EZH2 mutations at diagnosis in follicular lymphoma: a promising biomarker to guide frontline treatment.

EZH2 is mutated in nearly 25% of follicular lymphoma (FL) cases. Little is known about how EZH2 affects patients' response to therapy. In this context, the aim of this study was to retrospectively analyze the frequency of mutations in EZH2 at diagnosis in tissue and ctDNA in patients with FL and to assess the patients' outcomes after receiving immunochemotherapy, depending on the EZH2 mutation status. Among the 154 patients included in the study, 27% had mutated EZH2 (46% with high-grade and 26% with low-grade FL). Of the mutated tissue samples, the mutation in ctDNA was identified in 44% of cases. EZH2 mutation in ctDNA was not identified in any patient unmutated in the tissue.Unmutated patients who received R-CHOP had significantly more relapses than patients who received R-Bendamustine (16/49 vs. 2/23, p = 0.040). Furthermore, our results show that patients with mutated EZH2 treated with R-CHOP vs. those treated with R-Bendamustine present a lower incidence of relapse (10% vs. 42% p = 0.09 at 4 years), a higher PFS (92% vs. 40% p = 0.039 at 4 years), and higher OS (100% vs. 78% p = 0.039 at 4 years). Based on these data, RCHOP could be a more suitable regimen for mutated patients, and R-bendamustine for unmutated patients. These findings could mean the first-time identification of a useful biomarker to guide upfront therapy in FL.

The Cumulative and Differential Relation of Adverse Childhood Experiences and Substance Use During Emerging Adulthood.

Adverse childhood experiences (ACEs) have far-reaching effects on a wide range of health outcomes in adulthood, however, less is known about their consequences in emerging adulthood or in a geographically distinct sample. We examined the cumulative and individual relation of ACEs and two risky behaviors: alcohol and illegal drugs consumed by 490 Spanish emerging adults (mean age = 18.9). Participants answered the ACEs questionnaire, and two items about alcohol and illegal drugs consumption. Results showed that the overall experience of suffering different ACEs was a significant predictor of drug but not of alcohol consumption. Moreover, ACEs subtypes presented differential effects on substance use. Whereas some increased the likelihood of either drug or alcohol use, others reduced it. This study supports the importance of examining specific adverse experiences rather than only using an overall measure and provides some counterintuitive results that may be linked to resilient mechanisms.

Optical detection of radio waves through a nanomechanical transducer.

Low-loss transmission and sensitive recovery of weak radio-frequency and microwave signals is a ubiquitous challenge, crucial in radio astronomy, medical imaging, navigation, and classical and quantum communication. Efficient up-conversion of radio-frequency signals to an optical carrier would enable their transmission through optical fibres instead of through copper wires, drastically reducing losses, and would give access to the set of established quantum optical techniques that are routinely used in quantum-limited signal detection. Research in cavity optomechanics has shown that nanomechanical oscillators can couple strongly to either microwave or optical fields. Here we demonstrate a room-temperature optoelectromechanical transducer with both these functionalities, following a recent proposal using a high-quality nanomembrane. A voltage bias of less than 10 V is sufficient to induce strong coupling between the voltage fluctuations in a radio-frequency resonance circuit and the membrane's displacement, which is simultaneously coupled to light reflected off its surface. The radio-frequency signals are detected as an optical phase shift with quantum-limited sensitivity. The corresponding half-wave voltage is in the microvolt range, orders of magnitude less than that of standard optical modulators. The noise of the transducer--beyond the measured 800 pV Hz-1/2 Johnson noise of the resonant circuit--consists of the quantum noise of light and thermal fluctuations of the membrane, dominating the noise floor in potential applications in radio astronomy and nuclear magnetic imaging. Each of these contributions is inferred to be 60 pV Hz-1/2 when balanced by choosing an electromechanical cooperativity of ~150 with an optical power of 1 mW. The noise temperature of the membrane is divided by the cooperativity. For the highest observed cooperativity of 6,800, this leads to a projected noise temperature of 40 mK and a sensitivity limit of 5 pV Hz-1/2. Our approach to all-optical, ultralow-noise detection of classical electronic signals sets the stage for coherent up-conversion of low-frequency quantum signals to the optical domain.

Exome sequencing reveals three homozygous missense variants in SNRPA in two sisters with syndromic intellectual disability.

Splicing-related gene mutations might affect the expression of a single gene or multiple genes and cause clinically heterogeneous diseases. With the advent of next-generation sequencing, several splicing gene mutations have been exposed, yet most major spliceosome genes have no reports of germline mutations and therefore, their effects are largely unknown. We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in 2 female siblings with 3 homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. Although both patients exhibited some clinical features seen in other spliceosomal disorders, their complete clinical phenotype appears to be rather uncommon, a finding that may further support the notion that mutations in components of the major spliceosome do not strictly lead to the same syndromes/phenotypes.

Clinical features of Mexican patients with Mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive lysosomal storage disorder caused by a deficiency or absence of α--iduronidase, which is involved in the catabolism of glycosaminoglycans (GAGs). This deficiency leads to the accumulation of GAGs in several organs. Given the wide spectrum of the disease, MPS-I has historically been classified into 3 clinical subtypes - severe (Hurler syndrome), intermediate (Hurler-Scheie syndrome), and mild (Scheie syndrome) - none of which is determined by residual enzyme activity. Eleven Mexican patients with MPS-I from northwestern México were evaluated. Diagnoses were confirmed through quantification of GAGs in urine and enzyme assay for α--iduronidase. Regardless of phenotype, all patients had various degrees of infiltrated facies, short stature, dysostosis multiplex, joint contractures, and corneal opacity typical of the disease. A better understanding of the spectrum of this disease can assist in diagnosis, treatment, and improvement in the quality of life for these patients.

Evidence of Surface Loss as Ubiquitous Limiting Damping Mechanism in SiN Micro- and Nanomechanical Resonators.

Silicon nitride (SiN) micro- and nanomechanical resonators have attracted a lot of attention in various research fields due to their exceptionally high quality factors (Qs). Despite their popularity, the origin of the limiting loss mechanisms in these structures has remained controversial. In this Letter we propose an analytical model combining acoustic radiation loss with intrinsic loss. The model accurately predicts the resulting mode-dependent Qs of low-stress silicon-rich and high-stress stoichiometric SiN membranes. The large acoustic mismatch of the low-stress membrane to the substrate seems to minimize radiation loss and Qs of higher modes (n∧m≥3) are limited by intrinsic losses. The study of these intrinsic losses in low-stress membranes reveals a linear dependence with the membrane thickness. This finding was confirmed by comparing the intrinsic dissipation of arbitrary (membranes, strings, and cantilevers) SiN resonators extracted from literature, suggesting surface loss as ubiquitous damping mechanism in thin SiN resonators with Q_{surf}=ßh and ß=6×10^{10}±4×10^{10} m^{-1}. Based on the intrinsic loss the maximal achievable Qs and Qf products for SiN membranes and strings are outlined.

Nonlinear mode-coupling in nanomechanical systems.

Understanding and controlling nonlinear coupling between vibrational modes is critical for the development of advanced nanomechanical devices; it has important implications for applications ranging from quantitative sensing to fundamental research. However, achieving accurate experimental characterization of nonlinearities in nanomechanical systems (NEMS) is problematic. Currently employed detection and actuation schemes themselves tend to be highly nonlinear, and this unrelated nonlinear response has been inadvertently convolved into many previous measurements. In this Letter we describe an experimental protocol and a highly linear transduction scheme, specifically designed for NEMS, that enables accurate, in situ characterization of device nonlinearities. By comparing predictions from Euler-Bernoulli theory for the intra- and intermodal nonlinearities of a doubly clamped beam, we assess the validity of our approach and find excellent agreement.

Surpassing fundamental limits of oscillators using nonlinear resonators.

In its most basic form an oscillator consists of a resonator driven on resonance, through feedback, to create a periodic signal sustained by a static energy source. The generation of a stable frequency, the basic function of oscillators, is typically achieved by increasing the amplitude of motion of the resonator while remaining within its linear, harmonic regime. Contrary to this conventional paradigm, in this Letter we show that by operating the oscillator at special points in the resonator's anharmonic regime we can overcome fundamental limitations of oscillator performance due to thermodynamic noise as well as practical limitations due to noise from the sustaining circuit. We develop a comprehensive model that accounts for the major contributions to the phase noise of the nonlinear oscillator. Using a nanoelectromechanical system based oscillator, we experimentally verify the existence of a special region in the operational parameter space that enables suppressing the most significant contributions to the oscillator's phase noise, as predicted by our model.

Association of the tumor necrosis factor-alpha -308G>A polymorphism with breast cancer in Mexican women.

The tumor necrosis factor-alpha (TNF-α) gene plays an important role in cell proliferation, differentiation, apoptosis, lipid metabolism, coagulation, insulin resistance, and endothelial function. Polymorphisms of TNF-α have been associated with cancer. We examined the role of the -308G>A polymorphism in this gene by comparing the genotypes of 294 healthy Mexican women with those of 465 Mexican women with breast cancer. The observed genotype frequencies for controls and breast cancer patients were 1 and 14% for AA, 13 and 21% for GA, and 86 and 65% for GG, respectively. We found that the odds ratio (OR) for AA genotype was 2.4, with a 95% confidence interval (95%CI) of 5.9-101.1 (P = 0.0001). The association was also evident when comparing the distribution of the AA-GA genotype in patients in the following categories: 1) premenopause and obesity I (OR = 3.5, 95%CI = 1.3-9.3, P = 0.008), 2) Her-2 neu and tumor stage I-II (OR = 2.5, 95%CI = 1.31-4.8, P = 0.004), 3) premenopause and tumor stage III-IV (OR = 1.7, 95%CI = 1.0-2.9, P = 0.034), 4) chemotherapy non-response and abnormal hematocrit (OR = 2.4, 95%CI = 1.2-4.8, P = 0.015), 5) body mass index and Her-2 neu and III-IV tumor stage (OR = 2.8, 95%CI = 1.2- 6.6, P = 0.016), and 6) nodule metastasis and K-I67 (OR = 4.0, 95%CI = 1.01-15.7, P = 0.038). We concluded that the genotypes AA-GA of the -308G>A polymorphism in TNF-α significantly contribute to breast cancer susceptibility in the analyzed sample from the Mexican population.

Low-temperature processing of screen-printed piezoelectric KNbO3 with integration onto biodegradable paper substrates.

The development of fully solution-processed, biodegradable piezoelectrics is a critical step in the development of green electronics towards the worldwide reduction of harmful electronic waste. However, recent printing processes for piezoelectrics are hindered by the high sintering temperatures required for conventional perovskite fabrication techniques. Thus, a process was developed to manufacture lead-free printed piezoelectric devices at low temperatures to enable integration with eco-friendly substrates and electrodes. A printable ink was developed for screen printing potassium niobate (KNbO3) piezoelectric layers in microns of thickness at a maximum processing temperature of 120 °C with high reproducibility. Characteristic parallel plate capacitor and cantilever devices were designed and manufactured to assess the quality of this ink and evaluate its physical, dielectric, and piezoelectric characteristics; including a comparison of behaviour between conventional silicon and biodegradable paper substrates. The printed layers were 10.7-11.2 µm thick, with acceptable surface roughness values in the range of 0.4-1.1 µm. The relative permittivity of the piezoelectric layer was 29.3. The poling parameters were optimised for the piezoelectric response, with an average longitudinal piezoelectric coefficient for samples printed on paper substrates measured as d 33, eff, paper = 13.57 ± 2.84 pC/N; the largest measured value was 18.37 pC/N on paper substrates. This approach to printable biodegradable piezoelectrics opens the way forward for fully solution-processed green piezoelectric devices.

Stress-induced variations in the stiffness of micro- and nanocantilever beams.

The effect of surface stress on the stiffness of cantilever beams remains an outstanding problem in the physical sciences. While numerous experimental studies report significant stiffness change due to surface stress, theoretical predictions are unable to rigorously and quantitatively reconcile these observations. In this Letter, we present the first controlled measurements of stress-induced change in cantilever stiffness with commensurate theoretical quantification. Simultaneous measurements are also performed on equivalent clamped-clamped beams. All experimental results are quantitatively and accurately predicted using elasticity theory. We also present conclusive experimental evidence for invalidity of the long-standing and unphysical axial force model, which has been widely applied to interpret measurements using cantilever beams. Our findings will be of value in the development of micro- and nanoscale resonant mechanical sensors.

Passive phase noise cancellation scheme.

We introduce a new method for reducing phase noise in oscillators, thereby improving their frequency precision. The noise reduction is realized by a passive device consisting of a pair of coupled nonlinear resonating elements that are driven parametrically by the output of a conventional oscillator at a frequency close to the sum of the linear mode frequencies. Above the threshold for parametric instability, the coupled resonators exhibit self-oscillations which arise as a response to the parametric driving, rather than by application of active feedback. We find operating points of the device for which this periodic signal is immune to frequency noise in the driving oscillator, providing a way to clean its phase noise. We present results for the effect of thermal noise to advance a broader understanding of the overall noise sensitivity and the fundamental operating limits.

Association of TP53 gene codon 72 polymorphism with endometriosis in Mexican women.

The TP53 tumor suppressor gene plays an important role in cell cycle regulation; polymorphisms of this gene have been associated with endometriosis. We examined the role of TP53 codon 72 polymorphism by comparing genotypes of 235 healthy Mexican women (controls with surgically excluded endometriosis) with the genotypes of 151 Mexican women with endometriosis. The observed genotype frequencies for controls and endometriosis patients were 8 and 22% for proline/proline (Pro/Pro), 30 and 34% for proline/arginine (Pro/Arg), and 62 and 44% for arginine/arginine (Arg/Arg), respectively. We found that odds ratio (OR) = 3.3; 95% confidence intervals (95%CI) = 1.7-6.4; P = 0.0001. The association was also evident in the comparison of the distributions of genotypes Pro/Pro and Pro/Arg in patients with moderate-to-severe endometriosis; OR = 1.9; 95%CI = 0.95-3.9; P = 0.049. We suggest that genotype Pro/Pro of codon 72 polymorphism in TP53 contributes significantly to endometriosis susceptibility in the Mexican population.

A nanoscale parametric feedback oscillator.

We describe and demonstrate a new oscillator topology, the parametric feedback oscillator (PFO). The PFO paradigm is applicable to a wide variety of nanoscale devices and opens the possibility of new classes of oscillators employing innovative frequency-determining elements, such as nanoelectromechanical systems (NEMS), facilitating integration with circuitry and system-size reduction. We show that the PFO topology can also improve nanoscale oscillator performance by circumventing detrimental effects that are otherwise imposed by the strong device nonlinearity in this size regime.

Hydro-climatic changes of wetlandscapes across the world.

Assessments of ecosystem service and function losses of wetlandscapes (i.e., wetlands and their hydrological catchments) suffer from knowledge gaps regarding impacts of ongoing hydro-climatic change. This study investigates hydro-climatic changes during 1976-2015 in 25 wetlandscapes distributed across the world's tropical, arid, temperate and cold climate zones. Results show that the wetlandscapes were subject to precipitation (P) and temperature (T) changes consistent with mean changes over the world's land area. However, arid and cold wetlandscapes experienced higher T increases than their respective climate zone. Also, average P decreased in arid and cold wetlandscapes, contrarily to P of arid and cold climate zones, suggesting that these wetlandscapes are located in regions of elevated climate pressures. For most wetlandscapes with available runoff (R) data, the decreases were larger in R than in P, which was attributed to aggravation of climate change impacts by enhanced evapotranspiration losses, e.g. caused by land-use changes.

Fast and robust hydrogen sensors based on discontinuous palladium films on polyimide, fabricated on a wafer scale.

Fast hydrogen sensors based on discontinuous palladium (Pd) films on supporting polyimide layers, fabricated by a cost-efficient and full-wafer compatible process, are presented. The films, deposited by electron-beam evaporation with a nominal thickness of 1.5 nm, consist of isolated Pd islands that are separated by nanoscopic gaps. On hydrogenation, the volume expansion of Pd brings initially separated islands into contact which leads to the creation of new electrical pathways through the film. The supporting polyimide layer provides both sufficient elasticity for the Pd nanoclusters to expand on hydrogenation and a sufficiently high surface energy for good adhesion of both film and contacting electrodes. The novel order of the fabrication processes involves a dicing step prior to the Pd deposition and stencil lithography for the patterning of microelectrodes. This allows us to preserve the as-deposited film properties. The devices work at room temperature, show response times of a few seconds and have a low power consumption of some tens of nW.

Response of six strawberry (Fragaria x ananassa Duch.) cultivars to the root lesion nematode (Pratylenchus penetrans Filipjev and Schurmanns Stekhoven).

In the Philippines, strawberry is grown only in Benguet Province because of its unique climatic conditions. It has been a lucrative source of income for Benguet farmers and adds to the revenue of Benguet Province. The root lesion nematode, Pratylenchus penetrans is an economically important pest of strawberry in the area. It can cause substantial losses to strawberry growers, both by reducing vegetative plant growth and by reducing strawberry yields. The nematode has a very wide host range and hence, is not readily controlled by crop rotation. An alternative approach which growers may wish to consider trying is planting of strawberry varieties which are either resistant or tolerant to this nematode. The relative susceptibility/tolerance of six strawberry cultivars to the root lesion nematode, P. penetrans was evaluated under greenhouse and field conditions. Inoculation of 500 nematodes/pot did not significantly affect the fresh top weight, fresh root weight, and yield of strawberry cultivars Festival, Whitney, Winterdawn, Earlibrite, and Camarosa. The said cultivars had significantly higher number of nematodes recovered from the roots. On the other hand, the highest strawberry yield was recorded in cv Sweet Charlie, however, this was significantly reduced by nematode inoculation .Surprisingly, the number of nematodes recovered from the roots of this cultivar was significantly the lowest among the cultivars tested. Results of the field experiment showed that strawberry cv Sweet Charlie gave the highest marketable yield which was significantly different from the rest of the cultivars tested. This was followed by Festival, and Earlibrite. On the other hand, Camarosa and Whitney gave significantly lower yield than the above cultivars but significantly higher than Winterdawn. In terms of nematodes recovered from the roots, the highest was noted in Whitney, followed by Sweet Charlie and Earlibrite. The lowest was obtained from Camarosa, followed by Festival and Winterdawn. Based on the results of the greenhouse experiment, Festival, Whitney, Winterdawn, Earlibrite and Camarosa can be considered tolerant while Sweet Charlie was slightly susceptible to P. penetrans. However, based on the field trial, Sweet Charlie, Festival and Earlibrite were tolerant while Whitney, Camarosa and Winterdawn were slightly susceptible.

Management of root knot nematode, Meloidogyne incognita in cucumber (Cucumis sativus) using silicon.

Silicon (Si) has been reported to effectively manage some pests and diseases of plants. This study was conducted to determine the effect of Si concentration, mode, and frequency of application in managing Meloidogyne incognita in cucumber. A susceptible cultivar of cucumber (cv. Cyclone) was planted in pots containing heat-sterilized soil. Three weeks after planting, the plants were inoculated with 1,000 juveniles/ pot. Uninoculated plants were provided to serve as control. Three concentrations of Si in the form of sodium metasilicate was applied on the leaves and roots alone and also on both the leaves and roots. Application was done once during the growing period and weekly until seven days before harvest. Leaf and root application of Si was found to significantly increase (p = 0.0029) the fresh top weight of inoculated and uninoculated plants. On the other hand, inoculation of root-knot nematode significantly increased the fresh root weight of cucumber which could be due to enlargement of roots or formation of galls. Interestingly, the inoculated plants gave significantly higher marketable yield than uninoculated ones. Application of Si at the rate of 200 ppm significantly increased the marketable yield compared to the higher rate of Si (400 ppm). At 200 ppm, one application of Si both on the leaves and roots significantly reduced the number of galls in inoculated plants. This was comparable to the same concentration applied continuously on the roots and at higher concentration (400 ppm) applied continuously on the leaves and on the roots. On the other hand, single root application of Si at the rate of 400 ppm gave the lowest number of eggmasses, however, it was comparable to the same Si concentration applied singly on the leaves and applied continuously both on the leaves and roots. These treatments, however, were at par with continuous application of the lower rate of Si (200 ppm) on the leaves and both leaves and roots.

Plasma observations near neptune: initial results from voyager 2.

The plasma science experiment on Voyager 2 made observations of the plasma environment in Neptune's magnetosphere and in the surrounding solar wind. Because of the large tilt of the magnetic dipole and fortuitous timing, Voyager entered Neptune's magnetosphere through the cusp region, the first cusp observations at an outer planet. Thus the transition from the magnetosheath to the magnetosphere observed by Voyager 2 was not sharp but rather appeared as a gradual decrease in plasma density and temperature. The maximum plasma density observed in the magnetosphere is inferred to be 1.4 per cubic centimeter (the exact value depends on the composition), the smallest observed by Voyager in any magnetosphere. The plasma has at least two components; light ions (mass, 1 to 5) and heavy ions (mass, 10 to 40), but more precise species identification is not yet available. Most of the plasma is concentrated in a plasma sheet or plasma torus and near closest approach to the planet. A likely source of the heavy ions is Triton's atmosphere or ionosphere, whereas the light ions probably escape from Neptune. The large tilt of Neptune's magnetic dipole produces a dynamic magnetosphere that changes configuration every 16 hours as the planet rotates.