Effect of Harmonicity on the Detection of a Signal in a Complex Masker and on Spatial Release from Masking

The amount of masking of sounds from one source (signals) by sounds from a competing source (maskers) heavily depends on the sound characteristics of the masker and the signal and on their relative spatial location. Numerous studies investigated the ability to detect a signal in a speech or a noise masker or the effect of spatial separation of signal and masker on the amount of masking, but there is a lack of studies investigating the combined effects of many cues on the masking as is typical for natural listening situations. The current study using free-field listening systematically evaluates the combined effects of harmonicity and inharmonicity cues in multi-tone maskers and cues resulting from spatial separation of target signal and masker on the detection of a pure tone in a multi-tone or a noise masker. A linear binaural processing model was implemented to predict the masked thresholds in order to estimate whether the observed thresholds can be accounted for by energetic masking in the auditory periphery or whether other effects are involved. Thresholds were determined for combinations of two target frequencies (1 and 8 kHz), two spatial configurations (masker and target either co-located or spatially separated by 90 degrees azimuth), and five different masker types (four complex multi-tone stimuli, one noise masker). A spatial separation of target and masker resulted in a release from masking for all masker types. The amount of masking significantly depended on the masker type and frequency range. The various harmonic and inharmonic relations between target and masker or between components of the masker resulted in a complex pattern of increased or decreased masked thresholds in comparison to the predicted energetic masking. The results indicate that harmonicity cues affect the detectability of a tonal target in a complex masker

Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4

<p>Abstract</p> <p>Background</p> <p>Sall4 is a key factor for the maintenance of pluripotency and self-renewal of embryonic stem cells (ESCs). Our previous studies have shown that Sall4 is a robust stimulator for human hematopoietic stem and progenitor cell (HSC/HPC) expansion. The purpose of the current study is to further evaluate how Sall4 may affect HSC/HPC activities in a murine system.</p> <p>Methods</p> <p>Lentiviral vectors expressing Sall4A or Sall4B isoform were used to transduce mouse bone marrow Lin-/Sca1+/c-Kit+ (LSK) cells and HSC/HPC self-renewal and differentiation were evaluated.</p> <p>Results</p> <p>Forced expression of Sall4 isoforms led to sustained <it>ex vivo </it>proliferation of LSK cells. In addition, Sall4 expanded HSC/HPCs exhibited increased <it>in vivo </it>repopulating abilities after bone marrow transplantation. These activities were associated with dramatic upregulation of multiple HSC/HPC regulatory genes including HoxB4, Notch1, Bmi1, Runx1, Meis1 and Nf-ya. Consistently, downregulation of endogenous Sall4 expression led to reduced LSK cell proliferation and accelerated cell differentiation. Moreover, in myeloid progenitor cells (32D), overexpression of Sall4 isoforms inhibited granulocytic differentiation and permitted expansion of undifferentiated cells with defined cytokines, consistent with the known functions of Sall4 in the ES cell system.</p> <p>Conclusion</p> <p>Sall4 is a potent regulator for HSC/HPC self-renewal, likely by increasing self-renewal activity and inhibiting differentiation. Our work provides further support that Sall4 manipulation may be a new model for expanding clinically transplantable stem cells.</p

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Differential Effects of Attention-, Compassion-, and Socio-Cognitively Based Mental Practices on Self-Reports of Mindfulness and Compassion

Research on the effects of mindfulness- and compassion-based interventions is flourishing along with self-report scales to assess facets of these broad concepts. However, debates remain as to which mental practices are most appropriate to develop the attentional, cognitive, and socio-affective facets of mindfulness and compassion. One crucial question is whether present-moment, attention-focused mindfulness practices are sufficient to induce a cascade of changes across the different proposed facets of mindfulness, including nonjudgmental acceptance, as well as compassion or whether explicit socio-affective training is required. Here, we address these questions in the context of a 9-month longitudinal study (the ReSource Project) by examining the differential effects of three different 3-month mental training modules on subscales of mindfulness and compassion questionnaires. The “Presence” module, which aimed at cultivating present-moment-focused attention and body awareness, led to increases in the observing, nonreacting, and presence subscales, but not to increases in acceptance or nonjudging. These latter facets benefitted from specific cultivation through the socio-cognitive “Perspective” module and socio-affective, compassion-based “Affect” module, respectively. These modules also led to further increases in scores on the subscales affected by the Presence module. Moreover, scores on the compassion scales were uniquely influenced by the Affect module. Thus, whereas a present-moment attention-focused training, as implemented in many mindfulness-based programs, was indeed able to increase attentional facets of mindfulness, only socio-cognitive and compassion-based practices led to broad changes in ethical-motivational qualities like a nonjudgmental attitude, compassion, and self-compassion

Complex Deleterious Interactions Associated with Malic Enzyme May Contribute to Reproductive Isolation in the Copepod Tigriopus californicus

Dobzhansky-Muller incompatibilities can result from the interactions of more than a single pair of interacting genes and there are several different models of how such complex interactions can be structured. Previous empirical work has identified complex conspecific epistasis as a form of complex interaction that has contributed to postzygotic reproductive isolation between taxa, but other forms of complexity are also possible. Here, I probe the genetic basis of reproductive isolation in crosses of the intertidal copepod Tigriopus californicus by looking at the impact of markers in genes encoding metabolic enzymes in F2 hybrids. The region of the genome associated with the locus ME2 is shown to have strong, repeatable impacts on the fitness of hybrids in crosses and epistatic interactions with another chromosomal region marked by the GOT2 locus in one set of crosses. In a cross between one of these populations and a third population, these two regions do not appear to interact despite the continuation of a large effect of the ME2 region itself in both crosses. The combined results suggest that the ME2 chromosomal region is involved in incompatibilities with several unique partners. If these deleterious interactions all stem from the same factor in this region, that would suggest a different form of complexity from complex conspecific epistasis, namely, multiple independent deleterious interactions stemming from the same factor. Confirmation of this idea will require more fine-scale mapping of the interactions of the ME2 region of the genome

Alveolar Epithelial Type II Cells Activate Alveolar Macrophages and Mitigate P. Aeruginosa Infection

Although alveolar epithelial type II cells (AECII) perform substantial roles in the maintenance of alveolar integrity, the extent of their contributions to immune defense is poorly understood. Here, we demonstrate that AECII activates alveolar macrophages (AM) functions, such as phagocytosis using a conditioned medium from AECII infected by P. aeruginosa. AECII-derived chemokine MCP-1, a monocyte chemoattractant protein, was identified as a main factor in enhancing AM function. We proposed that the enhanced immune potency of AECII may play a critical role in alleviation of bacterial propagation and pneumonia. The ability of phagocytosis and superoxide release by AM was reduced by MCP-1 neutralizing antibodies. Furthermore, MCP-1−/− mice showed an increased bacterial burden under PAO1 and PAK infection vs. wt littermates. AM from MCP-1−/− mice also demonstrated less superoxide and impaired phagocytosis over the controls. In addition, AECII conditioned medium increased the host defense of airway in MCP-1−/− mice through the activation of AM function. Mechanistically, we found that Lyn mediated NFκB activation led to increased gene expression and secretion of MCP-1. Consequently Lyn−/− mice had reduced MCP-1 secretion and resulted in a decrease in superoxide and phagocytosis by AM. Collectively, our data indicate that AECII may serve as an immune booster for fighting bacterial infections, particularly in severe immunocompromised conditions

Stem Cell Factor SALL4 Represses the Transcriptions of PTEN and SALL1 through an Epigenetic Repressor Complex

Background The embryonic stem cell (ESC) factor, SALL4, plays an essential role in both development and leukemogenesis. It is a unique gene that is involved in self-renewal in ESC and leukemic stem cell (LSC).Methodology/Principal Findings To understand the mechanism(s) of SALL4 function(s), we sought to identify SALL4-associated proteins by tandem mass spectrometry. Components of a transcription repressor Mi-2/Nucleosome Remodeling and Deacetylase (NuRD) complex were found in the SALL4-immunocomplexes with histone deacetylase (HDAC) activity in ESCs with endogenous SALL4 expression and 293T cells overexpressing SALL4. The SALL4-mediated transcriptional regulation was tested on two potential target genes: PTEN and SALL1. Both genes were confirmed as SALL4 downstream targets by chromatin-immunoprecipitation, and their expression levels, when tested by quantitative reverse transcription polymerase chain reaction (qRT-PCR), were decreased in 293T cells overexpressing SALL4. Moreover, SALL4 binding sites at the promoter regions of PTEN and SALL1 were co-occupied by NuRD components, suggesting that SALL4 represses the transcriptions of PTEN and SALL1 through its interactions with the Mi-2/NuRD complex. The in vivo repressive effect(s) of SALL4 were evaluated in SALL4 transgenic mice, where decreased expressions of PTEN and SALL1 were associated with myeloid leukemia and cystic kidneys, respectively.Conclusions/Significance In summary, we are the first to demonstrate that stem cell protein SALL4 represses its target genes, PTEN and SALL1, through the epigenetic repressor Mi-2/NuRD complex. Our novel finding provides insight into the mechanism(s) of SALL4 functions in kidney development and leukemogenesis

Excision of HIV-1 Proviral DNA by Recombinant Cell Permeable Tre-Recombinase

Over the previous years, comprehensive studies on antiretroviral drugs resulted in the successful introduction of highly active antiretroviral therapy (HAART) into clinical practice for treatment of HIV/AIDS. However, there is still need for new therapeutic approaches, since HAART cannot eradicate HIV-1 from the infected organism and, unfortunately, can be associated with long-term toxicity and the development of drug resistance. In contrast, novel gene therapy strategies may have the potential to reverse the infection by eradicating HIV-1. For example, expression of long terminal repeat (LTR)-specific recombinase (Tre-recombinase) has been shown to result in chromosomal excision of proviral DNA and, in consequence, in the eradication of HIV-1 from infected cell cultures. However, the delivery of Tre-recombinase currently depends on the genetic manipulation of target cells, a process that is complicating such therapeutic approaches and, thus, might be undesirable in a clinical setting. In this report we demonstrate that E.coli expressed Tre-recombinases, tagged either with the protein transduction domain (PTD) from the HIV-1 Tat trans-activator or the translocation motif (TLM) of the Hepatitis B virus PreS2 protein, were able to translocate efficiently into cells and showed significant recombination activity on HIV-1 LTR sequences. Tre activity was observed using episomal and stable integrated reporter constructs in transfected HeLa cells. Furthermore, the TLM-tagged enzyme was able to excise the full-length proviral DNA from chromosomal integration sites of HIV-1-infected HeLa and CEM-SS cells. The presented data confirm Tre-recombinase activity on integrated HIV-1 and provide the basis for the non-genetic transient application of engineered recombinases, which may be a valuable component of future HIV eradication strategies

Global Phylogeography with Mixed-Marker Analysis Reveals Male-Mediated Dispersal in the Endangered Scalloped Hammerhead Shark (Sphyrna lewini)

Background: The scalloped hammerhead shark, Sphyrna lewini, is a large endangered predator with a circumglobal distribution, observed in the open ocean but linked ontogenetically to coastal embayments for parturition and juvenile development. A previous survey of maternal (mtDNA) markers demonstrated strong genetic partitioning overall (global W ST = 0.749) and significant population separations across oceans and between discontinuous continental coastlines. Methodology/Principal Findings: We surveyed the same global range with increased sample coverage (N = 403) and 13 microsatellite loci to assess the male contribution to dispersal and population structure. Biparentally inherited microsatellites reveal low or absent genetic structure across ocean basins and global genetic differentiation (FST = 0.035) over an order of magnitude lower than the corresponding measures for maternal mtDNA lineages (W ST = 0.749). Nuclear allelic richness and heterozygosity are high throughout the Indo-Pacific, while genetic structure is low. In contrast, allelic diversity is low while population structure is higher for populations at the ends of the range in the West Atlantic and East Pacific. Conclusions/Significance: These data are consistent with the proposed Indo-Pacific center of origin for S. lewini, and indicate that females are philopatric or adhere to coastal habitats while males facilitate gene flow across oceanic expanses. This study includes the largest sampling effort and the most molecular loci ever used to survey the complete range of

LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson's disease and dementia with Lewy bodies

Loss-of-function variants in the low-density lipoprotein receptor-related protein 10 (LRP10) gene have been associated with autosomal-dominant Parkinson's disease (PD), PD dementia, and dementia with Lewy bodies (DLB). Moreover, LRP10 variants have been found in individuals diagnosed with progressive supranuclear palsy and amyotrophic lateral sclerosis. Despite this genetic evidence, little is known about the expression and function of LRP10 protein in the human brain under physiological or pathological conditions. To better understand how LRP10 variants lead to neurodegeneration, we first performed an in-depth characterisation of LRP10 expression in post-mortem brains and human-induced pluripotent stem cell (iPSC)-derived astrocytes and neurons from control subjects. In adult human brain, LRP10 is mainly expressed in astrocytes and neurovasculature but undetectable in neurons. Similarly, LRP10 is highly expressed in iPSC-derived astrocytes but cannot be observed in iPSC-derived neurons. In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). Furthermore, although LRP10 expression and localisation in the substantia nigra of most idiopathic PD and DLB patients and LRP10 variant carriers diagnosed with PD or DLB appeared unchanged compared to control subjects, significantly enlarged LRP10-positive vesicles were detected in a patient carrying the LRP10 p.Arg235Cys variant. Last, LRP10 was detected in Lewy bodies (LB) at late maturation stages in brains from idiopathic PD and DLB patients and in LRP10 variant carriers. In conclusion, high LRP10 expression in non-neuronal cells and undetectable levels in neurons of control subjects indicate that LRP10-mediated pathogenicity is initiated via cell non-autonomous mechanisms, potentially involving the interaction of LRP10 with SORL1 in vesicle trafficking pathways. Together with the specific pattern of LRP10 incorporation into mature LBs, these data support an important mechanistic role for disturbed vesicle trafficking and loss of LRP10 function in neurodegenerative diseases