Observation of universal Hall response in strongly interacting Fermions.

The Hall effect, which originates from the motion of charged particles in magnetic fields, has deep consequences for the description of materials, extending far beyond condensed matter. Understanding such an effect in interacting systems represents a fundamental challenge, even for small magnetic fields. In this work, we used an atomic quantum simulator in which we tracked the motion of ultracold fermions in two-leg ribbons threaded by artificial magnetic fields. Through controllable quench dynamics, we measured the Hall response for a range of synthetic tunneling and atomic interaction strengths. We unveil a universal interaction-independent behavior above an interaction threshold, in agreement with theoretical analyses. The ability to reach hard-to-compute regimes demonstrates the power of quantum simulation to describe strongly correlated topological states of matter.

A combined molecular dynamics simulation and DFT study on mercapto-benzamide inhibitors for the HIV NCp7 protein.

Molecular dynamics and quantum simulations are performed to elucidate some aspects of the action mechanism of mercapto-benzamides, a proposed class of antivirals against HIV-1. These molecules act as prodrugs that, after modifications in the biological environment, are able to denature the HIV nucleocapsid protein 7, a metal binder protein, with two zinc finger motifs, vital for RNA maturation and viral replication. Despite their attractive features, these molecules and their biological target are not well understood. Simulations were performed to support a proposed action mechanism, based on the activation of mercapto-benzamides by acetylation, targeting a relatively rare protein hydrolyzed state, followed by trans-molecular acetylation from the molecule to the protein and finally the direct interaction of the molecular sulphur atom of mercapto-benzamides with the zinc atom coordinated by the protein. Our simulation results are in agreement with the NMR data about the zinc finger binding protein equilibrium configurations.

Development of Three Molecular Diagnostic Tools for the Identification of the False Codling Moth (Lepidoptera: Tortricidae).

Three molecular protocols using qPCR TaqMan probe, SYBR Green, and loop-mediated isothermal amplification (LAMP) methods were set up for the identification of larvae and adults of an African invasive moth, Thaumatotibia leucotreta (Meyrick, 1913) (Lepidoptera: Tortricidae). The DNA extracts from larval and adult samples of T. leucotreta were perfectly amplified with an average Ct value of 19.47 ± 2.63. All assays were demonstrated to be inclusive for T. leucotreta and exclusive for the nontarget species tested; the absence of false positives for nontarget species showed a 100% of diagnostic specificity and diagnostic sensitivity for all assays. With the SYBR Green protocol, the Cq values were only considered for values less than 22 (cutoff value) to prevent false-positive results caused by the late amplification of nonspecific amplicons. The limit of detection (LoD) for the qPCR probe protocol was equal to 0.02 pg/µl while a value equal to 0.128 pg/µl for the qPCR SYBR Green assay and LAMP method were established, respectively. The intrarun variabilities of reproducibility and repeatability in all the assays evaluated as CV%, ranged between 0.21 and 6.14, and between 0.33 and 9.52, respectively; the LAMP values were slightly higher than other assays, indicating a very low interrun variability. In order for an operator to choose the most desirable method, several parameters were considered and discussed. For future development of these assays, it is possible to hypothesize the setup of a diagnostic kit including all the three methods combined, to empower the test reliability and robustness.

Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study.

BACKGROUND: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. METHODS: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. RESULTS: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients. CONCLUSIONS: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

Locomotor patterns during obstacle avoidance in children with cerebral palsy.

We investigated how early injuries to developing brain affect the interaction of locomotor patterns with the voluntary action required by obstacle clearance. This task requires higher cognitive load and specific anticipatory sensorimotor integration than more automated steady-state gait. To this end, we compared the adaptive gait patterns during obstacle clearance in 40 children with cerebral palsy (CP) (24 diplegic, 16 hemiplegic, 2-12 yr) and 22 typically developing (TD) children (2-12 yr) by analyzing gait kinematics, joint moments during foot elevation, electromyographic (EMG) activity of 11 pairs of bilateral muscles, and muscle modules evaluated by factorization of the EMG signals. The results confirmed generally slower task performance, plus difficulty in motor planning and control in CP. Thus ~30% of diplegic children failed to perform the task. Children with CP demonstrated higher foot lift, smaller range of motion of distal segments, difficulties in properly activating the hamstring muscles at liftoff, and a modified hip strategy when elevating the trailing limb. Basic muscle modules were generally roughly similar to TD patterns, though they showed a limited adaptation. Thus a distinct activation burst in the adaptable muscle module timed to the voluntary task (liftoff) was less evident in CP. Children with CP also showed prolonged EMG burst durations. Impaired obstacle task performance may reflect impaired or less adaptable supraspinal and spinal control of gait when a locomotor task is superimposed with the voluntary movement. Neurorehabilitation of gait in CP may thus be beneficial by adding voluntary tasks such as obstacle clearance during gait performance.NEW & NOTEWORTHY Previous studies mainly evaluated the neuromuscular pattern generation in cerebral palsy (CP) during unobstructed gait. Here we characterized impairments in the obstacle task performance associated with a limited adaptation of the task-relevant muscle module timed to the foot lift during obstacle crossing. Impaired task performance in children with CP may reflect basic developmental deficits in the adaptable control of gait when the locomotor task is superimposed with the voluntary movement.

Early manifestation of arm-leg coordination during stepping on a surface in human neonates.

The accomplishment of mature locomotor movements relies upon the integrated coordination of the lower and upper limbs and the trunk. Human adults normally swing their arms and a quadrupedal limb coordination persists during bipedal walking despite a strong corticospinal control of the upper extremities that allows to uncouple this connection during voluntary activities. Here we investigated arm-leg coordination during stepping responses on a surface in human neonates. In eight neonates, we found the overt presence of alternating arm-leg oscillations, the arms moving up and down in alternation with ipsilateral lower limb movements. These neonates moved the diagonal limbs together, and the peak of the arm-to-trunk angle (i.e., maximum vertical excursion of the arm) occurred around the end of the ipsilateral stance phase, as it occurs during typical adult walking. Although episodes of arm-leg coordination were sporadic in our sample of neonates, their presence provides significant evidence for a neural coupling between the upper and lower limbs during early ontogenesis of locomotion in humans.

Corrigendum: Foot Placement Characteristics and Plantar Pressure Distribution Patterns during Stepping on Ground in Neonates.

[This corrects the article on p. 784 in vol. 8, PMID: 29066982.].

Foot Placement Characteristics and Plantar Pressure Distribution Patterns during Stepping on Ground in Neonates.

Stepping on ground can be evoked in human neonates, though it is rather irregular and stereotyped heel-to-toe roll-over pattern is lacking. Such investigations can provide insights into the role of contact- or load-related proprioceptive feedback during early development of locomotion. However, the detailed characteristics of foot placements and their association with motor patterns are still incompletely documented. We elicited stepping in 33 neonates supported on a table. Unilateral limb kinematics, bilateral plantar pressure distribution and EMG activity from up to 11 ipsilateral leg muscles were recorded. Foot placement characteristics in neonates showed a wide variation. In ~25% of steps, the swinging foot stepped onto the contralateral foot due to generally small step width. In the remaining steps with separate foot placements, the stance phase could start with forefoot (28%), midfoot (47%), or heel (25%) touchdowns. Despite forefoot or heel initial contacts, the kinematic and loading patterns markedly differed relatively to toe-walking or adult-like two-peaked vertical force profile. Furthermore, while the general stepping parameters (cycle duration, step length, range of motion of proximal joints) were similar, the initial foot contact was consistently associated with specific center-of-pressure excursion, range of motion in the ankle joint, and the center-of-activity of extensor muscles (being shifted by ~5% of cycle toward the end of stance in the "heel" relative to "forefoot" condition). In sum, we found a variety of footfall patterns in conjunction with associated changes in motor patterns. These findings suggest the potential contribution of load-related proprioceptive feedback and/or the expression of variations in the locomotor program already during early manifestations of stepping on ground in human babies.

Synthetic Dimensions and Spin-Orbit Coupling with an Optical Clock Transition.

We demonstrate a novel way of synthesizing spin-orbit interactions in ultracold quantum gases, based on a single-photon optical clock transition coupling two long-lived electronic states of two-electron ^{173}Yb atoms. By mapping the electronic states onto effective sites along a synthetic "electronic" dimension, we have engineered fermionic ladders with synthetic magnetic flux in an experimental configuration that has allowed us to achieve uniform fluxes on a lattice with minimal requirements and unprecedented tunability. We have detected the spin-orbit coupling with fiber-link-enhanced clock spectroscopy and directly measured the emergence of chiral edge currents, probing them as a function of the flux. These results open new directions for the investigation of topological states of matter with ultracold atomic gases.

Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab.

BACKGROUND: Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. PATIENTS AND METHODS: Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. RESULTS: The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. CONCLUSIONS: Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.

Observation of chiral edge states with neutral fermions in synthetic Hall ribbons.

Chiral edge states are a hallmark of quantum Hall physics. In electronic systems, they appear as a macroscopic consequence of the cyclotron orbits induced by a magnetic field, which are naturally truncated at the physical boundary of the sample. Here we report on the experimental realization of chiral edge states in a ribbon geometry with an ultracold gas of neutral fermions subjected to an artificial gauge field. By imaging individual sites along a synthetic dimension, encoded in the nuclear spin of the atoms, we detect the existence of the edge states and observe the edge-cyclotron orbits induced during quench dynamics. The realization of fermionic chiral edge states opens the door for edge state interferometry and the study of non-Abelian anyons in atomic systems.

Neuromuscular adjustments of gait associated with unstable conditions.

A compact description of coordinated muscle activity is provided by the factorization of electromyographic (EMG) signals. With the use of this approach, it has consistently been shown that multimuscle activity during human locomotion can be accounted for by four to five modules, each one comprised of a basic pattern timed at a different phase of gait cycle and the weighting coefficients of synergistic muscle activations. These modules are flexible, in so far as the timing of patterns and the amplitude of weightings can change as a function of gait speed and mode. Here we consider the adjustments of the locomotor modules related to unstable walking conditions. We compared three different conditions, i.e., locomotion of healthy subjects on slippery ground (SL) and on narrow beam (NB) and of cerebellar ataxic (CA) patients on normal ground. Motor modules were computed from the EMG signals of 12 muscles of the right lower limb using non-negative matrix factorization. The unstable gait of SL, NB, and CA showed significant changes compared with controls in the stride length, stride width, range of angular motion, and trunk oscillations. In most subjects of all three unstable conditions, >70% of the overall variation of EMG waveforms was accounted for by four modules that were characterized by a widening of muscle activity patterns. This suggests that the nervous system adopts the strategy of prolonging the duration of basic muscle activity patterns to cope with unstable conditions resulting from either slippery ground, reduced support surface, or pathology.

A compact ultranarrow high-power laser system for experiments with 578 nm ytterbium clock transition.

In this paper, we present the realization of a compact, high-power laser system able to excite the ytterbium clock transition at 578 nm. Starting from an external-cavity laser based on a quantum dot chip at 1156 nm with an intra-cavity electro-optic modulator, we were able to obtain up to 60 mW of visible light at 578 nm via frequency doubling. The laser is locked with a 500 kHz bandwidth to an ultra-low-expansion glass cavity stabilized at its zero coefficient of thermal expansion temperature through an original thermal insulation and correction system. This laser allowed the observation of the clock transition in fermionic (173)Yb with a <50 Hz linewidth over 5 min, limited only by a residual frequency drift of some 0.1 Hz/s.

Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients.

BACKGROUND: Ipilimumab improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to benefit from treatment. The aim of this study was to identify an upfront marker for treatment benefit. METHODS: A total of 187 metastatic melanoma patients treated in three Italian Institutions with 3 mg kg(-1) ipilimumab, and 27 patients treated with 10 mg kg(-1) ipilimumab, were evaluated. Neutrophil-to-lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied, adjusting for confounders and other prognostic factors. RESULTS: In the training cohort of 69 patients treated at European Institute of Oncology, pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses. Patients with baseline NLR<5 had a significantly improved PFS (HR=0.38; 95% CI: 0.22-0.66; P=0.0006) and OS (HR=0.24; 95% CI: 0.13-0.46; P<0.0001) compared with those with a NLR⩾5. Associations of low NLR with improved survival were confirmed in three validation cohorts of patients. CONCLUSION: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve to identify patients most likely to benefit from this therapy.

Strongly Interacting Gas of Two-Electron Fermions at an Orbital Feshbach Resonance.

We report on the experimental observation of a strongly interacting gas of ultracold two-electron fermions with an orbital degree of freedom and magnetically tunable interactions. This realization has been enabled by the demonstration of a novel kind of Feshbach resonance occurring in the scattering of two (173)Yb atoms in different nuclear and electronic states. The strongly interacting regime at resonance is evidenced by the observation of anisotropic hydrodynamic expansion of the two-orbital Fermi gas. These results pave the way towards the realization of new quantum states of matter with strongly correlated fermions with an orbital degree of freedom.

Direct observation of coherent interorbital spin-exchange dynamics.

We report on the first direct observation of fast spin-exchange coherent oscillations between different long-lived electronic orbitals of ultracold 173Yb fermions. We measure, in a model-independent way, the strength of the exchange interaction driving this coherent process. This observation allows us to retrieve important information on the interorbital collisional properties of 173Yb atoms and paves the way to novel quantum simulations of paradigmatic models of two-orbital quantum magnetism.

Effects of TIPS-functionalization and perhalogenation on the electronic, optical, and transport properties of angular and compact dibenzochrysene.

We report a systematic comparative study on dibenzo[b,def]chrysene (angular) and dibenzo[def,mno] chrysene (compact) polyaromatic hydrocarbons and their bis-triisopropylsilylethynyl (TIPS)-functionalized and perhalogenated (F, Cl) counterparts. We used density functional theory (DFT) and time-dependent DFT to quantify the effects of morphology and chemical modifications on the electronic, optical, and transport properties. In particular, we compared electron affinity, ionization energy, fundamental gap, optical absorption, exciton binding energy, and reorganization energies for holes and electrons. For both TIPS-functionalization and halogen substitutions, we found larger electron affinities (nearly tripled with perchlorination). Ionization energies are found to be reduced for TIPS-functionalization (by ∼5%) and enhanced following halogen substitution (up to 17%). In both compact and angular dibenzochrysenes, the above trends reflect in a general reduction of the fundamental gap (up to 22%) following chemical modification. The effect of perhalogenation and TIPS-functionalization is always to increase molecular reorganization energies for both holes and electrons. Concerning the optical properties, we observe a redshift of the optical onset in all cases; for TIPS-functionalized molecules, in particular, we additionally found a remarkable enhancement of the absorption in the visible region.

Plasticity and modular control of locomotor patterns in neurological disorders with motor deficits.

Human locomotor movements exhibit considerable variability and are highly complex in terms of both neural activation and biomechanical output. The building blocks with which the central nervous system constructs these motor patterns can be preserved in patients with various sensory-motor disorders. In particular, several studies highlighted a modular burst-like organization of the muscle activity. Here we review and discuss this issue with a particular emphasis on the various examples of adaptation of locomotor patterns in patients (with large fiber neuropathy, amputees, stroke and spinal cord injury). The results highlight plasticity and different solutions to reorganize muscle patterns in both peripheral and central nervous system lesions. The findings are discussed in a general context of compensatory gait mechanisms, spatiotemporal architecture and modularity of the locomotor program.

Features of hand-foot crawling behavior in human adults.

Interlimb coordination of crawling kinematics in humans shares features with other primates and nonprimate quadrupeds, and it has been suggested that this is due to a similar organization of the locomotor pattern generators (CPGs). To extend the previous findings and to further explore the neural control of bipedal vs. quadrupedal locomotion, we used a crawling paradigm in which healthy adults crawled on their hands and feet at different speeds and at different surface inclinations (13°, 27°, and 35°). Ground reaction forces, limb kinematics, and electromyographic (EMG) activity from 26 upper and lower limb muscles on the right side of the body were collected. The EMG activity was mapped onto the spinal cord in approximate rostrocaudal locations of the motoneuron pools to characterize the general features of cervical and lumbosacral spinal cord activation. The spatiotemporal pattern of spinal cord activity significantly differed between quadrupedal and bipedal gaits. In addition, participants exhibited a large range of kinematic coordination styles (diagonal vs. lateral patterns), which is in contrast to the stereotypical kinematics of upright bipedal walking, suggesting flexible coupling of cervical and lumbosacral pattern generators. Results showed strikingly dissimilar directional horizontal forces for the arms and legs, considerably retracted average leg orientation, and substantially smaller sacral vs. lumbar motoneuron activity compared with quadrupedal gait in animals. A gradual transition to a more vertical body orientation (increasing the inclination of the treadmill) led to the appearance of more prominent sacral activity (related to activation of ankle plantar flexors), typical of bipedal walking. The findings highlight the reorganization and adaptation of CPG networks involved in the control of quadrupedal human locomotion and a high specialization of the musculoskeletal apparatus to specific gaits.