Human Memory B Cells Harbor Diverse Cross-Neutralizing Antibodies against BK and JC Polyomaviruses

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Subfunctionalization of arylalkylamine N‐acetyltransferases in the sea bass Dicentrarchus labrax: two‐ones for one two

Melatonin is an important component of the vertebrates circadian system, synthetized from serotonin by the successive action of the arylalkylamine N‐acetyltransferase (Aanat: serotonin→N‐acetylserotonin) and acetylserotonin‐O‐methyltransferase (Asmt: N‐acetylserotonin→melatonin). Aanat is responsible for the daily rhythm in melatonin production. Teleost fish are unique because they express two Aanat genes, aanat1 and aanat2, mainly expressed in the retina and pineal gland, respectively. In silico analysis indicated that the teleost‐specific whole‐genome duplication generated Aanat1 duplicates (aanat1a and aanat1b); some fish express both of them, while others express either one of the isoforms. Here, we bring the first information on the structure, function, and distribution of Aanat1a and Aanat1b in a teleost, the sea bass Dicentrarchus labrax. Aanat1a and Aanat1b displayed a wide and distinct distribution in the nervous system and peripheral tissues, while Aanat2 appeared as a pineal enzyme. Co‐expression of Aanats with asmt was found in the pineal gland and the three retinal nuclear layers. Enzyme kinetics indicated subtle differences in the affinity and catalytic efficiency of Aanat1a and Aanat1b for indolethylamines and phenylethylamines, respectively. Our data are consistent with the idea that Aanat2 is a pineal enzyme involved in melatonin production, while Aanat1 enzymes have a broader range of functions including melatonin synthesis in the retina, and catabolism of serotonin and dopamine in the retina and other tissues. The data are discussed in light of the recently uncovered roles of N‐acetylserotonin and N‐acetyldopamine as antioxidants, neuroprotectants, and modulators of cell proliferation and enzyme activities.     

Inorganic mercury detection by valve closure response in the freshwater clam Corbicula fluminea: integration of time and water metal concentration changes

The objective of the present study was to monitor water-quality assessment by a biological method. Optimum dissolved inorganic mercury sensitivity in the freshwater bivalve Corbicula fluminea was estimated using a combined approach to determine their potentials and limits in detecting contaminants. Detection by bivalves is based on shell closure, a protective strategy when exposed to a water contaminant. To take the rate of spontaneous closures into account, stress associated with fixation by one valve in common valvometers was integrated, and the spontaneous rhythm was associated with daily activity. The response in conditions where the probability of spontaneous closing is the lowest was thus taken into account. To develop dose-response curves, impedance valvometry, in which lightweight impedance electrodes are applied to study free-ranging animals in low-stress conditions, also was used combined with a new analytical approach. The logistic regression dose-response curves take into account variations in both response time and metal concentration in water to significantly improve the methods aiming at determining the optimal sensitivity threshold response. This approach demonstrates that in C. fluminea, inorganic mercury concentrations under the range of 2.0 to 5.1 microg/L (95% confidence interval) cannot be detected within 5 h of addition.     

Neutral genomic regions refine models of recent rapid human population growth

Human populations have experienced dramatic growth since the Neolithic revolution. Recent studies that sequenced a very large number of individuals observed an extreme excess of rare variants and provided clear evidence of recent rapid growth in effective population size, although estimates have varied greatly among studies. All these studies were based on protein-coding genes, in which variants are also impacted by natural selection. In this study, we introduce targeted sequencing data for studying recent human history with minimal confounding by natural selection. We sequenced loci far from genes that meet a wide array of additional criteria such that mutations in these loci are putatively neutral. As population structure also skews allele frequencies, we sequenced 500 individuals of relatively homogeneous ancestry by first analyzing the population structure of 9,716 European Americans. We used very high coverage sequencing to reliably call rare variants and fit an extensive array of models of recent European demographic history to the site frequency spectrum. The best-fit model estimates ∼3.4% growth per generation during the last ∼140 generations, resulting in a population size increase of two orders of magnitude. This model fits the data very well, largely due to our observation that assumptions of more ancient demography can impact estimates of recent growth. This observation and results also shed light on the discrepancy in demographic estimates among recent studies.Archeological and historical records reveal that modern human populations have experienced dramatic growth, likely driven by the Neolithic revolution about 10,000 y ago (1, 2). Since then, the worldwide human population size has increased at a fast pace, and faster yet in the last ∼2,000 y, giving rise to today’s population in excess of 7 billion people (3, 4). A central question in population genetics is how such demographic events affect the effective size (N_e) of populations over time, and as a consequence, how they have shaped extant patterns of genetic variation. [Effective population size, which is typically smaller than the census size, determines the genetic properties of a population (5).] Focusing often on human populations of European descent, estimates of N_e from genetic variation have been traditionally on the order of 10,000 individuals (6–11), although higher and lower estimates have also been obtained (12–16). More recent studies based on sequencing data from a relatively small number of individuals have considered recent population growth in fitting models to the observed site frequency spectrum (SFS) and reported as much as a 0.5% increase in N_e per generation, culminating in a N_e of a few tens of thousands today (13, 14). It has been recently hypothesized that these studies could not capture the full scope of population growth because a larger sample size of individuals is needed to observe single nucleotide variants (SNVs) that arose during the recent epoch of growth (4).With extreme recent population growth as experienced by human populations, the vast majority of SNVs are expected to be very young and rare, i.e., of very low allele frequency (4). Indeed, several recent sequencing studies with very large numbers of individuals have observed an unprecedented excess in the proportion of rare SNVs (17–19). Fitting models to the SFS, these studies have captured a clearer, more rapid recent population growth than earlier studies (17–19). At the same time, demographic estimates varied by as much as an order of magnitude between these studies (SI Appendix, Table S1).Not all rare SNVs are as recent as others, and a variant’s selective effect plays an important part in its frequency. Purifying (negative) selection acting on deleterious alleles is expected to give rise to an excess of rare variants, which has been demonstrated for human populations (17, 19, 20). Thus, the genetic signature left by purifying selection on the SFS confounds the signature left by recent growth (21). To minimize this confounding effect, recent studies based on protein-coding genes considered for modeling solely synonymous SNVs, which do not modify the amino acid sequence (17–19). However, synonymous mutations have been shown to be targeted by natural selection, e.g., due to their impact on translation efficiency and accuracy, splicing, and folding energy (17, 19, 22–26). Hence, to study recent human genetic history with minimal effects of selection, it is not only desirable to consider accurate sequencing data from a large number of individuals, but also to focus on genomic regions in which mutations are putatively neutral, i.e., not affected by natural selection. Another potential confounder of demographic inference is population structure. Because both large-scale and fine-scale population structures exist in European populations (27–30), pooling individuals of different European ancestries can lead—when not accounted for in modeling—to biases in the observed SFS and, consequently, in estimates of recent history (SI Appendix).In this study, we aim to capture recent demographic history and estimate the magnitude of the recent growth experienced by humans while limiting the confounding by natural selection and population structure. For this purpose, we selected a small set of genomic regions that are putatively neutral based on a wide array of criteria; the SFS of mutations in these regions is likely to reflect historical changes in N_e rather than selection. We sequenced these regions in a large sample of individuals that share a relatively similar genetic ancestry within Europe. Very deep sequencing coverage allowed us to reliably observe even singletons (SNVs with an allele appearing in a single copy in the sample). Based on this dataset, we explored different models of recent European demographic history. Our best-fit model estimates a growth of 3.4% per generation over the last 141 generations, which is more rapid than estimated in recent large-scale studies (17, 19). We show that differences among previous models (17, 19)—and between these models and ours—can be partially explained by a priori assumptions about more ancient demographic events.     

Gemcitabine-induced myopathy

Background

There have been few studies on muscle injury caused by cytotoxic agents used in cancer. In particular, only four cases of muscle manifestations have been reported in patients who received gemcitabine as single chemotherapy without adjuvant radiotherapy. In only one of these observations gemcitabine was considered to be the causative agent.

Methods

We report the case of a patient without comorbidity treated with gemcitabine monotherapy for 2 months for pancreatic adenocarcinoma, who developed a proximal motor deficiency of the lower limbs and myolysis (creatinine kinase 1858 IU/L) associated with an erythema of both thighs.

Results

Muscle MRI revealed the presence of edema on both the quadriceps muscles. A muscle biopsy showed post-necrotic regeneration and significant vascular proliferation. Only three small inflammatory infiltrates were observed, while expression of the major histocompatibility complex class I in muscle fibers was normal. There was no recurrence of cancer, anti-TIF-1γ antibodies tested negative, and discontinuation of gemcitabine, without further treatment, resulted in complete disappearance of symptoms.

Conclusions

The present observation suggests that gemcitabine monotherapy without adjuvant radiotherapy can cause myopathy through vascular lesions, a mechanism which also underlies the more common side effects of this treatment. These findings have obvious therapeutic implications.