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Non-standard errors
(2021)
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
Investigation of the sympathetic regulation in delayed onset muscle soreness: results of an RCT
(2021)
Sports-related pain and injury is directly linked to tissue inflammation, thus involving the autonomic nervous system (ANS). In the present experimental study, we disable the sympathetic part of the ANS by applying a stellate ganglion block (SGB) in an experimental model of delayed onset muscle soreness (DOMS) of the biceps muscle. We included 45 healthy participants (female 11, male 34, age 24.16 ± 6.67 years [range 18–53], BMI 23.22 ± 2.09 kg/m2) who were equally randomized to receive either (i) an SGB prior to exercise-induced DOMS (preventive), (ii) sham intervention in addition to DOMS (control/sham), or (iii) SGB after the induction of DOMS (rehabilitative). The aim of the study was to determine whether and to what extent sympathetically maintained pain (SMP) is involved in DOMS processing. Focusing on the muscular area with the greatest eccentric load (biceps distal fifth), a significant time × group interaction on the pressure pain threshold was observed between preventive SGB and sham (p = 0.034). There was a significant effect on pain at motion (p = 0.048), with post hoc statistical difference at 48 h (preventive SGB Δ1.09 ± 0.82 cm VAS vs. sham Δ2.05 ± 1.51 cm VAS; p = 0.04). DOMS mediated an increase in venous cfDNA -as a potential molecular/inflammatory marker of DOMS- within the first 24 h after eccentric exercise (time effect p = 0.018), with a peak at 20 and 60 min. After 60 min, cfDNA levels were significantly decreased comparing preventive SGB to sham (unpaired t-test p = 0.008). At both times, 20 and 60 min, cfDNA significantly correlated with observed changes in PPT. The 20-min increase was more sensitive, as it tended toward significance at 48 h (r = 0.44; p = 0.1) and predicted the early decrease of PPT following preventive stellate blocks at 24 h (r = 0.53; p = 0.04). Our study reveals the broad impact of the ANS on DOMS and exercise-induced pain. For the first time, we have obtained insights into the sympathetic regulation of pain and inflammation following exercise overload. As this study is of a translational pilot character, further research is encouraged to confirm and specify our observations.
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Inorganic phosphate is one of the most abundant and essential nutrients in living organisms. It plays an indispensable role in energy metabolism and serves as a building block for major cellular components such as the backbones of DNA and RNA, headgroups of phospholipids and in posttranslational modifcations of many proteins. Disturbances in cellular phosphate homeostasis have a detrimental effect on the viability of cells. There- fore, both the import and export of phosphate is strictly regulated in eukaryotic cells. In the eukaryotic model organism Saccharomyces cerevisiae, the uptake of phosphate is carried out either by transporters with high affinity or by transporters with low affinity, depending on the cytosolic phosphate concentration. While structures are available for homologues of the high-affinity transporters, no structures of low-affinity transporters have been solved so far. Interestingly, only the low-affinity transporters have a regulatory SPX domain, which is found in various proteins involved in phosphate homeostasis.
In this work, structures of Pho90 from Saccharomyces cerevisiae, a low-affinity phosphate transporter, were solved by cryo-EM, providing insights into its transport mechanism. The dimeric structure resembles the structures of proteins of the divalent anion symporter superfamily (DASS) and of mammalian transporters of the solute carrier 13 (SLC13) family. The transmembrane domain of each protomer consists of 13 helical elements and can be subdivided into scaffold and transport domains. The structure of ScPho90 in the presence of phosphate shows the phosphate binding site within the transporter domain in an outward-open conformation with a bound phosphate ion and two sodium ions. In the absence of phosphate, an asymmetric dimer structure was determined, with one protomer adopting an inward-open conformation. While the dimer contact and the scaffold domain are identical in both conformations, the transport domain is rotated by about 30° and shifted by 11 Å towards the cytoplasmic side, leading to the accessibility of the binding pocket from the cytoplasm. Based on these findings and by comparison with known structures, a phosphate transport mechanism is proposed in the present work that involves substrate binding on the extracellular side, conformational change by a rigid-body motion of the transport domain, in an "elevator-like" motion, and substrate release into the cytoplasm. The regulatory SPX domain is not well resolved in the ScPho90 structures, so that no direct conclusions were drawn about its regulatory mechanism. The findings provide new insights into the function and mechanism of eukaryotic low-affinity phosphate transporters.
While eukaryotic cells express various phosphate import proteins, most eukaryotes have only a single highly conserved and essential phosphate exporter. These exporters show no sequence homology to other transporters of known structure, but also possess a regulatory SPX domain. In this work, the structural basis for eukaryotic phosphate export is investigated by elucidating the structures of the homologous phosphate exporters Syg1 from Saccharomyces cerevisiae and Xpr1 from Homo sapiens, using cryo-EM. The structures of ScSyg1 and HsXpr1 show a conserved homodimeric structure and the transmembrane part of each protomer consists of 10 TM helices. Helix TM1 establishes the dimer contact by means of a glycine zipper motif, which is a known oligomerization motif. Helices TM2-5 form a hydrophobic pocket that has density for a lipid molecule. Whether the lipid binding into the hydrophobic pocket has an allosteric effect on the phosphate export activity or only serves protein stabilization is not known. Helices TM5-10 form a six-helix bundle, which constitutes a putative phosphate translocation pathway in its center. This bundle is formed by the protein sequence annotated as EXS domain.
The respective phosphate translocation pathways of ScSyg1 and HsXpr1 show structural differences. While the translocation pathway in HsXpr1 is accessible from the cytoplasm, in ScSyg1 it is closed by a large loop of the SPX domain. Interestingly, this loop is not conserved in higher eukaryotes and is therefore not present in HsXpr1. Another difference are distinct conformations of helix TM9. In ScSyg1, TM9 adopts a kinked conformation, which results in the translocation pathway being open to the extracellular side. In contrast, TM9 adopts a straight conformation in HsXpr1, resulting in the placement of a highly conserved tryptophane residue in the middle of the translocation pathway. As a result, the translocation pathway in HsXpr1 is closed to the extracellular side.
Highlights
• Cryo-EM structures of the yeast low-affinity phosphate importer ScPho90
• Complementary structures reveal insights into the substrate translocation mechanism
• Comparisons with homologous transporters highlight the conserved transport mechanism
• Regulation by the SPX domain is discussed
Summary
Phosphate homeostasis is essential for all living organisms. Low-affinity phosphate transporters are involved in phosphate import and regulation in a range of eukaryotic organisms. We have determined the structures of the Saccharomyces cerevisiae phosphate importer Pho90 by electron cryomicroscopy in two complementary states at 2.3 and 3.1 Å resolution. The symmetrical, outward-open structure in the presence of phosphate indicates bound substrate ions in the binding pocket. In the absence of phosphate, Pho90 assumes an asymmetric structure with one monomer facing inward and one monomer facing outward, providing insights into the transport mechanism. The Pho90 transport domain binds phosphate ions on one side of the membrane, then flips to the other side where the substrate is released. Together with functional experiments, these complementary structures illustrate the transport mechanism of eukaryotic low-affinity phosphate transporters.