A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells

Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics

Could Public Restrooms Be an Environment for Bacterial Resistomes?

PMCID: PMC3547874This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease

Peer reviewedPublisher PD

Does Public Health Policy Matter?: Explaining Variation in COVID-19 Outcomes Across the 50 States

The Covid-19 pandemic has prompted debate about what factors cause wide variations in mortality and infection rates across the United States and raised questions about what can be done to limit the spread of future outbreaks. In the comparative international politics literature, there are four explanations that determine how well a country can contain outbreaks: leadership, state capacity, demographics, and state culture. Currently, there are no studies that show a comprehensive evaluation of what has caused variations in mortality rate among the fifty states. This study aims to examine state variation among the 50 states in the U.S. and its influence on Covid-19 infection and mortality rate. The study will utilize a mixed-method approach to determine which factors have the most impact on mortality and infection rate. Using a multivariate and case study analysis, I aim to show how the four explanations predicted the pandemic case and death rates. In the findings of this study, I found that several factors, including Republican party control, urbanization, and race, predicted a state’s Covid-19 outcomes. The purpose of this study is to urge states to repair weaknesses in pandemic response plans, address structural discrimination within the healthcare system, and facilitate national cooperation that will better equip states with the ability to contain an outbreak

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Statische Autoregulation der intrakraniellen venösen Hämodynamik unter Orthostase und Änderungen des Unterkörperumgebungsdrucks

Bisher ist nur wenig über die Regulation des intrakraniellen venösen Ausstroms bekannt. Kenntnisse der normalen Regulation sind aber notwendig, um pathologische Befunde einordnen zu können. Die vorliegende Studie untersucht das Verhalten der intrakraniellen venösen Hämodynamik unter Bedingungen, die Blutvolumenverschiebungen im Körper verursachen, wie dies auch bei natürlichen Veränderungen der Körperlage (Stehen/ Liegen) geschieht. Zu diesem Zweck wurden bei 19 gesunden Probanden (Alter: 26,2 ± 4,1 Jahre; 14 Frauen und 5 Männer) folgende Parameter kontinuierlich aufgezeichnet: Die Flussgeschwindigkeit im Sinus rectus über einem okzipitalen Schallfenster und die Flussgeschwindigkeit in der A. cerebri media (ACM) über einem temporalen Schallfenster mittels cw-Doppler sowie der nicht invasiv gemessene systemische Blutdruck und die Herzfrequenz. Autoregulationsprozesse wurden induziert durch Änderung des Lower Body Pressures (LBP) sowie durch ein Kipptischmanöver. Neben der Auswertung der mittleren Flussgeschwindigkeiten wurden zudem deren Pulsamplituden und der Zeitversatz zwischen arterieller und venöser Pulsation mittels Kreuzkorrelation analysiert. Die vier Phasen, in denen sich der Lower Body Pressure änderte, waren nochmals in jeweils vier Abschnitte unterteilt, in denen der Kippwinkel des Tisches verändert wurde. Somit wurde jede mögliche Kombination der Reize (Druck x Lage) ermöglicht und unter diesen Bedingungen wurden die oben genannten physiologischen Parameter erfasst. Es wurde gezeigt, dass unter LBPP die mittlere venöse Flussgeschwindigkeit signifikant gegenüber atmosphärischem Druck anstieg, während sie unter LBNP signifikant (p< 0.01) abfiel. Eine Kippung zu den Füßen (HUT) wirkte gleichsinnig zum LBNP, während eine Kippung Kopf über (HDT) sich zu LBPP gleichsinnig verhielt. Daraus ergibt sich eine Addition der Effekte sowohl von LBNP und HUT als auch von LBPP und HDT. In den Abschnitten dieser Kombination waren die Änderungen zur Ausgangsposition am größten. Die venöse Flussgeschwindigkeitsreaktion auf das Kippen war relativ unabhängig von dem herrschenden Unterkörperumgebungsdruck. Die physiologische Reaktion auf den Druck konnte also die entgegengesetzt wirkende Kippung nicht aufheben. Die Gleichsinnigkeit der Wirkung ist auf die Blutvolumenverschiebung zurückzuführen, die durch die angewendeten Verfahren induziert wurde. Die Ergebnisse der vorliegenden Studie erweisen sich als diametral entgegengesetzt zu den vorhergehenden Erwartungen: Bei erhöhtem intrakraniellen und intrathorakalen Druck (LBPP und HDT) fließt das venöse Blut schneller ab, während es langsamer abfließt, wenn der intrakranielle Druck und intrathorakale Druck (LBNP und HUT) niedrig ist, z.B. im Stehen. Das läßt sich durch zwei Phänomene erklären: Erstens ändern sich die Abflusswege des Blutes abhängig von der Körperposition. Während im Liegen vornehmlich die V. jugularis für den Abfluss verantwortlich ist, kollabiert diese schon bei einer Kippung um +15°. Der vertebrale Venenplexus wird hingegen auch bei negativem Druck durch seine feste Verankerung offengehalten (Valdueza et al., 2000). Zweitens erklärt ein steigender intrakranieller Druck die erhöhte venöse Flussgeschwindigkeit und den Anstieg der Pulsamplitude durch Verminderung der Volumencompliance (Shakhnovich et al.,1999). Die erhöhte venöse Flussgeschwindigkeit ist somit eine Reaktion auf den erhöhten intrakraniellen Druck und trägt zu seiner Minderung bei. Diese Beobachtung wirft ein neues Licht auf die zerebrale Hämodynamik, im besonderen auf den venösen Blutausstrom. In zukünftigen Studien wäre es nun interessant herauszufinden, ob sich das hämodynamische Geschehen bei pathologisch hohem intrakraniellen Druck ähnlich wie bei den hier gezeigten Ergebnissen verhält.Little knowledge exists about the regulation of cerebral venous outflow. In order to interpret pathological results, we need information about the physiological regulation of cerebral vessels. This study investigates the intracranial venous haemodynamics by changing body position and changing lower body pressure (LBP). The following parameters were investigated in 19 healthy volunteers, 14 women and 5 men, aged 26.2 +/- 4.1 years: - Flow velocity in the straight sinus and - Flow velocity in the middle cerebral artery via cw-doppler. Further heart rate and blood pressure were sampled. Auto-regulation processes were induced by changing LBP [lower body positive (LBPP) and negative pressure (LBNP) +/- 30 mmHg] and the tilt of an examination table [Head-down tilt (HDT) 20 degrees and head-up tilt (HUT) 30 degrees]. Besides the flow velocity, the pulse amplitude and the time lag between the venous and the arterial blood flow were included. There were four Phases of changing LBP. Each Phase provided four sequences of different table positions, therefore each possible combination of stimulus (pressure x position) was prepared to investigate the parameters. Under LBPP condition venous outflow was significantly higher than in atmospheric LBP, while under LBNP condition venous outflow significantly decreased (p < 0.01). HUT had the same effect on the venous outflow as LBNP. HDT had the same effect as LBPP. Therefore the two stimuli added their effects. The impact of tilt on the venous blood flow velocity was independent of LBP. The physiological reaction to the pressure could not neutralize the opposing tilt-effect. The summation of the effects of LBP and tilt is considered to be a result of the shift of blood volume. The results of the study proved the opposite of what was expected. Increased intracranial pressure and intra-thoracic pressure (LBPP and HDT) makes cerebral venous outflow faster, while under decreased intracranial and intra-thoracic pressure, blood flows slower in the cerebral veins (e.g. compared to an upright and standing position). This effect might be explained by two phenomena: - Firstly, pathways of venous outflow are dependent on the body position. While in a lying position, when the jugular vein is in use for cerebral venous outflow, this vein collapses at a HUT of 15 degrees. The vertebral venous plexus stays open under negative pressure due to its strong fixing (Valdueza et al., 2000). - Secondly, the increased intracranial pressure explains the increased venous outflow and increased pulse amplitude by decrease of compliance of volume (Shakhnovich et al., 1999). Therefore increased venous outflow reduces intracranial pressure, which could be considered as a protective mechanism. These observations provide new insight into aspects of cerebral haemodynamics, especially the cerebral venous outflow. In future studies, it would be interesting to investigate whether pathologically-increased intracranial pressure has the same impact on cerebral venous outflow as in the present study. Little knowledge exists about the regulation of cerebral venous outflow. In order to interpret pathological results, we need information about the physiological regulation of cerebral vessels. This study investigates the intracranial venous haemodynamics by changing body position and changing lower body pressure (LBP). The following parameters were investigated in 19 healthy volunteers, 14 women and 5 men, aged 26.2 +/- 4.1 years: - Flow velocity in the straight sinus and - Flow velocity in the middle cerebral artery via cw-doppler. Further heart rate and blood pressure were sampled. Auto-regulation processes were induced by changing LBP [lower body positive (LBPP) and negative pressure (LBNP) +/- 30 mmHg] and the tilt of an examination table [Head-down tilt (HDT) 20 degrees and head-up tilt (HUT) 30 degrees]. Besides the flow velocity, the pulse amplitude and the time lag between the venous and the arterial blood flow were included. There were four Phases of changing LBP. Each Phase provided four sequences of different table positions, therefore each possible combination of stimulus (pressure x position) was prepared to investigate the parameters. Under LBPP condition venous outflow was significantly higher than in atmospheric LBP, while under LBNP condition venous outflow significantly decreased (p < 0.01). HUT had the same effect on the venous outflow as LBNP. HDT had the same effect as LBPP. Therefore the two stimuli added their effects. The impact of tilt on the venous blood flow velocity was independent of LBP. The physiological reaction to the pressure could not neutralize the opposing tilt-effect. The summation of the effects of LBP and tilt is considered to be a result of the shift of blood volume. The results of the study proved the opposite of what was expected. Increased intracranial pressure and intra-thoracic pressure (LBPP and HDT) makes cerebral venous outflow faster, while under decreased intracranial and intra-thoracic pressure, blood flows slower in the cerebral veins (e.g. compared to an upright and standing position). This effect might be explained by two phenomena: - Firstly, pathways of venous outflow are dependent on the body position. While in a lying position, when the jugular vein is in use for cerebral venous outflow, this vein collapses at a HUT of 15 degrees. The vertebral venous plexus stays open under negative pressure due to its strong fixing (Valdueza et al., 2000). - Secondly, the increased intracranial pressure explains the increased venous outflow and increased pulse amplitude by decrease of compliance of volume (Shakhnovich et al., 1999). Therefore increased venous outflow reduces intracranial pressure, which could be considered as a protective mechanism. These observations provide new insight into aspects of cerebral haemodynamics, especially the cerebral venous outflow. In future studies, it would be interesting to investigate whether pathologically-increased intracranial pressure has the same impact on cerebral venous outflow as in the present study

The physical oceanography of the transport of floating marine debris

Marine plastic debris floating on the ocean surface is a major environmental problem. However, its distribution in the ocean is poorly mapped, and most of the plastic waste estimated to have entered the ocean from land is unaccounted for. Better understanding of how plastic debris is transported from coastal and marine sources is crucial to quantify and close the global inventory of marine plastics, which in turn represents critical information for mitigation or policy strategies. At the same time, plastic is a unique tracer that provides an opportunity to learn more about the physics and dynamics of our ocean across multiple scales, from the Ekman convergence in basin-scale gyres to individual waves in the surfzone. In this review, we comprehensively discuss what is known about the different processes that govern the transport of floating marine plastic debris in both the open ocean and the coastal zones, based on the published literature and referring to insights from neighbouring fields such as oil spill dispersion, marine safety recovery, plankton connectivity, and others. We discuss how measurements of marine plastics (both in situ and in the laboratory), remote sensing, and numerical simulations can elucidate these processes and their interactions across spatio-temporal scales

The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study

&lt;p&gt;Introduction: Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.&lt;/p&gt; &lt;p&gt;Patients and Methods: 100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.&lt;/p&gt; &lt;p&gt;Results: 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).&lt;/p&gt; &lt;p&gt;Conclusions: This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.&lt;/p&gt

Beating uncontrolled eating: Training inhibitory control to reduce food intake and food cue sensitivity

In our food-rich environment we must constantly resist appealing food in order to maintain a healthy lifestyle. Previous studies have found that food-specific inhibition training can produce changes in eating behaviour, such as a reduction in snack consumption. However, the mechanisms that drive the effect of inhibition training on eating behaviour remain unknown. Identifying the mechanism underlying food-specific inhibition training could lead to more targeted training interventions increasing the potential efficacy of such interventions. In the current study, we investigated directly whether training-induced effects on inhibitory control might underlie the predicted change in eating behaviour. Healthy individuals who scored high on uncontrolled eating were randomly assigned to receive six online training sessions over six consecutive days of either food-specific response inhibition training (active group; n = 21) or response inhibition training without food stimuli (control group; n = 20). We measured pre- and post-training inhibitory control in the context of food and food cue sensitivity, as well as food consumption in a bogus taste test. As expected, food-specific inhibition training decreased snack consumption in the bogus taste test relative to control training. However, the active training did not improve inhibitory control towards food, nor did it reduce food cue sensitivity above and beyond the control training. Future studies are needed to investigate the potential underlying mechanism of food-specific inhibition training, as it remains unclear what drives the reliable effect on eating behaviour