Generating rate equations for complex enzyme systems by a computer-assisted systematic method

<p>Abstract</p> <p>Background</p> <p>While the theory of enzyme kinetics is fundamental to analyzing and simulating biochemical systems, the derivation of rate equations for complex mechanisms for enzyme-catalyzed reactions is cumbersome and error prone. Therefore, a number of algorithms and related computer programs have been developed to assist in such derivations. Yet although a number of algorithms, programs, and software packages are reported in the literature, one or more significant limitation is associated with each of these tools. Furthermore, none is freely available for download and use by the community.</p> <p>Results</p> <p>We have implemented an algorithm based on the schematic method of King and Altman (KA) that employs the topological theory of linear graphs for systematic generation of valid reaction patterns in a GUI-based stand-alone computer program called <it>KAPattern</it>. The underlying algorithm allows for the assumption steady-state, rapid equilibrium-binding, and/or irreversibility for individual steps in catalytic mechanisms. The program can automatically generate MathML and MATLAB output files that users can easily incorporate into simulation programs.</p> <p>Conclusion</p> <p>A computer program, called <it>KAPattern</it>, for generating rate equations for complex enzyme system is a freely available and can be accessed at <url>http://www.biocoda.org</url>.</p

Health Status and Permanent Loss to Follow up of Ellisras Longitudinal Study Subjects: Rural South African Context

Noncommunicable diseases (NCDs) are responsible for two out of three deaths worldwide with their profile changing from one country to another. But evidence to sustained these changes are still very limited in rural South African population. The well-characterized Ellisras Longitudinal Study (ELS) provides a unique opportunity of mapping some of these changes in vulnerable adolescent and young adults. The objective is we determined the extent of NCD risk factors derived from anthropometric and blood pressure measurements affected Ellisras Longitudinal Study (ELS) subjects over time for those who died or permanently lost to follow-up. A total of 2238 subjects aged 3–10 years (born between 1994 and 1986) were randomly selected to take part of the Ellisras Longitudinal Study (ELS) in November 1996. The attrition rate of ELS subjects based on death ranges between 0.71 and 3.73% for boys and 0.75 and 4.89% for girls. The prevalence of sever undernutrition ranges from 3.2 to 53%, moderate undernutrition ranges from 9.7 to 28.8%, while mild undernutrition ranges from 17.9 to 59.1% for both males and females. The prevalence of undernutrition was high while hypertension, obesity, and overweight were low in the population. The identification of appropriate NCD indicators for mortality in rural South African population needs more consideration and evaluation

Cervical radiculopathy: Incidence and treatment of 1,420 consecutive cases

Study DesignRetrospective case series.PurposeTo determine the incidence of cervical radiculopathy requiring operative intervention by level and to report on the methods of treatment.Overview of LiteratureCervical radiculopathy is a common cause of pain and can result in progressive neurological deficits. Although the pathology is well understood, the actual incidence of cervical radiculopathy at particular spinal levels ultimately requiring operative intervention is unknown.MethodsA large consecutive series of patients operated on by a single surgeon were retrospectively analyzed. The incidence of cervical radiculopathy at each level was defined for every patient. Procedures used for operative treatment were noted. Health related quality of life (HRQL) scores were collected both pre-operatively and postoperatively.ResultsThere were 1305 primary and 115 revision operations performed. The most common primary procedures performed were anterior cervical discectomy and fusion (ACDF, 50%) and anterior cervical corpectomy and fusion (ACCF, 28%). The most commonly affected levels were C6 (66%) and C7 (62%). Reasons for revision were pseudarthrosis (27%), clinical adjacent segment pathology (CASP, 63%), persistent radiculopathy (11%), and hardware-related (2.6%). The most common procedures performed in the revision group were posterior cervical decompression and fusion (PCDF, 42%) and ACDF (40%). The most commonly affected levels were C7 (43%) and C5 (30%). Among patients that had their index surgery at our institution, the revision rate was 6.4%. In both primary and revision cases there was a significant improvement in Neck Disability Index and visual analogue scale scores postoperatively. Postoperative HRQL scores in the revision cases were significantly worse than those in the primary cases (p <0.01).ConclusionsThis study provides the largest description of the incidence of cervical radiculopathy by level and operative outcomes in patients undergoing cervical decompression. The incidence of CASP was 4.2% in 3.3 years in this single institution series

Evidence for Target Outer-Shell Excitation Mediated by Electron Correlation in Single-Electron-Capture Collisions of Slow He²⁺ Ions with Ar Atoms

We have performed kinematically complete experiments on single-electron capture in slow He2+-Ar collisions. Besides the pure capture to the He+ (n = 2) level, capture into the deep He+ ( n= 1) state with simultaneous excitation of another target electron is also observed. In contrast to the pure capture, the total cross section for this two-electron transition decreases with increasing collision energy, and its angular-differential cross section exhibits a much slighter slope. We take these observations as evidence for electron capture mediated by electron-electron interactions

Identification of Novel Tumor Antigens With Patient-Derived Immune-Selected Antibodies

The identification of tumor antigens capable of eliciting an immune response in vivo may be an effective method to identify therapeutic cancer targets. We have developed a method to identify such antigens using frozen tumor-draining lymph node samples from breast cancer patients. Immune responses in tumor-draining lymph nodes were identified by immunostaining lymph node sections for B-cell markers (CD20&CD23) and Ki67 which revealed cell proliferation in germinal center zones. Antigen-dependent somatic hypermutation (SH) and clonal expansion (CE) were present in heavy chain variable (VH) domain cDNA clones obtained from these germinal centers, but not from Ki67 negative germinal centers. Recombinant VH single-domain antibodies were used to screen tumor proteins and affinity select potential tumor antigens. Neuroplastin (NPTN) was identified as a candidate breast tumor antigen using proteomic identification of affinity selected tumor proteins with a recombinant VH single chain antibody. NPTN was found to be highly expressed in approximately 20% of invasive breast carcinomas and 50% of breast carcinomas with distal metastasis using a breast cancer tissue array. Additionally, NPTN over-expression in a breast cancer cell line resulted in a significant increase in tumor growth and angiogenesis in vivo which was related to increased VEGF production in the transfected cells. These results validate NPTN as a tumor-associated antigen which could promote breast tumor growth and metastasis if aberrantly expressed. These studies also demonstrate that humoral immune responses in tumor-draining lymph nodes can provide antibody reagents useful in identifying tumor antigens with applications for biomarker screening, diagnostics and therapeutic interventions

Associations of Medicaid Expansion with Insurance Coverage, Stage at Diagnosis, and Treatment among Patients with Genitourinary Malignant Neoplasms

Importance: Health insurance coverage is associated with improved outcomes in patients with cancer. However, it is unknown whether Medicaid expansion through the Patient Protection and Affordable Care Act (ACA) was associated with improvements in the diagnosis and treatment of patients with genitourinary cancer. Objective: To assess the association of Medicaid expansion with health insurance status, stage at diagnosis, and receipt of treatment among nonelderly patients with newly diagnosed kidney, bladder, or prostate cancer. Design, Setting, and Participants: This case-control study included adults aged 18 to 64 years with a new primary diagnosis of kidney, bladder, or prostate cancer, selected from the National Cancer Database from January 1, 2011, to December 31, 2016. Patients in states that expanded Medicaid were the case group, and patients in nonexpansion states were the control group. Data were analyzed from January 2020 to March 2021. Exposures: State Medicaid expansion status. Main Outcomes and Measures: Insurance status, stage at diagnosis, and receipt of cancer and stage-specific treatments. Cases and controls were compared with difference-in-difference analyses. Results: Among a total of 340552 patients with newly diagnosed genitourinary cancers, 94033 (27.6%) had kidney cancer, 25770 (7.6%) had bladder cancer, and 220749 (64.8%) had prostate cancer. Medicaid expansion was associated with a net decrease in uninsured rate of 1.1 (95% CI, -1.4 to -0.8) percentage points across all incomes and a net decrease in the low-income population of 4.4 (95% CI, -5.7 to -3.0) percentage points compared with nonexpansion states. Expansion was also associated with a significant shift toward early-stage diagnosis in kidney cancer across all income levels (difference-in-difference, 1.4 [95% CI, 0.1 to 2.6] percentage points) and among individuals with low income (difference-in-difference, 4.6 [95% CI, 0.3 to 9.0] percentage points) and in prostate cancer among individuals with low income (difference-in-difference, 3.0 [95% CI, 0.3 to 5.7] percentage points). Additionally, there was a net increase associated with expansion compared with nonexpansion in receipt of active surveillance for low-risk prostate cancer of 4.1 (95% CI, 2.9 to 5.3) percentage points across incomes and 4.5 (95% CI, 0 to 9.0) percentage points among patients in low-income areas. Conclusions and Relevance: These findings suggest that Medicaid expansion was associated with decreases in uninsured status, increases in the proportion of kidney and prostate cancer diagnosed in an early stage, and higher rates of active surveillance in the appropriate, low-risk prostate cancer population. Associations were concentrated in population residing in low-income areas and reinforce the importance of improving access to care to all patients with cancer

Malaria Life Cycle Intensifies Both Natural Selection and Random Genetic Drift

Analysis of genome sequences of 159 isolates of Plasmodium falciparum from Senegal yields an extraordinarily high proportion (26.85%) of protein-coding genes with the ratio of nonsynonymous to synonymous polymorphism greater than one. This proportion is much greater than observed in other organisms. Also unusual is that the site-frequency spectra of synonymous and nonsynonymous polymorphisms are virtually indistinguishable. We hypothesized that the complicated life cycle of malaria parasites might lead to qualitatively different population genetics from that predicted from the classical Wright-Fisher (WF) model, which assumes a single random-mating population with a finite and constant population size in an organism with nonoverlapping generations. This paper summarizes simulation studies of random genetic drift and selection in malaria parasites that take into account their unusual life history. Our results show that random genetic drift in the malaria life cycle is more pronounced than under the WF model. Paradoxically, the efficiency of purifying selection in the malaria life cycle is also greater than under WF, and the relative efficiency of positive selection varies according to conditions. Additionally, the site-frequency spectrum under neutrality is also more skewed toward low-frequency alleles than expected with WF. These results highlight the importance of considering the malaria life cycle when applying existing population genetic tools based on the WF model. The same caveat applies to other species with similarly complex life cycles.Organismic and Evolutionary Biolog

Neck pain following laminoplasty

Cervical laminoplasty, a surgical technique pioneered in Japan, is used increasingly in the United States. Axial neck pain following laminoplasty has been previously reported.1–9 This concern over postoperative neck pain may deter som