bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of 1600 replication origins in S. cerevisiae
Authors: Foss Eric J , Lichauco Carmina , Gatbonton-Schwager Tonibelle , Gonske Sara J , Lofts Brandon , Lao Uyen , Bedalov Antonio
Published: February 2024

There are approximately 500 known origins of replication in the yeast genome, and the process by which DNA replication initiates at these locations is well understood. In particular, these sites are made competent to initiate replication by loading of the Mcm replicative helicase prior to the start of S phase; thus, ‘a site that binds Mcm in G1’ might be considered to provide an operational definition of a replication origin. By fusing a subunit of Mcm to micrococcal nuclease, we previously showed that known origins are typically bound by a single Mcm double hexamer, loaded adjacent to the ARS consensus sequence (ACS). Here, we extend this analysis from known origins to the entire genome, identifying candidate Mcm binding sites whose signal intensity varies over at least three orders of magnitude. Published data quantifying single-stranded DNA (ssDNA) during S phase revealed replication initiation among the most abundant 1600 of these sites, with replication activity decreasing with Mcm abundance and disappearing at the limit of detection of ssDNA. Three other hallmarks of replication origins were apparent among the most abundant 5500 sites. Specifically, these sites: (1) appeared in intergenic nucleosome-free regions flanked on one or both sides by well-positioned nucleosomes; (2) were flanked by ACSs; and (3) exhibited a pattern of GC skew characteristic of replication initiation. We conclude that, if sites at which Mcm double hexamers are loaded can function as replication origins, then DNA replication origins are at least threefold more abundant than previously assumed, and we suggest that replication may occasionally initiate in essentially every intergenic region. These results shed light on recent reports that as many as 15% of replication events initiate outside of known origins, and this broader distribution of replication origins suggest that S phase in yeast may be less distinct from that in humans than widely assumed.
Structural constraints on the emergence of oscillations in multi-population neural networks
Authors: Zang Jie , Liu Shenquan , Helson Pascal , Kumar Arvind
Published: February 2024

Oscillations arise in many real-world systems and are associated with both functional and dysfunctional states. Whether a network can oscillate can be estimated if we know the strength of interaction between nodes. But in real-world networks (in particular in biological networks) it is usually not possible to know the exact connection weights. Therefore, it is important to determine the structural properties of a network necessary to generate oscillations. Here, we provide a proof that uses dynamical system theory to prove that an odd number of inhibitory nodes and strong enough connections are necessary to generate oscillations in a single cycle threshold-linear network. We illustrate these analytical results in a biologically plausible network with either firing-rate based or spiking neurons. Our work provides structural properties necessary to generate oscillations in a network. We use this knowledge to reconcile recent experimental findings about oscillations in basal ganglia with classical findings.
The molecular basis of Abelson kinase regulation by its αI-helix
Authors: Paladini Johannes , Maier Annalena , Habazettl Judith Maria , Hertel Ines , Sonti Rajesh , Grzesiek Stephan
Published: February 2024

Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2 and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force towards the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI- helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl’s activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.
Visual homogeneity computations in the brain enable solving property-based visual tasks
Authors: Jacob Georgin , Pramod RT , Arun SP
Published: February 2024

Most visual tasks involve looking for specific object features. But we also often perform property-based tasks where we look for specific property in an image, such as finding an odd item, deciding if two items are same, or if an object has symmetry. How do we solve such tasks? These tasks do not fit into standard models of decision making because their underlying feature space and decision process is unclear. Using well-known principles governing multiple object representations, we show that displays with repeating elements can be distinguished from heterogeneous displays using a property we define as visual homogeneity. In behavior, visual homogeneity predicted response times on visual search, same-different and symmetry tasks. Brain imaging during visual search and symmetry tasks revealed that visual homogeneity was localized to a region in the object-selective cortex. Thus, property-based visual tasks are solved in a localized region in the brain by computing visual homogeneity.
Chromosome Structure II: Stem-loops and circle-loops
Authors: Ke Wenfan , Fujioka Miki , Schedl Paul , Jaynes James B.
Published: February 2024

The chromosomes in multicellular eukaryotes are organized into a series of topologically independent loops called TADs. In flies, TADs are formed by physical interactions between neighboring boundaries. Fly boundaries exhibit distinct partner preferences, and pairing interactions between boundaries are typically orientation dependent. Pairing can be head-to-tail or head-to-head. The former generates a stem-loop TAD, while the latter gives a circle-loop TAD. The TAD that encompasses the
Drosophila even skipped
(
eve
) gene is formed by the head-to-tail pairing of the
nhomie
and
homie
boundaries. To explore the relationship between loop topology and the physical and regulatory landscape, we flanked the
nhomie
boundary region with two attP sites. The attP sites were then used to generate four boundary replacements:
λ DNA, nhomie forward
(WT orientation),
nhomie reverse
(opposite of WT), and
homie forward
(same as WT
homie
). The
nhomie forward
replacement restores the WT physical and regulatory landscape: In MicroC experiments, the
eve
TAD is a volcano triangle topped by a plume, and the
eve
gene and its regulatory elements are sequestered from interactions with neighbors. The
λ DNA
replacement lacks boundary function: the endpoint of the “new”
eve
TAD on the
nhomie
side is ill-defined, and
eve
stripe enhancers activate a nearby gene,
eIF3j.
While
nhomie reverse
and
homie forward
restore the
eve
TAD, the topology is a circle-loop, and this changes the local physical and regulatory landscape. In MicroC experiments, the
eve
TAD interacts with its neighbors, and the plume at the top of the
eve
volcano triangle is replaced by a cloud of contacts with the next-door TADs. Consistent with the loss of isolation afforded by the stem-loop topology, the
eve
enhancers weakly activate genes in the neighboring TADs. Conversely,
eve
function is partially disrupted.
A survey of the NHS reporting radiographer workforce in England
Authors: Lockwood Paul , Burton Christopher , Shaw Theresa , Woznitza Nicholas
Published: February 2024

Introduction: At present there is no national register of the population size and scope of reporting radiographers in England. This makes operational workforce and succession planning for sustainable healthcare services in the National Health Service England (NHSE) difficult, affecting implementing NHSE policies and priorities such as 50% of X-rays reported by reporting radiographers and decreasing reporting Turnaround Times (TATs). This survey aimed to establish the workforce population employed as reporting radiographers in NHSE.
Methods: An online anonymous seven question survey was distributed on social media and at the UK Imaging and Oncology Congress. Participant criteria included NHSE radiology staff (diagnostic radiographer, reporting radiographer, radiology manager, imaging superintendent modality lead, consultant radiologist, etc.) or a student diagnostic radiographer working within an NHSE trust. The survey recorded the participant's NHSE region (North Western, North Eastern and Yorkshire, Midlands, East of England, London, South Eastern and South Western regions), Integrated Care Systems (ICS), NHSE Trust, hospital, the amount of reporting radiographers and trainees employed, the Agenda for Change (AfC) job banding and imaging modality reported (X-ray, CT, MRI, NM, PET, DEXA). The data analysis applied descriptive statistics for estimating patterns and trends in the distrubtion of data (English region, AfC banding and imaging modality).
Results: Responses were received from all seven of the NHSE regions (n=36/43 ICSs). The data demonstrated a larger workforce in the north of England than in the south, with employment at a range of AfC bandings from 5-8. The imaging modalities reported by radiographers in England demonstrated X-ray (n=34), the most reported imaging examination by region, and Nuclear Medicine (n=3) the least, with evidence of clinical reporting for CT (n=20), MRI (n=18), DEXA (n=16), Mammography (n=13) and fluoroscopy (n=12) being completed by radiographers in England.
Conclusion: The findings for England (n=704 reporters; n=142 trainees) provide an estimate based on the response rate of the current reporting radiographer workforce across the NHSE regions, and their contribution to the skills mix radiology reporting service delivery. It is hoped future surveys will provide ongoing workforce estimates for the diagnostic radiographer reporting workforce in NHSE to support workforce transformation and sustainability plans for the radiography profession and to meet government healthcare targets and priorities.
Spectrum of Radiological Findings in Pulmonary Tuberculosis- A Tertiary Care Hospital-based Retrospective Descriptive Study
Authors: Vishnupriyasriee GV , Chakradhar Ravipati , Yuvaraj Muralidharan , Krishna Ramakrishnan Karthik , Muthiah Pitchandi
Published: February 2024

Introduction: Tuberculosis is a worldwide public health problem associated with high morbidity and mortality. Tuberculosis can manifest in active and latent forms. Improving the diagnosis, treatment, and screening of tuberculosis is crucial for effective tuberculosis control. Chest X-ray and Computed Tomography chest play a vital role in diagnosing and screening for tuberculosis. Aim: To analyse the spectrum of radiological findings in pulmonary tuberculosis. Materials and Methods: The present retrospective descriptive study was conducted at a teritary care hospital in the Department of Radiodiagnosis, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India. The data of 160 patients diagnosed with pulmonary tuberculosis between January 2019 and December 2020 were accessed and analysed. The recorded variables included forms of pulmonary tuberculosis, age/gender distribution, co-morbidities, Acid-fast Bacillus (AFB) smear status, and radiological findings and distribution. Descriptive statistics are presented in frequency and percentage. Results: Among the 160 cases of pulmonary tuberculosis, 30 (18.75%) cases were active primary tuberculosis, 105 (65.63%) cases were active post-primary tuberculosis, and 25 (15.62%) cases were inactive tuberculosis. Among the 30 cases of active primary tuberculosis, 14 (46.67%) cases had consolidation with air bronchogram, and 6 (20%) cases had consolidation without air bronchogram. Among the 105 cases of active post-primary tuberculosis, 65 (61.9%) cases had consolidation, 50 (47.62%) cases had cavities, and 56 (81.9%) cases had centrilobular nodules with a tree-in-bud appearance. Among the 25 cases of inactive tuberculosis, 18 (72%) cases had fibrosis with bronchiectasis, while 4 (16%) cases had fibrosis without bronchiectasis, and 3 (12%) cases had calcified granulomas. Conclusion: The study conclusively demonstrates the diverse radiological manifestations of pulmonary tuberculosis in different patient demographics. It highlights a higher incidence of active post-primary tuberculosis, especially in patients above 45 years, with varying radiological findings such as consolidation, cavitation, and fibrosis.
Key Elements of the Inter-professional Education (IPE): Perceptions amongst Pre-Registration Students in the Different Health Professions in Sri Lanka
Authors: Perera A. D. P. , Jayasinghe H. W. U. S.
Published: February 2024

Aims: Inter-professional education (IPE) is important in developing good working relationships between different health professionals. The key elements of IPE have entitled as clinical situations, skills expected in IPE and teaching / learning methods. Health professional students in Sri Lanka experience informal inter-professional learning opportunities during clinical years. The aim of this research was to explore student perceptions on these key elements of IPE.

Study Design:  A cross sectional study.

Place and Duration of Study: The study was conducted with the students who have had prior clinical training for a period of 1 year, from 8 health professional groups (Medical, Physiotherapy, Nursing Diploma, Nursing Degree, Medical Laboratory Science, Pharmacy, Audiology, Speech & Language Therapy) at different health educational institutions.

Methodology: A total of 686 students were invited to complete a self-administered questionnaire. The data was entered and analyzed using SPSS. The part of the data was analyzed using descriptive statistics. The response rate for the survey was 84.8%.

Results: The findings suggest that the key elements of IPE are important to improve the aims of IPE. Most health care students agree that management of an acute situation, community based care and rehabilitative care are the most important clinical situations where students can learn to work as a team, one of the main aims of inter-professional learning. Respect for each other and communication skills were identified as the most imperative skills that can be improved through interprofessional learning. Most students strongly agree that demonstration and work based tasks in wards are key teaching methods for achieving the aims of IPE.

Conclusion: This study suggests some focused approaches for IPE in Sri Lanka and students may need more clarity on the aim of IPE.
The Coffee Shop Functions as Facilities, Pattern of Interaction and Social Intervention in Jeneponto Regency, South Sulawesi, Indonesia
Authors: Hakim Maksud
Published: February 2024

This study aims to determine the process of changing the function of a coffee shop as a facility and pattern of social interaction and determine the change in the meaning of a coffee shop as a social intervention.
This type of research is a case study research because this research is specific by using a qualitative descriptive approach. The purposive sampling technique carries out the determination of informants. This type of research also uses a naturalistic (qualitative) paradigm approach to analyze and construct changes in the meaning of coffee shops as a means of social interaction and intervention patterns in Jeneponto Regency, South Sulawesi. The writer chose this location with the consideration that Jeneponto Regency has a heterogeneous population.
Data analysis was carried out by data reduction, which focused on the selection, simplification, abstraction and transformation of rough data from field notes, followed by data presentation and concluding.
The results of this study indicate that the change in the function of a coffee shop into a means and pattern of social interaction and intervention is marked by the development of simple facilities into public spaces equipped with facilities and information such as television, newspapers, and the internet networks. To meet the needs and satisfaction of visitors. As facilities, pattern of interaction and social intervention as a unifier in association without distinction of race, religion and so on, in solving problems, both formally and informally.
Different Fractions of Sulphur, Their Correlations with Soil Properties and Yield of Soybean and Safflower Influenced by Long Term Fertilizers Experiment under Vertisol
Authors: Khandare Ramprasad , Shirale Sudam , Gajbhiye Bhagyaresha , Yerma Suchita
Published: February 2024

Sulphur is an important element in Indian soils, and it has been found as a major limitation for increasing the oil seed productivity. The results emerged out from experimental field showed that 100% NPK + FYM @ 5 t ha-1 recorded significantly maximum fractions of sulphur, namely organic sulphur (37.13 mg kg-1), non-sulphate sulphur (118.28 mg kg-1), water soluble sulphur (12.28 mg kg-1), heat soluble sulphur (1.45 mg kg-1) and total sulphur (153.65 mg kg-1) followed by only application of organic manuring as FYM @ 10 t ha-1. Different sulphur fractions exhibited negative correlation with pH and EC while, found positive significant with organic carbon, available N, P, K and S. Similarly, soybean and safflower both crops produced higher yields of grain (18.30 and 8.66 q ha-1) and straw (28.70 and 27.73 q ha-1), respectively. However, higher N (131.80 kg ha-1), P (26.27 kg ha-1), K (56.44 kg ha-1), S (15.43 kg ha-1) and Zn (253.90 g ha-1 ) uptake were observed by soybean whereas,  N  (54.43 kg ha-1), P(16.47 kg ha-1), K( 69.90 kg ha-1), S ( 11.29 kg ha-1 ) and Zn (162.19 g ha-1) were observed by safflower in application of 100 % NPK + FYM @ 5 t ha-1.
Nanomaterial-Induced Modifications in Plant Physiology and Genetics for Optimal Crop Production Strategies
Authors: Meher Rose , Thakur Bhavna , Surekha S  , Kiran  , Pratap Dheer , Kumar Sunil , Tripathi Utkarsh , Jayakkannan Logeshwaran
Published: February 2024

Nanotechnology has ushered in a new era in agriculture, offering transformative solutions to address the pressing challenges of feeding a burgeoning global population while adapting to a changing climate. At the forefront of this revolution are nanomaterials, characterized by their unique properties at the nanoscale. This article explores the intricate and dynamic relationship between nanomaterials and plants, unveiling how they induce profound changes in plant physiology and genetics. These changes, while complex, hold the key to unlocking novel approaches for crop improvement and sustainable agriculture. However, the core of this study delves into understanding how nanomaterials are taken up by plants and transported within their intricate biological systems. The mechanisms underlying nanomaterial uptake and distribution within plants are unveiled, offering possibilities for precise nutrient targeting and enhanced uptake efficiency. Subsequent sections meticulously dissect the consequences of nanomaterial exposure on plant physiology, including growth, development, and stress responses. The intricate genetic modifications and epigenetic changes that nanomaterials induce in plants are explored, revealing the potential for tailored crop improvement strategies. Notably, we demonstrate the practical implications of these nanomaterial-induced changes, showcasing their relevance for optimizing crop yields, resilience to environmental stressors, and nutritional quality. This article also takes a holistic approach by addressing the environmental and safety considerations that accompany the use of nanomaterials in agriculture. It emphasizes the necessity of responsible application, ecological impact assessment, and the establishment of regulatory frameworks to guide safe utilization. In conclusion, this article serves as an illuminating exploration of the nascent field where nanomaterials meet plant physiology and genetics, with implications that could reshape the future of agriculture.
Clinical Characteristics and Risk Factors for Mortality of Hospitalized Patients with Severe COVID-19 in Intensive Care Unit: A Retrospective Cohort Study
Authors: Paulos Ricardo Antonio de , Fontes Cor Jesus Fernandes , Souto Francisco José Dutra
Published: February 2024

Objective: To describe the clinical characteristics, complications, and risk factors for mortality of hospitalized patients with severe coronavirus disease 2019 (COVID-19) during intensive care therapy.

Methods: This single-center retrospective cohort study included 149 patients with severe COVID-19 admitted to an intensive care unit (ICU) from April 2020 to August 2021. Demographic characteristics, medical history, underlying comorbidities, laboratory findings, complications occurring during ICU stay, and mortality were collected and analyzed. Survival and Cox regression analysis were performed to identify risk factors associated with mortality.

Results: Out of 149 patients, 97 (65.1%) were women, and 67 of them were either pregnant or in the early postpartum period. The patients' ages ranged from 16 to 89 years, with a mean (SD) of 44.4 (18.9) years. The need for mechanical ventilation (72.5%) and the development of acute kidney injury (32.9%) were the most frequent complications. Thirty-eight (25.5%) patients died. The subgroup analysis of women showed that being pregnant/postpartum was not associated with a lower frequency of death. However, after adjustment, only increasing age (p<0.001) and a high AST-to-ALT ratio (p<0.001) were independent predictors of death. After adjustment, increasing age (p<0.001) and high AST-to-ALT ratio at admission (p<0.001) were independent predictors of death both in total sample and among women sub-group. High white blood cell count was also associated to death in the total sample analysis.

Conclusion: The most common complications among severe COVID-19 patients in the ICU were the need for mechanical ventilation and acute kidney injury. Increasing age and a high AST-to-ALT ratio at admission were independent predictors of fatality among all patients and even among pregnant/postpartum women.
Performance Evaluation of Manual Seeder Machine for Precision Farming
Authors: Balas P. R. , Lakhani A. L. , Pargi S. J. , Mehta T. D. , Makavana J. M.
Published: February 2024

Proper placement of seeds in the field is the most important operation to obtain an optimum yield of the crop. In India, about 75% of the landholders are small and have marginal land-holding capacity. Considering the limitations due to costly seed, the traditional method of manual dibbling, labor shortage, and small marginal land holding pattern there is a need for small manual planters for small and marginal landholders. Cotton, the white gold, is the king of textile, fibers and it is an important worldwide cash crop. The sowing of cotton is labor intensive as its planting requires 3-4 man-days/ha. Because of the above, the manual seeder was tested in the laboratory as well as in the field as per IS code: 6316-1993 with specific objectives. Laboratory analysis of manual seeder as seed rate (2.85 kg/ha and 2.88 kg/ha), seed damage (7.84% and 7.74%), and seed uniformity (62 cm and 64 cm) of cotton and castor crop respectively. Field analysis of manual seeder as coefficient of uniformity (91.63% and 93.23%), depth of seed placement (5.7 cm and 5.9 cm), speed of operation (1.82 km/h 1.84 km/h), theoretical field capacity (0.93 ha/h and 0.93 ha/h), effective field capacity (0.166 ha/h 0.171 ha/h), field efficiency (86.01% and 88.60%), draft (9.54 kgf and 10.46 kgf), energy consumption (10.93 MJ/ha and 10.04 MJ/ha) and cost of operation (440 Rs/ha and 445 Rs/ha) of cotton and castor crop respectively.
Hemodynamically Unstable Pelvic Fractures: Recent Care and New Guidelines
Authors: Heetveld Martin J. , Harris Ian , Schlaphoff Glen , Balogh Zsolt , D’Amours Scott K. , Sugrue Michael
Published: September 2004

Consistent care of hemodynamically unstable pelvic fracture patients is a major management issue. It was uncertain whether the introduction of newly developed clinical practice guidelines would require much change in current delivery of care at our institution. Assessment of recent care was undertaken and compared with the newly developed evidence‐based best practice guidelines. A multidisciplinary project team developed clinical practice guidelines for determination of early optimum management of hemodynamically unstable patients with pelvic fractures. The guidelines recommend a definitive management plan to arrest hemorrhage within 30 minutes. Intra‐abdominal hemorrhage should be assessed with diagnostic peritoneal aspiration (DPA) and/or focused assessment with sonography for trauma (FAST). Early noninvasive stabilization of the pelvis followed by angiography within 90 minutes are recommended if intra‐abdominal hemorrhage is not found. Recent care was assessed in a historical cohort of patients, identified in a prospectively maintained trauma registry, between June 1999 and December 2001. Investigations, interventions, and times were then compared with the new guidelines. The delivery of care to 30 patients (mortality 37%, mean ISS 37.8 ± 20.9) was studied. Compared with the new guidelines, the abdominal assessment rate with DPA and/or FAST was 53% and early (< 90 minutes) angiography rate was 38%. A form of pelvic external stabilization was applied in 27% of cases. Noninvasive pelvic stabilization was not performed at all. The recent care of hemodynamically unstable pelvic fracture patients was not in line with newly developed guidelines. There is an opportunity to markedly improve the rates of initial assessment of the abdomen, pelvic stabilization, and early angiography.
Time to Death and Pattern of Death in Recurrence following Curative Resection of Gastric Carcinoma: Analysis Based on Depth of Invasion
Authors: Otsuji Eigo , Kuriu Yoshiaki , Ichikawa Daisuke , Okamoto Kazuma , Ochiai Toshiya , Hagiwara Akeo , Yamagishi Hisakazu
Published: September 2004

It is difficult to predict recurrence in patients who undergo curative gastrectomy for gastric carcinoma. If the timing and site of recurrence can be predicted, it becomes easier to detect recurrent disease. Records of 290 patients who died of tumor recurrence after curative gastrectomy for gastric carcinoma were retrospectively analyzed to determine whether the depth of carcinoma invasion is independently correlated with the time to death due to tumor recurrence. Additionally, the relation between the pattern of recurrence and the depth of invasion of the gastric wall was examined. Postoperative survival in patients with tumors with deep invasion was shorter than that of patients with tumors with shallow invasion. Depth of invasion was a predictor of survival on multivariate analysis. When carcinoma invaded into deeper layers, the incidence of peritoneal metastasis and local recurrence rose and that of hematogenous metastasis fell. In conclusion, the timing of death and the site of recurrence after gastrectomy for gastric carcinoma might be predicted by the depth of invasion of the gastric wall.
Treatment and Risk Factors for Recurrence after Curative Resection of Gastrointestinal Stromal Tumors of the Stomach
Authors: Mochizuki Yoshinari , Kodera Yasuhiro , Ito Seiji , Yamamura Yoshitaka , Kanemitsu Yukihide , Shimizu Yasuhiro , Hirai Takashi , Yasui Kenzo , Inada Ken‐ichi , Kato Tomoyuki
Published: September 2004

The current definitive treatment for gastrointestinal stromal tumor (GIST) of the stomach is complete resection. GIST has a highly variable clinical course, and recurrent disease sometimes develops despite curative treatment. Although several known risk factors for recurrence exist, adequate treatment strategies are lacking. This study evaluated factors associated with relapse after curative treatment. Sixty patients with gastric GIST were identified from a hospital disease registry database. Clinicopathologic characteristics of these patients were reviewed and the Cox proportional hazards regression analysis was used to identify recurrent risk factors. With a median follow‐up of 60 months (range 5–286 months), recurrence occurred in eight (13%) patients, three of whom underwent resection of the recurrent disease and are alive to date. Univariate analysis demonstrated that invasion of the adjacent organs (p = 0.0005), tumor size (p = 0.0046), and expression of proliferative markers [MIB‐1 proliferative index (PI) ≥ 10%] (p = 0.0001) were significant risk factors for recurrence. Multivariate analysis with these three factors as variables revealed that only MIB‐1 PI was a significant independent risk factor for recurrence (p = 0.0051). In conclusion, surgical resection may be indicated whenever a recurrent GIST is considered resectable. A high MIB‐1 PI was identified as an independent indicator of risk for recurrent disease following curative surgery.
Richard Lower, M.D., Physician and Surgeon (1631–1691)
Authors: Donovan Arthur J.
Published: September 2004

Richard Lower (1631–1691) was a follower of William Harvey and conducted extensive studies of the physiology of the cardiovascular and respiratory systems. He employed surgery as a key component of his experimental work. He described and employed cardiac massage and maintained arterial oxygenation through positive‐pressure respiration. Making good use of these procedures, he established the role of the lungs in the “admixture of air” to the blood. Lower performed exchange transfusion in dogs and transfused the blood of a sheep into a human. He recognized the role of blood transfusion in replacing blood lost from hemorrhage or other causes. In his work on exchange transfusion, he employed extracorporeal vascular conduits, including arterial heterografts. Through surgical experiments he established that all mesenteric lymph passes through the thoracic duct to the subclavian vein. He performed a variety of procedures through an open thorax, closed the thoracotomy, and observed the animals over a period of days. Lower has not received the recognition he deserves as a pioneer surgical investigator.
Monitoring the SO2 concentration at the summit of Mt. Fuji and a comparison with other trace gases during winter
Authors: Igarashi Yasuhito , Sawa Yosuke , Yoshioka Katsuhiro , Matsueda Hidekazu , Fujii Kenji , Dokiya Yukiko
Published: September 2004

An SO2 continuous monitor consisting of a commercially available pulsed UV fluorescence instrument with zero and span gas calibration was installed at the summit of Mt. Fuji (3776 m asl) in September 2002. The system produces data with a time resolution comparable with other trace gases. The instrumental feasibility was tested onsite, and the SO2 concentration level at the summit was thereafter routinely observed. The present detection capability of the system, expressed in terms of the critical level (Lc, definition by International Union of Pure and Applied Chemistry and International Organization for Standardization), was estimated to be about 0.05 ppbv. Thus it was difficult to observe the temporal change of very low background SO2. However, the system is satisfactory for observing episodic transport of SO2, particularly during winter. No high SO2 episodes were observed during summer, in contrast to winter. One extraordinary episode was observed in late October 2003, the only one attributable to the Miyake‐jima SO2 volcanic plume. High SO2 episodes were more evident (with longer duration and higher concentration level) in February 2003 among the winter months observed. Typical February conditions were determined using backward trajectory, a surface weather map, and other indicators. A comparison of the temporal changes in SO2, CO, and 222Rn concentrations in the winter months suggests that these gases in the free troposphere over Japan may have been transported together in most cases from the same source regions somewhere in the Asian continent. The correlation between SO2 and 222Rn in such episodes may also suggest a short timescale for transport from the source to Mt. Fuji of within a few days. The chemical time series data of SO2 at Mt. Fuji is important for understanding the free tropospheric chemical nature, such as the Asian outflow over the North Pacific.
Acetaminophen hepatotoxicity: NO to the rescue
Authors: Wallace John L
Published: September 2004

Severe liver injury as a result of overdose or chronic use of acetaminophen (paracetamol) remains a significant clinical problem, accounting for as much as 40% of cases of acute liver failure. The mechanisms underlying the liver injury caused by acetaminophen have become much better understood in recent years. In this issue, Fiorucci et al. report that delivery of nitric oxide (NO) in small amounts to the liver, via a novel derivative of the bile acid ursodeoxycholic acid, results in significant protection of the liver from acetaminophen‐induced damage. NO appears to produce these beneficial actions through several mechanisms, including the suppression of synthesis of several proinflammatory cytokines. There is also substantial evidence that a NO‐releasing derivative of acetaminophen offers several advantages over acetaminophen itself, including enhanced analgesic potency and reduced liver toxicity.

British Journal of Pharmacology (2004) 143, 1–2. doi:10.1038/sj.bjp.0705781
Differential agonist sensitivity of glycine receptor α2 subunit splice variants
Authors: Miller Paul S , Harvey Robert J , Smart Trevor G
Published: September 2004

The glycine receptor (GlyR) α2A and α2B splice variants differ by a dual, adjacent amino acid substitution from α2AV58,T59 to α2BI58,A59 in the N‐terminal extracellular domain.

Comparing the effects of the GlyR agonists, glycine, β‐alanine and taurine, on the GlyR α2 isoforms, revealed a significant increase in potency for all three agonists at the α2B variant.

The sensitivities of the splice variants to the competitive antagonist, strychnine, and to the biphasic modulator Zn2+, were comparable. In contrast, the allosteric inhibitor picrotoxin was more potent on GlyR α2A compared to GlyR α2B receptors.

Coexpression of α2A or α2B subunits with the GlyR β subunit revealed that the higher agonist potencies observed with the α2B homomer were retained for the α2Bβ heteromer.

The identical sensitivity to strychnine combined with a reduction in the maximum current induced by the partial agonist taurine at the GlyR α2A homomer, suggested that the changed sensitivity to agonists is in accordance with a modulation of agonist efficacy rather than agonist affinity.

An effect on agonist efficacy was also supported by using a structural model of the GlyR, localising the region of splice variation to the proposed docking region between GlyR loop 2 and the TM2‐3 loop, an area associated with channel activation.

The existence of a spasmodic mouse phenotype linked to a GlyR α1A52S mutation, the equivalent position to the source of the α2 splice variation, raises the possibility that the GlyR α2 splice variants may be responsible for distinct roles in neuronal function.

British Journal of Pharmacology (2004) 143, 19–26. doi:10.1038/sj.bjp.0705875
Serum albumin induces iNOS expression and NO production in RAW 267.4 macrophages
Authors: Poteser Michael , Wakabayashi Ichiro
Published: September 2004

We investigated the effects of serum albumin on inducible nitric oxide synthase (iNOS) expression in RAW 267.4 macrophages. Crude fraction‐V type albumin as well as bovine serum albumin filtrated for endotoxin induced concentration‐dependent iNOS expression in macrophages. Accordingly, NO production (estimated by supernatant nitrite) was markedly (up to 10‐fold) increased in the presence of albumin.

Albumin‐induced expression of iNOS protein was inhibited by cycloheximide and NO production was abolished after incubation of the cells with an iNOS inhibitor, NG‐monomethyl‐L‐arginine (LNMMA).

An inhibitor of the NF‐κB pathway, pyrrolidine dithiocarbamate (PDTC), as well as inhibitors of JAK2/STAT and ERK, AG490 and U0126, respectively, significantly reduced albumin‐induced iNOS expression and NO production, while an inhibitor of the p38 pathway, SB203580, did not significantly affect NO production induced by albumin.

Both types of serum albumin were contaminated with traces of endotoxin. The endotoxin levels were found not to be sufficient for the observed induction of nitrite production in RAW 267.4 cells. In addition, the albumin‐stimulated induction of iNOS was not reduced by preincubation of albumin‐containing media with polymyxin B, a LPS inhibitor.

Polymerised albumin fractions were detected in the commercially available albumin tested in this study. A monomeric albumin‐rich fraction, separated by ultrafiltration, showed a potent inducing effect on iNOS expression and NO production, while a polymer‐rich fraction showed a smaller effect.

Advanced glycation endproducts (AGE) of albumin were not formed by interaction with glucose in incubation medium, as AGE was not increased even after long‐time (4 weeks) incubation in albumin‐containing media [3.2–4.4 μg ml−1 (basal) vs 4.8–5.6 μg ml−1 (in glucose‐containing media)]. However, the duration of albumin exposure to glucose influenced the basal stimulatory properties of albumin.

Our results suggest that serum albumin fractions, as gained by cold alcoholic extraction, may include determinants that stimulate or further enhance stimulation of RAW 267.4 cells and are different from endotoxin, polymeric albumin and AGE.

British Journal of Pharmacology (2004) 143, 143–151. doi:10.1038/sj.bjp.0705897
Effect of a neuroprotective drug, eliprodil on cardiac repolarisation: importance of the decreased repolarisation reserve in the development of proarrhythmic risk
Authors: Lengyel Csaba , Dézsi László , Biliczki Péter , Horváth Csilla , Virág László , Iost Norbert , Németh Miklós , Tálosi László , Papp Julius Gy , Varró András
Published: September 2004

The aim of this study was to analyse the effects of eliprodil, a noncardiac drug with neuroprotective properties, on the cardiac repolarisation under in vitro circumstances, under normal conditions and after the attenuation of the ‘repolarisation reserve’ by blocking the inward rectifier potassium current (IK1) current with BaCl2.

In canine right ventricular papillary muscle by applying the conventional microelectrode technique, under normal conditions, eliprodil (1 μM) produced a moderate reverse rate‐dependent prolongation of the action potential duration (7.4±1.5, 8.9±2.1 and 9.9±1.8% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=9).

This effect was augmented in preparations where IK1 was previously blocked by BaCl2 (10 μM). BaCl2 alone lengthened APD in a reverse frequency‐dependent manner (7.0±1.3, 14.2±1.6 and 28.1±2.1% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). When eliprodil (1 μM) was administered to these preparations, the drug induced a marked further lengthening relative to the APD values measured after the administration of BaCl2 (12.5±1.0, 17.6±1.5 and 20.5±0.9% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8).

In the normal Langendorff‐perfused rabbit heart, eliprodil (1 μM) produced a significant QTc prolongation at 1 Hz stimulation frequency (12.7±1.8%, n=9). After the attenuation of the ‘repolarisation reserve’ by the IK1 blocker BaCl2 (10 μM), the eliprodil‐evoked QTc prolongation was greatly enhanced (28.5±7.9%, n=6). In two out of six Langendorff preparations, this QTc lengthening degenerated into torsade de pointes ventricular tachycardia.

Eliprodil significantly decreased the amplitude of rapid component of the delayed rectifier potassium current (IKr), but slow component (IKs), transient outward current (Ito) and IK1 were not considerably affected by the drug when measured in dog ventricular myocytes by applying the whole‐cell configuration of the patch‐clamp technique.

The results indicate that eliprodil, under normal conditions, moderately lengthens cardiac repolarisation by inhibition of IKr. However, after the attenuation of the normal ‘repolarisation reserve’, this drug can induce marked QT interval prolongation, which may result in proarrhythmic action.

British Journal of Pharmacology (2004) 143, 152–158. doi:10.1038/sj.bjp.0705901
The NOP (ORL1) receptor antagonist Compound B stimulates mesolimbic dopamine release and is rewarding in mice by a non‐NOP‐receptor‐mediated mechanism
Authors: Koizumi Miwako , Sakoori Kazuto , Midorikawa Naoko , Murphy Niall P
Published: September 2004

Compound B (1‐[(3R, 4R)‐1‐cyclooctylmethyl‐3‐hydroxymethyl‐4‐piperidyl]‐3‐ethyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐one, CompB) is a nociceptin/orphanin FQ (N/OFQ) antagonist showing high selectivity for the NOP (ORL1) receptor over classical opioid receptors. We studied the effect of subcutaneous CompB administration on the release of mesolimbic dopamine (DA) and the expression of hedonia in mice.

CompB (0.3–30 mg kg−1) dose dependently stimulated mesolimbic DA release as measured by in vivo freely moving microdialysis, without any change in locomotor activity. However, intracerebroventricular administered N/OFQ (endogenous agonist of the NOP receptor, 6 nmol) did not influence CompB‐ (10 mg kg−1) induced DA release, despite clearly suppressing release when administered alone.

Studies using NOP receptor knockout mice and no‐net‐flux microdialysis revealed mildly, but not statistically significantly higher endogenous DA levels in mice lacking the NOP receptor compared to wild‐type mice. Administration of CompB (10 mg kg−1) induced identical increases in mesolimbic DA release in wild‐type and NOP receptor knockout mice.

CompB was rewarding in approximately the same dose range in which CompB induced major increases in mesolimbic DA release when assayed using a conditioned place preference paradigm. The rewarding effect of CompB (30 mg kg−1) was maintained in NOP receptor knockout mice.

These results show that CompB stimulates mesolimbic DA release and is rewarding by an action independent of the NOP receptor, the precise site of which is unclear. Consequently, caution should be exercised when interpreting the results of studies using this drug, particularly when administered by a peripheral route.

British Journal of Pharmacology (2004) 143, 53–62. doi:10.1038/sj.bjp.0705906
In vitro and in vivo characterization of a novel naphthylamide ATP‐sensitive K+ channel opener, A‐151892
Authors: Gopalakrishnan Murali , Buckner Steven A , Shieh Char‐Chang , Fey Thomas , Fabiyi Adebola , Whiteaker Kristi L , Davis‐Taber Rachel , Milicic Ivan , Daza Anthony V , Scott Victoria E S , Castle Neil A , Printzenhoff David , London Brecht , Turner Sean C , Carroll William A , Sullivan James P , Coghlan Michael J , Brune Michael E
Published: September 2004

Openers of ATP‐sensitive K+ channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N‐[2‐(2,2,2‐trifluoro‐1‐hydroxy‐1‐trifluoromethyl‐ethyl)‐naphthalen‐1‐yl]‐acetamide (A‐151892), as an opener of the ATP‐sensitive potassium channels.

A‐151892 was found to be a potent and efficacious potassium channel opener (KCO) as assessed by glibenclamide‐sensitive whole‐cell current and fluorescence‐based membrane potential responses (−log EC50=7.63) in guinea‐pig bladder smooth muscle cells.

Evidence for direct interaction with KCO binding sites was derived from displacement of binding of the 1,4‐dihydropyridine opener [125I]A‐312110. A‐151892 displaced [125I]A‐312110 binding to bladder membranes with a −log Ki value of 7.45, but lacked affinity against over 70 neurotransmitter receptor and ion channel binding sites.

In pig bladder strips, A‐151892 suppressed phasic, carbachol‐evoked and electrical field stimulus‐evoked contractility in a glibenclamide‐reversible manner with −log IC50 values of 8.07, 7.33 and 7.02 respectively, comparable to that of the potencies of the prototypical cyanoguanidine KCO, P1075. The potencies to suppress contractions in thoracic aorta (−log IC50=7.81) and portal vein (−log IC50=7.98) were not substantially different from those observed for suppression of phasic contractility of the bladder smooth muscle.

In vivo, A‐151892 was found to potently suppress unstable bladder contractions in obstructed models of unstable contractions in both pigs and rats with pED35% values of 8.05 and 7.43, respectively.

These results demonstrate that naphthylamide analogs exemplified by A‐151892 are novel KATP channel openers and may serve as chemotypes to exploit additional analogs with potential for the treatment of overactive bladder and lower urinary tract symptoms.

British Journal of Pharmacology (2004) 143, 81–90. doi:10.1038/sj.bjp.0705908
Novel diacylglycerol kinase inhibitor selectively suppressed an U46619‐induced enhancement of mouse portal vein contraction under high glucose conditions
Authors: Nobe Koji , Miyatake Mari , Nobe Hiromi , Sakai Yasushi , Takashima Junko , Momose Kazutaka
Published: September 2004

Diacylglycerol kinase (DG kinase) is a key enzyme in vascular contraction; however, alterations of the regulatory mechanisms in vascular dysfunction are poorly understood. In this study, the effect of a novel DG kinase inhibitor, stemphone, on vascular contraction was investigated.

The conventional DG kinase inhibitor, 6‐[2‐(4‐[(4‐fluorophenyl)phenyl‐methylene]‐1‐piperidinyl)ethyl]‐7‐methyl‐5H‐thiazolo [3,2‐α] pyrimidine‐5‐one (R59022) (0.1–30 μM), inhibited thromboxane A2 analogue 9,11‐dideoxy‐11α,9α‐epoxymethanoprostaglandin F2α (U46619)‐induced sustained contractions in mouse aorta and porcine coronary artery in a dose‐dependent manner. Treatment with stemphone did not affect contractions in these tissues. However, stemphone significantly inhibited (>0.3 μM) U46619‐induced spontaneous phasic contraction in mouse portal vein. This inhibitory effect was not detected following R59022 treatment in portal vein. Therefore, stemphone demonstrated selectivity in terms of portal vein contraction.

Under high glucose (22.2 mM) conditions, U46619‐induced contraction was enhanced in these three types of vascular tissue. Inhibitory effects of R59022 were attenuated under these conditions; however, effects of stemphone were observed. These results indicated that stemphone could inhibit portal vein contraction under high glucose conditions, for example, diabetes. These data suggested the possibility that DG kinase may be a target of hyperportal pressure.

Total mass of DG was enhanced under high glucose conditions. DG was derived from incorporated glucose via de novo synthesis in the absence of phospholipase C pathway mediation. This enhanced DG under high glucose conditions activated a calcium‐independent protein kinase C (PKC). This PKC was associated with calcium‐independent DG kinase activation. Treatment with stemphone also inhibited calcium‐independent DG kinase. These signal transduction pathways were distinguishable from a DG–PKC pathway under normal glucose conditions.

The present investigation suggested that stemphone selectively inhibited overcontraction of portal vein induced by high glucose levels. This phenomenon was attributable to inhibition of calcium‐independent DG kinase activation that occurred under high glucose conditions mediated by both DG synthesized from glucose and calcium‐independent PKC activation.

British Journal of Pharmacology (2004) 143, 166–178. doi:10.1038/sj.bjp.0705910