The disordered protein SERF promotes α-Synuclein aggregation through liquid-liquid phase separation.

The aggregation of α-Synuclein (α-Syn) into amyloid fibrils is the hallmark of Parkinson's disease. Under stress or other pathological conditions, the accumulation of α-Syn oligomers is the main contributor to the cytotoxicity. A potential approach for treating Parkinson's disease involves preventing the accumulation of these α-Syn oligomers. In this study, we present a novel mechanism involving a conserved group of disorderly proteins known as small EDRK-rich factor (SERF), which promotes the aggregation of α-Syn through a cophase separation process. Using diverse methods like confocal microscopy, fluorescence recovery after photobleaching assays, solution-state NMR spectroscopy, and Western blot, we determined that the N-terminal domain of SERF1a plays a role in the interactions that occur during cophase separation. Within these droplets, α-Syn undergoes a gradual transformation from solid condensates to amyloid fibrils, while SERF1a is excluded from the condensates and dissolves into the solution. Notably, in vivo experiments show that SERF1a cophase separation with α-Syn significantly reduces the deposition of α-Syn oligomers and decreases its cellular toxicity under stress. These findings suggest that SERF1a accelerates the conversion of α-Syn from highly toxic oligomers to less toxic fibrils through cophase separation, thereby mitigating the biological damage of α-Syn aggregation.

The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation.

While aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with protein segments enriched in negatively charged and hydrophobic, aromatic amino acids. The absence of such segments, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In protein aggregation models in the nematode worm Caenorhabditis elegans, protein aggregation and toxicity were suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that MOAG-4 and SERF2 drive protein aggregation and toxicity by interactions with negatively charged segments in aggregation-prone proteins. Such charge interactions might accelerate primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our study points at charge interactions between cellular modifiers and amyloidogenic proteins as potential targets for interventions to reduce age-related protein toxicity.

A tale of dual functions of SERF family proteins in regulating amyloid formation.

The abnormal aggregation of proteins is a significant pathological hallmark of diseases, such as the amyloid formation associated with fused in sarcoma protein (FUS) in frontotemporal lobar degeneration and amyotrophic lateral sclerosis diseases. Understanding which cellular components and how these components regulate the process of abnormal protein aggregation in living organisms is crucial for the prevention and treatment of neurodegenerative diseases. MOAG-4/SERF is a conserved family of proteins with rich positive charged residues, which was initially identified as an enhancer for the formation of amyloids in C. elegans. Knocking out SERF impedes the amyloid formation of various proteins, including α-synuclein and ß-amyloid, which are linked to Parkinson's and Alzheimer's diseases, respectively. However, recent studies revealed SERF exhibited dual functions, as it could both promote and inhibit the fibril formation of the neurodegenerative disease-related amyloidogenic proteins. The connection between functions and structure basis of SERF in regulating the amyloid formation is still unclear. This review will outline the hallmark proteins in neurodegenerative diseases, summarize the contradictory role of the SERF protein family in promoting and inhibiting the aggregation of neurodegenerative proteins, and finally explore the potential structural basis and functional selectivity of the SERF protein.

Extracting Scalar Couplings From Complex 1H NMR Spectra Using a Simple 2D J-Resolved Sequence.

Measurement of scalar couplings between protons is a very challenging task because of complex multiplet patterns and severe overlapping of these multiplets in congested 1D spectra. Numerous 2D J-resolved sequences now exist that utilize either the Zangger-Sterk or PSYCHE or z-filter elements along with selective refocusing and pure-shift schemes to generate high-resolution phase-sensitive spectra with simple doublets in F 1 $$ {F}_1 $$ dimension. Herein, we present a 2D J-resolved sequence that employs a simple element consisting of hard pulses and inter-pulse delays to generate phase-sensitive spectra. This simple element in combination with selective refocusing eliminates all the undesired components including the intense axial peaks, thus provides clean 2D J-resolved spectra with signals of only two targeted protons with simple doublets in F 1 $$ {F}_1 $$ dimension and full multiplets of target protons in F 2 $$ {F}_2 $$ dimension. This high selectivity thus obviates the need for extra filtering elements and pure-shift acquisition schemes that are integrated into existing sequences to facilitate coupling measurements in overcrowded signals. It is therefore anticipated that this sequence, with the ease of implementation and ability to extract coupling values from highly congested spectra, should turn out an important tool for structural and conformational analyses in chemical and biological studies.

Automated Machine Learning Strategies for Multi-Parameter Optimisation of a Caesium-Based Portable Zero-Field Magnetometer.

Machine learning (ML) is an effective tool to interrogate complex systems to find optimal parameters more efficiently than through manual methods. This efficiency is particularly important for systems with complex dynamics between multiple parameters and a subsequent high number of parameter configurations, where an exhaustive optimisation search would be impractical. Here we present a number of automated machine learning strategies utilised for optimisation of a single-beam caesium (Cs) spin exchange relaxation free (SERF) optically pumped magnetometer (OPM). The sensitivity of the OPM (T/Hz), is optimised through direct measurement of the noise floor, and indirectly through measurement of the on-resonance demodulated gradient (mV/nT) of the zero-field resonance. Both methods provide a viable strategy for the optimisation of sensitivity through effective control of the OPM's operational parameters. Ultimately, this machine learning approach increased the optimal sensitivity from 500 fT/Hz to <109fT/Hz. The flexibility and efficiency of the ML approaches can be utilised to benchmark SERF OPM sensor hardware improvements, such as cell geometry, alkali species and sensor topologies.

Magnetic Source Imaging Using a Pulsed Optically Pumped Magnetometer Array.

We have developed a pulsed optically pumped magnetometer (OPM) array for detecting magnetic field maps originated from an arbitrary current distribution. The presented magnetic source imaging (MSI) system features 24 OPM channels, has a data rate of 500 S/s, a sensitivity of 0.8 p T / H z , and a dynamic range of 72 dB. We have employed our pulsed- OPM MSI system for measuring the magnetic field map of a test coil structure. The coils are moved across the array in an indexed fashion to measure the magnetic field over an area larger than the array. The captured magnetic field maps show excellent agreement with the simulation results. Assuming a 2D current distribution, we have solved the inverse problem, using the measured magnetic field maps, and the reconstructed current distribution image is compared to that of the simulation.

Vector magnetocardiography using compact optically-pumped magnetometers.

Optically pumped magnetometers can provide functionality for bio-magnetic field detection and mapping. This has attracted widespread attention from researchers in the biomedical science field. Magnetocardiography has been proven to be an effective method for examining heart disease. Notably, vector magnetocardiography obtains more spatial information than the conventional method by only taking a component that is perpendicular to the chest surface. In this work, a spin-exchange-relaxation-free (SERF) magnetometer with a compact size of 14 mm × 25 mm × 90 mm was developed. The device has a high sensitivity of 25 fT/ Hz. Meanwhile, in the multichannel working mode, synchronous sensor manipulation and data acquisition can be achieved through our control software without additional data acquisition boards. Since a typical SERF magnetometer only responds to dual-axis magnetic fields, two sensors are orthogonally arranged to form a vector detection channel. Our system consists of seven channels and allows 7 × 9 vector MCG mapping by scanning. High-quality heart vector signals are measured, and P peak, QRS peak, and T peak can be distinguished clearly. To better demonstrate the vectorial information, a vector scatter plot form is also provided. Through a basic bio-electric current model, it demonstrates that triaxial MCG measurements capture a richer spatial current information than traditional uniaxial MCG, offering substantial diagnostic potential for heart diseases and shedding more light on the inversion of cardiac issues.

Backbone 1H, 13C, and 15N chemical shift assignments for human SERF2.

Human small EDRK-rich factor protein SERF2 is a cellular driver of protein amyloid formation, a process that has been linked to neurodegenerative diseases including Alzheimer's and Parkinson's disease. SERF2 is a 59 amino acid protein, highly charged, and well conserved whose structure and physiological function is unclear. SERF family proteins including human SERF2 have shown a tendency to form fuzzy complexes with misfolded proteins such as α-Synuclein which has been linked to Parkinson's disease. SERF family proteins have been recently identified to bind nucleic acids, but the binding mechanism(s) remain enigmatic. Here, using multidimensional solution NMR, we report the 1H, 15N, and 13C chemical shift assignments (~ 86% of backbone resonance assignments) for human SERF2. TALOS-N predicted secondary structure of SERF2 showed three very short helices (3-4 residues long) in the N-terminal region of the protein and a long helix in the C-terminal region spanning residues 37-46 which is consistent with the helical content indicated by circular dichroism spectroscopy. Paramagnetic relaxation enhancement NMR analysis revealed that a short C-terminal region E53-K55 is in the proximity of the N-terminus. Having the backbone assignment of SERF2 allowed us to probe its interaction with α-Synuclein and to identify the residues in SERF2 binding interfaces that likely promote α-Synuclein aggregation.

Amyloid Modifier SERF1a Accelerates Alzheimer's Amyloid-ß Fibrillization and Exacerbates the Cytotoxicity.

Alzheimer's disease (AD) is a devastating, progressive neurodegenerative disease affecting the elderly in the world. The pathological hallmark senile plaques are mainly composed of amyloid-ß (Aß), in which the main isoforms are Aß40 and Aß42. Aß is prone to aggregate and ultimately forms amyloid fibrils in the brains of AD patients. Factors that alter the Aß aggregation process have been considered to be potential targets for treatments of AD. Modifier of aggregation 4 (MOAG-4)/small EDRK-rich factor (SERF) was previously selected from a chemical mutagenesis screen and identified as an amyloid modifier that promotes amyloid aggregation for α-synuclein, huntingtin, and Aß40. The interaction and effect of yeast ScSERF on Aß40 were previously described. Here, we examined the human SERF1a effect on Aß40 and Aß42 fibrillization by the Thioflavin T assay and found that SERF1a accelerated Aß fibrillization in a dose-dependent manner without changing the fibril amount and without incorporation. By Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM), we found that SERF1a altered the secondary structures and the morphology of Aß fibrils. The electrospray ionization mass spectrometry (ESI-MS) and analytical ultracentrifugation (AUC) results showed that SERF1a binds to Aß in a 1:1 stoichiometry. Moreover, the NMR study showed that SERF1a interacts with Aß via its N-terminal region. Cytotoxicity assay demonstrated that SERF1a enhanced toxicity of Aß intermediates, and the effect can be rescued by SERF1a antibody. Overall, our study provides the underlying molecular mechanism for the SERF1a effect on Aß fibrillization and facilitates the therapeutic development of AD.

Binding structures of SERF1a with NT17-polyQ peptides of huntingtin exon 1 revealed by SEC-SWAXS, NMR and molecular simulation.

The aberrant fibrillization of huntingtin exon 1 (Httex1) characterized by an expanded polyglutamine (polyQ) tract is a defining feature of Huntington's disease, a neurodegenerative disorder. Recent investigations underscore the involvement of a small EDRK-rich factor 1a (SERF1a) in promoting Httex1 fibrillization through interactions with its N terminus. By establishing an integrated approach with size-exclusion-column-based small- and wide-angle X-ray scattering (SEC-SWAXS), NMR, and molecular simulations using Rosetta, the analysis here reveals a tight binding of two NT17 fragments of Httex1 (comprising the initial 17 amino acids at the N terminus) to the N-terminal region of SERF1a. In contrast, examination of the complex structure of SERF1a with a coiled NT17-polyQ peptide (33 amino acids in total) indicates sparse contacts of the NT17 and polyQ segments with the N-terminal side of SERF1a. Furthermore, the integrated SEC-SWAXS and molecular-simulation analysis suggests that the coiled NT17 segment can transform into a helical conformation when associated with a polyQ segment exhibiting high helical content. Intriguingly, NT17-polyQ peptides with enhanced secondary structures display diminished interactions with SERF1a. This insight into the conformation-dependent binding of NT17 provides clues to a catalytic association mechanism underlying SERF1a's facilitation of Httext1 fibrillization.

Polymorphism of SERF2, the gene encoding a heat-resistant obscure (Hero) protein with chaperone activity, is a novel link in ischemic stroke.

Background: Ischemic stroke (IS) is one of the most serious cardiovascular events associated with high risk of death or disability. The growing body of evidence highlights molecular chaperones as especially important players in the pathogenesis of the disease. Since six small proteins called "Hero" have been recently identified as a novel class of chaperones we aimed to evaluate whether SNP rs4644832 in SERF2 gene encoding the member of Hero-proteins, is associated with the risk of IS. Methods: A total of 1929 unrelated Russians (861 patients with IS and 1068 healthy individuals) from Central Russia were recruited into the study. Genotyping was done using a probe-based PCR approach. Statistical analysis was carried out in the whole group and stratified by age, gender and smoking status. Results: Analysis of the link between rs4644832 SERF2 and IS showed that G allele is the risk factor of IS only in females (OR=1.29, 95%CI 1.02-1.64, Padj=0.035). In addition, the analysis of associations of rs4644832 SERF2 and IS depending on the smoking status revealed that this genetic variant is associated with an increased risk of IS exclusively in non-smoking individuals (OR=1.26, 95%CI 1.01-1.56, P = 0.041). Discussion: Sex- and smoking interactions between rs4644832 polymorphism and IS may be related to the impact of tobacco components metabolism and sex hormones on SERF2 expression. Conclusion: The present study reveals the novel genetic association between rs4644832 polymorphism and the risk of IS suggesting that SERF2, the part of the protein quality control system, contributes to the pathogenesis of the disease.

SERF, a family of tiny highly conserved, highly charged proteins with enigmatic functions.

Amyloid formation is a misfolding process that has been linked to age-related diseases, including Alzheimer's and Huntington's. Understanding how cellular factors affect this process in vivo is vital in realizing the dream of controlling this insidious process that robs so many people of their humanity. SERF (small EDRK-rich factor) was initially isolated as a factor that accelerated polyglutamine amyloid formation in a C. elegans model. SERF knockouts inhibit amyloid formation of a number of proteins that include huntingtin, α-synuclein and ß-amyloid which are associated with Huntington's, Parkinson's and Alzheimer's disease, respectively, and purified SERF protein speeds their amyloid formation in vitro. SERF proteins are highly conserved, highly charged and conformationally dynamic proteins that form a fuzzy complex with amyloid precursors. They appear to act by specifically accelerating the primary step of amyloid nucleation. Brain-specific SERF knockout mice, though viable, appear to be more prone to deposition of amyloids, and show modified fibril morphology. Whole-body knockouts are perinatally lethal due to an apparently unrelated developmental issue. Recently, it was found that SERF binds RNA and is localized to nucleic acid-rich membraneless compartments. SERF-related sequences are commonly found fused to zinc finger sequences. These results point towards a nucleic acid-binding function. How this function relates to their ability to accelerate amyloid formation is currently obscure. In this review, we discuss the possible biological functions of SERF family proteins in the context of their structural fuzziness, modulation of amyloid pathway, nucleic acid binding and their fusion to folded proteins.

Advances in atomic gyroscopes: a view from inertial navigation applications.

With the rapid development of modern physics, atomic gyroscopes have been demonstrated in recent years. There are two types of atomic gyroscope. The Atomic Interferometer Gyroscope (AIG), which utilizes the atomic interferometer to sense rotation, is an ultra-high precision gyroscope; and the Atomic Spin Gyroscope (ASG), which utilizes atomic spin to sense rotation, features high precision, compact size and the possibility to make a chip-scale one. Recent developments in the atomic gyroscope field have created new ways to obtain high precision gyroscopes which were previously unavailable with mechanical or optical gyroscopes, but there are still lots of problems that need to be overcome to meet the requirements of inertial navigation systems. This paper reviews the basic principles of AIG and ASG, introduces the recent progress in this area, focusing on discussing their technical difficulties for inertial navigation applications, and suggests methods for developing high performance atomic gyroscopes in the near future.

Comparing net returns in the feedlot: Bos Taurus vs. Bos Indicus influenced steers with varying anabolic implant intensity.

There are two main beef cattle breed types: Bos Taurus (BT) and Bos Indicus (BI). Past research has demonstrated various expected differences in growth, temperament, feeding behavior, and carcass characteristics between these breed types when administered varying levels of anabolic implant. However, little is known about the differences in expected economic returns between these cattle types. The objective of this research is to simulate and compare the expected net returns of BT, Angus (AN) steers and BI influenced, Santa Gertrudis (SG) steers, with moderate or high intensity levels of implants relative to a control with no implant. The animal performance and carcass data for this economic analysis was provided from a recent feeding experiment of AN and SG influenced steers. In the experiment, sixty steers were stratified by weight and breed in a 2 × 3 factorial design examining the two different breeds: AN (N = 38) or SG influenced (N = 22), and three implant strategies: no implant (N = 20), a moderate intensity implant protocol (d0 implant: Revalor-G, d56 implant: Revalor-IS, d112 implant: Revalor-S; n=20), or a high intensity implant protocol (d0 implant: Revalor-IS, d56 implant: Revalor-S, d112 implant: Revalor-200; N = 20). The steers performance and carcass data were used together with publicly available price and input costs data in the simulation of net returns per animal for each of the treatment groups. Results demonstrated that both moderate and high intensity implanted BT steers have higher expected net return (US$78.70/hd. and US$75.84/hd., respectively) compared to BI moderate and high intensity implanted steers (US$47.03/hd. and $6.98/hd., respectively). Stochastic efficiency analysis with respect to a function demonstrated when certainty equivalent values are constrained to those ≥US$0, only the moderate implanted BT steers would be included in the efficient set.

Study on the Magnetic Noise Characteristics of Amorphous and Nanocrystalline Inner Magnetic Shield Layers of SERF Co-Magnetometer.

With the widespread use of magneto-sensitive elements, magnetic shields are an important part of electronic equipment, ultra-sensitive atomic sensors, and in basic physics experiments. Particularly in Spin-exchange relaxation-free (SERF) co-magnetometers, the magnetic shield is an important component for maintaining the SERF state. However, the inherent noise of magnetic shield materials is an important factor limiting the measurement sensitivity and accuracy of SERF co-magnetometers. In this paper, both amorphous and nanocrystalline materials were designed and applied as the innermost magnetic shield of an SERF co-magnetometer. Magnetic noise characteristics of different amorphous and nanocrystalline materials used as the internal magnetic shielding layer of the magnetic shielding system were analyzed. In addition, the effects on magnetic noise due to adding aluminum to amorphous and nanocrystalline materials were studied. The experimental results show that compared with an amorphous material, a nanocrystalline material as the inner magnetic shield layer can effectively reduce the magnetic noise and improve the sensitivity and precision of the rotation measurement. Nanocrystalline material is very promising for inner shield composition in SERF co-magnetometers. Furthermore, its ultra-thin structure and low cost have significant application value in the miniaturization of SERF co-magnetometers.

Analysis and Suppression of Thermal Magnetic Noise of Ferrite in the SERF Co-Magnetometer.

The ferrite magnetic shield is widely used in ultra-high-sensitivity atomic sensors because of its low noise characteristics. However, its noise level varies with temperature and affects the performance of the spin-exchange relaxation-free (SERF) co-magnetometer. Therefore, it is necessary to analyze and suppress the thermal magnetic noise. In this paper, the thermal magnetic noise model of a ferrite magnetic shield is established, and the thermal magnetic noise of ferrite is calculated more accurately by testing the low-frequency complex permeability at different temperatures. A temperature suppression method based on the improved heat dissipation efficiency of the ferrite magnetic shield is also proposed. The magnetic noise of the ferrite is reduced by 46.7%. The experiment is basically consistent with the theory. The sensitivity of the co-magnetometer is decreased significantly, from 1.21 × 10-5°/s/Hz1/2 to 7.02 × 10-6°/s/Hz1/2 at 1 Hz. The experimental results demonstrate the effectiveness of the proposed method. In addition, the study is also helpful for evaluating the thermal magnetic noise of other materials.

Analysis and Measurement of Differential-Mode Magnetic Noise in Mn-Zn Soft Ferrite Shield for Ultra-Sensitive Sensors.

The magnetic noise generated by the ferrite magnetic shield affects the performance of ultra-sensitive atomic sensors. Differential measurement can effectively suppress the influence of common-mode (CM) magnetic noise, but the limit of suppression capability is not clear at present. In this paper, a finite element analysis model using power loss to calculate differential-mode (DM) magnetic noise under a ferrite magnetic shield is proposed. The experimental results confirm the feasibility of the model. An ultrahigh-sensitive magnetometer was built, the single channel magnetic noise measured and the differential-mode (DM) magnetic noise are 0.70 fT/Hz1/2 and 0.10 fT/Hz1/2 @30 Hz. The DM magnetic noise calculated by the proposed model is less than 5% different from the actual measured value. To effectively reduce DM magnetic noise, we analyze and optimize the structure parameters of the shield on the DM magnetic noise. When the outer diameter is fixed, the model is used to analyze the influence of the ratio of ferrite magnetic shielding thickness to outer diameter, the ratio of length to outer diameter, and the air gap between magnetic annuli on DM magnetic noise. The results show that the axial DM magnetic noise and radial DM magnetic noise reach the optimal values when the thickness to outer diameter ratio is 0.08 and 0.1. The ratio of length to outer diameter is negatively correlated with DM magnetic noise, and the air gap (0.1-1 mm) is independent of DM magnetic noise. The axial DM magnetic noise is less than that of radial DM magnetic noise. These results are useful for suppressing magnetic noise and breaking through the sensitivity of the magnetometer.

Impact of using genotyping to predict SERF negative phenotype in Thai blood donor populations.

BACKGROUND: SERF(+) is a high prevalence antigen in the Cromer blood group system that is encoded by a CROM*01.12 allele. The SERF(-) on red cells is caused by a single nucleotide variation, c.647C＞T, in exon 5 of the Decay-accelerating factor, DAF gene. Alloanti-SERF was found in a pregnant Thai woman, and a SERF(-) individual was found among Thai blood donors. Since anti-SERF is commercially unavailable, this study aimed to develop appropriate genotyping methods for CROM*01.12 and CROM*01.-12 alleles and predict the SERF(-) phenotype in Thai blood donors. METHODS: DNA samples obtained from 1,580 central, 300 northern, and 427 southern Thai blood donors were genotyped for CROM*01.12 and CROM*01.-12 allele detection using in-house PCR with sequence-specific primer (PCR-SSP) confirmed by DNA sequencing. RESULTS: Validity of the PCR-SSP genotyping results agreed with DNA sequencing; CROM*01.12/ CROM*01.12 was the most common (98.42%, 98.00%, and 98.59%), followed by CROM*01.12/CROM*01.-12 (1.58%, 2.00%, and 1.41%) among central, northern, and southern Thais, respectively. CROM*01.-12/CROM*01.-12 was not detected in all three populations. The alleles found in central Thais did not significantly differ from those found in northern and southern Thais. CONCLUSION: This study is the first to distinguish the predicted SERF phenotypes from genotyping results obtained using in-house PCR-SSP, confirming that the CROM*01.-12 allele frequency ranged from 0.007 to 0.010 in three Thai populations. This helps identify the SERF(-) phenotype among donors and patients, ultimately preventing adverse transfusion reactions.

Structural Fuzziness of the RNA-Organizing Protein SERF Determines a Toxic Gain-of-interaction.

The mechanisms by which protein complexes convert from functional to pathogenic are the subject of intensive research. Here, we report how functionally unfavorable protein interactions can be induced by structural fuzziness, i.e., by persisting conformational disorder in protein complexes. We show that extreme disorder in the bound state transforms the intrinsically disordered protein SERF1a from an RNA-organizing factor into a pathogenic enhancer of alpha-synuclein (aSyn) amyloid toxicity. We demonstrate that SERF1a promotes the incorporation of RNA into nucleoli and liquid-like artificial RNA-organelles by retaining an unusually high degree of conformational disorder in the RNA-bound state. However, this type of structural fuzziness also determines an undifferentiated interaction with aSyn. RNA and aSyn both bind to one identical, positively charged site of SERF1a by an analogous electrostatic binding mode, with similar binding affinities, and without any observable disorder-to-order transition. The absence of primary or secondary structure discriminants results in SERF1a being unable to select between nucleic acid and amyloidogenic protein, leading the pro-amyloid aSyn:SERF1a interaction to prevail in the cytosol under conditions of cellular stress. We suggest that fuzzy disorder in SERF1a complexes accounts for an adverse gain-of-interaction which favors toxic binding to aSyn at the expense of nontoxic RNA binding, thereby leading to a functionally distorted and pathogenic process. Thus, structural fuzziness constitutes a direct link between extreme conformational flexibility, amyloid aggregation, and the malfunctioning of RNA-associated cellular processes, three signatures of neurodegenerative proteinopathies.

Practical Bioethics for the Humanitarian Surgeon: The Development, Implementation and Assessment of an Ethics Curriculum for Residents Participating in Humanitarian Missions.

BACKGROUND: Humanitarian surgeons face many ethical challenges. Despite increasing resident participation during humanitarian activities, minimal literature exists describing premission ethics training. METHODS: A systematic literature review was conducted to identify publications on humanitarian surgery. A 3-tiered review was performed assessing for ethical conflicts and guidelines. A Humanitarian Ethics Curriculum (HEC) was developed based on these findings and administered to residents prior to a humanitarian mission. Postmission essays were assigned to describe an ethical dilemma they encountered. The HEC's value was evaluated by identifying the ACGME core competencies represented in the essays. RESULTS: 49 eligible publications were identified. Several areas of consensus were found. Controversies identified included: trainee involvement, surgical innovation, and operating on patients with dismal prognosis. All residents stated that the HEC was vital. 61% of ethical dilemmas involved surgical patients. Core competencies emphasized included systems-based practice, patient care, professionalism, interpersonal/communication skills, and medical knowledge. CONCLUSIONS: There is consensus regarding ethical principles that surgeons should follow during humanitarian activities. However, areas of controversy persist. Premission HEC should be administered to residents participating in humanitarian missions.