Title: 2-Minute Walk Every Hour May Help Offset Effects of Sitting
Category: Health News
Created: 4/30/2015 12:00:00 AM
Last Editorial Review: 5/1/2015 12:00:00 AM

Title: Pharmacists Can Manage Some Chronic Conditions Effectively, Study Suggests
Category: Health News
Created: 4/25/2016 12:00:00 AM
Last Editorial Review: 4/26/2016 12:00:00 AM

Title: Omega-3 Fish Oil Supplements Might Boost Antidepressants' Effects
Category: Health News
Created: 4/26/2016 12:00:00 AM
Last Editorial Review: 4/27/2016 12:00:00 AM

Title: Study Confirms Safety, Effectiveness of Children's Vaccines
Category: Health News
Created: 4/23/2020 12:00:00 AM
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Title: Recommended Diuretic Drug Tied to Harmful Side Effects
Category: Health News
Created: 2/18/2020 12:00:00 AM
Last Editorial Review: 2/19/2020 12:00:00 AM

Title: Birth Control Options (Types and Side Effects)
Category: Diseases and Conditions
Created: 9/13/1999 12:00:00 AM
Last Editorial Review: 4/10/2020 12:00:00 AM

Title: Lasix Side Effects, Warnings, and Drug Interactions
Category: Medications
Created: 3/4/2020 12:00:00 AM
Last Editorial Review: 3/4/2020 12:00:00 AM

Title: Birth Control Pills (List of Oral Contraceptives and Side Effects)
Category: Medications
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 1/30/2020 12:00:00 AM

Title: Could Viagra, Cialis Work Largely by Placebo Effect?
Category: Health News
Created: 3/26/2020 12:00:00 AM
Last Editorial Review: 3/27/2020 12:00:00 AM

Title: Allergy Med Singulair to Get 'Black Box' Warning Over Psych Side Effects: FDA
Category: Health News
Created: 3/4/2020 12:00:00 AM
Last Editorial Review: 3/5/2020 12:00:00 AM

Title: AI May Help Guide Patients to Most Effective Antidepressant
Category: Health News
Created: 2/10/2020 12:00:00 AM
Last Editorial Review: 2/11/2020 12:00:00 AM

TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5–induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro. Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo. Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.

Interprofessional education (IPE) is based on collaborative practices that increase the occasions for communication among those in various health professions. However, there is a paucity of literature about the effectiveness of IPE programs in health professions education. The aim of this systematic review and meta-analysis was to objectively assess the literature on the effectiveness of IPE in improving health professions students’ attitudes after training. The major scholarly databases were searched for relevant IPE studies involving predoctoral health professions students. Two independent researchers selected the studies, extracted the data, and assessed the quality of the studies. Meta-analyses of the outcomes were performed using random effects models. Sixteen articles were ultimately selected for detailed review and meta-analysis. The meta-analysis showed that IPE training had a significant influence on students’ understanding of collaboration and resulted in better attitudes about interprofessional teamwork. Subscale analysis showed that one subscale score (roles and responsibilities) did not statistically significantly improve after IPE training (p=0.06), whereas the other four subscale items showed statistically significant improvements (p<0.01). The test for overall effects showed that IPE training had a significantly positive influence on students’ attitudes about IPE (Z=6.85, p<0.01). Subgroup results showed that medical students had more positive attitudes about IPE than did dental students. Regardless of profession, women students responded with significantly more positive feedback than did men students (p=0.02). These results suggest that intervention through IPE training has had positive effects in health professions education. Gender was an important factor impacting the outcomes of IPE. However, further clinical practice interventions may be helpful to enhance the IPE competence of health professions students.

Purpose: The purpose of this study was to determine strength of muscles involved with instrumentation (scaling) by dental hygienists and the additive effects of cellular (mobile) phone usage, as indicated by measurements of muscular force generation.Methods: A convenience sample of licensed dental hygienists currently in clinical practice (n=16) and an equal number of individuals not currently using devices/tools repetitively for work (n=16), agreed to participate in this pilot study. All participants completed a modified cell phone usage questionnaire to determine their use pattern and frequency. Upon completion of the questionnaire, participants' force production in six muscle groups was measured using a hand-held dynamometer. Descriptive statistics were used to analyze the data.Results: A total of 16 licensed dental hygienists (n=16) and 16 participants with no history of using tools/devices repetitively for work (n=16), comprised the experimental and control groups, repectively. The control group generated greater muscle force than the experimental group for the abductor pollicis longus (p=0.045). Significant differences were identified when comparing the low mobile phone users in the experimental group to the control group for the flexor pollicis brevis (p=0.031), abductor pollicis longus (p=0.031), and flexor digitorum (p=0.006), with the control group demonstrating higher muscle force. Years in clinical practice and mobile phone use was shown to have a significant effect on muscular force generation for the flexor pollicis brevis (F=3.645, df=3, p=0.020) and flexor digitorum (F=3.560, df=3, p=0.022); subjects who practiced dental hygiene the longest produced the least amount of muscle force.Conclusion: Results from this pilot study indicate there are no significant additive effects of cell phone use and dental hygiene practice on finger muscles used for instrumentation. However, results indicate that dental hygiene practice demonstrated significant effects on muscular strength as compared to individuals who do not use tools/devices repetitively for work. The small sample size may have impacted results and the study should be repeated with a larger sample.

ABSTRACT

The ubiquitous parasite Toxoplasma gondii exhibits an impressive ability to maintain chronic infection of its host for prolonged periods. Despite this, little is known regarding whether and how T. gondii bradyzoites, a quasi-dormant life stage residing within intracellular cysts, manipulate the host cell to maintain persistent infection. A previous proteomic study of the cyst wall, an amorphous layer of proteins that forms underneath the cyst membrane, identified MYR1 as a putative cyst wall protein in vitro. Because MYR1 is known to be involved in the translocation of parasite-derived effector proteins into the host cell, we sought to determine whether parasites transitioning toward the bradyzoite life stage retain the capacity to translocate proteins via this pathway. By epitope tagging the endogenous loci of four known effectors that translocate from the parasitophorous vacuole into the host cell nucleus, we show, by immunofluorescence assays, that most effectors accumulate in the host nucleus at early but not late time points after infection, during the tachyzoite-to-bradyzoite transition and when parasites further along the bradyzoite differentiation continuum invade a new host cell. We demonstrate that the suppression of interferon gamma signaling, which was previously shown to be mediated by the effector TgIST, also occurs in the context of prolonged infection with bradyzoites and that TgIST export is a process that occurs beyond the early stages of host cell infection. These findings have important implications regarding how this highly successful parasite maintains persistent infection of its host.

IMPORTANCE Toxoplasma bradyzoites persist within tissue cysts and are refractory to current treatments, serving as a reservoir for acute complications in settings of compromised immunity. Much remains to be understood regarding how this life stage successfully establishes and maintains persistent infection. In this study, we investigated whether the export of parasite effector proteins into the host cell occurs during the development of in vitro tissue cysts. We quantified the presence of four previously described effectors in host cell nuclei at different time points after bradyzoite differentiation and found that they accumulated largely during the early stages of infection. Despite a decline in nuclear accumulation, we found that one of these effectors still mediated its function after prolonged infection with bradyzoites, and we provide evidence that this effector is exported beyond early infection stages. These findings suggest that effector export from within developing tissue cysts provides one potential mechanism by which this parasite achieves chronic infection.

ABSTRACT

Toxoplasma gondii is a ubiquitous, intracellular protozoan parasite with a broad range of intermediate hosts, including humans and rodents. In many hosts, T. gondii establishes a latent long-term infection by converting from its rapidly dividing or lytic form to its slowly replicating and encysting form. In humans and rodents, the major organ for encystment is the central nervous system (CNS), which has led many to investigate how this persistent CNS infection might influence rodent and human behavior and, more recently, neurodegenerative diseases. Given the interest in this topic, here we seek to take a global approach to the data for and against the effects of latent T. gondii on behavior and neurodegeneration and the proposed mechanisms that might underlie behavior modifications.

ABSTRACT

Legionella pneumophila governs its interactions with host cells by secreting >300 different "effector" proteins. Some of these effectors contain eukaryotic domains such as the RCC1 (regulator of chromosome condensation 1) repeats promoting the activation of the small GTPase Ran. In this report, we reveal a conserved pattern of L. pneumophila RCC1 repeat genes, which are distributed in two main clusters of strains. Accordingly, strain Philadelphia-1 contains two RCC1 genes implicated in bacterial virulence, legG1 (Legionella eukaryotic gene 1), and ppgA, while strain Paris contains only one, pieG. The RCC1 repeat effectors localize to different cellular compartments and bind distinct components of the Ran GTPase cycle, including Ran modulators and the small GTPase itself, and yet they all promote the activation of Ran. The pieG gene spans the corresponding open reading frames of legG1 and a separate adjacent upstream gene, lpg1975. legG1 and lpg1975 are fused upon addition of a single nucleotide to encode a protein that adopts the binding specificity of PieG. Thus, a point mutation in pieG splits the gene, altering the effector target. These results indicate that divergent evolution of RCC1 repeat effectors defines the Ran GTPase cycle targets and that modulation of different components of the cycle might fine-tune Ran activation during Legionella infection.

IMPORTANCE Legionella pneumophila is a ubiquitous environmental bacterium which, upon inhalation, causes a life-threatening pneumonia termed Legionnaires’ disease. The opportunistic pathogen grows in amoebae and macrophages by employing a "type IV" secretion system, which secretes more than 300 different "effector" proteins into the host cell, where they subvert pivotal processes. The function of many of these effector proteins is unknown, and their evolution has not been studied. L. pneumophila RCC1 repeat effectors target the small GTPase Ran, a molecular switch implicated in different cellular processes such as nucleocytoplasmic transport and microtubule cytoskeleton dynamics. We provide evidence that one or more RCC1 repeat genes are distributed in two main clusters of L. pneumophila strains and have divergently evolved to target different components of the Ran GTPase activation cycle at different subcellular sites. Thus, L. pneumophila employs a sophisticated strategy to subvert host cell Ran GTPase during infection.

ABSTRACT

Intracellular bacterial pathogens remodel cellular functions during their infectious cycle via the coordinated actions of effector molecules delivered through dedicated secretion systems. While the function of many individual effectors is known, how they interact to promote pathogenesis is rarely understood. The zoonotic bacterium Brucella abortus, the causative agent of brucellosis, delivers effector proteins via its VirB type IV secretion system (T4SS) which mediate biogenesis of the endoplasmic reticulum (ER)-derived replicative Brucella-containing vacuole (rBCV). Here, we show that T4SS effectors BspB and RicA display epistatic interactions in Brucella replication. Defects in rBCV biogenesis and Brucella replication caused by deletion of bspB were dependent on the host GTPase Rab2a and suppressed by the deletion of ricA, indicating a role of Rab2-binding effector RicA in these phenotypic defects. Rab2a requirements for rBCV biogenesis and Brucella intracellular replication were abolished upon deletion of both bspB and ricA, demonstrating that the functional interaction of these effectors engages Rab2-dependent transport in the Brucella intracellular cycle. Expression of RicA impaired host secretion and caused Golgi fragmentation. While BspB-mediated changes in ER-to-Golgi transport were independent of RicA and Rab2a, BspB-driven alterations in Golgi vesicular traffic also involved RicA and Rab2a, defining BspB and RicA’s functional interplay at the Golgi interface. Altogether, these findings support a model where RicA modulation of Rab2a functions impairs Brucella replication but is compensated by BspB-mediated remodeling of Golgi apparatus-associated vesicular transport, revealing an epistatic interaction between these T4SS effectors.

IMPORTANCE Bacterial pathogens with an intracellular lifestyle modulate many host cellular processes to promote their infectious cycle. They do so by delivering effector proteins into host cells via dedicated secretion systems that target specific host functions. While the roles of many individual effectors are known, how their modes of action are coordinated is rarely understood. Here, we show that the zoonotic bacterium Brucella abortus delivers the BspB effector that mitigates the negative effect on bacterial replication that the RicA effector exerts via modulation of the host small GTPase Rab2. These findings provide an example of functional integration between bacterial effectors that promotes proliferation of pathogens.

ABSTRACT

The profiling of gene expression by RNA sequencing (RNA-seq) has enabled powerful studies of global transcriptional patterns in all organisms, including bacteria. Because the vast majority of RNA in bacteria is rRNA, it is standard practice to deplete the rRNA from a total RNA sample such that the reads in an RNA-seq experiment derive predominantly from mRNA. One of the most commonly used commercial kits for rRNA depletion, the Ribo-Zero kit from Illumina, was recently discontinued abruptly and for an extended period of time. Here, we report the development of a simple, cost-effective, and robust method for depleting rRNA that can be easily implemented by any lab or facility. We first developed an algorithm for designing biotinylated oligonucleotides that will hybridize tightly and specifically to the 23S, 16S, and 5S rRNAs from any species of interest. Precipitation of these oligonucleotides bound to rRNA by magnetic streptavidin-coated beads then depletes rRNA from a complex, total RNA sample such that ~75 to 80% of reads in a typical RNA-seq experiment derive from mRNA. Importantly, we demonstrate a high correlation of RNA abundance or fold change measurements in RNA-seq experiments between our method and the Ribo-Zero kit. Complete details on the methodology are provided, including open-source software for designing oligonucleotides optimized for any bacterial species or community of interest.

IMPORTANCE The ability to examine global patterns of gene expression in microbes through RNA sequencing has fundamentally transformed microbiology. However, RNA-seq depends critically on the removal of rRNA from total RNA samples. Otherwise, rRNA would comprise upward of 90% of the reads in a typical RNA-seq experiment, limiting the reads coming from mRNA or requiring high total read depth. A commonly used kit for rRNA subtraction from Illumina was recently unavailable for an extended period of time, disrupting routine rRNA depletion. Here, we report the development of a "do-it-yourself" kit for rapid, cost-effective, and robust depletion of rRNA from total RNA. We present an algorithm for designing biotinylated oligonucleotides that will hybridize to the rRNAs from a target set of species. We then demonstrate that the designed oligonucleotides enable sufficient rRNA depletion to produce RNA-seq data with 75 to 80% of reads coming from mRNA. The methodology presented should enable RNA-seq studies on any species or metagenomic sample of interest.

BACKGROUND:

More than 80% of children with cancer become long-term survivors, yet most survivors experience late effects of treatment. Little is known about how parents and physicians consider late-effects risks against a potential survival benefit when making treatment decisions.

BACKGROUND:

Although autodialer centralized reminder and recall (C-R/R) from state immunization information systems (IISs) has been shown to raise childhood vaccination rates, its impact on human papillomavirus (HPV) vaccination rates is unclear.

Single-cross hybrids have been critical to the improvement of maize (Zea mays L.), but the characterization of their genetic architectures remains challenging. Previous studies of hybrid maize have shown the contribution of within-locus complementation effects (dominance) and their differential importance across functional classes of loci. However, they have generally considered panels of limited genetic diversity, and have shown little benefit from genomic prediction based on dominance or functional enrichments. This study investigates the relevance of dominance and functional classes of variants in genomic models for agronomic traits in diverse populations of hybrid maize. We based our analyses on a diverse panel of inbred lines crossed with two testers representative of the major heterotic groups in the U.S. (1106 hybrids), as well as a collection of 24 biparental populations crossed with a single tester (1640 hybrids). We investigated three agronomic traits: days to silking (DTS), plant height (PH), and grain yield (GY). Our results point to the presence of dominance for all traits, but also among-locus complementation (epistasis) for DTS and genotype-by-environment interactions for GY. Consistently, dominance improved genomic prediction for PH only. In addition, we assessed enrichment of genetic effects in classes defined by genic regions (gene annotation), structural features (recombination rate and chromatin openness), and evolutionary features (minor allele frequency and evolutionary constraint). We found support for enrichment in genic regions and subsequent improvement of genomic prediction for all traits. Our results suggest that dominance and gene annotations improve genomic prediction across diverse populations in hybrid maize.

Real geography is continuous, but standard models in population genetics are based on discrete, well-mixed populations. As a result, many methods of analyzing genetic data assume that samples are a random draw from a well-mixed population, but are applied to clustered samples from populations that are structured clinally over space. Here, we use simulations of populations living in continuous geography to study the impacts of dispersal and sampling strategy on population genetic summary statistics, demographic inference, and genome-wide association studies (GWAS). We find that most common summary statistics have distributions that differ substantially from those seen in well-mixed populations, especially when Wright’s neighborhood size is < 100 and sampling is spatially clustered. "Stepping-stone" models reproduce some of these effects, but discretizing the landscape introduces artifacts that in some cases are exacerbated at higher resolutions. The combination of low dispersal and clustered sampling causes demographic inference from the site frequency spectrum to infer more turbulent demographic histories, but averaged results across multiple simulations revealed surprisingly little systematic bias. We also show that the combination of spatially autocorrelated environments and limited dispersal causes GWAS to identify spurious signals of genetic association with purely environmentally determined phenotypes, and that this bias is only partially corrected by regressing out principal components of ancestry. Last, we discuss the relevance of our simulation results for inference from genetic variation in real organisms.

Age-at-onset is one of the critical traits in cohort studies of age-related diseases. Large-scale genome-wide association studies (GWAS) of age-at-onset traits can provide more insights into genetic effects on disease progression and transitions between stages. Moreover, proportional hazards (or Cox) regression models can achieve higher statistical power in a cohort study than a case-control trait using logistic regression. Although mixed-effects models are widely used in GWAS to correct for sample dependence, application of Cox mixed-effects models (CMEMs) to large-scale GWAS is so far hindered by intractable computational cost. In this work, we propose COXMEG, an efficient R package for conducting GWAS of age-at-onset traits using CMEMs. COXMEG introduces fast estimation algorithms for general sparse relatedness matrices including, but not limited to, block-diagonal pedigree-based matrices. COXMEG also introduces a fast and powerful score test for dense relatedness matrices, accounting for both population stratification and family structure. In addition, COXMEG generalizes existing algorithms to support positive semidefinite relatedness matrices, which are common in twin and family studies. Our simulation studies suggest that COXMEG, depending on the structure of the relatedness matrix, is orders of magnitude computationally more efficient than coxme and coxph with frailty for GWAS. We found that using sparse approximation of relatedness matrices yielded highly comparable results in controlling false-positive rate and retaining statistical power for an ethnically homogeneous family-based sample. By applying COXMEG to a study of Alzheimer’s disease (AD) with a Late-Onset Alzheimer’s Disease Family Study from the National Institute on Aging sample comprising 3456 non-Hispanic whites and 287 African Americans, we identified the APOE 4 variant with strong statistical power (P = 1e–101), far more significant than that reported in a previous study using a transformed variable and a marginal Cox model. Furthermore, we identified novel SNP rs36051450 (P = 2e–9) near GRAMD1B, the minor allele of which significantly reduced the hazards of AD in both genders. These results demonstrated that COXMEG greatly facilitates the application of CMEMs in GWAS of age-at-onset traits.

Legionella pneumophila, the etiological agent of Legionnaires’ disease, employs an arsenal of hundreds of Dot/Icm-translocated effector proteins to facilitate replication within eukaryotic phagocytes. Several effectors, called metaeffectors, function to regulate the activity of other Dot/Icm-translocated effectors during infection. The metaeffector Lpg2505 is essential for L. pneumophila intracellular replication only when its cognate effector, SidI, is present. SidI is a cytotoxic effector that interacts with the host translation factor eEF1A and potently inhibits eukaryotic protein translation by an unknown mechanism. Here, we evaluated the impact of Lpg2505 on SidI-mediated phenotypes and investigated the mechanism of SidI function. We determined that Lpg2505 binds with nanomolar affinity to SidI and suppresses SidI-mediated inhibition of protein translation. SidI binding to eEF1A and Lpg2505 is not mutually exclusive, and the proteins bind distinct regions of SidI. We also discovered that SidI possesses GDP-dependent glycosyl hydrolase activity and that this activity is regulated by Lpg2505. We have therefore renamed Lpg2505 MesI (metaeffector of SidI). This work reveals novel enzymatic activity for SidI and provides insight into how intracellular replication of L. pneumophila is regulated by a metaeffector.

Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV.

IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.

Irene Verhagen, Barbara M. Tomotani, Phillip Gienapp, and Marcel E. Visser

Phenotypic plasticity is an important mechanism by which an individual can adapt its seasonal timing to predictable, short-term environmental changes by using predictive cues. Identification of these cues is crucial to forecast the response of species to long-term environmental change and to study their potential to adapt. Individual great tits (Parus major) start reproduction early under warmer conditions in the wild, but whether this effect is causal is not well known. We housed 36 pairs of great tits in climate-controlled aviaries and 40 pairs in outdoor aviaries, where they bred under artificial contrasting temperature treatments or in semi-natural conditions, respectively, for two consecutive years, using birds from lines selected for early and late egg laying. We thus obtained laying dates in two different thermal environments for each female. Females bred earlier under warmer conditions in climate-controlled aviaries, but not in outdoor aviaries. The latter was inconsistent with laying dates from our wild population. Further, early selection line females initiated egg laying consistently ~9 days earlier than late selection line females in outdoor aviaries, but we found no difference in the degree of plasticity (i.e. the sensitivity to temperature) in laying date between selection lines. Because we found that temperature causally affects laying date, climate change will lead to earlier laying. This advancement is, however, unlikely to be sufficient, thereby leading to selection for earlier laying. Our results suggest that natural selection may lead to a change in mean phenotype, but not to a change in the sensitivity of laying dates to temperature.

Yves Bötsch, Zulima Tablado, Bettina Almasi, and Lukas Jenni

Outdoor recreational activities are booming and most animals perceive humans as predators, which triggers behavioural and/or physiological reactions [e.g. heart rate increase, activation of the hypothalamic–pituitary–adrenal (HPA) axis]. Physiological stress reactions have been shown to affect the immune system of an animal and therefore may also affect the amount of maternal antibodies a female transmits to her offspring. A few studies have revealed that the presence of predators affects the amount of maternal antibodies deposited into eggs of birds. In this study, using Eurasian blue and great tit offspring (Cyanistes caeruleus and Parus major) as model species, we experimentally tested whether human recreation induces changes in the amount of circulating antibodies in young nestlings and whether this effect is modulated by habitat and competition. Moreover, we investigated whether these variations in antibody titre in turn have an impact on hatching success and offspring growth. Nestlings of great tit females that had been disturbed by experimental human recreation during egg laying had lower antibody titres compared with control nestlings. Antibody titre of nestling blue tits showed a negative correlation with the presence of great tits, rather than with human disturbance. The hatching success was positively correlated with the average amount of antibodies in great tit nestlings, independent of the treatment. Antibody titre in the first days of life in both species was positively correlated with body mass, but this relationship disappeared at fledging and was independent of treatment. We suggest that human recreation may have caused a stress-driven activation of the HPA axis in breeding females, chronically increasing their circulating corticosterone, which is known to have an immunosuppressive function. Either, lower amounts of antibodies are transmitted to nestlings or impaired transfer mechanisms lead to lower amounts of immunoglobulins in the eggs. Human disturbance could, therefore, have negative effects on nestling survival at early life-stages, when nestlings are heavily reliant on maternal antibodies, and in turn lead to lower breeding success and parental fitness. This is a so far overlooked effect of disturbance on early life in birds.

Daniel P. Small, Piero Calosi, Samuel P. S. Rastrick, Lucy M. Turner, Stephen Widdicombe, and John I. Spicer

Regulation of extracellular acid–base balance, while maintaining energy metabolism, is recognised as an important aspect when defining an organism's sensitivity to environmental changes. This study investigated the haemolymph buffering capacity and energy metabolism (oxygen consumption, haemolymph [l-lactate] and [protein]) in early benthic juveniles (carapace length <40 mm) of the European lobster, Homarus gammarus, exposed to elevated temperature and P_CO2. At 13°C, H. gammarus juveniles were able to fully compensate for acid–base disturbances caused by the exposure to elevated seawater P_CO2 at levels associated with ocean acidification and carbon dioxide capture and storage (CCS) leakage scenarios, via haemolymph [HCO₃^–] regulation. However, metabolic rate remained constant and food consumption decreased under elevated P_CO2, indicating reduced energy availability. Juveniles at 17°C showed no ability to actively compensate haemolymph pH, resulting in decreased haemolymph pH particularly under CCS conditions. Early benthic juvenile lobsters at 17°C were not able to increase energy intake to offset increased energy demand and therefore appear to be unable to respond to acid–base disturbances due to increased P_CO2 at elevated temperature. Analysis of haemolymph metabolites suggests that, even under control conditions, juveniles were energetically limited. They exhibited high haemolymph [l-lactate], indicating recourse to anaerobic metabolism. Low haemolymph [protein] was linked to minimal non-bicarbonate buffering and reduced oxygen transport capacity. We discuss these results in the context of potential impacts of ongoing ocean change and CCS leakage scenarios on the development of juvenile H. gammarus and future lobster populations and stocks.

Juha Nuutila, Anna E. Honkanen, Kyösti Heimonen, and Matti Weckström

Using tethered American cockroaches walking on a trackball in a spherical virtual reality environment, we tested optomotor responses to horizontally moving black-and-white gratings of different vertical extent under six different light intensities. We found that shortening the vertical extent of the wide-field stimulus grating within a light level weakened response strength, reduced average velocity, and decreased angular walking distance. Optomotor responses with the vertically shortened stimuli persisted down to light intensity levels of 0.05 lx. Response latency seems to be independent of both the height of the stimulus and light intensity. The optomotor response started saturating at the light intensity of 5 lx, where the shortest behaviourally significant stimulus was 1°. This indicates that the number of vertical ommatidial rows needed to elicit an optomotor response at 5 lx and above is in the single digits, maybe even just one. Our behavioural results encourage further inquiry into the interplay of light intensity and stimulus size in insect dim-light vision.

Qingxiang Guo, Yang Liu, Yanhua Zhai, and Zemao Gu

Disassembling the parasitic spores and acquiring the main subunits is a prerequisite for deep understanding of the basic biology of parasites. Herein we present a fast and efficient method to dissect the myxospores in a few steps, which mainly involved sonication, sucrose density gradient and Percoll density gradient. We tested our method on three myxozoans species and demonstrated this method allows the dismembering of myxospores, isolation of intact and clean nematocysts and shell valves within 2h by low-cost. This new tool will facilitate subsequent analyses and enable a better understanding of the ecological and evolutionary significance of parasitic spores.

Yi Huang, Jazmin Osorio Mendoza, Catherine Hambly, Baoguo Li, Zengguang Jin, Li Li, Moshen Madizi, Sumei Hu, and John R. Speakman

The heat dissipation limit theory predicts lactating female mice consuming diets with lower specific dynamic action (SDA) should have enhanced lactation performance. Dietary fat has lower SDA than other macronutrients. Here we tested the effects of graded dietary fat levels on lactating Swiss mice. We fed females five diets varying in fat content from 8.3 to 66.6%. Offspring of mothers fed diets of 41.7% fat and above were heavier and fatter at weaning compared to those of 8.3% and 25% fat diets. Mice on dietary fat contents of 41.7% and above had greater metabolizable energy intake at peak lactation (8.3%: 229.4±39.6, 25%: 278.8±25.8, 41.7%: 359.6±51.5, 58.3%: 353.7±43.6, 66.6%: 346±44.7 kJ day^–1), lower daily energy expenditure (8.3%: 128.5±16, 25%: 131.6±8.4, 41.7%: 124.4±10.8, 58.3%: 115.1±10.5, 66.6%: 111.2±11.5 kJ day^–1) and thus delivered more milk energy to their offspring (8.3%: 100.8±27.3, 25%: 147.2±25.1, 41.7%: 225.1±49.6, 58.3%: 238.6±40.1, 66.6%: 234.8±41.1 kJ day^–1). Milk fat content (%) was unrelated to dietary fat content, indicating females on higher fat diets (> 41.7%) produced more rather than richer milk. Mothers consuming diets with 41.7% fat or above enhanced their lactation performance compared to those on 25% or less, probably by diverting dietary fat directly into the milk, thereby avoiding the costs of lipogenesis. At dietary fat contents above 41.7% they were either unable to transfer more dietary fat to the milk, or they chose not to do so, potentially because of a lack of benefit to the offspring that were increasingly fatter as maternal dietary fat increased.

Lewis C. Naisbett-Jones, Nathan F. Putman, Michelle M. Scanlan, David L. G. Noakes, and Kenneth J. Lohmann

A variety of animals sense Earth's magnetic field and use it to guide movements over a wide range of spatial scales. Little is known, however, about the mechanisms that underlie magnetic field detection. Among teleost fish, growing evidence suggests that crystals of the mineral magnetite provide the physical basis of the magnetic sense. In this study, juvenile Chinook salmon (Oncorhynchus tshawytscha) were exposed to a brief but strong magnetic pulse capable of altering the magnetic dipole moment of biogenic magnetite. Orientation behaviour of pulsed fish and untreated control fish was then compared in a magnetic coil system under two conditions: (1) the local magnetic field; and (2) a magnetic field that exists near the southern boundary of the natural oceanic range of Chinook salmon. In the local field, no significant difference existed between the orientation of the control and pulsed groups. By contrast, orientation of the two groups was significantly different in the magnetic field from the distant site. These results demonstrate that a magnetic pulse can alter the magnetic orientation behaviour of a fish and are consistent with the hypothesis that salmon have magnetite-based magnetoreception.

Thomas J. Lisney, Shaun P. Collin, and Jennifer L. Kelley

Ecological factors such as spatial habitat complexity and diet can explain variation in visual morphology, but few studies have sought to determine whether visual specialisation can occur among populations of the same species. We used a small Australian freshwater fish (the western rainbowfish, Melanotaenia australis) to determine whether populations showed variation in eye size and eye position, and whether this variation could be explained by environmental (light availability, turbidity) and ecological (predation risk, habitat complexity, invertebrate abundance) variables. We investigated three aspects of eye morphology, (1) eye size relative to body size, (2) pupil size relative to eye size, and (3) eye position in the head, for fish collected from 14 sites in a major river catchment in northwest Western Australia. We found significant variation among populations in all three measures of eye morphology, but no effect of sex on eye size or eye position. Variation in eye diameter and eye position was best explained by the level of habitat complexity. Specifically, fish occurring in habitats with low complexity (i.e. open water) tended to have smaller, more dorsally-located eyes, than those occurring in more complex habitats (i.e. vegetation present). The size of the pupil relative to the size of the eye was most influenced by the presence of surrounding rock formations; fish living in gorge habitats had significantly smaller pupils (relative to eye size) than those occupying semi-gorge sites or open habitats. Our findings reveal that different ecological and environmental factors contribute to habitat-specific visual specialisations within a species.

Emily J. Lombardi, Candice L. Bywater, and Craig R. White

The Oxygen and Capacity-Limited Thermal Tolerance (OCLTT) hypothesis proposes that the thermal tolerance of an animal is shaped by its capacity to deliver oxygen in relation to oxygen demand. Studies testing this hypothesis have largely focused on measuring short-term performance responses in animals under acute exposure to critical thermal maximums. The OCLTT hypothesis, however, emphasises the importance of sustained animal performance over acute tolerance. The present study tested the effect of chronic hypoxia and hyperoxia during development on medium to long-term performance indicators at temperatures spanning the optimal temperature for growth in the speckled cockroach, Nauphoeta cinerea. In contrast to the predictions of the OCLTT hypothesis, development under hypoxia did not significantly reduce growth rate or running performance, and development under hyperoxia did not significantly increase growth rate or running performance. The effect of developmental temperature and oxygen on tracheal morphology and metabolic rate were also not consistent with OCLTT predictions, suggesting that oxygen delivery capacity is not the primary driver shaping thermal tolerance in this species. Collectively, these findings suggest that the OCLTT hypothesis does not explain moderate-to-long-term thermal performance in Nauphoeta cinerea, which raises further questions about the generality of the hypothesis.

Background

Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload.

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation—sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)—can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter–2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Sulfotransferase (SULT) 4A1 is a brain-selective sulfotransferase-like protein that has recently been shown to be essential for normal neuronal development in mice. In the present study, SULT4A1 was found to colocalize with SULT1A1/3 in human brain neurons. Using immunoprecipitation, SULT4A1 was shown to interact with both SULT1A1 and SULT1A3 when expressed in human cells. Mutation of the conserved dimerization motif located in the C terminus of the sulfotransferases prevented this interaction. Both ectopically expressed and endogenous SULT4A1 decreased SULT1A1/3 protein levels in neuronal cells, and this was also prevented by mutation of the dimerization motif. During differentiation of neuronal SH-SY5Y cells, there was a loss in SULT1A1/3 protein but an increase in SULT4A1 protein. This resulted in an increase in the toxicity of dopamine, a substrate for SULT1A3. Inhibition of SULT4A1 using small interference RNA abrogated the loss in SULT1A1/3 and reversed dopamine toxicity. These results show a reciprocal relationship between SULT4A1 and the other sulfotransferases, suggesting that it may act as a chaperone to control the expression of SULT1A1/3 in neuronal cells.

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

Loess, a wind-blown silty soil, can be deposited under a variety of moisture conditions, including dry deposition, wet deposition and gravitational settling of aggregations formed in moist air by capillary forces at grain contacts. This experimental study uses single and double oedometer tests to assess the effect of depositional water content on the collapse potential of reconstituted samples of the Langley Silt Member, known as Brickearth, a natural loessic soil. A freefall sample preparation technique was used to mimic loess formation and environmental scanning electron microscopy was used to relate the observed behaviour to sample fabric. The results show that loess deposited at higher water contents has a greater collapse potential, which is shown to be related to its looser, more granular fabric.

Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research.

For manufacturers of both sterile and nonsterile pharmaceuticals, there is an expectation that the manufacturing process is performed in a manner that prevents extraneous contamination so that the products are provided in a safe, integral, pure, and unadulterated form. As part of that process, cleaning and disinfection are an absolute necessity. Although cleaning and disinfection support control of microbial contamination through preventive and corrective action, specific compendia methods do not currently exist. The intent of this paper is to provide a general guidance on how to perform disinfectant efficacy validation and implementation. This includes how to make sure the concepts are understood, how to interpret facility data and utilize it to demonstrate control awareness for your facilities, and how to leverage the data to reduce redundancies in validation or verification. This paper represents the thoughts and best practices of the authoring team and their respective companies and provides an efficient way to qualify disinfectants without impacting the quality of the study. If you choose to follow the recommendations in this paper, you must ensure that the appropriate rationale is sound and the scientific data is documented. It is the belief of the authoring team that only then will this approach meet regulatory requirements.

Glass is the favorite material for parenteral packaging because of its physico-chemical properties. Type I borosilicate glass is worldwide use at this scope, but it may have some issues related to breakage, corrosion and delamination that might compromise the drug quality, safety and efficacy. These issues can be mitigated and avoided starting from the appropriate selection of the most suitable raw material at the early stage of the glass container design. In this study, Type I borosilicate glass vials manufactured using two glass tubes having different chemical compositions, were studied and compared in terms of their resistance to corrosion. Testing design was applied with the aim to select the best practice approach comparing different storage simulation conditions: ageing treatment through autoclaving and stability testing (real-time and accelerated). Clear differences were found between the different glass types in terms of hydrolytic and corrosion resistance that highlighted the relation between chemical composition and glass chemical durability. Non-negligible differences were also observed using different storage conditions.

Planktonic foraminifera are a source of important geochemical, palaeoceanographic, and palaeontological data. However, many aspects of their ecology remain poorly understood, including whether or not gross morphology has an ecological function. Here, we measure the force needed to crush multiple planktonic foraminiferal morphotypes from modern core top and tow samples. We find significant differences in the resistance of different morphotypes to compressional force. Three species, Globorotalia tumida (biconvex, keeled), Menardella menardii (discoidal, keeled), Truncorotalia truncatulinoides (conical, keeled), require on average 59% more force (1.07 v. 0.47 N) to crush than the least resistant species (Orbulina universa and Trilobatus sacculifer) in core-top samples. Towed samples of pre-gametogenic individuals also show significant differences of the same magnitude (0.693 v. 0.53 N) between the conical (T. truncatulinoides) and globular/spherical morphologies (Globoconella inflata and O. universa). We hypothesize that the greater compressional strength of certain shapes confers a fitness advantage against predators and could contribute to the repeated, convergent evolution of keeled, conical and bi-convex forms in planktonic foraminifer lineages.

Supplementary material: Raw data for all crushing experiments, wall thickness measurements, and results for all pair-wise Kolmogorov-Smirnov Tests are available at https://doi.org/10.6084/m9.figshare.c.3725236.v1

BACKGROUND

Continuous glucose monitoring (CGM) provides important information to aid in achieving glycemic targets in people with diabetes.

OBJECTIVE

Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes.

OBJECTIVE

Metformin is the first pharmacological option for treating type 2 diabetes. However, the use of this drug is not recommended in individuals with impaired kidney function because of the perceived risk of lactic acidosis. We aimed to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD).

OBJECTIVE

We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes.