Charge Relaying within a Phospho-Motif Rescue Binding Competency of a Disordered Transcription Factor.

Structural disorder in proteins is central to cellular signaling, where conformational plasticity equips molecules to promiscuously interact with different partners. By engaging with multiple binding partners via the rearrangement of its three helices, the nuclear coactivator binding domain (NCBD) of the CBP/p300 transcription factor is a paradigmatic example of promiscuity. Recently, molecular simulations and experiments revealed that, through the establishment of long-range electrostatic interactions, intended as salt-bridges formed between the post-translationally inserted phosphate and positively charged residues in helix H3 of NCBD, phosphorylation triggers NCBD compaction, lowering its affinity for binding partners.

DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2.

More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble models prevents their mechanistic decoding. Here we integrate single-molecule FRET and NMR spectroscopy with molecular simulations showing that DNA binding can lead to complex changes in the IDR ensemble and accessibility.

Multilayered allosteric modulation of coupled folding and binding by phosphorylation, peptidyl-prolyl cis/trans isomerization, and diversity of interaction partners.

Intrinsically disordered proteins (IDPs) play key roles in cellular regulation, including signal transduction, transcription, and cell-cycle control. Accordingly, IDPs can commonly interact with numerous different target proteins, and their interaction networks are expected to be highly regulated. However, many of the underlying regulatory mechanisms have remained unclear.

Simulating Polyproline II-Helix-Rich Peptides with the Latest Kirkwood-Buff Force Field: A Direct Comparison with AMBER and CHARMM.

We simulated the dynamics of a set of peptides characterized by ensembles rich in PPII-helical content, to assess the ability of the most recent Kirkwood-Buff force field (KBFF20) to sample this conformational peculiarity. KBFF has been previously shown to capably reproduce experimental dimensions of disordered proteins, while being limited in confidently sampling structured proteins. Further development of the force field bridged this gap.

Protein intrinsic disorder on a dynamic nucleosomal landscape.

The complex nucleoprotein landscape of the eukaryotic cell nucleus is rich in dynamic proteins that lack a stable three-dimensional structure. Many of these intrinsically disordered proteins operate directly on the first fundamental level of genome compaction: the nucleosome. Here we give an overview of how disordered interactions with and within nucleosomes shape the dynamics, architecture, and epigenetic regulation of the genetic material, controlling cellular transcription patterns.

Evidence of absence regression: a binomial N-mixture model for estimating fatalities at wind energy facilities.

Estimating bird and bat fatalities caused by wind-turbine facilities is challenging when carcasses are rare and produce counts that are either exactly or very near zero. The rarity of found carcasses is exacerbated when live members of a particular species are rare and when carcasses degrade quickly, are removed by scavengers, or are not detected by observers. With few observed carcass counts, common statistical methods like logistic, Poisson, or negative binomial regression are unreliable (statistically biased) and often fail to provide answers (i.

Spatio-temporal dynamics in maturation and spawning of Patagonian toothfish Dissostichus eleginoides on the sub-Antarctic Kerguelen Plateau.

This study investigated maturation and spawning of Patagonian toothfish Dissostichus eleginoides in the Heard Island and McDonald Islands (HIMI) fishery on the Kerguelen Plateau in the Indian Sector of the Southern Ocean based on gonads and otoliths collected between 2004 and 2015 and using histological analyses and calibration of macroscopic staging criteria. Dissostichus eleginoides at HIMI spawn throughout the austral late autumn and winter months of May-August and spawning activity is concentrated on slopes along the west and south of the plateau around HIMI at depths of 1500-1900 m. Comparison between histological analyses and macroscopic gonad staging indicated that many fish that had spawned, as indicated by the presence of post-ovulatory follicles, returned to a resting stage which was macroscopically indistinguishable from maturing fish.

Interdomain conformational flexibility underpins the activity of UGGT, the eukaryotic glycoprotein secretion checkpoint.

Glycoproteins traversing the eukaryotic secretory pathway begin life in the endoplasmic reticulum (ER), where their folding is surveyed by the 170-kDa UDP-glucose:glycoprotein glucosyltransferase (UGGT). The enzyme acts as the single glycoprotein folding quality control checkpoint: it selectively reglucosylates misfolded glycoproteins, promotes their association with ER lectins and associated chaperones, and prevents premature secretion from the ER. UGGT has long resisted structural determination and sequence-based domain boundary prediction.

FDG PET in early stage cutaneous malignant melanoma.

Introduction: Fluorodeoxyglucose positron emission tomography (FDG PET) is not recommended in early stage melanoma; however, a significant number of cases are referred to our institution for FDG PET. We refer to early stage disease as American Joint Committee on Cancer (AJCC) stage I and II, which includes all cases without metastases. A retrospective review was undertaken to determine the clinical utility of FDG PET in this patient group.

Assessors' views. Health data is not enough.

Experts who sat on the world class commissioning assessment panels share their views on how primary care trusts are performing - and their top tips

Dormancy and germination characteristics of herbaceous species in the seasonally dry tropics of northern Australia.

This study investigated changes in dormancy and germination over 8 months for 23 common species (annual and perennial grasses, legumes and other dicotyledons) from herbaceous communities in northern Australia. Seeds were exposed to three storage treatments: relatively constant laboratory conditions, an oven with fluctuating temperatures similar to those found on the soil surface (25/60°C), or exposed on the soil surface at Townsville. There were wide ranges of initial levels of dormancy (9-100%), rates of change of dormancy and response to the different storage conditions showing that species with several types of dormancy characteristics are able to coexist in these communities.

Survival after embolization of the internal iliac arteries in ten patients with severe haematuria due to recurrent pelvic carcinoma.

Therapeutic embolization of the internal iliac arteries is a well established technique for controlling severe haematuria caused by malignant disease, but there are few reports of the long term outcome. We performed iliac artery embolization procedures on 10 patients with severe haematuria secondary to widespread inoperable pelvic carcinoma, between 1979 and 1992, and have followed these patients until death. Prior to embolization, the mean transfusion requirement was 12 units (range 2-39 units).

The effect of long-term thyroxine on bone mineral density and serum cholesterol.

The effect of thyrotrophin suppression on bone mineral density (BMD) and serum cholesterol concentration was assessed in 31 treated hypothyroid women. Measurements of the BMD of the lumbar spine and femoral neck were repeated in seven of those with the lowest value after an average period of 22.7 months.

Pregnancy after uterine artery embolization to control haemorrhage from gestational trophoblastic tumour.

Gestational trophoblastic tumour (GTT) of the uterus can cause severe and even life threatening haemorrhage in patients who may be contemplating future pregnancy. Three cases of successful pregnancy after uterine artery embolization to control severe haemorrhage from uterine GTT are reported. Both uterine arteries had been selectively catheterized and embolized in these patients.

Inspiratory coactivation of the genioglossus enlarges retroglossal space in laryngectomized humans.

To investigate the relationship between the electrical activity of the genioglossus (GG-EMG) and associated tongue movement, seven laryngectomized subjects breathing through a tracheal stoma (without pressure or flow change in the upper airway) were studied in the supine position. Tongue movement, with the use of lateral fluoroscopy, and GG-EMG expressed as a percentage of maximum voluntary genioglossal activation were monitored simultaneously during 1) spontaneous inspiration (SI), 2) resistive loaded inspiration (LI), and 3) rapid inspiration (RI). Tongue position during each maneuver was compared with its position during spontaneous expiration.

Ultrasonography in developmental hip dysplasia.

With the evolving use of ultrasonography, there has been an increasing emphasis on the technically oriented diagnosis of developmental hip dysplasia. Graf's alpha and beta angles and Harcke's bony rim percentage are two of the more common criteria, but their repeatability and reliability have not been well documented. Fifty-eight hip ultrasounds of 29 infants were measured independently by three physicians, and statistical analysis was performed.

Renal artery embolization with ethanol and gelfoam for the treatment of ureteric fistulae with one year follow-up.

Two patients with ureteric fistulae who were unfit for reconstructive surgery were treated by renal ablation using intra-arterial ethanol, gelfoam fragments and in one case coils. In both cases the fistulae dried-up on the same day and both patients are well and normotensive a year later. Our conclusion is that renal ablation by arterial embolization with ethanol can be a valuable alternative to surgery to treat ureteric fistulae in patients who are poor surgical risks.

245 transaxillary arteriograms in arteriopathic patients: success rate and complications.

Two hundred and forty-five transaxillary arteriograms were attempted at Charing Cross Hospital between 1982 and 1991 on 195 arteriopathic patients (mean age 64 years) in whom the femoral route was contra-indicated due to absent pulses (94), previous surgery (108), femoral artery aneurysm (5), severe aorto-iliac disease (8) or previous failure by the femoral route (30). Most arteriograms (211) were carried out to investigate peripheral vascular disease, the others were carried out to perform transluminal angioplasty (16) to assess cerebrovascular disease (10) and to investigate arterial insufficiency of the kidneys, alimentary tract and upper limb (8). There were two (0.

Thoracic lordosis in idiopathic scoliosis.

Lordosis, a significant aspect of thoracic scoliosis, is difficult to assess with routine clinical radiographs. Computerized analysis of 138 sets of standardized anteroposterior and lateral radiographs served to elicit the three-dimensional structure of scoliosis. Spinal curvatures in the usual anatomic planes and in the sagittal and frontal planes of the apical vertebrae were measured.

Survival after transhepatic embolization of gastro-oesophageal varices.

Twenty-five transhepatic embolization procedures were carried out between 1984 and 1989 on 24 patients with life-threatening haemorrhage from gastric or oesophageal varices after conservative methods had failed. There were two deaths related to the procedure and another 17 patients died during the following year. There were five survivors at 1 year, four are alive and well 4 years later, the fifth was lost to follow-up at 2 1/2 years.