Citrobacter rodentium possesses a functional type II secretion system necessary for successful host infection.

Infectious diarrheal diseases are the third leading cause of mortality in young children, many of which are driven by Gram-negative bacterial pathogens. To establish successful host infections these pathogens employ a plethora of virulence factors necessary to compete with the resident microbiota, and evade and subvert the host defenses. The type II secretion system (T2SS) is one such conserved molecular machine that allows for the delivery of effector proteins into the extracellular milieu. To explore the role of the T2SS during natural host infection, we used Citrobacter rodentium, a murine enteric pathogen, as a model of human intestinal disease caused by pathogenic Escherichia coli such as Enteropathogenic and Enterohemorrhagic E. coli (EPEC and EHEC). In this study, we determined that the C. rodentium genome encodes one T2SS and 22 potential T2SS-secreted protein effectors, as predicted via sequence homology. We demonstrated that this system was functional in vitro, identifying a role in intestinal mucin degradation allowing for its utilization as a carbon source, and promoting C. rodentium attachment to a mucus-producing colon cell line. During host infection, loss of the T2SS or associated effectors led to a significant colonization defect and lack of systemic spread. In mice susceptible to lethal infection, T2SS-deficient C. rodentium was strongly attenuated, resulting in reduced morbidity and mortality in infected hosts. Together these data highlight the important role of the T2SS and its effector repertoire during C. rodentium pathogenesis, aiding in successful host mucosal colonization.

A novel pathway of levodopa metabolism by commensal Bifidobacteria.

The gold-standard treatment for Parkinson's disease is levodopa (L-DOPA), which is taken orally and absorbed intestinally. L-DOPA must reach the brain intact to exert its clinical effect; peripheral metabolism by host and microbial enzymes is a clinical management issue. The gut microbiota is altered in PD, with one consistent and unexplained observation being an increase in Bifidobacterium abundance among patients. Recently, certain Bifidobacterium species were shown to have the ability to metabolize L-tyrosine, an L-DOPA structural analog. Using both clinical cohort data and in vitro experimentation, we investigated the potential for commensal Bifidobacteria to metabolize this drug. In PD patients, Bifidobacterium abundance was positively correlated with L-DOPA dose and negatively with serum tyrosine concentration. In vitro experiments revealed that certain species, including B. bifidum, B. breve, and B. longum, were able to metabolize this drug via deamination followed by reduction to the compound 3,4-dihydroxyphenyl lactic acid (DHPLA) using existing tyrosine-metabolising genes. DHPLA appears to be a waste product generated during regeneration of NAD +. This metabolism occurs at low levels in rich medium, but is significantly upregulated in nutrient-limited minimal medium. Discovery of this novel metabolism of L-DOPA to DHPLA by a common commensal may help inform medication management in PD.

Interactions between epiphytes during canopy soil formation: an experiment in a lower montane cloud forest of southeast Mexico.

In several montane forests around the world, epiphytes coexist in mats, sharing the rhizosphere and forming histosol-type soils rich in nutrients. The role of these epiphytes in the formation of canopy soil and the fitness costs that epiphytes face when cohabiting in these mats are unknown. In a lower montane cloud forest in central Veracruz, Mexico, a 2-year factorial experiment was carried out with the presence/absence of ramets of Phlebodium areolatum (Polypodiaceae), Tillandsia kirchhoffiana, T. multicaulis and T. punctulata (Bromeliaceae). We examined (i) which epiphyte species contribute to the formation of canopy soil, (ii) the role of epiphyte composition in the soil nutrient composition, and (iii) the fitness costs faced by epiphytes when cohabiting. Canopy soil formation highest when P. areolatum is present. Soil nutrient content does not change with epiphyte composition, is influenced by the microbiota, and P content decreases with the presence of epiphytes. The fitness costs show that the species compete, decreasing their survival and growth, but the competitive capacity differs between the species. We conclude that P. areolatum is an ecosystem engineer that promotes the creation of canopy soil but is a poor competitor. The results coincide with the model of succession by facilitation. Canopy soil is a slow-created component whose nutrient content does not depend on the epiphytic flora. In epiphyte mats, the dominant interactions are competitive, but there is also facilitation.

Controlling Fragmentation of the Acetylene Cation in the Vacuum Ultraviolet via Transient Molecular Alignment.

An open-loop control scheme of molecular fragmentation based on transient molecular alignment combined with single-photon ionization induced by a short-wavelength free electron laser (FEL) is demonstrated for the acetylene cation. Photoelectron spectra are recorded, complementing the ion yield measurements, to demonstrate that such control is the consequence of changes in the electronic response with molecular orientation relative to the ionizing field. We show that stable C2H2+ cations are mainly produced when the molecules are parallel or nearly parallel to the FEL polarization, while the hydrogen fragmentation channel (C2H2+ → C2H+ + H) predominates when the molecule is perpendicular to that direction, thus allowing one to distinguish between the two photochemical processes. The experimental findings are supported by state-of-the art theoretical calculations.

Performance of the SolWat system operating in static mode vs. dynamic for wastewater treatment: Power generation and obtaining reclaimed water.

Two hybrid SolWat systems operating in static (without flow circulation) versus dynamic (with flow circulation) mode were simultaneously compared. This work aims to demonstrate the viability of SolWat in dynamic mode to: a) adapt to the operation of the WWTP with a continuous flow, in which the wastewater flows continuously for treatment, b) treat a larger volume of water in the system and c) increase the cooling of the PV modules thanks to the cooling of the temperature of the water sample to improve the energy efficiency in the system. Real secondary wastewater effluents from wastewater treatment plants were used, using solar energy for water disinfection and photovoltaic energy production, in order to use the SolWat systems and implement it as a tertiary treatment. A total of five experiments were performed during autumn, winter, spring and summer. Solar disinfection of Escherichia coli, Enterococcus faecalis and Clostridium perfringens was assessed, and physicochemical parameters were also analysed. The UV dose received by the SolWat systems was the same, but not for the microorganisms in the water sample. The static SolWat irradiated a particle (microorganism) for 4 h, while the dynamic SolWat irradiated intermittently, so the latter system received a shorter UV exposure time, and therefore a lower UV dose. Results indicated that, although the microorganisms did not obtain the absolute bacterial inactivation during the SODIS treatment in any SolWat system, adequate inactivation levels were achieved to allow the reuse of the water for various uses (Royal Decree 1620/2007, Regulation (EU) 2020/741), although to a lesser extent for SolWat in dynamic mode, which treated twice the volume of water and reached cooler temperatures. C. perfringens proved to be the most resistant bacterium tested. The total photovoltaic energy production in the dynamic mode system was more energy efficient than the static mode, being even more efficient than the single PV reference system during the spring (3.5%) and summer (2.7%) test, due to the compensating effect by the cooling of the water on the photovoltaic module against the losses caused by radiation.

Effectiveness of family connections intervention for family members of persons with personality disorders in two different formats: Online vs face-to-face.

Introduction: Personality disorders (PD) have a serious impact on the lives of individuals who suffer from them and those around them. It is common for family members to experience high levels of burden, anxiety, and depression, and deterioration in their quality of life. It is curious that few interventions have been developed for family members of people with PD. However, Family Connections (FC) (Hoffman and Fruzzetti, 2005) is the most empirically supported intervention for family members of people with Borderline Personality Disorder (BPD). Aim: The aim of this study is to explore the effectiveness of online vs face-to-face FC. Given the current social constraints resulting from SARS-CoV-2, interventions have been delivered online and modified. Method: This was a non-randomized pilot study with a pre-post evaluation and two conditions: The sample consisted of 45 family members distributed in two conditions: FC face-to-face (20) performed by groups before the pandemic, and FC online (25), performed by groups during the pandemic. All participants completed the evaluation protocol before and after the intervention. Results: There is a statistically significant improvement in levels of burden (η 2 = 0.471), depression, anxiety, and stress (η 2 = 0.279), family empowerment (η 2 = 0.243), family functioning (η 2 = 0.345), and quality of life (µ2 η 2 = 0.237). There were no differences based on the application format burden (η 2 = 0.134); depression, anxiety, and stress (η 2 = 0.087); family empowerment (η 2 = 0,27), family functioning (η 2 = 0.219); and quality of life (η 2 = 0.006), respectively). Conclusions: This study provides relevant data about the possibility of implementing an intervention in a sample of family members of people with PD in an online format without losing its effectiveness. During the pandemic, and despite the initial reluctance of family members and the therapists to carry out the interventions online, this work shows the effectiveness of the results and the satisfaction of the family members. These results are particularly relevant in a pandemic context, where there was no possibility of providing help in other ways. All of this represents a great step forward in terms of providing psychological treatment.

Attosecond photoionisation time delays reveal the anisotropy of the molecular potential in the recoil frame.

Photoionisation time delays carry structural and dynamical information on the target system, including electronic correlation effects in atoms and molecules and electron transport properties at interfaces. In molecules, the electrostatic potential experienced by an outgoing electron depends on the emission direction, which should thus lead to anisotropic time delays. To isolate this effect, information on the orientation of the molecule at the photoionisation instant is required. Here we show how attosecond time delays reflect the anisotropic molecular potential landscape in CF4 molecules. The variations in the measured delays can be directly related to the different heights of the potential barriers that the outgoing electrons see in the vicinity of shape resonances. Our results indicate the possibility to investigate the spatial characteristics of the molecular potential by mapping attosecond photoionisation time delays in the recoil-frame.

Deactivating environmental strains of Escherichia coli, Enterococcus faecalis and Clostridium perfringens from a real wastewater effluent using UV-LEDs.

Environmental bacteria strains are known to be more resistant but studies on UV-LEDs are scarce, especially for Clostridium perfringens and Enterococcus faecalis. UV-LEDs of different wavelengths (268 nm, 279 nm and 307 nm) have been used for treating real wastewater from the effluent of the municipal plant in Linares (Spain), with real organic matter content, for E. coli, Enterococcus faecalis and Clostridium perfringens disinfection. Experimental results demonstrate that 268 nm was the most effective wavelength for inactivation of the three different bacteria strains: E. coli showed an inactivation rate of 0.561 at 268 nm vs. 0.245 at 279 nm and 0.0029 for 307 nm; E. faecalis inactivation rate was 0.313 at 268 nm, 0.231 at 279 nm and 0.0023 at 307 nm; and C. perfringens inactivation rate was 0.084 at 268 nm, 0.033 at 279 nm and 6.9e-4 at 307 nm. In general, 307 nm wavelength showed a significantly lower inactivation rate so it would not be recommended for practical applications. C. Perfringens required higher UV doses and longer times to achieve complete inactivation.

Efecto del ácido alfa lipoico sobre la peroxidación no enzimática en mitocondrias de corazón y cerebro de rata / Effect of alpha-lipoic acid against non-enzymatic peroxidation of rat heart and brain mitochondria

RESUMEN El ácido alfa lipoico (AAL) ha sido caracterizado como un antioxidante eficiente. Se ha propuesto como un agente terapéutico potencial en el tratamiento o prevención de diferentes alteraciones que pueden estar relacionadas con un desequilibrio del estado celular oxidoreductor. El objetivo de este trabajo fue analizar la sensibilidad a la peroxidación no enzimática (PNE) (ascorbato-Fe++ dependiente) en mitocondrias de corazón y cerebro de ratas incubadas con una solución de AAL. La PNE fue evaluada por el método de quimioluminiscencia (QL). Cuando se compararon las muestras control (sin el agregado del ascorbato-Fe++) con las muestras ascorbato-Fe++ dependientes, se observó un incremento significativo en la emisión lumínica. Simultáneamente, se incubaron las mitocondrias de ambos órganos con diferentes concentraciones de AAL (0,05, 0,15 y 0,25 mg/ml) observándose una protección diferencial. Las mitocondrias de cerebro de rata incubadas con dosis de 0,15 y 0,25 mg/ml de AAL fueron protegidas de los efectos de la PNE, mientras que, en las mitocondrias cardíacas, solo se observó protección con la dosis más alta de AAL (0,25 mg/ml). El análisis de QL indicó que las mitocondrias de cerebro fueron protegidas de manera más eficiente que las mitocondrias de corazón de rata. En este último caso, será necesario probar nuevas dosis de AAL para demostrar los efectos en estas membranas. En conclusión, AAL actuó como un antioxidante protector de las membranas de ambos órganos contra el daño peroxidativo.

ABSTRACT Alphalipoc acid (ALA) has been characterized as an efficient antioxidant. It has been proposed as a potential therapeutic agent in the treatment or prevention of different pathologies that may be related to an imbalance of the oxido reductive cell state. The objective of this work was to analyze the sensitivity to non-enzymatic peroxidation (NEP) (ascorbate-Fe++ dependent) in heart and brain mitochondria of rats incubated with an ALA solution. NEP was evaluated by the chemiluminescence method (CL). When the control samples (without the addition of ascorbate-Fe++) were compared with the ascorbate-Fe++ dependent samples, a significant increase in the light emission. Simultaneously, the mitochondria of both organs were incubated with different concentrations of ALA (0.05, 0,15 and 0,25 mg/ml), observing a differential protection. Rat brain mitochondria incubated with doses of 0.15 and 0,25 mg/ml of ALA were protected from the effects of NEP, while in cardiac mitochondria, protection was only observed with the highest dose of ALA (0,25 mg/ml). The CL analysis indicated that rat brain mitochondria were protected more efficiently than rat heart mitochondria. In the latter case, it will be necessary to test new doses of ALA to demonstrate the effects on these membranes. In conclusion, ALA acted as a protective antioxidant of the membranes of both organs against peroxidative damage.

Structural and Cellular Insights into the l,d-Transpeptidase YcbB as a Therapeutic Target in Citrobacter rodentium, Salmonella Typhimurium, and Salmonella Typhi Infections.

The bacterial cell wall plays a key role in viability and is an important drug target. The cell wall is made of elongated polymers that are cross-linked to one another to form a load-bearing mesh. An alternative cell wall cross-linking mechanism used by the l,d-transpeptidase YcbB has been implicated in the stress-regulated roles of ß-lactam resistance, outer membrane defect rescue, and typhoid toxin release. The role for this stress-linked cross-linking in the context of a host infection was unclear. Here, we resolve the crystallographic structures of both Salmonella Typhi YcbB and Citrobacter rodentium YcbB acylated with ertapenem that delineate the conserved structural characteristics of YcbB. In parallel, we show that the general involvement of YcbB in peptidoglycan reinforcement under conditions of bacterial outer envelope stress does not play a significant role in acute infections of mice by C. rodentium and S Typhimurium. Cumulatively, in this work we provide a foundation for the development of novel YcbB-specific antibacterial therapeutics to assist in treatment of increasingly drug-resistant S Typhi infections.

Promotion of mental health in young adults via mobile phone app: study protocol of the ECoWeB (emotional competence for well-being in Young adults) cohort multiple randomised trials.

BACKGROUND: Promoting well-being and preventing poor mental health in young people is a major global priority. Building emotional competence (EC) skills via a mobile app may be an effective, scalable and acceptable way to do this. However, few large-scale controlled trials have examined the efficacy of mobile apps in promoting mental health in young people; none have tailored the app to individual profiles. METHOD/DESIGN: The Emotional Competence for Well-Being in Young Adults cohort multiple randomised controlled trial (cmRCT) involves a longitudinal prospective cohort to examine well-being, mental health and EC in 16-22 year olds across 12 months. Within the cohort, eligible participants are entered to either the PREVENT trial (if selected EC scores at baseline within worst-performing quartile) or to the PROMOTE trial (if selected EC scores not within worst-performing quartile). In both trials, participants are randomised (i) to continue with usual practice, repeated assessments and a self-monitoring app; (ii) to additionally receive generic cognitive-behavioural therapy self-help in app; (iii) to additionally receive personalised EC self-help in app. In total, 2142 participants aged 16 to 22 years, with no current or past history of major depression, bipolar disorder or psychosis will be recruited across UK, Germany, Spain, and Belgium. Assessments take place at baseline (pre-randomisation), 1, 3 and 12 months post-randomisation. Primary endpoint and outcome for PREVENT is level of depression symptoms on the Patient Health Questionnaire-9 at 3 months; primary endpoint and outcome for PROMOTE is emotional well-being assessed on the Warwick-Edinburgh Mental Wellbeing Scale at 3 months. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and cost-effectiveness are secondary outcomes. Compliance, adverse events and potentially mediating variables will be carefully monitored. CONCLUSIONS: The trial aims to provide a better understanding of the causal role of learning EC skills using interventions delivered via mobile phone apps with respect to promoting well-being and preventing poor mental health in young people. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective Mobile-health public health strategies for preventing poor mental health and promoting well-being. TRIAL REGISTRATION: ClinicalTrials.gov ( www.clinicaltrials.org ). Number of identification: NCT04148508 November 2019.

Attosecond timing of electron emission from a molecular shape resonance.

Shape resonances in physics and chemistry arise from the spatial confinement of a particle by a potential barrier. In molecular photoionization, these barriers prevent the electron from escaping instantaneously, so that nuclei may move and modify the potential, thereby affecting the ionization process. By using an attosecond two-color interferometric approach in combination with high spectral resolution, we have captured the changes induced by the nuclear motion on the centrifugal barrier that sustains the well-known shape resonance in valence-ionized N2. We show that despite the nuclear motion altering the bond length by only 2%, which leads to tiny changes in the potential barrier, the corresponding change in the ionization time can be as large as 200 attoseconds. This result poses limits to the concept of instantaneous electronic transitions in molecules, which is at the basis of the Franck-Condon principle of molecular spectroscopy.

Epiphyte associations and canopy soil volume: nutrient capital and factors influencing soil retention in the canopy.

Canopy soil (CS) volume reflect epiphyte community maturity, but little is known about the factors that retain CS or species succession within it. Humus fern species (e.g. Phlebodium areolatum) appear capable of retaining CS. In ten Quercus spp. we sampled 987 epiphyte mats to examine the role of the common epiphyte species and crown traits determining CS volume, in order to infer successional stages and identify pioneer and late successional species. Branch traits (height, diameter and slope), CS volume and cover of the epiphyte species were determined for each mat. Nutrient content was determined in CS random samples of 12 epiphyte associations and sizes (one sample from each size quintile). A total of 60% of the mats lack CS. Cover of P. areolatum was the main variable explaining CS volume, and this species was present in 46.8% of those with CS. Epiphyte composition was highly variable, but pioneer (species appearing in monospecific mats, without CS) and late successional species could be identified. Canopy soil nutrient content was similar among the associations of epiphytes. Magnesium, Ca and pH decreased with CS volume, while P and N increased. Phlebodium areolatum is associated with high CS volumes and could act as a key species in its retention. Monospecific mats of pioneer species lack CS or have low volumes, while CS is much higher in mats with late successional species, but the mechanisms of CS formation and nutrient retention in response to interactions between epiphyte species remain to be tested.

Sulforaphane protects from myocardial ischemia-reperfusion damage through the balanced activation of Nrf2/AhR.

The activation of the transcription factor Nrf2 and the consequent increment in the antioxidant response might be a powerful strategy to contend against reperfusion damage. In this study we compared the effectiveness between sulforaphane (SFN), a well known activator of Nrf2 and the mechanical maneuver of post-conditioning (PostC) to confer cardioprotection in an in vivo cardiac ischemia-reperfusion model. We also evaluated if additional mechanisms, besides Nrf2 activation contribute to cardioprotection. Our results showed that SFN exerts an enhanced protective response as compared to PostC. Bot, strategies preserved cardiac function, decreased infarct size, oxidative stress and inflammation, through common protective pathways; however, the aryl hydrocarbon receptor (AhR) also participated in the protection conferred by SFN. Our data suggest that SFN-mediated cardioprotection involves transient Nrf2 activation, followed by phase I enzymes upregulation at the end of reperfusion, as a long-term protection mechanism.

Individual differences and health in chronic pain: are sex-differences relevant?

BACKGROUND: Because psychological variables are known to intercorrelate, the goal of this investigation was to compare the unique association between several well-established psychological constructs in pain research and pain-related outcomes. Sex differences are considered because pain is experienced differently across sex groups. METHODS: Participants were 456 consecutive chronic pain patients attending a tertiary pain clinic (mean age = 58.4 years, SD = 14.8, 63.6% women). The study design was cross-sectional. Psychological constructs included personality (NEO-Five Factor Inventory), irrational thinking (General Attitudes and Beliefs Scale), and coping (Social Problem Solving Inventory). Outcomes were pain severity and interference (Brief Pain Inventory) and physical, general, and mental health status (Short Form-36). To decide whether the bivariate analyses and the two-block, multivariate linear regressions for each study outcome (block 1 = age, sex, and pain severity; block 2 = psychological variables) should be conducted with the whole sample or split by sex, we first explored whether sex moderated the relationship between psychological variables and outcomes. An alpha level of 0.001 was set to reduce the risk of type I errors due to multiple comparisons. RESULTS: The moderation analyses indicated no sex differences in the association between psychological variables and study outcomes (all interaction terms p > .05). Thus, further analyses were calculated with the whole sample. Specifically, the bivariate analyses revealed that psychological constructs were intercorrelated in the expected direction and mostly correlated with mental health and overall perceived health status. In the regressions, when controlling for age, sex, and pain severity, psychological factors as a block significantly increased the explained variance of physical functioning (ΔR2 = .037, p < .001), general health (ΔR2 = .138, p < .001), and mental health (ΔR2 = .362, p < .001). However, unique associations were only obtained for mental health and neuroticism (ß = - 0.30, p < .001) and a negative problem orientation (ß = - 0.26, p < .001). CONCLUSIONS: There is redundancy in the relationship between psychological variables and pain-related outcomes and the strength of this association is highest for mental health status. The association between psychological characteristics and health outcomes was comparable for men and women, which suggests that the same therapeutic targets could be selected in psychological interventions of pain patients irrespective of sex.

Author Correction: Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

In vitro biofilm formation on different ceramic biomaterial surfaces: Coating with two bactericidal glasses.

OBJECTIVES: To compare biofilm formation on the surface of different ceramic biomaterials to be used in implant dentistry. METHODS: In vitro biofilm formation was investigated from mixtures of standard reference strains of Streptococcus oralis, Veillonella parvula, Actinomyces naeslundii, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Sterile ceramic calcium hydroxyapatite discs (HA) as control, sterile Al2O3/Ce-TZP nanocomposite sandblasted discs (material A1) and sterile Al2O3/Ce-TZP nanocomposite sandblasted discs and coated with two types of antimicrobial glasses (materials A2 and A3) were used. Biofilms were grown on the four surfaces and evaluated after 12, 24, 48 and 72 h of incubation. Biofilms were examined by confocal laser scanning microscopy (CLSM). In addition, counts of live bacterial cells of the target species A. actinomycetemcomitans, F. nucleatum and P. gingivalis were calculated by quantitative polymerase chain reaction (qPCR) combined with propidium monoazide (PMA). For data analysis, bacterial counts were compared with a multivariate general lineal model. RESULTS: Using CLSM, cell vitality decreased in A2 and A3. With qPCR-PMA, significant differences in vitality were observed forA. actinomycetemcomitans in A3 after 48 and 72 h of incubation. With respect to the development of the biofilms, a significant increase in counts on HA and materials A1 and A2 was observed for A. actinomycetemcomitans and F. nucleatum. Conversely, for P. gingivalis, no differences were found for HA and materials A1 and A2. SIGNIFICANCE: Differences in biofilm formation were detected among the different tested materials. The ceramic material A3 has an effect on the vitality of A. actinomycetemcomitans growing in an in vitro biofilm model.

Charge migration in photo-ionized aromatic amino acids.

Attosecond pump-probe spectroscopy is a unique tool for the direct observation of the light-activated electronic motion in molecules and it offers the possibility to capture the first instants of a chemical reaction. Recently, advances in attosecond technology allowed the charge migration processes to be revealed in biochemically relevant molecules. Although this purely electronic process might be key for a future chemistry at the electron time scale, the influence of this ultrafast charge flow on the reactivity of a molecule is still debated. In this work, we exploit extreme ultraviolet attosecond pulses to activate charge migration in two aromatic amino acids, namely phenylalanine and tryptophan. Advanced numerical calculations are performed to interpret the experimental data and to discuss the effects of the nuclear dynamics on the activated quantum coherences. By comparing the experimental results obtained in the two molecules, we show that the presence of different functional groups strongly affects the fragmentation pathways, as well as the charge rearrangement. The observed charge dynamics indeed present peculiar aspects, including characteristic periodicities and decoherence times. Numerical results indicate that, even for a very large molecule such as tryptophan, the quantum coherences can survive the nuclear dynamics for several femtoseconds. These results open new and important perspectives for a deeper understanding of the photo-induced charge dynamics, as a promising tool to control the reactivity of bio-relevant molecules via photo-excitation. This article is part of the theme issue 'Measurement of ultrafast electronic and structural dynamics with X-rays'.

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.