Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty.

This study explores how researchers' analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers' expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each team's workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers' results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.

Bioinspired sonar reflectors as guiding beacons for autonomous navigation.

Sonar sensors are universally applied in autonomous vehicles such as robots and driverless cars as they are inexpensive, energy-efficient, and provide accurate range measurements; however, they have some limitations. Their measurements can lead to ambiguous estimates and echo clutter can hamper target detection. In nature, echolocating bats experience similar problems when searching for food, especially if their food source is close to vegetation, as is the case for gleaning bats and nectar-feeding bats. However, nature has come up with solutions to overcome clutter problems and acoustically guide bats. Several bat-pollinated plants have evolved specially shaped floral parts that act as sonar reflectors, making the plants acoustically conspicuous. Here we show that artificial sonar beacons inspired by floral shapes streamline the navigation efficacy of sonar-guided robot systems. We developed floral-inspired reflector forms and demonstrate their functionality in 2 proof-of-principle experiments. First we show that the reflectors are easily recognized among dense clutter, and second we show that it is possible to discern different reflector shapes and use this identification to guide a robot through an unfamiliar environment. Bioinspired sonar reflectors could have a wide range of applications that could significantly advance sonar-guided systems.

Structural determinants and cellular environment define processed actin as the sole substrate of the N-terminal acetyltransferase NAA80.

N-terminal (Nt) acetylation is a major protein modification catalyzed by N-terminal acetyltransferases (NATs). Methionine acidic N termini, including actin, are cotranslationally Nt acetylated by NatB in all eukaryotes, but animal actins containing acidic N termini, are additionally posttranslationally Nt acetylated by NAA80. Actin Nt acetylation was found to regulate cytoskeletal dynamics and motility, thus making NAA80 a potential target for cell migration regulation. In this work, we developed potent and selective bisubstrate inhibitors for NAA80 and determined the crystal structure of NAA80 in complex with such an inhibitor, revealing that NAA80 adopts a fold similar to other NAT enzymes but with a more open substrate binding region. Furthermore, in contrast to most other NATs, the substrate specificity of NAA80 is mainly derived through interactions between the enzyme and the acidic amino acids at positions 2 and 3 of the actin substrate and not residues 1 and 2. A yeast model revealed that ectopic expression of NAA80 in a strain lacking NatB activity partially restored Nt acetylation of NatB substrates, including yeast actin. Thus, NAA80 holds intrinsic capacity to posttranslationally Nt acetylate NatB-type substrates in vivo. In sum, the presence of a dominant cotranslational NatB in all eukaryotes, the specific posttranslational actin methionine removal in animals, and finally, the unique structural features of NAA80 leave only the processed actins as in vivo substrates of NAA80. Together, this study reveals the molecular and cellular basis of NAA80 Nt acetylation and provides a scaffold for development of inhibitors for the regulation of cytoskeletal properties.

Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4).

Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3) resulted in an EC50 of 61µM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent.

Optimized bisubstrate inhibitors for the actin N-terminal acetyltransferase NAA80.

Acetylation of protein N-termini is one of the most common protein modifications in the eukaryotic cell and is catalyzed by the N-terminal acetyltransferase family of enzymes. The N-terminal acetyltransferase NAA80 is expressed in the animal kingdom and was recently found to specifically N-terminally acetylate actin, which is the main component of the microfilament system. This unique animal cell actin processing is essential for the maintenance of cell integrity and motility. Actin is the only known substrate of NAA80, thus potent inhibitors of NAA80 could prove as important tool compounds to study the crucial roles of actin and how NAA80 regulates this by N-terminal acetylation. Herein we describe a systematic study toward optimizing the peptide part of a bisubstrate-based NAA80 inhibitor comprising of coenzyme A conjugated onto the N-terminus of a tetrapeptide amide via an acetyl linker. By testing various combinations of Asp and Glu which are found at the N-termini of ß- and γ-actin, respectively, CoA-Ac-EDDI-NH2 was identified as the best inhibitor with an IC50 value of 120 nM.

Context-specific grasp movement representation in macaque ventral premotor cortex.

Hand grasping requires the transformation of sensory signals to hand movements. Neurons in area F5 (ventral premotor cortex) represent specific grasp movements (e.g., precision grip) as well as object features like orientation, and are involved in movement preparation and execution. Here, we examined how F5 neurons represent context-dependent grasping actions in macaques. We used a delayed grasping task in which animals grasped a handle either with a power or a precision grip depending on context information. Additionally, object orientation was varied to investigate how visual object features are integrated with context information. In 420 neurons from two animals, object orientation and grip type were equally encoded during the instruction epoch (27% and 26% of all cells, respectively). While orientation representation dropped during movement execution, grip type representation increased (20% vs 43%). According to tuning onset and offset, we classified neurons as sensory, sensorimotor, or motor. Grip type tuning was predominantly sensorimotor (28%) or motor (25%), whereas orientation-tuned cells were mainly sensory (11%) or sensorimotor (15%) and often also represented grip type (86%). Conversely, only 44% of grip-type tuned cells were also orientation-tuned. Furthermore, we found marked differences in the incidence of preferred conditions (power vs precision grips and middle vs extreme orientations) and in the anatomical distribution of the various cell classes. These results reveal important differences in how grip type and object orientation is processed in F5 and suggest that anatomically and functionally separable cell classes collaborate to generate hand grasping commands.

Adjusting the Residual Stress State in Wire Drawing Products via In-Process Modification of Tool Geometries.

After conventional forming processes, the residual stress distribution in wires is frequently unfavorable for subsequent processes, such as bending operations. High tensile residual stresses typically occur near the wire surface and normally limit further processability of the material. Additional heat treatment operations or shot peening are often used to influence the residual stress distribution in the material after conventional manufacturing, which is time- and energy-consuming. This paper presents an approach for influencing the residual stress distribution by modifying the forming process, especially regarding die geometry. The aim is to reduce the resulting tensile stress levels near the surface. Specific forming elements are integrated into the dies to achieve this residual stress reduction. These modifications in the forming zone have a significant influence on process properties, such as plastic strain and deformation direction, but typically do not influence product geometry. This paper describes the theoretical approach and model setup, the FE simulation, and the results of the experimental tests. The characterization of the residual stress states in the specimen was carried out through X-ray diffraction using the sin2Ψ method.

Context-specific grasp movement representation in the macaque anterior intraparietal area.

To perform grasping movements, the hand is shaped according to the form of the target object and the intended manipulation, which in turn depends on the context of the action. The anterior intraparietal cortex (AIP) is strongly involved in the sensorimotor transformation of grasping movements, but the extent to which it encodes context-specific information for hand grasping is unclear. To explore this issue, we recorded 571 single-units in AIP of two macaques during a delayed grasping task, in which animals were instructed by an external context cue (LED) to perform power or precision grips on a handle that was presented in various orientations. While 55% of the recorded neurons encoded the object orientation from the cue epoch on, the number of cells encoding the grip type increased from 25% during the cue epoch to 58% during movement execution. Furthermore, a classification of cells according to the time of their tuning onset revealed differences in the function and anatomical location of early- versus late-tuned cells. In a cue separation task, when the object was presented first, neurons representing power or precision grips were activated simultaneously until the actual grip type was instructed. In contrast, when the grasp type instruction was presented before the object, type information was only weakly represented in AIP, but was strongly encoded after the grasp target was revealed. We conclude that AIP encodes context specific hand grasping movements to perceived objects, but in the absence of a grasp target, the encoding of context information is weak.

A High-Throughput-Screening Method for the Identification of Active and Enantioselective Hydrolases.

A rapid and reliable test for the determination of hydrolase activity and enantioselectivity comprises the conversion of acetic acid released from acetates to NADH by using a commercially available enzymatic test-kit. The NADH is spectrophotometrically quantified in a microtiter plate format.

Continuous respiratory monitoring for sleep apnea screening by ambulatory hemodynamic monitor.

AIM: To validate the sleep-disordered breathing components of a portable electrocardiography and hemodynamic monitor to be used for sleep apnea screening. METHODS: Sleep-disordered breathing (SDB) is associated with cardiovascular disease. Patients with existing cardiovascular disease may have unrecognized SDB or may develop SDB while under the care of a cardiologist. A screening device for SDB, easy to use and appealing to cardiologists, would assist in referral of appropriate patients for full polysomnography (PSG). A cardiac and respiratory monitor (CPAM) was attached to patients undergoing PSG and an apnea/hypopnea index (AHI) generated. The CPAM device produced respiration rate, snoring rate, individual apnea/hypopnea events and an SDB severity score (SDBSS). In addition to AHI, an expert over-reader annotated individual breaths, snores and SDB breathing events to which the automated algorithms were compared. RESULTS: The test set consisted of data from 85 patients (age: 50.5 ± 12.4 years). Of these, 57 had a positive PSG defined as AHI ≥ 5.0 (mean: 30.0 ± 29.8, negative group mean: 1.5 ± 1.2). The sensitivity and specificity of the SDBSS compared to AHI was 57.9% and 89.3%, respectively. The correlation of snoring rate by CPAM compared to the expert over-reader was r = 0.58 (mean error: 1.52 snores/min), while the automated respiration rate had a correlation of r = 0.90 (mean error: 0.70 breaths/min). CONCLUSION: This performance assessment shows that CPAM can be a useful portable monitor for screening and follow-up of subjects for SDB.

Which patients benefit from hemodialysis therapy in hepatorenal syndrome?

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) occurs in patients with advanced liver cirrhosis and has a poor outcome. The aim of the present study was to investigate which patients with HRS are likely to benefit from hemodialysis. METHODS: Data were collected prospectively from 30 patients with Child-Pugh C liver cirrhosis and HRS. Patients were either treated with continuous veno-venous hemodialysis (CVVHD) if they were mechanically ventilated, or with intermittent hemodialysis (HD) if they were not mechanically ventilated. Prognosis was assessed by the Child-Pugh and by the Model for End-Stage Liver Disease (MELD) score. The primary aim of the study was the analysis of overall and 30-day patient survival during hemodialysis therapy. To identify predictive factors of survival, variables obtained before the initiation of dialysis therapy were evaluated. RESULTS: Patients' 30-day survival was 8/30 (median survival time 21 days). Among patients treated with mechanical ventilation, 30-day survival time was 0/15 while 8/15 patients without mechanical ventilation survived more than 30 days (P < 0.001). Using a multivariate model, the relative hazards for serum albumin, international normalized ratio (INR) and catecholamine therapy were not different from one another (P > 0.05), indicating that these parameters were not independent predictors of survival. Mechanical ventilation was an independent risk factor for 30-day (relative hazard 6.6 [1.6-27.7], P < 0.001) and overall survival (relative hazard 6.3 [1.5-26.5], P = 0.01). Child-Pugh (P < 0.01) and the MELD (P < 0.01) score were predictive for overall survival independent of mechanical ventilation. CONCLUSIONS: Patients with HRS without mechanical ventilation may benefit from hemodialysis, whereas hemodialysis seems to be futile in patients with mechanical ventilation.