Engineered nanoparticles enable deep proteomics studies at scale by leveraging tunable nano-bio interactions.

SignificanceDeep profiling of the plasma proteome at scale has been a challenge for traditional approaches. We achieve superior performance across the dimensions of precision, depth, and throughput using a panel of surface-functionalized superparamagnetic nanoparticles in comparison to conventional workflows for deep proteomics interrogation. Our automated workflow leverages competitive nanoparticle-protein binding equilibria that quantitatively compress the large dynamic range of proteomes to an accessible scale. Using machine learning, we dissect the contribution of individual physicochemical properties of nanoparticles to the composition of protein coronas. Our results suggest that nanoparticle functionalization can be tailored to protein sets. This work demonstrates the feasibility of deep, precise, unbiased plasma proteomics at a scale compatible with large-scale genomics enabling multiomic studies.

Outcomes of male patients with HR+/HER2- advanced breast cancer receiving palbociclib in the real-world POLARIS study.

PURPOSE: Data on treatments for male breast cancer patients are limited owing to rarity and underrepresentation in clinical trials. The real-world POLARIS study gathers data on palbociclib use for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in female and male patients. This sub-analysis describes real-world palbociclib treatment patterns, clinical outcomes, and quality of life (QoL) in male patients. METHODS: POLARIS is a prospective, noninterventional, multicenter, real-world study of patients with HR+/HER2- ABC receiving palbociclib. Assessments included medical record reviews, patient QoL questionnaires (European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30), site characteristics questionnaires, and physician treatment selection surveys. Variables included demographics, disease history, global health status/QoL, clinical assessments and adverse events. Analyses were descriptive in nature. For clinical outcomes, real-world tumor responses and progression were determined by physician assessment in routine clinical practice. Real-world progression-free survival (rwPFS) was described using the Kaplan-Meier method. RESULTS: At data cutoff, 15 male patients were enrolled (median age, 66 years). Nine patients received palbociclib as a first-line treatment and 6 as a second-line or later treatment. Patients received a median of 20 cycles of palbociclib. Neutropenia was experienced by 2 patients and grade ≥ 3 adverse events were reported in 11 patients. Global health status/QoL scores remained generally consistent during the study. One patient (6.7%) achieved a complete tumor response, 4 (26.7%) a partial response, and 8 (53.3%) stable disease. Median rwPFS was 19.8 months (95% CI, 7.4-38.0). Median follow-up duration was 24.7 months (95% CI, 20.0-35.7). CONCLUSION: This real-world analysis showed that palbociclib was well tolerated and provides preliminary data on treatment patterns and outcomes with palbociclib in male patients with HR+/HER2- ABC, helping inform the use of palbociclib in this patient subgroup. TRIAL IDENTIFIER: NCT03280303.

Shaping Graphene Superconductivity with Nanometer Precision.

Graphene holds great potential for superconductivity due to its pure 2D nature, the ability to tune its carrier density through electrostatic gating, and its unique, relativistic-like electronic properties. At present, still far from controlling and understanding graphene superconductivity, mainly because the selective introduction of superconducting properties to graphene is experimentally very challenging. Here, a method is developed that enables shaping at will graphene superconductivity through a precise control of graphene-superconductor junctions. The method combines the proximity effect with scanning tunnelling microscope (STM) manipulation capabilities. Pb nano-islands are first grown that locally induce superconductivity in graphene. Using a STM, Pb nano-islands can be selectively displaced, over different types of graphene surfaces, with nanometre scale precision, in any direction, over distances of hundreds of nanometres. This opens an exciting playground where a large number of predefined graphene-superconductor hybrid structures can be investigated with atomic scale precision. To illustrate the potential, a series of experiments are performed, rationalized by the quasi-classical theory of superconductivity, going from the fundamental understanding of superconductor-graphene-superconductor heterostructures to the construction of superconductor nanocorrals, further used as "portable" experimental probes of local magnetic moments in graphene.

Observation of the Nonreciprocal Magnon Hanle Effect.

The precession of magnon pseudospin about the equilibrium pseudofield, the latter capturing the nature of magnonic eigenexcitations in an antiferromagnet, gives rise to the magnon Hanle effect. Its realization via electrically injected and detected spin transport in an antiferromagnetic insulator demonstrates its high potential for devices and as a convenient probe for magnon eigenmodes and the underlying spin interactions in the antiferromagnet. Here, we observe a nonreciprocity in the Hanle signal measured in hematite using two spatially separated platinum electrodes as spin injector or detector. Interchanging their roles was found to alter the detected magnon spin signal. The recorded difference depends on the applied magnetic field and reverses sign when the signal passes its nominal maximum at the so-called compensation field. We explain these observations in terms of a spin transport direction-dependent pseudofield. The latter leads to a nonreciprocity, which is found to be controllable via the applied magnetic field. The observed nonreciprocal response in the readily available hematite films opens interesting opportunities for realizing exotic physics predicted so far only for antiferromagnets with special crystal structures.

Headache related to personal protective equipment in healthcare workers during COVID-19 pandemic in Mexico: baseline and 6-month follow-up.

BACKGROUND AND AIM: Headaches related to the use of personal protective equipment (PPE) could affect performance at work in healthcare personnel. Our aim was to describe the prevalence and risk factors for headaches related to PPE, in the personnel of a specialized coronavirus disease 2019 (COVID-19) tertiary hospital. METHODS: In this cross-sectional survey study, we invited healthcare workers from COVID-19 referral center in Mexico (May 22-June 19, 2020) to answer a standardized structure questionnaire on characteristics of new-onset PPE-related headache or exacerbation of primary headache disorder. Participants were invited regardless of whether they had a current headache to avoid selection bias. This is the primary analysis of these data. RESULTS: Two hundred and sixty-eight subjects were analyzed, 181/268 (67.5%) women, 177/268 (66%) nurses, mean age 28 years. The prevalence of PPE-related headache was 210/268 (78.4%). Independent risk factors were occupation other than physician (OR 1.59, 95% CI 1.20-2.10), age > 30 years (OR 2.54, 95% CI 1.25-5.14), and female sex (OR 3.58, 95% CI 1.86-6.87). In the 6-month follow-up, 13.1% of subjects evolve to chronic headache, with stress as predictive risk factor. CONCLUSION: The frequency of PPE-associated headache is high, and a subgroup could evolve to chronic headache. More studies are necessary to improve the knowledge about this condition.

A comparison of opioid-containing anesthesia versus opioid-free anesthesia using the Cortínez-Sepúlveda model on differential cytokine responses in obese patients undergoing gastric bypass surgery: a randomized controlled trial.

BACKGROUND: Opioid anesthetic agents can modulate the impaired immune response in obese patients through mechanisms that involve the expression and release of cytokines. For this reason, anesthetic care for obese patients remains controversial. Therefore, the aim of the study was to compare the effect of opioid-containing anesthesia (OCA) vs opioid-free anesthesia (OFA) using the Cortínez-Sepúlveda model on IL-6, IL-1ß and TNF-α serum levels before and after surgery in obese patients undergoing bypass surgery. METHODS: This randomized cross-sectional study conducted among 40 unrelated obese adults was performed in the Civil Hospital of Guadalajara "Dr. Juan I. Menchaca". Before undergoing laparoscopic Roux-en-Y gastric bypass, patients were randomly assigned to two anesthesia groups: OCA (n = 20) or OFA (n = 20). Fentanyl was the opioid used in the OCA group. The Cortínez-Sepúlveda pharmacokinetic model was used to characterize the disposition of intravenous propofol for the target-controlled infusion technique in obese patients. Body mass was determined to the nearest 0.05 kg using a balance scale (Seca 703; Seca, Hamburg, Germany). Blood samples were taken before and immediately after surgery and cytokine concentrations were determined by ELISA. Pain was assessed using a numerical pain rating scale. Adverse effects were collected within the first 24 h after surgery. RESULTS: A total of 6 men and 34 women were included (37.9 ± 10.6 years). Pre-surgery IL-6 and TNF-α serum levels were not detected in study subjects. However, IL-1ß levels significantly decreased after surgery (49.58 pg/mL (18.50-112.20)-before surgery vs 13 pg/mL (5.43-22)-after surgery, p = 0.019). IL-6 concentrations were significantly higher in subjects who received OCA (with fentanyl) compared to subjects with OFA (224.5 pg/mL (186.3-262.8) vs 99.5 pg/mL (60.8-138.2), respectively, p < 0.001; adjusted by age, gender, and BMI). In addition, the use of opioids confers an increased risk for higher IL-6 levels in obese patients (OR = 2.95, 95% CI: 1.2-7.2, p = 0.010). A linear regression model showed that the operative time (in hours) of bypass surgery and anesthetic technique were positively correlated with IL-6 levels. CONCLUSION: Anesthesia with opioids correlated positively with IL-6 serum levels in obese patients undergoing bypass surgery. This finding could have clinical relevance when an appropriate anesthetic management plan is selected for bariatric surgical patients. TRIAL REGISTRATION: The study was retrospectively registered at ClinicalTrials.gov Identification Number: NCT04854252, date 22/04/2021.

First evidence of regional migration of the copper shark Carcharhinus brachyurus (Günther, 1870) in the Southwest Atlantic.

Regional migration of the copper shark Carcharhinus brachyurus was recorded for the first time in the Southwest Atlantic (SWA) from Argentina (latitude: -38.1037, longitude: -57.5371) to Brazil (latitude: -20.6833, longitude: -40.2846) as a result of a citizen science tagging project. The recaptured specimen was a female (103 kg weight), with 18 developing embryos within the uterus. The total distance was at least 2566 km, and it is the longest ever recorded for the species. Furthermore, it extends its northern distribution in the SWA.

Radiative heat transfer in the extreme near field.

Radiative transfer of energy at the nanometre length scale is of great importance to a variety of technologies including heat-assisted magnetic recording, near-field thermophotovoltaics and lithography. Although experimental advances have enabled elucidation of near-field radiative heat transfer in gaps as small as 20-30 nanometres (refs 4-6), quantitative analysis in the extreme near field (less than 10 nanometres) has been greatly limited by experimental challenges. Moreover, the results of pioneering measurements differed from theoretical predictions by orders of magnitude. Here we use custom-fabricated scanning probes with embedded thermocouples, in conjunction with new microdevices capable of periodic temperature modulation, to measure radiative heat transfer down to gaps as small as two nanometres. For our experiments we deposited suitably chosen metal or dielectric layers on the scanning probes and microdevices, enabling direct study of extreme near-field radiation between silica-silica, silicon nitride-silicon nitride and gold-gold surfaces to reveal marked, gap-size-dependent enhancements of radiative heat transfer. Furthermore, our state-of-the-art calculations of radiative heat transfer, performed within the theoretical framework of fluctuational electrodynamics, are in excellent agreement with our experimental results, providing unambiguous evidence that confirms the validity of this theory for modelling radiative heat transfer in gaps as small as a few nanometres. This work lays the foundations required for the rational design of novel technologies that leverage nanoscale radiative heat transfer.

Tunneling explains efficient electron transport via protein junctions.

Metalloproteins, proteins containing a transition metal ion cofactor, are electron transfer agents that perform key functions in cells. Inspired by this fact, electron transport across these proteins has been widely studied in solid-state settings, triggering the interest in examining potential use of proteins as building blocks in bioelectronic devices. Here, we report results of low-temperature (10 K) electron transport measurements via monolayer junctions based on the blue copper protein azurin (Az), which strongly suggest quantum tunneling of electrons as the dominant charge transport mechanism. Specifically, we show that, weakening the protein-electrode coupling by introducing a spacer, one can switch the electron transport from off-resonant to resonant tunneling. This is a consequence of reducing the electrode's perturbation of the Cu(II)-localized electronic state, a pattern that has not been observed before in protein-based junctions. Moreover, we identify vibronic features of the Cu(II) coordination sphere in transport characteristics that show directly the active role of the metal ion in resonance tunneling. Our results illustrate how quantum mechanical effects may dominate electron transport via protein-based junctions.

Dynamical Coulomb Blockade as a Local Probe for Quantum Transport.

Quantum fluctuations are imprinted with valuable information about transport processes. Experimental access to this information is possible, but challenging. We introduce the dynamical Coulomb blockade (DCB) as a local probe for fluctuations in a scanning tunneling microscope (STM) and show that it provides information about the conduction channels. In agreement with theoretical predictions, we find that the DCB disappears in a single-channel junction with increasing transmission following the Fano factor, analogous to what happens with shot noise. Furthermore we demonstrate local differences in the DCB expected from changes in the conduction channel configuration. Our experimental results are complemented by ab initio transport calculations that elucidate the microscopic nature of the conduction channels in our atomic-scale contacts. We conclude that probing the DCB by STM provides a technique complementary to shot noise measurements for locally resolving quantum transport characteristics.

Heat dissipation in atomic-scale junctions.

Atomic and single-molecule junctions represent the ultimate limit to the miniaturization of electrical circuits. They are also ideal platforms for testing quantum transport theories that are required to describe charge and energy transfer in novel functional nanometre-scale devices. Recent work has successfully probed electric and thermoelectric phenomena in atomic-scale junctions. However, heat dissipation and transport in atomic-scale devices remain poorly characterized owing to experimental challenges. Here we use custom-fabricated scanning probes with integrated nanoscale thermocouples to investigate heat dissipation in the electrodes of single-molecule ('molecular') junctions. We find that if the junctions have transmission characteristics that are strongly energy dependent, this heat dissipation is asymmetric--that is, unequal between the electrodes--and also dependent on both the bias polarity and the identity of the majority charge carriers (electrons versus holes). In contrast, junctions consisting of only a few gold atoms ('atomic junctions') whose transmission characteristics show weak energy dependence do not exhibit appreciable asymmetry. Our results unambiguously relate the electronic transmission characteristics of atomic-scale junctions to their heat dissipation properties, establishing a framework for understanding heat dissipation in a range of mesoscopic systems where transport is elastic--that is, without exchange of energy in the contact region. We anticipate that the techniques established here will enable the study of Peltier effects at the atomic scale, a field that has been barely explored experimentally despite interesting theoretical predictions. Furthermore, the experimental advances described here are also expected to enable the study of heat transport in atomic and molecular junctions--an important and challenging scientific and technological goal that has remained elusive.

Doping hepta-alanine with tryptophan: A theoretical study of its effect on the electrical conductance of peptide-based single-molecule junctions.

Motivated by a recent experiment [C. Guo et al., Proc. Natl. Acad. Sci. U. S. A. 113, 10785 (2016)], we carry out a theoretical study of electron transport through peptide-based single-molecule junctions. We analyze the pristine hepta-alanine and its functionalizations with a single tryptophan unit, which is placed in three different locations along the backbone. Contrary to expectations from the experiment on self-assembled monolayers, we find that insertion of tryptophan does not raise the electrical conductance and that the resulting peptides instead remain insulating in the framework of a coherent transport picture. The poor performance of these molecules as conductors can be ascribed to the strongly off-resonant transport and low electrode-molecule coupling of the frontier orbitals. Although the introduction of tryptophan increases the energy of the highest occupied molecular orbital (HOMO) of the peptides in the gas phase, the new HOMO states are localized on the tryptophan unit and therefore essentially do not contribute to coherent charge transport.

Nurses' characteristics and practice environments: Comparison between clusters with different attitude and utilisation profiles regarding nursing diagnosis.

AIM: To identify clusters of nurses in relation to the utilisation and attitude towards nursing diagnosis and to compare their profiles considering demographics, professional characteristics and nursing practice environments. BACKGROUND: Nursing diagnosis has benefits for both patients and nurses, and the attitude of nurses towards nursing diagnosis has been proposed as a determinant of its use. Therefore, an adequate understanding of nurses' attitude and utilisation profiles regarding nursing diagnosis is essential for the nursing managers who want to adopt nursing diagnosis as a practice framework. METHODS: A cross-sectional survey design was used. A sample of 239 nurses working in the Catalan primary health care system were categorised into clusters with similar attitude and utilisation profiles, which were compared with each other a posteriori. RESULTS: Nursing managers were grouped into more positive attitude clusters than clinical nurses. Nurses working in supportive nursing practice environments were classified into more positive attitude and higher utilisation clusters. CONCLUSION: The field of work and nursing practice environments were found as differential factors in profiles of nurses with different attitudes towards and/or utilisation of nursing diagnosis. IMPLICATIONS FOR NURSING MANAGEMENT: The promotion of supportive nursing practice environments could enhance the implementation and maintenance of nursing diagnosis as a practice framework in primary health care.

A Solid-State Protein Junction Serves as a Bias-Induced Current Switch.

A sample-type protein monolayer, that can be a stepping stone to practical devices, can behave as an electrically driven switch. This feat is achieved using a redox protein, cytochrome C (CytC), with its heme shielded from direct contact with the solid-state electrodes. Ab initio DFT calculations, carried out on the CytC-Au structure, show that the coupling of the heme, the origin of the protein frontier orbitals, to the electrodes is sufficiently weak to prevent Fermi level pinning. Thus, external bias can bring these orbitals in and out of resonance with the electrode. Using a cytochrome C mutant for direct S-Au bonding, approximately 80 % of the Au-CytC-Au junctions show at greater than 0.5 V bias a clear conductance peak, consistent with resonant tunneling. The on-off change persists up to room temperature, demonstrating reversible, bias-controlled switching of a protein ensemble, which, with its built-in redundancy, provides a realistic path to protein-based bioelectronics.

Ab initio electronic structure calculations of entire blue copper azurins.

We present a theoretical study of the blue-copper azurin extracted from Pseudomonas aeruginosa and several of its single amino acid mutants. For the first time, we consider the whole structure of this kind of protein rather than limiting our analysis to the copper complex only. This is accomplished by combining fully ab initio calculations based on density functional theory with atomic-scale molecular dynamics simulations. Beyond the main features arising from the copper complex, our study reveals the role played by the peripheral parts of the proteins. In particular, we find that oxygen atoms belonging to carboxyl groups which are distributed all over the protein contribute to electronic states near the HOMO. The contribution of the outer regions to the electronic structure of azurins had so far been overlooked. Our results highlight the need to investigate them thoroughly; this is especially important in prospect of understanding complex processes such as the electronic transport through metal-metalloprotein-metal junctions.

Bioengineering a Single-Protein Junction.

Bioelectronics moves toward designing nanoscale electronic platforms that allow in vivo determinations. Such devices require interfacing complex biomolecular moieties as the sensing units to an electronic platform for signal transduction. Inevitably, a systematic design goes through a bottom-up understanding of the structurally related electrical signatures of the biomolecular circuit, which will ultimately lead us to tailor its electrical properties. Toward this aim, we show here the first example of bioengineered charge transport in a single-protein electrical contact. The results reveal that a single point-site mutation at the docking hydrophobic patch of a Cu-azurin causes minor structural distortion of the protein blue Cu site and a dramatic change in the charge transport regime of the single-protein contact, which goes from the classical Cu-mediated two-step transport in this system to a direct coherent tunneling. Our extensive spectroscopic studies and molecular-dynamics simulations show that the proteins' folding structures are preserved in the single-protein junction. The DFT-computed frontier orbital of the relevant protein segments suggests that the Cu center participation in each protein variant accounts for the different observed charge transport behavior. This work is a direct evidence of charge transport control in a protein backbone through external mutagenesis and a unique nanoscale platform to study structurally related biological electron transfer.

A methyl transferase links the circadian clock to the regulation of alternative splicing.

Circadian rhythms allow organisms to time biological processes to the most appropriate phases of the day-night cycle. Post-transcriptional regulation is emerging as an important component of circadian networks, but the molecular mechanisms linking the circadian clock to the control of RNA processing are largely unknown. Here we show that PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5), which transfers methyl groups to arginine residues present in histones and Sm spliceosomal proteins, links the circadian clock to the control of alternative splicing in plants. Mutations in PRMT5 impair several circadian rhythms in Arabidopsis thaliana and this phenotype is caused, at least in part, by a strong alteration in alternative splicing of the core-clock gene PSEUDO RESPONSE REGULATOR 9 (PRR9). Furthermore, genome-wide studies show that PRMT5 contributes to the regulation of many pre-messenger-RNA splicing events, probably by modulating 5'-splice-site recognition. PRMT5 expression shows daily and circadian oscillations, and this contributes to the mediation of the circadian regulation of expression and alternative splicing of a subset of genes. Circadian rhythms in locomotor activity are also disrupted in dart5-1, a mutant affected in the Drosophila melanogaster PRMT5 homologue, and this is associated with alterations in splicing of the core-clock gene period and several clock-associated genes. Our results demonstrate a key role for PRMT5 in the regulation of alternative splicing and indicate that the interplay between the circadian clock and the regulation of alternative splicing by PRMT5 constitutes a common mechanism that helps organisms to synchronize physiological processes with daily changes in environmental conditions.

Quantum thermopower of metallic atomic-size contacts at room temperature.

We report conductance and thermopower measurements of metallic atomic-size contacts, namely gold and platinum, using a scanning tunneling microscope (STM) at room temperature. We find that few-atom gold contacts have an average negative thermopower, whereas platinum contacts present a positive thermopower, showing that for both metals, the sign of the thermopower in the nanoscale differs from that of bulk wires. We also find that the magnitude of the thermopower exhibits minima at the maxima of the conductance histogram in the case of gold nanocontacts while for platinum it presents large fluctuations. Tight-binding calculations and Green's function techniques, together with molecular dynamics simulations, show that these observations can be understood in the context of the Landauer-Büttiker picture of coherent transport in atomic-scale wires. In particular, we show that the differences in the thermopower between these two metals are due to the fact that the elastic transport is dominated by the 6s orbitals in the case of gold and by the 5d orbitals in the case of platinum.

Current rectification in a single molecule diode: the role of electrode coupling.

We demonstrate large rectification ratios (> 100) in single-molecule junctions based on a metal-oxide cluster (polyoxometalate), using a scanning tunneling microscope (STM) both at ambient conditions and at low temperature. These rectification ratios are the largest ever observed in a single-molecule junction, and in addition these junctions sustain current densities larger than 10(5) A cm(-2). By following the variation of the I-V characteristics with tip-molecule separation we demonstrate unambiguously that rectification is due to asymmetric coupling to the electrodes of a molecule with an asymmetric level structure. This mechanism can be implemented in other type of molecular junctions using both organic and inorganic molecules and provides a simple strategy for the rational design of molecular diodes.