Nusinersen treatment and cerebrospinal fluid neurofilaments: An explorative study on Spinal Muscular Atrophy type 3 patients

The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme-linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.     

The evolution of realized niches within freshwater Synechococcus

Understanding how ecological traits have changed over evolutionary time is a fundamental question in biology. Specifically, the extent to which more closely related organisms share similar ecological preferences due to phylogenetic conservation – or if they are forced apart by competition – is still debated. Here, we explored the co-occurrence patterns of freshwater cyanobacteria at the sub-genus level to investigate whether more closely related taxa share more similar niches and to what extent these niches were defined by abiotic or biotic variables. We used deep 16S rRNA gene amplicon sequencing and measured several abiotic environmental parameters (nutrients, temperature, etc.) in water samples collected over time and space in Furnas Reservoir, Brazil. We found that relatively more closely related Synechococcus (in the continuous range of 93%–100% nucleotide identity in 16S) had an increased tendency to co-occur with one another (i.e. had similar realized niches). This tendency could not be easily explained by shared preferences for measured abiotic niche dimensions. Thus, commonly measured abiotic parameters might not be sufficient to characterize, nor to predict community assembly or dynamics. Rather, co-occurrence between Synechococcus and the surrounding community (whether or not they represent true biological interactions) may be a more sensitive measure of realized niches. Overall, our results suggest that realized niches are phylogenetically conserved, at least at the sub-genus level and at the resolution of the 16S marker. Determining how these results generalize to other genera and at finer genetic resolution merits further investigation.     

Epidermal keratin 5 expression and distribution is under dermal influence

Human skin melanin pigmentation is regulated by systemic and local factors. According to the type of melanin produced by melanocytes, the transfer and degradation of melanosomes differ, thus accounting for most variations between ethnicities. We made the surprising observation that in a drastically changed environment, white and black phenotypes are reversible since Caucasian skin grafted onto nude mice can become black with all black phenotypic characteristics. Black xenografts differed essentially from other grafts by the levels of epidermal FGF‐2 and keratin 5. In vitro analysis confirmed that FGF‐2 directly regulates keratin 5. Interestingly, this phenomenon may be involved in human pathology. Keratin 5 mutations in Dowling–Degos Disease (DDD) have already been associated with the pheomelanosome–eumelanosome transition. In a DDD patient, keratin 5 was expressed in the basal and spinous layers, as observed in black xenografts. Furthermore, in a common age‐related hyperpigmentation disorder like senile lentigo (SL), keratin 5 distribution is also altered. In conclusion, modulation of keratin 5 expression and distribution either due to mutations or factors may account for the development of pigmentary disorders.     

What processes must we understand to forecast regional-scale population dynamics?

An urgent challenge facing biologists is predicting the regional-scale population dynamics of species facing environmental change. Biologists suggest that we must move beyond predictions based on phenomenological models and instead base predictions on underlying processes. For example, population biologists, evolutionary biologists, community ecologists and ecophysiologists all argue that the respective processes they study are essential. Must our models include processes from all of these fields? We argue that answering this critical question is ultimately an empirical exercise requiring a substantial amount of data that have not been integrated for any system to date. To motivate and facilitate the necessary data collection and integration, we first review the potential importance of each mechanism for skilful prediction. We then develop a conceptual framework based on reaction norms, and propose a hierarchical Bayesian statistical framework to integrate processes affecting reaction norms at different scales. The ambitious research programme we advocate is rapidly becoming feasible due to novel collaborations, datasets and analytical tools.     

Morphological divergence in giant fossil dormice

Insular gigantism—evolutionary increases in body size from small-bodied mainland ancestors—is a conceptually significant, but poorly studied, evolutionary phenomenon. Gigantism is widespread on Mediterranean islands, particularly among fossil and extant dormice. These include an extant giant population of Eliomys quercinus on Formentera, the giant Balearic genus †Hypnomys and the exceptionally large †Leithia melitensis of Pleistocene Sicily. We quantified patterns of cranial and mandibular shape and their relationships to head size (allometry) among mainland and insular dormouse populations, asking to what extent the morphology of island giants is explained by allometry. We find that gigantism in dormice is not simply an extrapolation of the allometric trajectory of their mainland relatives. Instead, a large portion of their distinctive cranial and mandibular morphology resulted from the population- or species-specific evolutionary shape changes. Our findings suggest that body size increases in insular giant dormice were accompanied by the evolutionary divergence of feeding adaptations. This complements other evidence of ecological divergence in these taxa, which span predominantly faunivorous to herbivorous diets. Our findings suggest that insular gigantism involves context-dependent phenotypic modifications, underscoring the highly distinctive nature of island faunas.     

Sit4p/PP6 regulates ER-to-Golgi traffic by controlling the dephosphorylation of COPII coat subunits

Traffic from the endoplasmic reticulum (ER) to the Golgi complex is initiated when the activated form of the GTPase Sar1p recruits the Sec23p-Sec24p complex to ER membranes. The Sec23p-Sec24p complex, which forms the inner shell of the COPII coat, sorts cargo into ER-derived vesicles. The coat inner shell recruits the Sec13p-Sec31p complex, leading to coat polymerization and vesicle budding. Recent studies revealed that the Sec23p subunit sequentially interacts with three different binding partners to direct a COPII vesicle to the Golgi. One of these binding partners is the serine/threonine kinase Hrr25p. Hrr25p phosphorylates the COPII coat, driving the membrane-bound pool into the cytosol. The phosphorylated coat cannot rebind to the ER to initiate a new round of vesicle budding unless it is dephosphorylated. Here we screen all known protein phosphatases in yeast to identify one whose loss of function alters the cellular distribution of COPII coat subunits. This screen identifies the PP2A-like phosphatase Sit4p as a regulator of COPII coat dephosphorylation. Hyperphosphorylated coat subunits accumulate in the sit4Δ mutant in vivo. In vitro, Sit4p dephosphorylates COPII coat subunits. Consistent with a role in coat recycling, Sit4p and its mammalian orthologue, PP6, regulate traffic from the ER to the Golgi complex.     

Granulovirus formulations efficiently protect stored and field potatoes from Phthorimaea operculella and Tecia solanivora in Costa Rica

The control efficiency of a Phthorimaea operculella granulovirus isolate from Costa Rica (PhopGV-CR1) against the concurrent insect pests P. operculella (Zeller) and Tecia solanivora (Povolny) (Lepidoptera: Gelechiidae) was evaluated. In warehouses, the best control efficiency was achieved with a powder formulate applied inside bags, which reduced injury over 70 % compared with the untreated controls. In the field, liquid and powder virus formulations significantly reduced injury between 56.2 and 81.7 % compared with the untreated controls, and were as efficient as chemical treatments. The efficiency of formulations stored at ?20 °C for six months (liquid) or at ambient temperature for three months (powder) was maintained, but higher temperatures and/or longer exposure times resulted in loss of pathogenicity. The data presented here favor the inclusion of granulovirus formulations of PhopGV-CR1 in Integrated Pest Management programs against tuberworms in Costa Rica and give clues on storage conditions for the growers in this country.     

An Inducible,Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency

The DNA mismatch repair system (MMR) maintains genome stability through recognition and repair of single-base mismatches and small insertion-deletion loops. Inactivation of the MMR pathway causes microsatellite instability and the accumulation of genomic mutations that can cause or contribute to cancer. In fact, 10-20% of certain solid and hematologic cancers are MMR-deficient. MMR-deficient cancers do not respond to some standard of care chemotherapeutics because of presumed increased tolerance of DNA damage, highlighting the need for novel therapeutic drugs. Toward this goal, we generated isogenic cancer cell lines for direct comparison of MMR-proficient and MMR-deficient cells. We engineered NCI-H23 lung adenocarcinoma cells to contain a doxycycline-inducible shRNA designed to suppress the expression of the mismatch repair gene MLH1, and compared single cell subclones that were uninduced (MLH1-proficient) versus induced for the MLH1 shRNA (MLH1-deficient). Here we present the characterization of these MMR-inducible cell lines and validate a novel class of rhodium metalloinsertor compounds that differentially inhibit the proliferation of MMR-deficient cancer cells.     

Isotopic Analysis of some Romanian Wines by 2H NMR and IRMS

Isotopic analyses are now official or standard methods in Europe and North America for routine use in testing the authenticity of several food products. These methods are based on the measurement of stable isotope content (²H, ¹³C, ¹⁸O) of the product or of a specific component such as an ingredient or target molecule of the product. The determinations carried out using nuclear magnetic resonance (NMR), and Isotopic Ratio Mass Spectrometry (IRMS), provide information on the botanical and geographical origin of the food product. A deuterium natural abundance quantitative NMR method (SNIF-NMR: Site-specific Natural Isotope Fractionation) was developed as an efficient and powerful tool capable of characterizing the chemical origins of organic molecules and distinguishing their biological and geographical origin. The SNIF method is based on the measurement of deuterium / hydrogen (D/H) ratios at the specific sites of the ethanol. Using these methods, we present the obtained results for a series of Romanian wines. Our results may be used like reference data set for authenticity and origin control of wines.