Gamma Limit for Transition Paths of Maximal Probability

Chemical reactions can be modelled via diffusion processes conditioned to make a transition between specified molecular configurations representing the state of the system before and after the chemical reaction. In particular the model of Brownian dynamics - gradient flow subject to additive noise - is frequently used. If the chemical reaction is specified to take place on a given time interval, then the most likely path taken by the system is a minimizer of the Onsager-Machlup functional. The Gamma limit of this functional is determined in the case where the temperature is small and the transition time scales as the inverse temperatur

Six-component measurements on a straight and a 35 degree swept-back trapezoidal wing with and without split flaps

In accord with me test program (published in reference 7) the wing in question is briefly designated as No. 5. It differs from the rectangular wing discussed in reference 7 by its taper and from the 35O swept-back trapezoidal wing treated in reference 8 by the absence of sweepbaok

Optimal uncertainty quantification for legacy data observations of Lipschitz functions

We consider the problem of providing optimal uncertainty quantification (UQ) --- and hence rigorous certification --- for partially-observed functions. We present a UQ framework within which the observations may be small or large in number, and need not carry information about the probability distribution of the system in operation. The UQ objectives are posed as optimization problems, the solutions of which are optimal bounds on the quantities of interest; we consider two typical settings, namely parameter sensitivities (McDiarmid diameters) and output deviation (or failure) probabilities. The solutions of these optimization problems depend non-trivially (even non-monotonically and discontinuously) upon the specified legacy data. Furthermore, the extreme values are often determined by only a few members of the data set; in our principal physically-motivated example, the bounds are determined by just 2 out of 32 data points, and the remainder carry no information and could be neglected without changing the final answer. We propose an analogue of the simplex algorithm from linear programming that uses these observations to offer efficient and rigorous UQ for high-dimensional systems with high-cardinality legacy data. These findings suggest natural methods for selecting optimal (maximally informative) next experiments.Comment: 38 page

TFIIH central activity in nucleotide excision repair to prevent disease

The heterodecameric transcription factor IIH (TFIIH) functions in multiple cellular processes, foremost in nucleotide excision repair (NER) and transcription initiation by RNA polymerase II. TFIIH is essential for life and hereditary mutations in TFIIH cause the devastating human syndromes xeroderma pigmentosum, Cockayne syndrome or trichothiodystrophy, or combinations of these. In NER, TFIIH binds to DNA after DNA damage is detected and, using its translocase and helicase subunits XPB and XPD, opens up the DNA and checks for the presence of DNA damage. This central activity leads to dual incision and removal of the DNA strand containing the damage, after which the resulting DNA gap is restored. In this review, we discuss new structural and mechanistic insights into the central function of TFIIH in NER. Moreover, we provide an elaborate overview of all currently known patients and diseases associated with inherited TFIIH mutations and describe how our understanding of TFIIH function in NER and transcription can explain the different disease features caused by TFIIH deficiency.</p

XPG: a multitasking genome caretaker

The XPG/ERCC5 endonuclease was originally identified as the causative gene for Xeroderma Pigmentosum complementation group G. Ever since its discovery, in depth biochemical, structural and cell biological studies have provided detailed mechanistic insight into its function in excising DNA damage in nucleotide excision repair, together with the ERCC1–XPF endonuclease. In recent years, it has become evident that XPG has additional important roles in genome maintenance that are independent of its function in NER, as XPG has been implicated in protecting replication forks by promoting homologous recombination as well as in resolving R-loops. Here, we provide an overview of the multitasking of XPG in genome maintenance, by describing in detail how its activity in NER is regulated and the evidence that points to important functions outside of NER. Furthermore, we present the various disease phenotypes associated with inherited XPG deficiency and discuss current ideas on how XPG deficiency leads to these different types of disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04194-5

Predictability of large future changes in a competitive evolving population

The dynamical evolution of many economic, sociological, biological and physical systems tends to be dominated by a relatively small number of unexpected, large changes (`extreme events'). We study the large, internal changes produced in a generic multi-agent population competing for a limited resource, and find that the level of predictability actually increases prior to a large change. These large changes hence arise as a predictable consequence of information encoded in the system's global state.Comment: 10 pages, 3 figure

Mutations in TFIIH causing trichothiodystrophy are responsible for defects in ribosomal RNA production and processing

The basal transcription/repair factor II H (TFIIH), found mutated in cancer-prone or premature aging diseases, plays a still unclear role in RNA polymerase I transcription. Furthermore, the impact of this function on TFIIHrelated diseases, such as trichothiodystrophy (TTD), remains to be explored. Here, we studied the involvement of TFIIH during the whole process of ribosome biogenesis, from RNAP1 transcription to maturation steps of the ribosomal RNAs. Our results show that TFIIH is recruited to the ribosomal DNA in an active transcription- dependent manner and functions in RNAP1 transcription elongation through ATP hydrolysis of the XPB subunit. Remarkably, we found a TFIIH allele-specific effect, affecting RNAP1 transcription and/or the pre-rRNA maturation process. Interestingly, this effect was observed in mutant TFIIH-TTD cells and also in the brains of TFIIH-TTD mice. Our findings provide evidence that defective ribosome synthesis represents a new faulty mechanism involved in the pathophysiology of TFIIH-related diseases.</p