Masses and Interactions of q-Fermionic Knots

The q-electroweak theory suggests a description of elementary particles as solitons labelled by the irreducible representations of SU_q(2). Since knots may also be labelled by the irreducible representations of SU_q(2), we study a model of elementary particles based on a one-to-one correspondence between the four families of Fermions (leptons, neutrinos, (-1/3) quarks, (2/3) quarks) and the four simplest knots (trefoils). In this model the three particles of each family are identified with the ground and first two excited states of their common trefoil. Guided by the standard electroweak theory we calculate conditions restricting the masses of the fermions and the interactions between them. In its present form the model predicts a fourth generation of fermions as well as a neutrino spectrum. The same model with q almost equal to 1 is compatible with the Kobayashi-Maskawa matrix. Depending on the test of these predictions, the model may be refined.Comment: 40 pages, 2 figures, latex forma

Diabetic kidney disease in type 2 diabetes: a consensus statement from the Swiss Societies of Diabetes and Nephrology.

Diabetic kidney disease is highly prevalent in patients with type 2 diabetes and is a major cause of end-stage renal disease in Switzerland. Patients with diabetic kidney disease are among the most complex patients in diabetes care. They require a multifactorial and multidisciplinary approach with the goal to slow the decline in glomerular filtration rate (GFR) and cardiovascular morbidity. With this consensus we propose an evidence-based guidance to health care providers involved in the care of type 2 diabetic patients with diabetic kidney disease.First, there is a need to increase physician awareness and improve screening for diabetic kidney disease as early intervention may improve clinical outcomes and the financial burden. Evaluation of estimated GFR (eGFR) and spot urine albumin/creatinine ratio is recommended at least annually. Once it is diagnosed, glucose control and optimisation of blood pressure control with renin-angiotensin system blockers have been recommended as mainstay management of diabetic kidney disease for more than 20 years. Recent, high quality randomised controlled trials have shown that sodium-glucose cotransporter-2 (SGLT2) inhibition slows eGFR decline and cardiovascular events beyond glucose control. Likewise, mineralocorticoid receptor antagonism with finerenone has cardiorenal protective effects in diabetic kidney disease. Glucagon-like peptide-1 (GLP1) receptor agonists improve weight loss if needed, and decrease albuminuria and cardiovascular morbidity. Lipid control is also important to decrease cardiovascular events. All these therapies are included in the treatment algorithms proposed in this consensus. With advancing kidney failure, other challenges may rise, such as hyperkalaemia, anaemia and metabolic acidosis, as well as chronic kidney disease-mineral and bone disorder. These different topics and treatment strategies are discussed in this consensus. Finally, an update on diabetes management in renal replacement therapy such as haemodialysis, peritoneal dialysis and renal transplantation is provided. With the recent developments of efficient therapies for diabetic kidney disease, it has become evident that a consensus document is necessary. We are optimistic that it will significantly contribute to a high-quality care for patients with diabetic kidney disease in Switzerland in the future

A toy model of the five-dimensional universe with the cosmological constant

A value of the cosmological constant in a toy model of the five-dimensional universe is calculated in such a manner that it remains in agreement with both astronomical observations and the quantum field theory concerning the zero-point fluctuations of the vacuum. The (negative) cosmological constant is equal to the inverse of the Planck length squared, which means that in the toy model the vanishing of the observed value of the cosmological constant is a consequence of the existence of an energy cutoff exactly at the level of the Planck scale. In turn, a model for both a virtual and a real particle-antiparticle pair is proposed which describes properly some energetic properties of both the vacuum fluctuations and created particles, as well as it allows one to calculate the discrete "bare" values of an elementary-particle mass, electric charge and intrinsic angular momentum (spin) at the energy cutoff. The relationships between the discussed model and some phenomena such as the Zitterbewegung and the Unruh-Davies effect are briefly analyzed, too. The proposed model also allows one to derive the Lorentz transformation and the Maxwell equations while considering the properties of the vacuum filled with the sea of virtual particles and their antiparticles. Finally, the existence of a finite value of the vacuum-energy density resulting from the toy model leads us to the formulation of dimensionless Einstein field equations which can be derived from the Lagrangian with a dimensionless (naively renormalized) coupling constant.Comment: 52 pages, 1 figure; a post-final, rewritten version with a number of new remarks and conclusion

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation

Background: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. Methods: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. Results: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. Conclusion: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money

A new role for FBP21 as regulator of Brr2 helicase activity

Splicing of eukaryotic pre-mRNA is carried out by the spliceosome, which assembles stepwise on each splicing substrate. This requires the concerted action of snRNPs and non-snRNP accessory proteins, the functions of which are often not well understood. Of special interest are B complex factors that enter the spliceosome prior to catalytic activation and may alter splicing kinetics and splice site selection. One of these proteins is FBP21, for which we identified several spliceosomal binding partners in a yeast-two-hybrid screen, among them the RNA helicase Brr2. Biochemical and biophysical analyses revealed that an intrinsically disordered region of FBP21 binds to an extended surface of the C-terminal Sec63 unit of Brr2. Additional contacts in the C-terminal helicase cassette are required for allosteric inhibition of Brr2 helicase activity. Furthermore, the direct interaction between FBP21 and the U4/U6 di-snRNA was found to reduce the pool of unwound U4/U6 di-snRNA. Our results suggest FBP21 as a novel key player in the regulation of Brr2

Kinematics and hydrodynamics of spinning particles

In the first part (Sections 1 and 2) of this paper --starting from the Pauli current, in the ordinary tensorial language-- we obtain the decomposition of the non-relativistic field velocity into two orthogonal parts: (i) the "classical part, that is, the 3-velocity w = p/m OF the center-of-mass (CM), and (ii) the so-called "quantum" part, that is, the 3-velocity V of the motion IN the CM frame (namely, the internal "spin motion" or zitterbewegung). By inserting such a complete, composite expression of the velocity into the kinetic energy term of the non-relativistic classical (i.e., newtonian) lagrangian, we straightforwardly get the appearance of the so-called "quantum potential" associated, as it is known, with the Madelung fluid. This result carries further evidence that the quantum behaviour of micro-systems can be adirect consequence of the fundamental existence of spin. In the second part (Sections 3 and 4), we fix our attention on the total 3-velocity v = w + V, it being now necessary to pass to relativistic (classical) physics; and we show that the proper time entering the definition of the four-velocity v^mu for spinning particles has to be the proper time tau of the CM frame. Inserting the correct Lorentz factor into the definition of v^mu leads to completely new kinematical properties for v_mu v^mu. The important constraint p_mu v^mu = m, identically true for scalar particles, but just assumed a priori in all previous spinning particle theories, is herein derived in a self-consistent way.Comment: LaTeX file; needs kapproc.st

Atomic structure of granulin determined from native nanocrystalline granulovirus using an X-ray free-electron laser

To understand how molecules function in biological systems, new methods are required to obtain atomic resolution structures from biological material under physiological conditions. Intense femtosecond-duration pulses from X-ray free-electron lasers (XFELs) can outrun most damage processes, vastly increasing the tolerable dose before the specimen is destroyed. This in turn allows structure determination from crystals much smaller and more radiation sensitive than previously considered possible, allowing data collection from room temperature structures and avoiding structural changes due to cooling. Regardless, high-resolution structures obtained from XFEL data mostly use crystals far larger than 1 μm3 in volume, whereas the X-ray beam is often attenuated to protect the detector from damage caused by intense Bragg spots. Here, we describe the 2 Å resolution structure of native nanocrystalline granulovirus occlusion bodies (OBs) that are less than 0.016 μm3 in volume using the full power of the Linac Coherent Light Source (LCLS) and a dose up to 1.3 GGy per crystal. The crystalline shell of granulovirus OBs consists, on average, of about 9,000 unit cells, representing the smallest protein crystals to yield a high-resolution structure by X-ray crystallography to date. The XFEL structure shows little to no evidence of radiation damage and is more complete than a model determined using synchrotron data from recombinantly produced, much larger, cryocooled granulovirus granulin microcrystals. Our measurements suggest that it should be possible, under ideal experimental conditions, to obtain data from protein crystals with only 100 unit cells in volume using currently available XFELs and suggest that single-molecule imaging of individual biomolecules could almost be within reach

On impact and volcanism across the Cretaceous-Paleogene boundary

The cause of the end-Cretaceous mass extinction is vigorously debated, owing to the occurrence of a very large bolide impact and flood basalt volcanism near the boundary. Disentangling their relative importance is complicated by uncertainty regarding kill mechanisms and the relative timing of volcanogenic outgassing, impact, and extinction. We used carbon cycle modeling and paleotemperature records to constrain the timing of volcanogenic outgassing. We found support for major outgassing beginning and ending distinctly before the impact, with only the impact coinciding with mass extinction and biologically amplified carbon cycle change. Our models show that these extinction-related carbon cycle changes would have allowed the ocean to absorb massive amounts of carbon dioxide, thus limiting the global warming otherwise expected from postextinction volcanism