Does Juvenile Stand Management Matter? Regional Scenarios of the Long-Term Effects on Wood Production

We analysed the regional level effects of juvenile stand management (early cleaning and precommercial thinning), shortly termed tending on wood production and the profitability of forest management. Altogether ca. 0.4 million hectares of juvenile stands from two significant forestry regions of Finland, South and North Savo, were examined. We used plot-level data of the 11th National Forest Inventory to represent the current status of juvenile stands in the study area, and the Motti stand simulator to predict the future developments of those stands for the next 100 years. We applied three scenarios: (i) Timely tending, (ii) delayed tending, and (iii) no tending, to examine differences between these alternative levels of juvenile stand management. The results showed the benefits of tending at a regional level. Timely tending was the most profitable option when low or modest interest rates (2–3%) were applied in the assessment. Even a short delay in tending clearly increased the tending costs. Delaying and neglecting tending resulted in significant losses, especially in sawlog removals and stumpage earnings. The financial gain from tending was the highest on fertile sites. Due to the high growth rate of trees, the situation may change very quickly on such sites. For the operational forestry, this means that fertile sites should have a high priority when conducting timely tendings

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors <em>in vitro</em>

Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD(+) as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.</p

Suomen LULUCF-sektorin 2021–2025 velvoitteen toteutuminen

Tämä työ on tehty Luonnonvarakeskuksessa Maa- ja metsätalousministeriön toimeksiannosta. Toimeksianto oli: Laaditaan selvitys syistä, miksi vuotta 2021 koskevissa kasvihuonekaasuinventaarion pikaennakkotiedoissa, jotka julkistettiin 06/2022, maankäyttösektori oli muuttunut päästölähteeksi, ja mitä se tarkoittaa 2021–2025 EU LULUCF-velvoitteen toteutumisen osalta. Ilmasto- ja energiaministeriryhmä tarkastelee selvityksen pohjalta tarvittavia lisätoimia. Toimeksiantoa tarkennettiin siten, että vuoden 2021 tilannetta tarkasteltiin käyttäen kasvihuonekaasuinventaarion ennakkotietoja LULUCF-sektorin päästöistä ja poistumista (14.12.2022) pikaennakkotietojen sijaan. 1. Vuoden 2021 kasvihuonekaasuinventaarion ennakontiedon mukaan LULUCF-sektorin nielujen muuttuminen päästöksi johtuu puuston kasvun ja poistuman erotuksen pienenemisestä lisääntyneiden hakkuiden ja alentuneen kasvun vuoksi. Metsät ovat edelleen nettonielu, mutta se oli laskenut niin alhaiseksi, ettei se kata muiden maankäyttöluokkien päästöjä. 2. Mäntymetsien ikärakenne on kehittynyt siten, että kasvu alenee. Metsien ikärakenne, kaikki puulajit huomioiden, selittää noin viidenneksen VMI12:n ja VMI13:n välillä havaitusta 4,5 miljoonan kuutiometrin kasvun alenemasta. Ikärakenteen puolesta puuston kasvu todennäköisesti pysyy nykyisellä tasolla tai voi edelleen hieman alentua lähivuosina. 3. Männyllä on ollut kolme heikkoa kasvukautta (2018–2020). Etelä-Suomessa nämä kasvukaudet ovat olleet poikkeuksellisen kuivia. Pohjois-Suomessa vain kasvukausi 2018 oli poikkeuksellisen kuiva, mutta vuosien 2019 ja 2020 kasvuntasoa on Pohjois-Suomessa heikentänyt männyn voimakas käpytuotanto. Useamman vuoden heikot kasvukaudet eivät ole todennäköisiä, mutta vaikka lähivuosina kasvukaudet olisivat keskimääräistä parempia, vuosien 2018–2020 heikompi männyn kasvu säilyy VMI13:n kasvutuloksissa. Nykyisellä hakkuiden tasolla kasvu voi lähivuosina nousta vain, jos ympäristötekijät (kasvukauden pituus, lämpösumma, sademäärä) ovat suotuisat. 4. Kasvihuonekaasuinventaarion ennakkotietojen mukaan tililuokan hoidettu metsämaa, sisältäen puutuotteet, hiilinielu oli -11,4 milj. t CO2-ekv., kun metsien vertailutaso kaudelle 2021–2025 on -29,4 milj. t CO2-ekv. vuodessa. Vertailutasoon tullaan tekemään inventaarion ja vertailutasolaskennan menetelmäeroista johtuvia teknisiä korjauksia. 5. Muussa maankäytössä ei arvioida tapahtuvan merkittäviä kauden 2021–2025 laskentatulokseen vaikuttavia muutoksia. Tämä koskee erityisesti EU-LULUCF-tilinpitoa. Vaikka maatalousmaihin kohdistuvat kosteikkotoimenpiteet muuttaisivat alueen maankäytön pois maataloudesta, tilinpidossa se tulee pysymään tililuokissa hoidettu viljelysmaa tai hoidettu ruohikkoalue. Metsityksen lisäämiseksi tehtävät toimet tulevat aikanaan vaikuttamaan hoidetun metsämaan nieluun enemmän kuin tililuokkaan metsitetyt alueet. Metsäkatoa ehkäisevien toimien vaikutus sen sijaan olisi välitön, mutta suunnitellut toimet eivät ennätä vaikuttaa vuosiin 2021–2025. 6. Vuoden 2022 teollisuuspuun hakkuut olivat lokakuun loppuun mennessä 3 prosenttia alemmat kuin vuonna 2021, mutta loppuvuoden 2022 aikana hakkuiden kokonaismäärä voi saavuttaa vuoden 2021 tason. Kotimaisen puun käyttö on lisääntynyt ja lisääntynee lähivuosina edelleen teollisuuden uusien investointipäätösten sekä Venäjältä tapahtuneen puuntuonnin loppumisen myötä. Tämän selvityksen pohjalta arvioidaan, että metsien hiilinielu kaudella 2021–2025 jää 50–100 miljoonaa CO2-ekvivalentti-tonnia pienemmäksi kuin vertailutaso. Arvio ei sisällä vertailutasoon tehtävien ns. teknisten korjausten vaikutusta. 7. Metsien hiilinielun aleneminen vaikeuttaa LULUCF-sektorin velvoitteen saavuttamista kaudella 2021–2025. Toteutuneen metsänielun ollessa 50–100 miljoonaa CO2-ekvivalenttitonnia ja muusta maankäytöstä aiheutuvien päästöjen ollessa nykytasolla, joudutaan metsäjouston ja Suomen erillisjouston lisäksi hankkimaan puuttuvat yksiköt muilta jäsenmailta tai kompensoimaan taakanjakosektorin yksiköillä. Tässä selvityksessä tarve arvioidaan noin 50–80 miljoonaan CO2-ekvivalenttitonnin suuruiseksi

Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

publishedVersio

Analysis of the Effects of Polymorphism on Pollen Profilin Structural Functionality and the Generation of Conformational, T- and B-Cell Epitopes

An extensive polymorphism analysis of pollen profilin, a fundamental regulator of the actin cytoskeleton dynamics, has been performed with a major focus in 3D-folding maintenance, changes in the 2-D structural elements, surface residues involved in ligands-profilin interactions and functionality, and the generation of conformational and lineal B- and T-cell epitopes variability. Our results revealed that while the general fold is conserved among profilins, substantial structural differences were found, particularly affecting the special distribution and length of different 2-D structural elements (i.e. cysteine residues), characteristic loops and coils, and numerous micro-heterogeneities present in fundamental residues directly involved in the interacting motifs, and to some extension these residues nearby to the ligand-interacting areas. Differential changes as result of polymorphism might contribute to generate functional variability among the plethora of profilin isoforms present in the olive pollen from different genetic background (olive cultivars), and between plant species, since biochemical interacting properties and binding affinities to natural ligands may be affected, particularly the interactions with different actin isoforms and phosphoinositides lipids species. Furthermore, conspicuous variability in lineal and conformational epitopes was found between profilins belonging to the same olive cultivar, and among different cultivars as direct implication of sequences polymorphism. The variability of the residues taking part of IgE-binding epitopes might be the final responsible of the differences in cross-reactivity among olive pollen cultivars, among pollen and plant-derived food allergens, as well as between distantly related pollen species, leading to a variable range of allergy reactions among atopic patients. Identification and analysis of commonly shared and specific epitopes in profilin isoforms is essential to gain knowledge about the interacting surface of these epitopes, and for a better understanding of immune responses, helping design and development of rational and effective immunotherapy strategies for the treatment of allergy diseases. [EN]This study was supported by the following European Regional Development Fund co-financed grants: MCINN BFU 2004-00601/BFI, BFU 2008-00629, BFU2011-22779, CICE (Junta de Andalucía) P2010-CVI15767, P2010-AGR6274 and P2011-CVI-7487, and by the coordinated project Spain/Germany MEC HA2004-0094. JCJ-L thanks Spanish CSIC and the European Marie Curie research program for his I3P-BPD-CSIC, and PIOF-GA-2011-301550 grants, respectively.Peer reviewe

Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis

Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach.

The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins and their complexes for scaffolding and/or poly(ADP-ribosyl)ation. Here, we provide guidance for predicting putative tankyrase-binding motifs, based on the previously delineated peptide sequence rules and existing structural information. We present a general method for the expression and purification of tankyrase ARCs from Escherichia coli and outline a fluorescence polarization assay to quantitatively assess direct ARC-TBM peptide interactions. We provide a basic protocol for evaluating binding and poly(ADP-ribosyl)ation of full-length candidate interacting proteins by full-length tankyrase in mammalian cells