A fixed point theorem for Meir-Keeler contractions in ordered metric spaces

[EN] The purpose of this paper is to present some fixed point theorems for Meir-Keeler contractions in a complete metric space endowed with a partial order. MSC: 47H10.

On some Banach space constants arising in nonlinear fixed point and eigenvalue theory

[EN] As is well known, in any infinite-dimensional Banach space one may find fixed point free self-maps of the unit ball, retractions of the unit ball onto its boundary, contractions of the unit sphere, and nonzero maps without positive eigenvalues and normalized eigenvectors. In this paper, we give upper and lower estimates, or even explicit formulas, for the minimal Lipschitz constant and measure of noncompactness of such maps.

A best proximity point theorem for Geraghty-contractions

[EN] The purpose of this paper is to provide sufficient conditions for the existence of a unique best proximity point for Geraghty-contractions.Our paper provides an extension of a result due to Geraghty (Proc. Am. Math. Soc. 40:604-608, 1973).

Hox genes and the regulation of programmed cell death in the embryonic central nervous system of Drosophila melanogaster

This study deals with the function and regulation of programmed cell death, or apoptosis, in the development of the embryonic central nervous system of Drosophila melanogaster. The first part provides a description of apoptosis-deficient embryos, which showed that preventing apoptosis does not cause gross morphological defects in the CNS, as it appears well organized despite the presence of too many cells. An analysis of the incidence and pattern of apoptosis over the course of development discloses a partly very orderly pattern suggesting tight spatio-temporal control, but also reveals random apoptotic cells, which suggests a certain amount of plasticity in the embryo. This analysis also allowed precise identification of some of the dying neural cells in the embryo, and establishment of single cell models for studying regulation of segment-specific apoptosis in the embryonic CNS. In the second part of the work, further investigations into mechanisms controlling segment-specific apoptosis revealed the involvement of two Hox genes, Antennapedia (Antp) and Ultrabithorax (Ubx), in this process. Hox genes control the formation of segment-specific structures in their domains of expression, but also regulate organ and tissue morphogenesis. The study presented here shows that Antp and Ubx play antagonistic roles in motoneuron survival in the embryo. Ubx expression in the CNS is strongly upregulated at a late point in development, when most cells have begun to differentiate. This upregulation shortly precedes Ubx-dependent, segment-specific apoptosis of two differentiated motoneurons. It could further be demonstrated that Antp is required for proper development of the NB7-3 lineage and for survival of the NB7-3 motoneuron in the anterior thoracic segments. In segments where Antp and Ubx expression overlaps, Ubx counteracts the anti-apoptotic function of Antp, resulting in cell death. Thus, these two Hox genes play opposing roles in the survival of differentiated neurons in the late developing nervous system. They thereby contribute to establishment of correct connections between outward-projecting neurons and their targets, which is crucial for the assembly of functional neural circuits, as these have to fulfill region-specific locomotion and sensory requirements along the antero-posterior body axis.

The role of central hypersensitivity in the determination of intradiscal mechanical hyperalgesia in discogenic pain

OBJECTIVE: The primary aim of the present study was to investigate whether there is a relationship between central hypersensitivity (assessed by pressure pain thresholds of uninjured tissues) and intradiscal pain threshold during discography. The secondary aim was to test the hypothesis that peripheral noxious stimulation dynamically modulates central hypersensitivity. PATIENTS: Twenty-four patients with positive provocation discography were tested for central hypersensitivity by pressure algometry before and after the intervention with assessments of pressure pain detection and tolerance thresholds. Intradiscal pain threshold was assessed by measuring intradiscal pressure at the moment of pain provocation during discography. Correlation analyses between intradiscal pain threshold and pressure algometry were made. For the secondary aim, pressure algometry data before and after discography were compared. RESULTS: Significant correlation with intradiscal pain threshold was found for pressure pain detection threshold at the toe (regression coefficient: 0.03, P = 0.05) and pressure pain tolerance thresholds at the nonpainful point at the back (0.02, P = 0.024). Tolerance threshold at the toe was a significant predictor for intradiscal pain threshold only in multiple linear regression (0.036, P = 0.027). Detection as well as tolerance thresholds significantly decreased after discography at the painful and the nonpainful point at the back, but not at the toe. CONCLUSIONS: Central hypersensitivity may influence intradiscal pain threshold, but with a modest quantitative impact. The diagnostic value of provocation discography is therefore not substantially impaired. Regional, but not generalized central hypersensitivity is dynamically modulated by ongoing peripheral nociceptive input.

Catastrophic Flooding In North-Central Pennsylvania: Geomorphic Findings From The September 2011 Event And Their Significance To

Tropical Storm Lee produced 25-36 cm of rainfall in north-central Pennsylvania on September 4th through 8th of 2011. Loyalsock Creek, Muncy Creek, and Fishing Creek experienced catastrophic flooding resulting in new channel formation, bank erosion, scour of chutes, deposition/reworking of point bars and chute bars, and reactivation of the floodplain. This study was created to investigate aspects of both geomorphology and sedimentology by studying the well-exposed gravel deposits left by the flood, before these features are removed by humans or covered by vegetation. By recording the composition of gravel bars in the study area and creating lithofacies models, it is possible to understand the 2011 flooding. Surficial clasts on gravel bars are imbricated, but the lack of imbrication and high matrix content of sediments at depth suggests that surface imbrication of the largest clasts took place during hyperconcentrated flow (40-70% sediment concentration). The imbricated clasts on the surface are the largest observed within the bars. The lithofacies recorded are atypical for mixed-load stream lithofacies and more similar to glacial outburst flood lithofacies. This paper suggests that the accepted lithofacies model for mixed-load streams with gravel bedload may not always be useful for interpreting depositional systems. A flume study, which attempted to duplicate the stratigraphy recorded in the field, was run in order to better understand hyperconcentrated flows in the study area. Results from the study in the Bucknell Geology Flume Laboratory indicate that surficial imbrication is possible in hyperconcentrated conditions. After flooding the flume to entrain large amounts of sand and gravel, deposition of surficially imbricated gravel with massive or upward coarsening sedimentology occurred. Imbrication was not observed at depth. These experimental flume deposits support our interpretation of the lithofacies discovered in the field. The sizes of surficial gravel bar clasts show clear differences between chute and point bars. On point bars, gravels fine with increasing distance from the channel. Fining also occurs at the downstream end of point bars. In chute deposits, dramatic fining occurs down the axis of the chute, and lateral grain sizes are nearly uniform. Measuring the largest grain size of sandstone clasts at 8-11 kilometer intervals on each river reveals anomalies in the downstream fining trends. Gravel inputs from bedrock outcrops, tributaries, and erosion of Pleistocene outwash terraces may explain observed variations in grain size along streams either incised into the Appalachian Plateau or located near the Wisconsinan glacial boundary. Atomic Mass Spectrometry (AMS) radiocarbon dating of sediment from recently scoured features on Muncy Creek and Loyalsock Creek returned respective ages of 500 BP and 2490 BP. These dates suggest that the recurrence interval of the 2011 flooding may be several hundred to several thousand years. This geomorphic interval of recurrence is much longer then the 120 year interval calculated by the USGS using historical stream gauge records.

The Constitutional-Judicial Control of the Legislative and Executive Powers in Central and Eastern European Countries

This project looked at the nature, contents, methods, means and legal and political effects of the influence that constitutional courts exercise upon the legislative and executive powers in the newly established democracies of Central and Eastern Europe. The basic hypothesis was that these courts work to provide a limitation of political power within the framework of the principal constitutional values and that they force the legislature and executive to exercise their powers and duties in strict accordance with the constitution. Following a study of the documentary sources, including primarily the relevant constitutional and statutory provisions and decisions of constitutional courts, Mr. Cvetkovski prepared a questionnaire on various aspects of the topics researched and sent it to the respective constitutional courts. A series of direct interviews with court officials in six of the ten countries then served to clarify a large number of questions relating to differences in procedures etc. that arose from the questionnaires. As a final stage, the findings were compared with those described in recent publications on constitutional control in general and in Central and Eastern Europe in particular. The study began by considering the constitutional and political environment of the constitutional courts' activities in controlling legislative and executive powers, which in all countries studied are based on the principles of the rule of law and the separation of powers. All courts are separate bodies with special status in terms of constitutional law and are independent of other political and judicial institutions. The range of matters within their jurisdiction is set by the constitution of the country in question but in all cases can be exercised only with the framework of procedural rules. This gives considerable significance to the question of who sets these rules and different countries have dealt with it in different ways. In some there is a special constitutional law with the same legal force as the constitution itself (Croatia), the majority of countries allow for regulation by an ordinary law, Macedonia gives the court the autonomy to create and change its own rules of procedure, while in Hungary the parliament fixes the rules on procedure at the suggestion of the constitutional court. The question of the appointment of constitutional judges was also considered and of the mechanisms for ensuring their impartiality and immunity. In the area of the courts' scope for providing normative control, considerable differences were found between the different countries. In some cases the courts' jurisdiction is limited to the normative acts of the respective parliaments, and there is generally no provision for challenging unconstitutional omissions by legislation and the executive. There are, however, some situations in which they may indirectly evaluate the constitutionality of legislative omissions, as when the constitution contains provision for a time limit on enacting legislation, when the parliament has made an omission in drafting a law which violates the constitutional provisions, or when a law grants favours to certain groups while excluding others, thereby violating the equal protection clause of the constitution. The control of constitutionality of normative acts can be either preventive or repressive, depending on whether it is implemented before or after the promulgation of the law or other enactment being challenged. In most countries in the region the constitutional courts provide only repressive control, although in Hungary and Poland the courts are competent to perform both preventive and repressive norm control, while in Romania the court's jurisdiction is limited to preventive norm control. Most countries are wary of vesting constitutional courts with preventive norm control because of the danger of their becoming too involved in the day-to-day political debate, but Mr. Cvetkovski points out certain advantages of such control. If combined with a short time limit it can provide early clarification of a constitutional issue, secondly it avoids the problems arising if a law that has been in force for some years is declared to be unconstitutional, and thirdly it may help preserve the prestige of the legislation. Its disadvantages include the difficulty of ascertaining the actual and potential consequences of a norm without the empirical experience of the administration and enforcement of the law, the desirability of a certain distance from the day-to-day arguments surrounding the political process of legislation, the possible effects of changing social and economic conditions, and the danger of placing obstacles in the way of rapid reactions to acute situations. In the case of repressive norm control, this can be either abstract or concrete. The former is initiated by the supreme state organs in order to protect abstract constitutional order and the latter is initiated by ordinary courts, administrative authorities or by individuals. Constitutional courts cannot directly oblige the legislature and executive to pass a new law and this remains a matter of legislative and executive political responsibility. In the case of Poland, the parliament even has the power to dismiss a constitutional court decision by a special majority of votes, which means that the last word lies with the legislature. As the current constitutions of Central and Eastern European countries are newly adopted and differ significantly from the previous ones, the courts' interpretative functions should ensure a degree of unification in the application of the constitution. Some countries (Bulgaria, Hungary, Poland, Slovakia and Russia) provide for the constitutional courts' decisions to have a binding role on the constitutions. While their decisions inevitably have an influence on the actions of public bodies, they do not set criteria for political behaviour, which depends rather on the overall political culture and traditions of the society. All constitutions except that of Belarus, provide for the courts to have jurisdiction over conflicts arising from the distribution of responsibilities between different organs and levels in the country, as well for impeachment procedures against the head of state, and for determining the constitutionality of political parties (except in Belarus, Hungary, Russia and Slovakia). All the constitutions studied guarantee individual rights and freedoms and most courts have jurisdiction over complaints of violation of these rights by the constitution. All courts also have some jurisdiction over international agreements and treaties, either directly (Belarus, Bulgaria and Hungary) before the treaty is ratified, or indirectly (Croatia, Czech Republic, Macedonia, Romania, Russia and Yugoslavia). In each country the question of who may initiate proceedings of norm control is of central importance and is usually regulated by the constitution itself. There are three main possibilities: statutory organs, normal courts and private individuals and the limitations on each of these is discussed in the report. Most courts are limited in their rights to institute ex officio a full-scale review of a point of law, and such rights as they do have rarely been used. In most countries courts' decisions do not have any binding force but must be approved by parliament or impose on parliament the obligation to bring the relevant law into conformity within a certain period. As a result, the courts' position is generally weaker than in other countries in Europe, with parliament remaining the supreme body. In the case of preventive norm control a finding of unconstitutionality may act to suspend the law and or to refer it back to the legislature, where in countries such as Romania it may even be overturned by a two-thirds majority. In repressive norm control a finding of unconstitutionality generally serves to take the relevant law out of legal force from the day of publication of the decision or from another date fixed by the court. If the law is annulled retrospectively this may or may not bring decisions of criminal courts under review, depending on the provisions laid down in the relevant constitution. In cases relating to conflicts of competencies the courts' decisions tend to be declaratory and so have a binding effect inter partes. In the case of a review of an individual act, decisions generally become effective primarily inter partes but is the individual act has been based on an unconstitutional generally binding normative act of the legislature or executive, the findings has quasi-legal effect as it automatically initiates special proceedings in which the law or other regulation is to be annulled or abrogated with effect erga omnes. This wards off further application of the law and thus further violations of individual constitutional rights, but also discourages further constitutional complaints against the same law. Thus the success of one individual's complaint extends to everyone else whose rights have equally been or might have been violated by the respective law. As the body whose act is repealed is obliged to adopt another act and in doing so is bound by the legal position of the constitutional court on the violation of constitutionally guaranteed freedoms and rights of the complainant, in this situation the decision of the constitutional court has the force of a precedent.

Late Pleistocene glaciation in the Central Andes: Temperature versus humidity control A case study from the eastern Bolivian Andes (17°S) and regional synthesis

A glacier–climate model was used to calculate climatic conditions in a test site on the east Andean slope around Cochabamba (17°S, Bolivia) for the time of the maximum Late Pleistocene glaciation. Results suggest a massive temperature reduction of about − 6.4 °C (+ 1.4/− 1.3 °C), combined with annual precipitation rates of about 1100 mm (+ 570 mm/− 280 mm). This implies no major change in annual precipitation compared with today. Summer precipitation was the source for the humidity in the past, as is the case today. This climate scenario argues for a maximum advance of the paleo-glaciers in the eastern cordillera during the global Last Glacial Maximum (LGM, 20 ka BP), which is confirmed by exposure age dates. In a synthesized view over the central Andes, the results point to an increased summer precipitation-driven Late Glacial (15–10 ka BP) maximum advance in the western part of the Altiplano (18°S–23°S), a temperature-driven maximum advance during full glacial times (LGM) in the eastern cordillera, and a pre- and post-LGM (32 ka BP/14 ka BP) maximum advance around 30°S related to increased precipitation and reduced temperature on the western slope of the Andes. The results indicate the importance of understanding the seasonality and details of the mass balance–climate interaction in order to disentangle drivers for the observed regionally asynchronous past glaciations in the central Andes.

Does point of care prothrombin time measurement reduce the transfusion of fresh frozen plasma in patients undergoing major surgery? The POC-OP randomized-controlled trial

BACKGROUND: Bleeding is a frequent complication during surgery. The intraoperative administration of blood products, including packed red blood cells, platelets and fresh frozen plasma (FFP), is often live saving. Complications of blood transfusions contribute considerably to perioperative costs and blood product resources are limited. Consequently, strategies to optimize the decision to transfuse are needed. Bleeding during surgery is a dynamic process and may result in major blood loss and coagulopathy due to dilution and consumption. The indication for transfusion should be based on reliable coagulation studies. While hemoglobin levels and platelet counts are available within 15 minutes, standard coagulation studies require one hour. Therefore, the decision to administer FFP has to be made in the absence of any data. Point of care testing of prothrombin time ensures that one major parameter of coagulation is available in the operation theatre within minutes. It is fast, easy to perform, inexpensive and may enable physicians to rationally determine the need for FFP. METHODS/DESIGN: The objective of the POC-OP trial is to determine the effectiveness of point of care prothrombin time testing to reduce the administration of FFP. It is a patient and assessor blind, single center randomized controlled parallel group trial in 220 patients aged between 18 and 90 years undergoing major surgery (any type, except cardiac surgery and liver transplantation) with an estimated blood loss during surgery exceeding 20% of the calculated total blood volume or a requirement of FFP according to the judgment of the physicians in charge. Patients are randomized to usual care plus point of care prothrombin time testing or usual care alone without point of care testing. The primary outcome is the relative risk to receive any FFP perioperatively. The inclusion of 110 patients per group will yield more than 80% power to detect a clinically relevant relative risk of 0.60 to receive FFP of the experimental as compared with the control group. DISCUSSION: Point of care prothrombin time testing in the operation theatre may reduce the administration of FFP considerably, which in turn may decrease costs and complications usually associated with the administration of blood products. TRIAL REGISTRATION: NCT00656396.

A point mutation in cpsE renders Streptococcus pneumoniae nonencapsulated and enhances its growth, adherence and competence

BackgroundThe polysaccharide capsule is a major virulence factor of the important human pathogen Streptococcus pneumoniae. However, S. pneumoniae strains lacking capsule do occur.ResultsHere, we report a nasopharyngeal isolate of Streptococcus pneumoniae composed of a mixture of two phenotypes; one encapsulated (serotype 18C) and the other nonencapsulated, determined by serotyping, electron microscopy and fluorescence isothiocyanate dextran exclusion assay.By whole genome sequencing, we demonstrated that the phenotypes differ by a single nucleotide base pair in capsular gene cpsE (C to G change at gene position 1135) predicted to result in amino acid change from arginine to glycine at position 379, located in the cytoplasmic, enzymatically active, region of this transmembrane protein. This SNP is responsible for loss of capsule production as the phenotype is transferred with the capsule operon. The nonencapsulated variant is superior in growth in vitro and is also 117-fold more adherent to and more invasive into Detroit 562 human epithelial cells than the encapsulated variant.Expression of six competence pathway genes and one competence-associated gene was 11 to 34-fold higher in the nonencapsulated variant than the encapsulated and transformation frequency was 3.7-fold greater.ConclusionsWe identified a new single point mutation in capsule gene cpsE of a clinical S. pneumoniae serotype 18C isolate sufficient to cause loss of capsule expression resulting in the co-existence of the encapsulated and nonencapsulated phenotype. The mutation caused phenotypic changes in growth, adherence to epithelial cells and transformability. Mutation in capsule gene cpsE may be a way for S. pneumoniae to lose its capsule and increase its colonization potential.

GABAergic modulation in central sensitization in humans: a randomized placebo-controlled pharmacokinetic-pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers

Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.

Climatology of Vb cyclones, physical mechanisms and their impact on extreme precipitation over Central Europe

Cyclones, which develop over the western Mediterranean and move northeastward are a major source of extreme weather and known to be responsible for heavy precipitation over the northern side of the Alpine range and Central Europe. As the relevant processes triggering these so-called Vb events and their impact on extreme precipitation are not yet fully understood, this study focuses on gaining insight into the dynamics of past events. For this, a cyclone detection and tracking tool is applied to the ERA-Interim reanalysis (1979–2013) to identify prominent Vb situations. Precipitation in the ERA-Interim and the E-OBS data sets is used to evaluate case-to-case precipitation amounts and to assess consistency between the two data sets. Both data sets exhibit high variability in precipitation amounts among different Vb events. While only 23 % of all Vb events are associated with extreme precipitation, around 15 % of all extreme precipitation days (99 percentile) over the northern Alpine region and Central Europe are induced by Vb events, although Vb cyclones are rare events (2.3 per year). To obtain a better understanding of the variability within Vb events, the analysis of the 10 heaviest and lowest precipitation Vb events reveals noticeable differences in the state of the atmosphere. These differences are most pronounced in the geopotential height and potential vorticity field, indicating a much stronger cyclone for heavy precipitation events. The related differences in wind direction are responsible for the moisture transport around the Alps and the orographical lifting along the northern slopes of the Alps. These effects are the main reasons for a disastrous outcome of Vb events, and consequently are absent in the Vb events associated with low precipitation. Hence, our results point out that heavy precipitation related to Vb events is mainly related to large-scale dynamics rather than to thermodynamic processes.

Material culture entanglements of early wetland sites in central Switzerland (4300-3850 BC)

In central Switzerland, the earliest wetland settlements with definitely attested finds and features date into the second half of the 5th millennium BC. Combining the information they have yielded with that from dryland sites, we can construct a detailed picture of material culture at the turn of the 5th to the 4th millennium. On this basis, the definition of clearly delimited archaeological cultures seems questionable, not only from a theoretical point of view. Similiarities and differences in the pottery show small-scale regional units defined via vessel forms as well as stylistic and technological aspects. Yet there are also inter-regional connections: roundbased vessels with opposing handles are typical for Lake Zurich, central and western Switzerland, the Valais and the central Rhône valley. In turn, ‘foreign‘ types such as shoulder-band beakers indicate regular connections between groups living in central Switzerland and those in Alsace and southern Germany. Are these beakers ‘imports‘ or locally produced items (‘imitations‘) indicating the adoption of ‘foreign‘ vessel types and concepts? This and similar material culture phenomena result in a picture of many material entanglements and problematise the kinds of relationships and mobility which might have existed. Our paper addresses these questions and discusses how and whether these interwoven connections changed in the early 4th millennium.

Developing a point-of-care electronic medical record system for TB/HIV co-infected patients: experiences from Lighthouse Trust, Lilongwe, Malawi.

BACKGROUND Implementation of user-friendly, real-time, electronic medical records for patient management may lead to improved adherence to clinical guidelines and improved quality of patient care. We detail the systematic, iterative process that implementation partners, Lighthouse clinic and Baobab Health Trust, employed to develop and implement a point-of-care electronic medical records system in an integrated, public clinic in Malawi that serves HIV-infected and tuberculosis (TB) patients. METHODS Baobab Health Trust, the system developers, conducted a series of technical and clinical meetings with Lighthouse and Ministry of Health to determine specifications. Multiple pre-testing sessions assessed patient flow, question clarity, information sequencing, and verified compliance to national guidelines. Final components of the TB/HIV electronic medical records system include: patient demographics; anthropometric measurements; laboratory samples and results; HIV testing; WHO clinical staging; TB diagnosis; family planning; clinical review; and drug dispensing. RESULTS Our experience suggests that an electronic medical records system can improve patient management, enhance integration of TB/HIV services, and improve provider decision-making. However, despite sufficient funding and motivation, several challenges delayed system launch including: expansion of system components to include of HIV testing and counseling services; changes in the national antiretroviral treatment guidelines that required system revision; and low confidence to use the system among new healthcare workers. To ensure a more robust and agile system that met all stakeholder and user needs, our electronic medical records launch was delayed more than a year. Open communication with stakeholders, careful consideration of ongoing provider input, and a well-functioning, backup, paper-based TB registry helped ensure successful implementation and sustainability of the system. Additional, on-site, technical support provided reassurance and swift problem-solving during the extended launch period. CONCLUSION Even when system users are closely involved in the design and development of an electronic medical record system, it is critical to allow sufficient time for software development, solicitation of detailed feedback from both users and stakeholders, and iterative system revisions to successfully transition from paper to point-of-care electronic medical records. For those in low-resource settings, electronic medical records for integrated care is a possible and positive innovation.

Molecular interactions of the central conserved domain of p53

p53 mutations are the most commonly observed genetic alterations in human cancers to date. A majority of these point mutations cluster in four evolutionarily conserved domains spanning amino acids 100-300. This region of p53 has been called its central conserved, or conformational domain. This domain of p53 is also targeted by the SV40 T antigen. Mutation, as well as interaction with SV40 T antigen results in inactivation of p53. We hypothesized that mutations and SV40 T antigen disrupt p53 function by interfering with the molecular interactions of the central conserved domain. Using a chimeric protein consisting of the central conserved domain of wild-type p53 (amino acids 115-295) and a protein A affinity tail, we isolated several cellular proteins that interact specifically with this domain of p53. These proteins range in size from 30K to 90K M$\rm\sb{r}.$ We also employed the p53 fusion protein to demonstrate that the central conserved domain of p53 possesses sequence-specific DNA-binding activity. Interestingly, the cellular proteins binding to the central conserved domain of p53 enhance the sequence-specific DNA-binding activity of full length p53. Partial purification of the individual proteins binding to the conformational domain of p53 by utilizing a sodium chloride step-gradient enabled further characterization of two proteins: (1) a 42K M$\rm\sb{r}$ protein that eluted at 0.5M NaCl, and bound DNA nonspecifically, and (2) a 35K M$\rm\sb{r}$ protein eluting into the 1.0M NaCl fraction, capable of enhancing the sequence-specific DNA-binding activity of p53. In order to determine the physiologic relevance of the molecular interactions of the conformational domain of p53, we examined the biochemical processes underlying the TNF-$\alpha$ mediated growth suppression of the NSCLC cell line H460. While growth suppression was accompanied by enhanced sequence-specific p53-DNA binding activity in TNF-$\alpha$ treated H460 nuclei, there was no increase in p53 protein levels. Furthermore, p35 was upregulated in TNF-$\alpha$ treated H460 cells, suggesting that the enhanced p53-DNA binding seen in these cells may be mediated by p35. Our studies define two novel interactions involving the central conserved domain of p53 that appear to be functionally relevant: (1) sequence-specific DNA-binding, and (2) interaction with other cellular proteins. ^