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Showing papers by "University of Naples Federico II published in 2015"


Journal ArticleDOI
03 Jun 2015-Thyroid
TL;DR: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC and developed 67 evidence-based recommendations to assist clinicians in the care of Patients with MTC.
Abstract: Introduction: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. Methods: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. Results: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. Conclusions: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendati...

1,504 citations


Journal ArticleDOI
J. Aasi1, J. Abadie1, B. P. Abbott1, Richard J. Abbott1  +884 moreInstitutions (98)
TL;DR: In this paper, the authors review the performance of the LIGO instruments during this epoch, the work done to characterize the detectors and their data, and the effect that transient and continuous noise artefacts have on the sensitivity of the detectors to a variety of astrophysical sources.
Abstract: In 2009–2010, the Laser Interferometer Gravitational-Wave Observatory (LIGO) operated together with international partners Virgo and GEO600 as a network to search for gravitational waves (GWs) of astrophysical origin. The sensitivity of these detectors was limited by a combination of noise sources inherent to the instrumental design and its environment, often localized in time or frequency, that couple into the GW readout. Here we review the performance of the LIGO instruments during this epoch, the work done to characterize the detectors and their data, and the effect that transient and continuous noise artefacts have on the sensitivity of LIGO to a variety of astrophysical sources.

1,266 citations


Journal ArticleDOI
TL;DR: This review aims to summarize the emerging efforts to address current challenges and solutions in the treatment of infectious diseases, particularly the use of nanosilver antimicrobials.
Abstract: Multi-drug resistance is a growing problem in the treatment of infectious diseases and the widespread use of broad-spectrum antibiotics has produced antibiotic resistance for many human bacterial pathogens. Advances in nanotechnology have opened new horizons in nanomedicine, allowing the synthesis of nanoparticles that can be assembled into complex architectures. Novel studies and technologies are devoted to understanding the mechanisms of disease for the design of new drugs, but unfortunately infectious diseases continue to be a major health burden worldwide. Since ancient times, silver was known for its anti-bacterial effects and for centuries it has been used for prevention and control of disparate infections. Currently nanotechnology and nanomaterials are fully integrated in common applications and objects that we use every day. In addition, the silver nanoparticles are attracting much interest because of their potent antibacterial activity. Many studies have also shown an important activity of silver nanoparticles against bacterial biofilms. This review aims to summarize the emerging efforts to address current challenges and solutions in the treatment of infectious diseases, particularly the use of nanosilver antimicrobials.

1,169 citations



Journal ArticleDOI
TL;DR: In this article, a review of the potential of dark fermentation of organic biomasses and its potential in green energy-efficient green chemistry applications is presented, with a brief review on the simulation and modeling of the dark fermentation processes and their energy balance.

711 citations


Journal ArticleDOI
TL;DR: In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera.
Abstract: Background Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. Methods We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. Results The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two g...

649 citations


Journal ArticleDOI
A. Aab1, P. Abreu2, Marco Aglietta3, Marco Aglietta4  +640 moreInstitutions (64)
TL;DR: The Pierre Auger Observatory as mentioned in this paper, the world's largest cosmic ray observatory, has been in successful operation since completion in 2008 and has recorded data from an exposure exceeding 40,000 km$^2$ sr yr.
Abstract: The Pierre Auger Observatory, located on a vast, high plain in western Argentina, is the world's largest cosmic ray observatory. The objectives of the Observatory are to probe the origin and characteristics of cosmic rays above $10^{17}$ eV and to study the interactions of these, the most energetic particles observed in nature. The Auger design features an array of 1660 water-Cherenkov particle detector stations spread over 3000 km$^2$ overlooked by 24 air fluorescence telescopes. In addition, three high elevation fluorescence telescopes overlook a 23.5 km$^2$, 61 detector infill array. The Observatory has been in successful operation since completion in 2008 and has recorded data from an exposure exceeding 40,000 km$^2$ sr yr. This paper describes the design and performance of the detectors, related subsystems and infrastructure that make up the Auger Observatory.

615 citations


Journal ArticleDOI
TL;DR: In this article, the current status of solar photocatalysis and future opportunities for research and industry in this field are identified, including recent relevant relevant bibliography, and an overview of several different solar photoreactors and the main operating process parameters are also provided.
Abstract: In the future, solar energy, along with other renewable resources, could play a key role in mass production of fine chemicals. It could also potentially solve environmental problems, as demonstrated by recent developments in the use of solar energy, such as solar photocatalysis. The solar photocatalytic technology has been demonstrated to be effective for: • Treating groundwater, drinking water, industrial wastewater, and air and soil pollution, • Water disinfection, and • Industrial production of fine chemicals. This report summarizes the current status of solar photocatalysis and identifies future opportunities for research and industry in this field, including recent relevant bibliography. The main commercial solar photocatalytic applications are described, included the technologies based on sunlight for antifogging and self-cleaning of coating materials, glass, and concrete. An overview of several different solar photoreactors and the main operating process parameters are also provided. For the estimation of capital costs, it is suggested the use of appropriate “figures of merit”. The present review would be of interest for researchers, technologists, engineers, and industrialists.

553 citations


Journal ArticleDOI
TL;DR: In this article, the authors define humic substances in a horticultural context and present a general schematic model of plant-humic responses, highlighting the relationship between the chemical properties of humified matter and its bioactivity with specific reference to the promotion of lateral root growth.

547 citations


Journal ArticleDOI
TL;DR: The present review discusses the potential of locusts, grasshoppers, termites, yellow mealworms, Asiatic rhinoceros beetles, superworms, domesticated silkworms, common houseflies, common mosquitoes and black soldier flies for use as fishmeal and/or fish oil replacement in the fish diet.

529 citations


Journal ArticleDOI
Vardan Khachatryan1, Albert M. Sirunyan1, Armen Tumasyan1, Wolfgang Adam2  +2802 moreInstitutions (215)
04 Jun 2015-Nature
TL;DR: In this paper, the branching fractions of the B meson (B-s(0)) and the B-0 meson decaying into two oppositely charged muons (mu(+) and mu(-)) were observed.
Abstract: The standard model of particle physics describes the fundamental particles and their interactions via the strong, electromagnetic and weak forces. It provides precise predictions for measurable quantities that can be tested experimentally. The probabilities, or branching fractions, of the strange B meson (B-s(0)) and the B-0 meson decaying into two oppositely charged muons (mu(+) and mu(-)) are especially interesting because of their sensitivity to theories that extend the standard model. The standard model predicts that the B-s(0)->mu(+)mu(-) and B-0 ->mu(+)mu(-) decays are very rare, with about four of the former occurring for every billion B-s(0) mesons produced, and one of the latter occurring for every ten billion B-0 mesons(1). A difference in the observed branching fractions with respect to the predictions of the standard model would provide a direction in which the standard model should be extended. Before the Large Hadron Collider (LHC) at CERN2 started operating, no evidence for either decay mode had been found. Upper limits on the branching fractions were an order of magnitude above the standard model predictions. The CMS (Compact Muon Solenoid) and LHCb(Large Hadron Collider beauty) collaborations have performed a joint analysis of the data from proton-proton collisions that they collected in 2011 at a centre-of-mass energy of seven teraelectronvolts and in 2012 at eight teraelectronvolts. Here we report the first observation of the B-s(0)->mu(+)mu(-) decay, with a statistical significance exceeding six standard deviations, and the best measurement so far of its branching fraction. Furthermore, we obtained evidence for the B-0 ->mu(+)mu(-) decay with a statistical significance of three standard deviations. Both measurements are statistically compatible with standard model predictions and allow stringent constraints to be placed on theories beyond the standard model. The LHC experiments will resume taking data in 2015, recording proton-proton collisions at a centre-of-mass energy of 13 teraelectronvolts, which will approximately double the production rates of B-s(0) and B-0 mesons and lead to further improvements in the precision of these crucial tests of the standard model.


Journal ArticleDOI
TL;DR: This review gives an up to date overview of the recent advances in the production of quality AMF inocula and in the biostimulant properties of AMF on plant health, nutrition and quality of horticultural crops (fruit trees, vegetables, flower crops and ornamentals).

Journal ArticleDOI
TL;DR: The sensory impact of the VOCs and their dynamics during storage is discussed to highlight their possible contribution to the spoilage of meat.

Journal ArticleDOI
TL;DR: The platooning problem is analyzed and solved by treating it as the problem of achieving consensus in a network of dynamical systems affected by time-varying heterogeneous delays due to wireless communication among vehicles.
Abstract: We analyze and solve the platooning problem by treating it as the problem of achieving consensus in a network of dynamical systems affected by time-varying heterogeneous delays due to wireless communication among vehicles Specifically, a platoon is modeled as a dynamical network where: 1) each vehicle, with its own dynamics, is a node; 2) the presence of communication links between neighboring vehicles is represented by edges; and 3) the structure of the intervehicle communication is encoded in the network topology A distributed control protocol, which acts on every vehicle in the platoon, is derived It is composed of two terms: a local action depending on the state variables of the vehicle itself (measured onboard) and an action depending on the information received from neighboring vehicles through the communication network The stability of the platoon is proven by using Lyapunov–Razumikhin theorem Numerical results are included to confirm and illustrate the theoretical derivation

Journal Article
TL;DR: Data suggest that in the hospital setting, in non–breast-fed infants and young children, lactose-free feeds can be considered in the management of gastroenteritis, and it is best managed using a few simple, well-defined medical interventions.
Abstract: Objectives: These guidelines update and extend evidence-based indications for the management of children with acute gastroenteritis in Europe. Methods: The guideline development group formulated questions, identified data, and formulated recommendations. The latter were graded with the Muir Gray system and, in parallel, with the Grading of Recommendations, Assessment, Development and Evaluations system. Results: Gastroenteritis severity is linked to etiology, and rotavirus is the most severe infectious agent and is frequently associated with dehydration. Dehydration reflects severity and should be monitored by established score systems. Investigations are generally not needed. Oral rehydration with hypoosmolar solution is the major treatment and should start as soon as possible. Breast-feeding should not be interrupted. Regular feeding should continue with no dietary changes including milk. Data suggest that in the hospital setting, in non–breast-fed infants and young children, lactose-free feeds can be considered in the management of gastroenteritis. Active therapy may reduce the duration and severity of diarrhea. Effective interventions include administration of specific probiotics such as Lactobacillus GG or Saccharomyces boulardii, diosmectite or racecadotril. Anti-infectious drugs should be given in exceptional cases. Ondansetron is effective against vomiting, but its routine use requires safety clearance given the warning about severe cardiac effects. Hospitalization should generally be reserved for children requiring enteral/parenteral rehydration; most cases may be managed in an outpatients setting. Enteral rehydration is superior to intravenous rehydration. Ultrarapid schemes of intravenous rehydration are not superior to standard schemes and may be associated with higher readmission rates. Conclusions: Acute gastroenteritis is best managed using a few simple, well-defined medical interventions.

Journal ArticleDOI
TL;DR: In this paper, the authors quantify the ultimate tensile strength and nominal strain at break of printed parts made from polylactic acid (PLA) with a Replicating Rapid prototyper (Rep-Rap) 3D printer, by varying three important process parameters: layer thickness, infill orientation and the number of shell perimeters.
Abstract: Purpose – This study aims to quantify the ultimate tensile strength and the nominal strain at break (ɛf) of printed parts made from polylactic acid (PLA) with a Replicating Rapid prototyper (Rep-Rap) 3D printer, by varying three important process parameters: layer thickness, infill orientation and the number of shell perimeters. Little information is currently available about mechanical properties of parts printed using open-source, low-cost 3D printers. Design/methodology/approach – A computer-aided design model of a tensile test specimen was created, conforming to the ASTM:D638. Experiments were designed, based on a central composite design. A set of 60 specimens, obtained from combinations of selected parameters, was printed on a Rep-Rap Prusa I3 in PLA. Testing was performed using a JJ Instruments – T5002-type tensile testing machine and the load was measured using a load cell of 1,100 N. Findings – This study investigated the main impact of each process parameter on mechanical properties and the effe...

Journal ArticleDOI
TL;DR: In this article, the spin-parity and tensor structure of the interactions of the recently discovered Higgs boson is performed using the H to ZZ, Z gamma*, gamma* gamma* to 4 l, H to WW to l nu l nu, and H to gamma gamma decay modes.
Abstract: The study of the spin-parity and tensor structure of the interactions of the recently discovered Higgs boson is performed using the H to ZZ, Z gamma*, gamma* gamma* to 4 l, H to WW to l nu l nu, and H to gamma gamma decay modes. The full dataset recorded by the CMS experiment during the LHC Run 1 is used, corresponding to an integrated luminosity of up to 5.1 inverse femtobarns at a center-of-mass energy of 7 TeV and up to 19.7 inverse femtobarns at 8 TeV. A wide range of spin-two models is excluded at a 99% confidence level or higher, or at a 99.87% confidence level for the minimal gravity-like couplings, regardless of whether assumptions are made on the production mechanism. Any mixed-parity spin-one state is excluded in the ZZ and WW modes at a greater than 99.999% confidence level. Under the hypothesis that the resonance is a spin-zero boson, the tensor structure of the interactions of the Higgs boson with two vector bosons ZZ, Z gamma, gamma gamma, and WW is investigated and limits on eleven anomalous contributions are set. Tighter constraints on anomalous HVV interactions are obtained by combining the HZZ and HWW measurements. All observations are consistent with the expectations for the standard model Higgs boson with the quantum numbers J[PC]=0[++].

Journal ArticleDOI
TL;DR: This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB

Journal ArticleDOI
TL;DR: Several studies have demonstrated that REE, like a number of other xenobiotics, follow hormetic concentration-related trends, implying stimulatory or protective effects at low levels, then adverse effects at higher concentrations, and another major role for REE-associated effects should be focused on pH-dependent REE speciation and hence toxicity.

Journal ArticleDOI
TL;DR: This definition, while representing a substantial progress with respect to moving away from the conceptualization of mental health as a state of absence of mental illness, raises several concerns and lends itself to potential misunderstandings when it identifies positive feelings and positive functioning as key factors for mental health.

Journal ArticleDOI
TL;DR: It was found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo.
Abstract: BackgroundCrohn’s disease–related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. MethodsIn a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn’s disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn’s Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. ResultsThe proportions of patients who reached the prim...

Journal ArticleDOI
TL;DR: In this article, the authors used long-term δ13C tree-ring measurements across a European forest network to reconstruct the physiologically driven response of intercellular CO2 caused by atmospheric CO2 (Ca) trends.
Abstract: Considering the combined effects of CO2 fertilization and climate change drivers on plant physiology leads to a modest increase in simulated European forest transpiration in spite of the effects of CO2-induced stomatal closure. The Earth’s carbon and hydrologic cycles are intimately coupled by gas exchange through plant stomata1,2,3. However, uncertainties in the magnitude4,5,6 and consequences7,8 of the physiological responses9,10 of plants to elevated CO2 in natural environments hinders modelling of terrestrial water cycling and carbon storage11. Here we use annually resolved long-term δ13C tree-ring measurements across a European forest network to reconstruct the physiologically driven response of intercellular CO2 (Ci) caused by atmospheric CO2 (Ca) trends. When removing meteorological signals from the δ13C measurements, we find that trees across Europe regulated gas exchange so that for one ppmv atmospheric CO2 increase, Ci increased by ∼0.76 ppmv, most consistent with moderate control towards a constant Ci/Ca ratio. This response corresponds to twentieth-century intrinsic water-use efficiency (iWUE) increases of 14 ± 10 and 22 ± 6% at broadleaf and coniferous sites, respectively. An ensemble of process-based global vegetation models shows similar CO2 effects on iWUE trends. Yet, when operating these models with climate drivers reintroduced, despite decreased stomatal opening, 5% increases in European forest transpiration are calculated over the twentieth century. This counterintuitive result arises from lengthened growing seasons, enhanced evaporative demand in a warming climate, and increased leaf area, which together oppose effects of CO2-induced stomatal closure. Our study questions changes to the hydrological cycle, such as reductions in transpiration and air humidity, hypothesized to result from plant responses to anthropogenic emissions.

Journal ArticleDOI
TL;DR: An overview of the biostimulant properties of PHs on productivity and product quality of horticultural crops, in particular fruit trees, vegetables, flower crops and ornamentals is given.

Journal ArticleDOI
TL;DR: Global warming is expected to affect the start, duration, and intensity of the pollen season, and the rate of asthma exacerbations due to air pollution, respiratory infections, and/or cold air inhalation, and other conditions on the other hand.

Journal ArticleDOI
TL;DR: Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within randomized trials, and this strongly supports the incorporation of patient-reported outcomes into toxicity reporting in clinical trials.
Abstract: Purpose Information about symptomatic toxicities of anticancer treatments is not based on direct report by patients, but rather on reports by clinicians in trials. Given the potential for under-reporting, our aim was to compare reporting by patients and physicians of six toxicities (anorexia, nausea, vomiting, constipation, diarrhea, and hair loss) within three randomized trials.

Journal ArticleDOI
TL;DR: A new algorithm for the accurate detection and localization of copy-move forgeries, based on rotation-invariant features computed densely on the image, is proposed, using a fast approximate nearest-neighbor search algorithm, PatchMatch, especially suited for the computation of dense fields over images.
Abstract: We propose a new algorithm for the accurate detection and localization of copy–move forgeries, based on rotation-invariant features computed densely on the image. Dense-field techniques proposed in the literature guarantee a superior performance with respect to their keypoint-based counterparts, at the price of a much higher processing time, mostly due to the feature matching phase. To overcome this limitation, we resort here to a fast approximate nearest-neighbor search algorithm, PatchMatch, especially suited for the computation of dense fields over images. We adapt the matching algorithm to deal efficiently with invariant features, so as to achieve higher robustness with respect to rotations and scale changes. Moreover, leveraging on the smoothness of the output field, we implement a simplified and reliable postprocessing procedure. The experimental analysis, conducted on databases available online, proves the proposed technique to be at least as accurate, generally more robust, and typically much faster than the state-of-the-art dense-field references.

Journal ArticleDOI
TL;DR: An interdisciplinary perspective of melanin pigments and related pathway is provided with a view to showing how it is possible to translate current knowledge about physical and chemical properties and control mechanisms into new bioinspired solutions for biomedical, dermocosmetic, and technological applications.
Abstract: During the past decade, melanins and melanogenesis have attracted growing interest for a broad range of biomedical and technological applications. The burst of polydopamine-based multifunctional coatings in materials science is just one example, and the list may be expanded to include melanin thin films for organic electronics and bioelectronics, drug delivery systems, functional nanoparticles and biointerfaces, sunscreens, environmental remediation devices. Despite considerable advances, applied research on melanins and melanogenesis is still far from being mature. A closer intersectoral interaction between research centers is essential to raise the interests and increase the awareness of the biomedical, biomaterials science and hi-tech sectors of the manifold opportunities offered by pigment cells and related metabolic pathways. Starting from a survey of biological roles and functions, the present review aims at providing an interdisciplinary perspective of melanin pigments and related pathway with a view to showing how it is possible to translate current knowledge about physical and chemical properties and control mechanisms into new bioinspired solutions for biomedical, dermocosmetic, and technological applications.

Journal ArticleDOI
TL;DR: In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin.
Abstract: BACKGROUND Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome METHODS We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event) The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events RESULTS The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (103% and 109%, respectively; relative risk, 094; 95% confidence interval [CI], 081 to 109; P = 044), nor was the rate of net adverse clinical events (112% and 124%, respectively; relative risk, 089; 95% CI, 078 to 103; P = 012) Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (110% and 119%, respectively; relative risk, 091; 95% CI, 074 to 111; P = 034) CONCLUSIONS In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrialsgov number, NCT01433627) abstr act

Journal ArticleDOI
TL;DR: This work demonstrates how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin–benzamidine system, and uncovers the complex pathways of unbinding trajectories with unprecedented detail.
Abstract: The ability to predict the mechanisms and the associated rate constants of protein–ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin–benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k o f f is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also obtain the binding rate k o n . Both rates are in agreement with reported experimental values. We uncover the complex pathways of unbinding trajectories and describe the critical rate-limiting steps with unprecedented detail. Our findings illuminate the role played by the coupling between subtle protein backbone fluctuations and the solvation by water molecules that enter the binding pocket and assist in the breaking of the shielded hydrogen bonds. We expect our approach to be useful in calculating rates for general protein–ligand systems and a valid support for drug design.