in critically ill patients with early AKI, suggesting that this should not be used as a reference method when validating new methods for assessing kidney function in this patient population. The commonly used estimating equations perform poorly when estimating GFR, with high biases and unacceptably high errors.
IL-4 induces a suppressive IL-10-producing CD8+ T cell population via a Cdkn2a-dependent mechanism
Authors: Zhao Yapu , Zhao Huiyuan , Sun Yuehong , Hao Jianlei , Qi Xiaofei , Zhou Xinglong , Wu Zhenzhou , Wang Puyue , Kaech Susan M , Weaver Casey T , Flavell Richard A , Zhao Liqing , Yao Zhi , Yin Zhinan
Published: June 2013

CD8+ T cells play an important role in immune regulation and effective immune responses against tumor cells, viral infection, and intracellular pathogens. In this report, using tiger or 10BiT mice, we defined a population of IL-10-producing CD8+ T cells that were induced by IL-4. These IL-10+CD8+ T cells possessed a strong inhibitory effect on the CD4+ T cell proliferation in an IL-10-dependent and cell contact-dependent fashion. In comparison with IL-10−CD8+ T cells, IL-10+CD8+ T cells expressed an array of Th2-like cytokines (IL-4, IL-5), perforin, and granzymes, as well as the cell cycle regulatory protein Cdkn2a. Interestingly, knockdown of cdkn2a using siRNA reduced IL-4-induced IL-10 production significantly. Furthermore, CD8+ T cells from Cdkn2a−/− mice produced a significantly lower amount of IL-10, and the effect was limited to CD8+ T cells but not observed in CD4+ T cells and APCs. Finally, IL-10+CD8+ T cells played a protective role in the TNBS-induced murine colitis model, indicating a critical role of this population of CD8+ T cells in regulatory immune responses. Taken together, we have defined a population of IL-10-producing CD8+ Tregs induced by IL-4 and mediated by Cdkn2a.
Cyclic AMP and c-KIT Signaling in Familial Testicular Germ Cell Tumor Predisposition
Authors: Azevedo Monalisa F. , Horvath Anelia , Bornstein Ethan R. , Almeida Madson Q. , Xekouki Paraskevi , Faucz Fabio R. , Gourgari Evgenia , Nadella Kiran , Remmers Elaine F. , Quezado Martha , de Alexandre Rodrigo Bertollo , Kratz Christian P. , Nesterova Maria , Greene Mark H. , Stratakis Constantine A.
Published: June 2013

Background:

Familial testicular germ cell tumors (FTGCTs) are hypothesized to result from the combined interaction of multiple low-penetrance genes. We reported inactivating germline mutations of the cAMP-binding phosphodiesterase 11A (PDE11A) as modifiers of FTGCT risk. Recent genome-wide association studies have identified single-nucleotide polymorphisms in the KITLG gene, the ligand for the cKIT tyrosine kinase receptor, as strong modifiers of susceptibility to both familial and sporadic testicular germ cell tumors.

Design:

We studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds, in whom the PDE11A gene had been sequenced by investigating the association between KITLG genome-wide association study single-nucleotide polymorphisms rs3782179 and rs4474514 and FTGCT risk in these patients and in 692 controls. We also examined cAMP and c-KIT signaling in testicular tissues and cell lines and extended the studies to 2 sporadic cases, one with a PDE11A defect and one without, as a comparison.

Results:

We found a higher frequency of the KITLG risk alleles in FTGCT patients who also had a PDE11A sequence variant, compared with those with a wild-type PDE11A sequence. In NTERA-2 and Tcam-2 cells transfected with the mutated forms of PDE11A (R52T, F258Y, Y727C, R804H, V820M, R867G, and M878V), cAMP levels were significantly higher, and the relative phosphodiesterase activity was lower than in the wild-type cells. KITLG expression was consistently increased in the presence of PDE11A-inactivating defects, both at the RNA and protein levels, in familial testicular germ cell tumors. The 2 sporadic cases that were studied, one with a PDE11A defect and another without, agreed with the data in FTGTCT and in the cell lines.

Conclusions:

Patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently. There may be an interaction between cAMP and c-KIT signaling in predisposition to testicular germ cell tumors.
New Genes in Bone Development: What's New in Osteogenesis Imperfecta
Authors: Marini Joan C. , Blissett Angela R.
Published: June 2013

Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by bone fragility and deformity and growth deficiency. Most cases of OI (classical types) have autosomal dominant inheritance and are caused by mutations in the type I collagen genes. During the past several years, a number of noncollagenous genes whose protein products interact with collagen have been identified as the cause(s) of rare forms of OI. This has led to a paradigm shift for OI as a collagen-related condition. The majority of the non-classical OI types have autosomal recessive inheritance and null mutations in their respective genes. The exception is a unique dominant defect in IFITM5, which encodes Bril and leads to hypertrophic callus and interosseous membrane ossification. Three recessive OI types arise from defects in any of the components of the collagen prolyl 3-hydroxylation complex (CRTAP, P3H1, CyPB), which modifies the collagen α1(I)Pro986 residue. Complex dysfunction leads to delayed folding of the procollagen triple helix and increased helical modification. Next, defects in collagen chaperones, HSP47 and FKBP65, lead to improper procollagen folding and deficient collagen cross-linking in matrix, respectively. A form of OI with a mineralization defect is caused by mutations in SERPINF1, whose protein product, PEDF, is a well-known antiangiogenesis factor. Defects in the C-propeptide cleavage enzyme, BMP1, also cause recessive OI. Additional genes, including SP7 and TMEM38B, have been implicated in recessive OI but are as yet unclassified. Elucidating the mechanistic pathways common to dominant and recessive OI may lead to novel therapeutic approaches to improve clinical manifestations.
Multiplicity of Hormone-Secreting Tumors: Common Themes About Cause, Expression, and Management
Authors: Marx Stephen J.
Published: June 2013

Context:

Multiplicity of hormone-secreting tumors occurs in a substantial portion of hormone-excess states. Multiplicity increases the difficulty of management and drives the selection of special strategies.

Evidence Acquisition:

This is a synthesis from publications about tumor development and expression, and also about types of clinical strategy for hormone-secreting tumors.

Evidence Synthesis:

Comparisons were made between patient groups with solitary tumors vs those with multiple tumors. Major themes with clinical relevance emerged. Usually, tumor multiplicity develops from a genetic susceptibility in all cells of a tissue. This applies to hormone-secreting tumors that begin as either polyclonal (such as in the parathyroids of familial hypocalciuric hypercalcemia) or monoclonal tumors (such as in the parathyroids of multiple endocrine neoplasia type 1 [MEN1]). High penetrance of a hereditary tumor frequently results in bilaterality and in several other types of multiplicity. Managements are better for the hormone excess than for the associated cancers. Management strategies can be categorized broadly as ablation that is total, subtotal, or zero. Examples are discussed for each category, and 1 example of each category is named here: 1) total ablation of the entire tissue with effort to replace ablated functions (for example, in C-cell neoplasia of multiple endocrine neoplasia type 2); 2) subtotal ablation with increased likelihood of persistent disease or recurrent disease (for example, in the parathyroid tumors of MEN1); or 3) no ablation of tissue with or without the use of pharmacotherapy (for example, with blockers for secretion of stomach acid in gastrinomas of MEN1).

Conclusions:

Tumor multiplicity usually arises from defects in all cells of the precursor tissue. Even the optimized managements involve compromises. Still, an understanding of pathophysiology and of therapeutic options should guide optimized management.
The C-terminus of S. pombe DDK subunit Dfp1 is required for meiosis-specific transcription and cohesin cleavage
Authors: Le Anh-Huy , Mastro Tara L. , Forsburg Susan L.
Published: June 2013

The DDK complex is a conserved kinase complex, consisting of a catalytic subunit, Hsk1 (Cdc7), and its regulatory subunit Dfp1 (Dbf4). This kinase is essential for DNA replication. In this work, we show that dfp1-r35, which truncates the Dfp1 C-terminus zinc finger, causes severe meiotic defects, including reduced spore viability, reduced formation of programmed double strand breaks, altered expression of meiotic genes, and disrupted chromosome segregation. There is a high frequency of dyad formation. Mutants are also defective in the phosphorylation and degradation of the meiotic cohesion, Rec8, resulting in a failure to proceed through the MII division. These defects are more pronounced in a haploid meiosis model than in a normal diploid meiosis. Thus, several critical meiotic functions are linked specifically to the C-terminus of Dfp1, which may target specific substrates for phosphorylation by Hsk1.
Ninein is essential for the maintenance of the cortical progenitor character by anchoring the centrosome to microtubules
Authors: Shinohara Hiroshi , Sakayori Nobuyuki , Takahashi Masanori , Osumi Noriko
Published: June 2013

The mammalian cerebral cortex develops from proliferative apical progenitor cells (APs) that exhibit cell cycle-dependent nuclear movement (interkinetic nuclear migration; INM), which may be important for efficient and continuous production of neurons. The Pax6 transcription factor plays a major role in INM by regulating various downstream molecules. We have previously observed abnormal INM and unstable localization of the centrosome in APs of the Pax6 homozygous mutant rat embryo. To understand the mechanisms of INM, we focused on the centrosomes of APs. One of the centrosomal proteins, ninein, is specifically localized in the centrosome of APs. We observed a dramatic downregulation of ninein in APs of the Pax6 mutant. Moreover, knockdown of ninein by RNAi induced ectopic distribution of reduced numbers of BrdU-positive (S-phase) and PH3-positive (M-phase) cells. Furthermore, time-lapsed imaging demonstrated that knockdown of ninein in vivo induced abnormal INM. Finally, we observed impaired microtubule regrowth in neural progenitors taken from Pax6 homozygous mutant rat embryos, which was recovered by via ninein overexpression. We also found that ninein knockdown enlarged the surface size area of apical endfeet of the APs. Our results suggest that ninein plays a role in the molecular machinery essential for INM by connecting microtubules to the centrosome.
Reversion of the Arabidopsis rpn12a-1 exon-trap mutation by an intragenic suppressor that weakens the chimeric 5’ splice site
Authors: Kurepa Jasmina , Li Yan , Smalle Jan A
Published: June 2013

Background: In the Arabidopsis 26S proteasome mutant rpn12a-1, an exon-trap T-DNA is inserted 531 base pairs downstream of the RPN12a STOP codon. We have previously shown that this insertion activates a STOP codon-associated latent 5' splice site that competes with the polyadenylation signal during processing of the pre-mRNA. As a result of this dual input from splicing and polyadenylation in the rpn12a-1 mutant, two RPN12a transcripts are produced and they encode the wild-type RPN12a and a chimeric RPN12a-NPTII protein. Both proteins form complexes with other proteasome subunits leading to the formation of wild-type and mutant proteasome versions. The net result of this heterogeneity of proteasome particles is a reduction of total cellular proteasome activity. One of the consequences of reduced proteasomal activity is decreased sensitivity to the major plant hormone cytokinin.

Methods: We performed ethyl methanesulfonate mutagenesis of rpn12a-1 and isolated revertants with wild-type cytokinin sensitivity.

Results: We describe the isolation and analyses of suppressor of rpn12a-1 (sor1). The sor1 mutation is intragenic and located at the fifth position of the chimeric intron. This mutation weakens the activated 5' splice site associated with the STOP codon and tilts the processing of the RPN12a mRNA back towards polyadenylation.

Conclusions: These results validate our earlier interpretation of the unusual nature of the rpn12a-1 mutation. Furthermore, the data show that optimal 26S proteasome activity requires RPN12a accumulation beyond a critical threshold. Finally, this finding reinforces our previous conclusion that proteasome function is critical for the cytokinin-dependent regulation of plant growth.
Quantifying Input Uncertainty via Simulation Confidence Intervals
Authors: Barton Russell R. , Nelson Barry L. , Xie Wei
Published: June 2013

We consider the problem of deriving confidence intervals for the mean response of a system that is represented by a stochastic simulation whose parametric input models have been estimated from “real-world” data. As opposed to standard simulation confidence intervals, we provide confidence intervals that account for uncertainty about the input model parameters; our method is appropriate when enough simulation effort can be expended to make simulation-estimation error relatively small. To achieve this we introduce metamodel-assisted bootstrapping that propagates input variability through to the simulation response via an equation-based model rather than by simulating. We develop a metamodel strategy and associated experiment design method that avoid the need for low-order approximation to the response and that minimizes the impact of intrinsic (simulation) error on confidence level accuracy. Asymptotic analysis and empirical tests over a wide range of simulation effort show that confidence intervals obtained via metamodel-assisted bootstrapping achieve the desired coverage.
An Exact Algorithm Based on Cut-and-Column Generation for the Capacitated Location-Routing Problem
Authors: Contardo Claudio , Cordeau Jean-François , Gendron Bernard
Published: June 2013

In this paper we present an exact algorithm for the capacitated location-routing problem (CLRP) based on cut-and-column generation. The CLRP is formulated as a set-partitioning problem that also inherits all of the known valid inequalities for the flow formulations of the CLRP. We introduce five new families of inequalities that are shown to dominate some of the cuts from the two-index formulation. The problem is solved by column generation, where the subproblem consists in finding a shortest path of minimum reduced cost under capacity constraints. We first use the two-index formulation for enumerating all of the possible subsets of depot locations that could lead to an optimal solution of cost less than or equal to a given upper bound. For each of these subsets, the corresponding multiple depot vehicle routing problem is then solved by means of column generation. The results show that we can improve the bounds found in the literature, solve to optimality some previously open instances, and improve the upper bounds on some other instances.
Online Sequential Optimization with Biased Gradients: Theory and Applications to Censored Demand
Authors: Huh Woonghee Tim , Rusmevichientong Paat
Published: June 2013

In this paper, we study a class of stochastic optimization problems, where although the objective functions may not be convex, they satisfy a generalization of convexity called the sequentially convex property. We focus on a setting where the distribution of the underlying uncertainty is unknown and the manager must make a decision in real time based on historical data. Because sequentially convex functions are not necessarily convex, they pose difficulties in applying standard adaptive methods for convex optimization. We propose a nonparametric algorithm based on a gradient descent method and show that the T-season average expected cost differs from the minimum cost by at most [Formula: see text]. Our analysis is based on a careful quantification of the bias that is inherent in gradient estimation because of the adaptive nature of the problem. We demonstrate the usefulness of the concept of sequential convexity by applying it to three canonical problems in inventory control, capacity allocation, and the lifetime buy decision, under the assumption that the manager does not know the demand distributions and has access only to historical sales (censored demand) data.
Missing Links: Referrer Behavior and Job Segregation
Authors: Rubineau Brian , Fernandez Roberto M.
Published: June 2013

The importance of networks in labor markets is well known, and their job-segregating effects in organizations is a given. Conventional wisdom attributes this segregation to the homophilous nature of contact networks, and leaves little role for organizational influences. Yet employee referrals are necessarily initiated within a firm by employee referrers subject to organizational policies. We build theory regarding the role of referrers in the segregating effects of network recruitment. Using mathematical and computational models, we investigate how empirically documented referrer behaviors affect job segregation. We show that referrer behaviors can segregate jobs beyond the effects of homophilous network recruitment. Furthermore, and contrary to past understandings, we show that referrer behaviors can also mitigate most, if not all, of the segregating effects of network recruitment. Although largely neglected in previous labor market network scholarship, referrers are the missing links revealing opportunities for organizations to influence the effects of network recruitment.

This paper was accepted by Jesper Sørensen. organizations.
Learning from My Success and from Others' Failure: Evidence from Minimally Invasive Cardiac Surgery
Authors: KC Diwas , Staats Bradley R. , Gino Francesca
Published: June 2013

Learning from past experience is central to an organization's adaptation and survival. A key dimension of prior experience is whether an outcome was successful or unsuccessful. Although empirical studies have investigated the effects of success and failure in organizational learning, to date, the phenomenon has received little attention at the individual level. Drawing on attribution theory in psychology, we investigate how individuals learn from their own past experiences with both failure and success and from the experiences of others. For our empirical analyses, we use 10 years of data from 71 cardiothoracic surgeons who completed more than 6,500 procedures using a new technology for cardiac surgery. We find that individuals learn more from their own successes than from their own failures, but they learn more from the failures of others than from others' successes. We also find that individuals' prior successes and others' failures can help individuals overcome their inability to learn from their own failures. Together, these findings offer both theoretical and practical insights into how individuals learn directly from their prior experience and indirectly from the experiences of others.

This paper was accepted by Jesper Sørensen, organizations.
Are Analysts' Forecasts Informative to the General Public?
Authors: Altınkılıç Oya , Balashov Vadim S. , Hansen Robert S.
Published: June 2013

Contrary to the common view that analysts are important information agents, intraday returns evidence shows that announcements of analysts' forecast revisions release little new information, on average. Further cross-sectional evidence from returns around the announcements confirms that revisions are virtually information free. Daily announcement returns used in the literature appear to overstate the analyst's role as information agent, because forecast announcements are often issued directly after reports of significant news about the followed firm. The evidence reveals a sequential relationship between events and news and forecast revisions indicative of analyst piggybacking, not prophecy. These new findings about the most sought-after analyst reports broaden significantly the evidence indicating that price reactions to analysts' reports reveal little new information.

This paper was accepted by Brad Barber, finance.
When the Tail Wags the Dog: Industry Leaders, Limited Attention, and Spurious Cross-Industry Information Diffusion
Authors: Cen Ling , Chan Kalok , Dasgupta Sudipto , Gao Ning
Published: June 2013

Within an industry, stock returns of larger firms lead those of smaller firms, suggesting an intraindustry information diffusion process. Most industry leaders, however, have business segments in other industries (henceforth, minor-segment industries), whereas most small firms are pure players operating in one industry only. If investors cannot filter out the irrelevant information from the leaders' minor segments, the pure players will be mispriced due to spurious cross-industry information diffusion (SCIID). Consistent with the SCIID hypothesis, we document both a strong contemporaneous and a lead–lag relation in stock returns between firms from industry leaders' minor-segment industries and pure players in the industry leaders' major-segment industry. Our results are not due to potential missing common factors or economic relationships between pure players and firms in the minor-segment industries.

This paper was accepted by Wei Xiong, finance.
How Does Rivals' Presence Affect Firms' Decision to Enter New Markets? Economic and Sociological Explanations
Authors: Koçak Özgecan , Özcan Serden
Published: June 2013

Four distinct theoretical programs have examined market entry decisions of multiunit firms, advancing different explanations for the relationship between a firm's likelihood of entry into a geographical market and the number of rivals that are already present in the target market. Within the strategy literature, theory of strategic interactions explains that firms will want to establish a foothold in markets where their multimarket competitors are scarce, but avoid markets where there are many multimarket competitors. Within economic geography, positive externalities such as increase in demand explain firms' desire to locate close to their rivals whereas negative externalities such as competition explain their desire to avoid them. Within the ecological tradition, density dependence theory explains this relationship in terms of legitimation of an organizational form in a particular market and subsequently increased competition for resources there. Within new institutional theory, the presence of rivals is seen as a signal that a particular market is suitable for entry. Although generally quoted and mentioned in the literature, these four explanations have not been sufficiently separated to indicate whether these four mechanisms all operate simultaneously or whether one of them might account for the often found inverse-U-shaped relationship. Distinguishing firms with different strategies and using various moderators, we test the four explanations jointly and demonstrate their scope of operation.

Data, as supplemental material, are available at http://dx.doi.org/10.1287/mnsc.2013.1723 .

This paper was accepted by Jesper Sørensen, organizations.
The Impact of Consumer Attentiveness and Search Costs on Firm Quality Disclosure: A Competitive Analysis
Authors: Ghosh Bikram , Galbreth Michael R.
Published: June 2013

Firms can invest to disclose quality information about their products to consumers, but consumers are not always perfectly attentive to these disclosures. Indeed, technologies such as digital video recorders have increased the ease with which disclosures can be avoided by consumers. Although such inattention may result in a consumer missing information from one or more competing firms, consumers who have missed disclosures might decide to search for quality information to become fully informed before making a purchase decision. In this paper we incorporate consumer attentiveness, as well as the related endogenous search decision, into a model of quality disclosure. Our results suggest that firms should disclose less quality information as the share of partially informed consumers (informed about one firm but not the other) increases, or as consumer search costs increase. We also provide insights into the potential impact of consumer trends toward lower attentiveness and lower search costs.

This paper was accepted by J. Miguel Villas-Boas, marketing.
Incentives' Effect in Influenza Vaccination Policy
Authors: Yamin Dan , Gavious Arieh
Published: June 2013

In the majority of developed countries, the level of influenza vaccination coverage in all age groups is suboptimal. Hence, the authorities offer different kinds of incentives for people to become vaccinated such as subsidizing immunization or placing immunization centers in malls to make the process more accessible. We built a theoretical epidemiological game model to find the optimal incentive for vaccination and the corresponding expected level of vaccination coverage. The model was supported by survey data from questionnaires about people's perceptions about influenza and the vaccination against it. Results suggest that the optimal magnitude of the incentives should be greater when less contagious seasonal strains of influenza are involved and greater for the nonelderly population rather than the elderly, and should rise as high as $57 per vaccinated individual so that all children between the ages of six months and four years will be vaccinated.

This paper was accepted by Yossi Aviv, operations management.
The Influence of Software Process Maturity and Customer Error Reporting on Software Release and Pricing
Authors: August Terrence , Niculescu Marius Florin
Published: June 2013

Software producers are making greater use of customer error reporting to discover defects and improve the quality of their products. We study how software development differences among producers (e.g., varying levels of process maturity) and software class and functionality differences (e.g., operating system versus productivity software) affect how these producers coordinate software release timing and pricing to optimally harness error reporting contributions from users. In settings where prices are fixed, we characterize the optimal release time and demonstrate why in some cases it can actually be preferable to delay release when customer error reporting rates increase. The manner in which a firm's optimal release time responds to increases in software functionality critically hinges on whether the added functionality enhances or dilutes user error reporting; in both cases, the effect of added functionality on release timing can go in either direction, depending on both firm and product market characteristics. For example, when processing costs are relatively large compared with goodwill costs, firms with lower process maturity will release earlier when per-module error reporting contributions become diluted and release later when these contributions become enhanced. We also examine how a firm adapts price with changes in error reporting levels and software functionality, and finally, we provide implications of how beta testing influences release timing.

This paper was accepted by Lorin Hitt, information systems.
Coproduct Technologies: Product Line Design and Process Innovation
Authors: Chen Ying-Ju , Tomlin Brian , Wang Yimin
Published: June 2013

The simultaneous production of different outputs (coproducts) is observed in the chemical, material, mineral, and semiconductor industries among others. Often, as with microprocessors, the outputs differ in quality in the vertical sense and firms classify the output into different grades (products). We analyze product line design and production for a firm operating a vertical coproduct technology. We examine how the product line and profit are influenced by the production cost and output distribution of the technology. We prove that production cost influences product line design in a fundamentally different manner for coproduct technologies than for uniproduct technologies where the firm can produce products independently. For example, with coproducts, the size and length of the product line can both increase in the production cost. Contrary to the oft-held view that variability is bad, we prove the firm benefits from a more variable output distribution if the production or classification cost is low enough.

Data, as supplemental material, are available at http://dx.doi.org/10.1287/mnsc.2013.1738 .

This paper was accepted by Serguei Netessine, operations management.
Dynamic Capacity Investment with Two Competing Technologies
Authors: Wang Wenbin , Ferguson Mark E. , Hu Shanshan , Souza Gilvan C.
Published: June 2013

With the recent focus on sustainability, firms making adjustments to their production or distribution capacity levels often have the option of investing in newer technologies with lower carbon footprints and/or energy consumption. These more sustainable technologies typically require a higher up-front investment but have lower operating (fuel or energy) costs. What complicates this decision is the fact that the projected dollar savings from the more sustainable technologies fluctuate considerably due to uncertainty in fuel prices, and the total capacity may not be utilized at 100% because of fluctuations in the demand for the product. We consider the firm's capacity adjustments over time given a portfolio of technology options when the demand and the fuel costs are stochastic and possibly dependent. Our model also allows for usage-based capacity deterioration. We provide the analytical structure of the optimal policy, which assigns different control limits for investing, staying put, and disinvesting in the capacities of the competing technology choices for each realization of demand and fuel costs at each period. We also present an application of our model to the problem of designing a delivery truck fleet for a beverage distributor.
Energy Efficiency in Small and Medium-Sized Manufacturing Firms: Order Effects and the Adoption of Process Improvement Recommendations
Authors: Muthulingam Suresh , Corbett Charles J. , Benartzi Shlomo , Oppenheim Bohdan
Published: June 2013

In many manufacturing operations, profitable energy efficiency opportunities remain unexploited. Although previous studies have tried to explain the underinvestment, we focus on how the way in which a portfolio of opportunities is presented in a list affects adoption decisions. We use information on over 100,000 energy-saving recommendations made to more than 13,000 small and medium-sized manufacturing firms under the Industrial Assessment Centers program of the U.S. Department of Energy. We find that adoption rates are higher for initiatives appearing early in a list of recommendations. This sequence effect is consistent and large: simply moving a recommendation one position lower has the same effect on average as increasing up-front implementation cost by at least 17% from the average value. Given this impact of sequence on adoption of individual recommendations, we utilize variations within our data to examine how various sequencing approaches affect adoption at the portfolio level. Sequences in which recommendations are listed from best to worst payback achieve higher potential energy savings given the investments in energy efficiency made by the firms. We also observe a choice overload effect at the portfolio level, but the magnitude of this effect is small.