Estimating Absolute Configurational Entropies of Macromolecules: The Minimally Coupled Subspace Approach

We develop a general minimally coupled subspace approach (MCSA) to compute absolute entropies of macromolecules, such as proteins, from computer generated canonical ensembles. Our approach overcomes limitations of current estimates such as the quasi-harmonic approximation which neglects non-linear and higher-order correlations as well as multi-minima characteristics of protein energy landscapes. Here, Full Correlation Analysis, adaptive kernel density estimation, and mutual information expansions are combined and high accuracy is demonstrated for a number of test systems ranging from alkanes to a 14 residue peptide. We further computed the configurational entropy for the full 67-residue cofactor of the TATA box binding protein illustrating that MCSA yields improved results also for large macromolecular systems

Experimental Characterization of Cis-Acting Elements Important for Translation and Transcription in Halophilic Archaea

The basal transcription apparatus of archaea is well characterized. However, much less is known about the mechanisms of transcription termination and translation initation. Recently, experimental determination of the 5′-ends of ten transcripts from Pyrobaculum aerophilum revealed that these are devoid of a 5′-UTR. Bioinformatic analysis indicated that many transcripts of other archaeal species might also be leaderless. The 5′-ends and 3′-ends of 40 transcripts of two haloarchaeal species, Halobacterium salinarum and Haloferax volcanii, have been determined. They were used to characterize the lengths of 5′-UTRs and 3′-UTRs and to deduce consensus sequence-elements for transcription and translation. The experimental approach was complemented with a bioinformatics analysis of the H. salinarum genome sequence. Furthermore, the influence of selected 5′-UTRs and 3′-UTRs on transcript stability and translational efficiency in vivo was characterized using a newly established reporter gene system, gene fusions, and real-time PCR. Consensus sequences for basal promoter elements could be refined and a novel element was discovered. A consensus motif probably important for transcriptional termination was established. All 40 haloarchaeal transcripts analyzed had a 3′-UTR (average size 57 nt), and their 3′-ends were not posttranscriptionally modified. Experimental data and genome analyses revealed that the majority of haloarchaeal transcripts are leaderless, indicating that this is the predominant mode for translation initiation in haloarchaea. Surprisingly, the 5′-UTRs of most leadered transcripts did not contain a Shine-Dalgarno (SD) sequence. A genome analysis indicated that less than 10% of all genes are preceded by a SD sequence and even most proximal genes in operons lack a SD sequence. Seven different leadered transcripts devoid of a SD sequence were efficiently translated in vivo, including artificial 5′-UTRs of random sequences. Thus, an interaction of the 5′-UTRs of these leadered transcripts with the 16S rRNA could be excluded. Taken together, either a scanning mechanism similar to the mechanism of translation initiation operating in eukaryotes or a novel mechanism must operate on most leadered haloarchaeal transcripts

Model-free functional MRI analysis based on unsupervised clustering

AbstractConventional model-based or statistical analysis methods for functional MRI (fMRI) are easy to implement, and are effective in analyzing data with simple paradigms. However, they are not applicable in situations in which patterns of neural response are complicated and when fMRI response is unknown. In this paper the “neural gas” network is adapted and rigourosly studied for analyzing fMRI data. The algorithm supports spatial connectivity aiding in the identification of activation sites in functional brain imaging. A comparison of this new method with Kohonen’s self-organizing map and with a fuzzy clustering scheme based on deterministic annealing is done in a systematic fMRI study showing comparative quantitative evaluations. The most important findings in this paper are: (1) both “neural gas” and the fuzzy clustering technique outperform Kohonen’s map in terms of identifying signal components with high correlation to the fMRI stimulus, (2) the “neural gas” outperforms the two other methods with respect to the quantization error, and (3) Kohonen’s map outperforms the two other methods in terms of computational expense. The applicability of the new algorithm is demonstrated on experimental data

Development of biological soil crusts in initial ecosystems in Lusatia, Germany

During initial ecosystem development vegetation cover is sparse, but the space between shrubs is not bare and is often covered by a topsoil biological crust composed by cyanobacteria, green algae, mosses and lichens. These cryptogames are the first colonizer of initial ecosystems. The development of soil surface crusts plays a major role for the further vegetation pattern and ecosystem development through changes to the physico-chemical conditions and influencing various ecosystem processes. We studied the development of biological soil crusts on quaternary substrate of the initial artificial water catchment ´Neuer Lugteich´ located in the former open-cast lignite mining area near Welzow (Brandenburg, Germany). Chlorophyll, Corg, pH were determined to classified various soil crusts types. Some of these Kryptogames excrete exopolysaccharides that bind the inorganic fine-grained particles that form the matrix of the topsoil crust. Due to lack of organic matter in the geological substrate, photoautotrophic organisms like green algae and cyanobacteria are important for soil organic matter accumulation in first millimetre of topsoil of initial ecosystems. The biological soil crusts decrease infiltration rates and influence the hydrological conditions

Massively Scalable Inverse Reinforcement Learning in Google Maps

Optimizing for humans' latent preferences is a grand challenge in route recommendation, where globally-scalable solutions remain an open problem. Although past work created increasingly general solutions for the application of inverse reinforcement learning (IRL), these have not been successfully scaled to world-sized MDPs, large datasets, and highly parameterized models; respectively hundreds of millions of states, trajectories, and parameters. In this work, we surpass previous limitations through a series of advancements focused on graph compression, parallelization, and problem initialization based on dominant eigenvectors. We introduce Receding Horizon Inverse Planning (RHIP), which generalizes existing work and enables control of key performance trade-offs via its planning horizon. Our policy achieves a 16-24% improvement in global route quality, and, to our knowledge, represents the largest instance of IRL in a real-world setting to date. Our results show critical benefits to more sustainable modes of transportation (e.g. two-wheelers), where factors beyond journey time (e.g. route safety) play a substantial role. We conclude with ablations of key components, negative results on state-of-the-art eigenvalue solvers, and identify future opportunities to improve scalability via IRL-specific batching strategies

Wie beeinflussen Kiefern (Pinus sylvestris L.) die Entwicklung der Benetzungshemmung auf Sandböden?

Die Wald-Kiefer (Pinus sylvestris L.) ist in den Wäldern des südlichen Brandenburgs die dominierende Baumart und besiedelt als Pionierbaumart die nährstoffarmen Sandböden der Offenlandschaften. Unter und neben den Kiefern wird aufgrund der Akkumulation hydrophob wirkender organischer Substanzen oft verstärkte Benetzungshemmung beobachtet. Wir untersuchten die Entwicklung von Benetzungshemmung ca. 20 km südlich von Cottbus in situ und im Labor anhand von Water Drop Penetration Time (WDPT)-Tests und Kontaktwinkelmessungen in verschieden alten Kiefernbeständen

Treatment outcome of IDH1/2 wildtype CNS WHO grade 4 glioma histologically diagnosed as WHO grade II or III astrocytomas

Background Isocitrate dehydrogenase (IDH)1/2 wildtype (wt) astrocytomas formerly classified as WHO grade II or III have significantly shorter PFS and OS than IDH mutated WHO grade 2 and 3 gliomas leading to a classification as CNS WHO grade 4. It is the aim of this study to evaluate differences in the treatment-related clinical course of these tumors as they are largely unknown. Methods Patients undergoing surgery (between 2016–2019 in six neurosurgical departments) for a histologically diagnosed WHO grade 2–3 IDH1/2-wt astrocytoma were retrospectively reviewed to assess progression free survival (PFS), overall survival (OS), and prognostic factors. Results This multi-center study included 157 patients (mean age 58 years (20–87 years); with 36.9% females). The predominant histology was anaplastic astrocytoma WHO grade 3 (78.3%), followed by diffuse astrocytoma WHO grade 2 (21.7%). Gross total resection (GTR) was achieved in 37.6%, subtotal resection (STR) in 28.7%, and biopsy was performed in 33.8%. The median PFS (12.5 months) and OS (27.0 months) did not differ between WHO grades. Both, GTR and STR significantly increased PFS (P < 0.01) and OS (P < 0.001) compared to biopsy. Treatment according to Stupp protocol was not associated with longer OS or PFS compared to chemotherapy or radiotherapy alone. EGFR amplification (P = 0.014) and TERT-promotor mutation (P = 0.042) were associated with shortened OS. MGMT-promoter methylation had no influence on treatment response. Conclusions WHO grade 2 and 3 IDH1/2 wt astrocytomas, treated according to the same treatment protocols, have a similar OS. Age, extent of resection, and strong EGFR expression were the most important treatment related prognostic factors

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function <it>in vivo</it>. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c.</p> <p>Methods</p> <p>In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth.</p> <p>Results</p> <p>These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival.</p> <p>Conclusions</p> <p>We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy.</p

Shallow non-inversion tillage in organic farming maintains crop yields and increases soil C stocks: a meta-analysis

Reduced tillage is increasingly promoted to improve sustainability and productivity of agricultural systems. Nonetheless, adoption of reduced tillage by organic farmers has been slow due to concerns about nutrient supply, soil structure, and weeds that may limit yields. Here, we compiled the results from both published and unpublished research comparing deep or shallow inversion tillage, with various categories of reduced tillage under organic management. Shallow refers to less than 25 cm. We found that (1) division of reduced tillage practices into different classes with varying degrees of intensity allowed us to assess the trade-offs between reductions in tillage intensity, crop yields, weed incidence, and soil C stocks. (2) Reducing tillage intensity in organic systems reduced crop yields by an average of 7.6 % relative to deep inversion tillage with no significant reduction in yield relative to shallow inversion tillage. (3) Among the different classes of reduced tillage practice, shallow non-inversion tillage resulted in non-significant reductions in yield relative to deep inversion; whereas deep non-inversion tillage resulted in the largest yield reduction, of 11.6 %. (4) Using inversion tillage to only a shallow depth resulted in minimal reductions in yield, of 5.5 %, but significantly higher soil C stocks and better weed control. This finding suggests that this is a good option for organic farmers wanting to improve soil quality while minimizing impacts on yields. (5) Weeds were consistently higher, by about 50 %, when tillage intensity was reduced, although this did not always result in reduced yields