julilili42/papers huggingface dataset:
PGE1-Containing Protocols Generate Mature (Leukemia-Derived) Dendritic Cells Directly from Leukemic Whole Blood
2019-09-17

Dendritic cells (DCs) and leukemia-derived DC (DCleu) are potent stimulators of various immunoreactive cells and they play a pivotal role in the (re-) activation of the immune system. As a potential treatment tool for patients with acute myeloid leukemia, we developed and analyzed two new PGE1-containing protocols (Pici-PGE1, Kit M) to generate DC/DCleu ex vivo from leukemic peripheral blood mononuclear cells (PBMCs) or directly from leukemic whole blood (WB) to simulate physiological conditions. Pici-PGE1 generated significantly higher amounts of DCs from leukemic and healthy PBMCs when compared to control and comparable amounts as the already established protocol Pici-PGE2. The proportions of sufficient DC-generation were even higher after DC/DCleu-generation with Pici-PGE1. With Kits, it was possible to generate DCs and DCleu directly from leukemic and healthy WB without induction of blast proliferation. The average amounts of generated DCs and DCleu-subgroups were comparable with all Kits. The PGE1 containing Kit M generated significantly higher amounts of mature DCs when compared to the PGE2-containing Kit K and increased the anti-leukemic-activity. In summary PGE1-containing protocols were suitable for generating DC/DCleu from PBMCs as well as from WB, which reliably (re-) activated immunoreactive cells, improved the overall ex vivo anti-leukemic activity, and influenced cytokine-release-profiles.
HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11
2019-09-17

To escape CD8+ T-cell immunity, human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans, classical MHC-I molecules are encoded by the highly polymorphic HLA-A, -B and -C gene loci. While HLA-C resists US11 degradation, the specificity for HLA-A and HLA-B products has not been systematically studied. In this study we analyzed the MHC-I peptide ligands in HCMV-infected cells. A US11-dependent loss of HLA-A ligands was observed, but not of HLA-B. We revealed a general ability of HLA-B to assemble with β2m and exit from the ER in the presence of US11. Surprisingly, a low-complexity region between the signal peptide sequence and the Ig-like domain of US11, was necessary to form a stable interaction with assembled MHC-I and, moreover, this region was also responsible for changing the pool of HLA-B ligands. Our data suggest a two-pronged strategy by US11 to escape CD8+ T-cell immunity, firstly, by degrading HLA-A molecules, and secondly, by manipulating the HLA-B ligandome.
More data needed for claims about the earliest Oldowan artifacts
2019-09-17

Recent claims about early tool making and use have proved controversial (1⇓⇓–4). In PNAS, Braun et al. (5) report Oldowan artifacts from Ledi-Geraru, Ethiopia. The claimed minimum age of 2.581 Ma for these artifacts would, even if accurate, imply a marginally older beginning for the Oldowan than the ∼2.58 Ma previously established ∼35 km to the west at Gona (6). While the Ledi-Geraru assemblage is a welcome addition to the limited number of early Oldowan occurrences, its bearing on our current understanding of the earliest tools and their makers (6, 7) is contingent on the accuracy of the inferred ... [↵][1]1To whom correspondence may be addressed. Email: yonatan.sahle{at}ifu.uni-tuebingen.de. [1]: #xref-corresp-1-1
Geoarchaeology of the Water Canyon Paleoindian site, west‐central New Mexico
2019-09-17

Abstract Water Canyon is a rare buried, multicomponent, stratified Paleoindian site in west‐central New Mexico. This paper presents a geoarchaeological assessment of the site as part of a broader interdisciplinary investigation of its paleoenvironmental history and archaeology. The archaeology is associated with ancient wetland deposits (Stratum 6) within an alluvial fan. The fan formed initially through the late Pleistocene. Formation of the fan stopped and wetland deposition began ~11,310 14 C yr BP (~13,170 cal yr BP). Stratum 6 evolved via wetland deposition and cut‐and‐fill cycles. The bulk of Stratum 6 dates &lt;10,300 14 C yr BP (&lt;12,200 cal yr BP). One, or possibly two, beds of bison bone, likely processing‐stations, were found on the margin of the paleowetland and date to ~9,200 14 C yr BP (~10,400 cal yr BP) (lower bone bed) and ~8,200 14 C yr BP (~9,150 cal yr BP) (upper bone bed). Farther out in the paleo‐wetland a probable kill site was discovered with an in situ Eden projectile point dated to at least ~8,955 14 C yr BP (~10,070 cal yr BP). The wetland landscape returned to an alluvial fan system &lt;8,000 14 C yr BP (&lt;8,900 cal yr BP) with two more cycles of fan deposition by ~6,500 cal yr.
Syntactic influences on numerical processing in adults: Limited but detectable
2019-09-17

In everyday situations, numbers appear in a linguistic context: we communicate and perceive numbers within phrases and sentences. However, languages differ in how they refer to numerosities, and such differences influence number acquisition in children. One of them is in the link between grammatical inflection and specific numbers. Here we asked whether such differences prevail in adults by using the peculiarities of the Polish language. The Polish language is characterized by a complex agreement system between conceptual number and grammatical number: numbers 2-4 require plural grammatical number inflection on the verb while numbers 5-9 require singular inflection. We expected this complex mapping to affect the numerical SNARC (Spatial Numerical Association of Response Codes; i.e., faster left / right-hand responses to small / large magnitude numbers, respectively) and grammatical SNARC (i.e., faster left / right-hand responses to singular / plural grammatical forms, respectively) effects at least when grammatical number is made salient. In a task-switching setup, Polish-, German- and English-speaking participants were presented with simple sentences ending in two-digit numbers. Depending on the cue, participants had to judge either the grammatical number of the verb, or the parity status of the number. Surprisingly, no numerical SNARC effect was observed in either task, however a reversed grammatical SNARC effect was found for Polish (but not German and English) in parity judgments. Moreover, only Polish speakers responded faster to parity in the case of grammatically correct sentences. We conclude that grammatical number has a limited, but detectable influence on numerical processing in adults.
Is Human Nature Today Different Than Before?
2019-09-17

The question comes unexpected. Nevertheless, it has a rationale to it: the existence of a historical anomaly. There exists a published scientific result which is doubted by no one in the scientific literature for the 11 years that it exists -- but no one pays any attention to it even though refraining from doing so goes against human nature as it has existed in the past
The role of the GABAA receptor Alpha 1 subunit in the ventral hippocampus in stress resilience
2019-09-18

Abstract Pre-pubertal stress increases post-traumatic stress disorder (PTSD) susceptibility. We have previously demonstrated that enriched environment (EE) intervention immediately after pre-pubertal stress protects from the effects of trauma in adulthood. Here, we examined whether exposure to EE would also be beneficial if applied after exposure to trauma in adulthood. We have recently shown that exposure to juvenile stress and under-water trauma (UWT) is associated with increased expression of GABA A receptor subunit α1 in the ventral hippocampus. However, differentiating between affected and unaffected individuals, this increased expression was confined to stress-exposed, behaviorally unaffected individuals, suggesting upregulation of α1 expression as a potential mechanism of resilience. We now examined whether EE-induced resilience renders increased expression of α1 in the ventral hippocampus redundant when facing a trauma later in life. Adult rats were exposed to UWT, with pre-exposure to juvenile stress, and tested in the open field and elevated plus maze paradigms four weeks later. EE exposure during juvenility prevented pre-pubertal stress-induced vulnerability, but not if performed following UWT in adulthood. Furthermore, juvenile EE exposure prevented the trauma-associated increase in α1 expression levels. Our findings emphasize the importance of early interventions in order to reduce the likelihood of developing psychopathologies in adulthood.
Model Selection of Nested and Non-Nested Item Response Models Using Vuong Tests
2019-09-18

In this paper, we apply Vuong's general approach of model selection to the comparison of nested and non-nested unidimensional and multidimensional item response theory (IRT) models. Vuong's approach of model selection is useful because it allows for formal statistical tests of both nested and non-nested models. However, only the test of non-nested models has been applied in the context of IRT models to date. After summarizing the statistical theory underlying the tests, we investigate the performance of all three distinct Vuong tests in the context of IRT models using simulation studies and real data. In the non-nested case we observed that the tests can reliably distinguish between the graded response model and the generalized partial credit model. In the nested case, we observed that the tests typically perform as well as or sometimes better than the traditional likelihood ratio test. Based on these results, we argue that Vuong's approach provides a useful set of tools for researchers and practitioners to effectively compare competing nested and non-nested IRT models.
In Staphylococcus aureus, the Particulate State of the Cell Envelope Is Required for the Efficient Induction of Host Defense Responses
2019-09-18

Upon microbial infection, host immune cells recognize bacterial cell envelope components through cognate receptors. Although bacterial cell envelope components function as innate immune molecules, the role of the physical state of the bacterial cell envelope (i.e., particulate versus soluble) in host immune activation has not been clearly defined.
Phase of sensorimotor μ‐oscillation modulates cortical responses to transcranial magnetic stimulation of the human motor cortex
2019-09-19

Key points Oscillatory brain activity coordinates the response of cortical neurons to synaptic inputs in a phase‐dependent manner. Larger motor‐evoked responses are obtained in a hand muscle when transcranial magnetic stimulation (TMS) is synchronized to the phase of the sensorimotor μ‐rhythm. In this study we further showed that TMS applied at the negative vs . positive peak of the μ‐rhythm is associated with higher absolute amplitude of the evoked EEG potential at 100 ms after stimulation. This demonstrates that cortical responses are sensitive to excitability fluctuation with brain oscillations Our results indicate that brain state‐dependent stimulation is a new useful technique for the investigation of stimulus‐related cortical dynamics. Abstract Oscillatory brain activity coordinates the response of cortical neurons to synaptic inputs in a phase‐dependent manner. Transcranial magnetic stimulation (TMS) of the human primary motor cortex elicits larger motor‐evoked potentials (MEPs) when applied at the negative vs . positive peak of the sensorimotor μ‐rhythm recorded with EEG, demonstrating that this phase represents a state of higher excitability of the cortico‐spinal system. Here, we investigated the influence of the phase of the μ‐rhythm on cortical responses to TMS as measured by EEG. We tested different stimulation intensities above and below resting motor threshold (RMT), and a realistic sham TMS condition. TMS at 110% RMT applied at the negative vs . positive peak of the μ‐rhythm was associated with higher absolute amplitudes of TMS‐evoked potentials at 70 ms (P70) and 100 ms (N100). Enhancement of the N100 was confirmed with negative peak‐triggered 90% RMT TMS, while phase of the μ‐rhythm did not influence evoked responses elicited by sham TMS. These findings extend the idea that TMS applied at the negative vs . positive peak of the endogenous μ‐oscillation recruits a larger portion of neurons as a function of stimulation intensity. This further corroborates that brain oscillations determine fluctuations in cortical excitability and establishes phase‐triggered EEG‐TMS as a sensitive tool to investigate the effects of brain oscillations on stimulus‐related cortical dynamics.
Theorising care: attentive interaction or distributive justice?
2019-09-19

A main reason for the slow advance of a political theory of care is the conceptual differences between two strands of approaching care. Ethico-political approaches of care ask how to better perform supportive interactivities. They aim to bring the traditional concept of justice out of the centre to achieve room for other normative viewpoints such as attentiveness. The welfare-resourcing strand asks who provides support and how the fact of its performance is linked with society’s unjust social structures. These researchers believe that making attentive interaction more central is likely to hinder a fairer distribution of needs-meeting activities, not help it.
Multiple Quantum Coherences Hyperpolarized at Ultra‐Low Fields
2019-09-19

Abstract The development of hyperpolarization technologies enabled several yet exotic NMR applications at low and ultra‐low fields (ULF), where without hyperpolarization even the detection of a signal from analytes is a challenge. Herein, we present a method for the simultaneous excitation and observation of homo‐ and heteronuclear multiple quantum coherences (from zero up to the third‐order), which give an additional degree of freedom for ULF NMR experiments, where the chemical shift variation is negligible. The approach is based on heteronuclear correlated spectroscopy (COSY); its combination with a phase‐cycling scheme allows the selective observation of multiple quantum coherences of different orders. The nonequilibrium spin state and multiple spin orders are generated by signal amplification by reversible exchange (SABRE) and detected at ULF with a superconducting quantum interference device (SQUID)‐based NMR system.
Hydridoorganostannylene Coordination: Group 4 Metallocene Dichloride Reduction in Reaction with Organodihydridostannate Anions
2019-09-19

Abstract Organodihydridoelement anions of germanium and tin were reacted with metallocene dichlorides of Group 4 metals Ti, Zr and Hf. The germate anion [Ar*GeH 2 ] − reacts with hafnocene dichloride under formation of the substitution product [Cp 2 Hf(GeH 2 Ar*) 2 ]. Reaction of the organodihydridostannate with metallocene dichlorides affords the reduction products [Cp 2 M(SnHAr*) 2 ] (M=Ti, Zr, Hf). Abstraction of a hydride substituent from the titanium bis(hydridoorganostannylene) complex results in formation of cation [Cp 2 M(SnAr*)(SnHAr*)] + exhibiting a short Ti–Sn interaction. (Ar*=2,6‐Trip 2 C 6 H 3 , Trip=2,4,6‐triisopropylphenyl).
Response to Comment on “Revised paleoaltimetry data show low Tibetan Plateau elevation during the Eocene”
2019-09-19

Valdes et al . contest our results, suggesting failings in our modeling approach as well as in our comparison with data. Although their comment points to interesting ideas of improvement, we find that their critique reflects an incomplete understanding of our methods and is not supported by the material they provide.
DJ-1 (Park7) affects the gut microbiome, metabolites and development of Innate Lymphoid cells (ILCs)
2019-09-19

Abstract The proper communication between gut and brain is pivotal for maintenance of health and dysregulation of the gut-brain axis can lead to several clinical disorders. Also, in Parkinson’s disease (PD) 85% of all patients experienced constipation long before showing any signs of motor phenotypes. For differential diagnosis and when it comes to preventive treatment there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperon protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 modifies the PD risk remains incompletely understood. In the present study we provide evidence that DJ-1 is implicated in shaping the gut microbiome including their metabolite production or innate immune cells (ILCs) development. We revealed that in 4 months old mice genetic deficiency of DJ-1 leads to significantly decrease in several bacterial genera and significantly increase in two specific genera, namely Alistipes and Rikenella . DJ-1 deficient mice have a higher production of calprotectin/MCP-1 inflammatory protein - a known protein involved in colonic inflammation – and significantly higher expression of glial fibrillary acidic protein (GFAP) than control littermates. Expression of a-Synuclein, a key protein in Lewy bodies, in the colon was not significantly different between genotypes. Metabolic profiles of feces extracts analysed by H 1 -NMR spectroscopy showed increased short chain fatty acids (SCFAs) and decreased amino acid levels, suggesting a general switch from protein towards fibre degrading strains in DJ-1 deficient mice. We observed that Malonate - which is known to influence the immune system – has significantly higher concentrations in DJ-1 deficient mice. Moreover, DJ-1 deficient mice have high levels of the phenol derivate 3-(3-Hydroxyphenyl) propanoic acid (3-HPPA) which is a breakdown product of aromatic substrates like tyrosine, phenylalanine and polyphenols. DJ-1 deficient mice also showed significantly reduced percentage of ILCs. Thus, our data suggests that absence of DJ-1 leads to increase in gut inflammatory bacteria composition, deregulated metabolites and dysregulated innate immunity which could be a key factor in the initiation of PD disease in the gut, and potentially also in brain during disease progression.
Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial
2019-09-20

OBJECTIVE To evaluate whether the sodium–glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of −1.8% (95% CI −3.4, −0.2; P = 0.02) and relative change in LFC of −22% (−36, −7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change −2.5 kg [−3.7, −1.4]; P &amp;lt; 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (−74 mol/L [−108, −42]; P &amp;lt; 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P &amp;lt; 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D.
Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs
2019-09-20

Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.
Chemovirotherapy for pancreatic cancer: Gemcitabine plus oncolytic measles vaccine virus
2019-09-20

Oncolytic virotherapy with vaccine viruses employs replicative vectors, which quite selectively infect tumor cells leading to massive virus replication followed by subsequent profound tumor cell death (oncolysis). Measles vaccine virus (MeV) has already shown great oncolytic activity against different types of cancers, including pancreatic cancer. Gemcitabine is a first line chemotherapeutic drug used for pancreatic cancer in palliative treatment plans. Furthermore, this drug can be used to induce senescence, a permanent cell cycle arrest, in tumor cells. In our preclinical work, three well-characterized immortalized human pancreatic cancer cell lines were used to investigate the combinatorial effect of MeV-based virotherapy together with the chemotherapeutic compound gemcitabine. Viability assays revealed that the combination of only small amounts of MeV together with subtherapeutic concentrations of gemcitabine resulted in a tumor cell mass reduction of >50%. To further investigate the replication of the oncolytic MeV vectors under these distinct combinatorial conditions, viral growth curves were generated. As a result, viral replication was found to be only slightly diminished in the presence of gemcitabine. As gemcitabine induces senescence, the effect of MeV on that phenomenon was explored using a senescence-associated β-galactosidase assay. Notably, gemcitabine-induced tumor cell senescence was not impaired by MeV. Accordingly, the chemovirotherapeutic combination of gemcitabine plus oncolytic MeV constitutes a novel therapeutic option for advanced pancreatic carcinoma that is characterized by the mutual improvement of the effectiveness of each therapeutic component.