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Here, we present a study combining Bayesian optimization structural inference with the machine learning interatomic potential Neural Equivariant Interatomic Potential (NequIP) to accelerate and enable the study of the adsorption of the conformationally flexible lignocellulosic molecules β-d-xylose and 1,4-β-d-xylotetraose on a copper surface. The number of structure evaluations needed to map out the relevant potential energy surfaces are reduced by Bayesian optimization, while NequIP minimizes the time spent on each evaluation, ultimately resulting in cost-efficient and reliable sampling of large systems and configurational spaces. Although the applicability of Bayesian optimization for the conformational analysis of the more flexible xylotetraose molecule is restricted by the sample complexity bottleneck, the latter can be effectively bypassed with external conformer search tools, such as the Conformer-Rotamer Ensemble Sampling Tool, facilitating the subsequent lower-dimensional global minimum adsorption structure determination. Finally, we demonstrate the applicability of the described approach to find adsorption structures practically equivalent to the density functional theory counterparts at a fraction of the computational cost.

The interaction of water with surfaces is crucially important in a wide range of natural and technological settings. In particular, at low temperatures, unveiling the atomistic structure of adsorbed water clusters would provide valuable data for understanding the ice nucleation process. Using high-resolution atomic force microscopy (AFM) and scanning tunneling microscopy, several studies have demonstrated the presence of water pentamers, hexamers, and heptamers (and of their combinations) on a variety of metallic surfaces, as well as the initial stages of 2D ice growth on an insulating surface. However, in all of these cases, the observed structures were completely flat, providing a relatively straightforward path to interpretation. Here, we present high-resolution AFM measurements of several water clusters on Au(111) and Cu(111), whose understanding presents significant challenges due to both their highly 3D configuration and their large size. For each of them, we use a combination of machine learning, atomistic modeling with neural network potentials, and statistical sampling to propose an underlying atomic structure, finally comparing its AFM simulated images to the experimental ones. These results provide insights into the early phases of ice formation, which is a ubiquitous phenomenon ranging from biology to astrophysics.

Cellulose, a renewable structural biopolymer, is ubiquitous in nature and is the basic reinforcement component of the natural hierarchical structures of living plants, bacteria, and tunicates. However, a detailed picture of the crystalline cellulose surface at the molecular level is still unavailable. Here, using atomic force microscopy (AFM) and molecular dynamics (MD) simulations, we revealed the molecular details of the cellulose chain arrangements on the surfaces of individual cellulose nanocrystals (CNCs) in water. Furthermore, we visualized the three-dimensional (3D) local arrangement of water molecules near the CNC surface using 3D AFM. AFM experiments and MD simulations showed anisotropic water structuring, as determined by the surface topologies and exposed chemical moieties. These findings provide important insights into our understanding of the interfacial interactions between CNCs and water at the molecular level. This may allow the establishment of the structure-property relationship of CNCs extracted from various biomass sources.

Chitin is one of the most abundant and renewable natural biopolymers. It exists in the form of crystalline microfibrils and is the basic structural building block of many biological materials. Its surface crystalline structure is yet to be reported at the molecular level. Herein, atomic force microscopy (AFM) in combination with molecular dynamics simulations reveals the molecular-scale structural details of the chitin nanocrystal (chitin NC)-water interface. High-resolution AFM images reveal the molecular details of chitin chain arrangements at the surfaces of individual chitin NCs, showing highly ordered, stable crystalline structures almost free of structural defects or disorder. 3D-AFM measurements with submolecular spatial resolution demonstrate that chitin NC surfaces interact strongly with interfacial water molecules creating stable, well-ordered hydration layers. Inhomogeneous encapsulation of the underlying chitin substrate by these hydration layers reflects the chitin NCs' multifaceted surface character with different chain arrangements and molecular packing. These findings provide important insights into chitin NC structures at the molecular level, which is critical for developing the properties of chitin-based nanomaterials. Furthermore, these results will contribute to a better understanding of the chemical and enzymatic hydrolysis of chitin and other native polysaccharides, which is also essential for the enzymatic conversion of biomass., (© 2022 The Authors. Small Methods published by Wiley-VCH GmbH.)

Artificial intelligence, or the discipline of developing computational algorithms able to perform tasks that requires human intelligence, offers the opportunity to improve our idea and delivery of precision medicine. Here, we provide an overview of artificial intelligence approaches for the analysis of large-scale RNA-sequencing datasets in cancer. We present the major solutions to disentangle inter- and intra-tumor heterogeneity of transcriptome profiles for an effective improvement of patient management. We outline the contributions of learning algorithms to the needs of cancer genomics, from identifying rare cancer subtypes to personalizing therapeutic treatments.

Heterogeneity is a fundamental feature of complex phenotypes. So far, genomic screenings have profiled thousands of samples providing insights into the transcriptome of the cell. However, disentangling the heterogeneity of these transcriptomic Big Data to identify defective biological processes remains challenging. Here we present GSECA, a method exploiting the bimodal behavior of RNA-sequencing gene expression profiles to identify altered gene sets in heterogeneous patient cohorts. Using simulated and experimental RNA-sequencing data sets, we show that GSECA provides higher performances than other available algorithms in detecting truly altered biological processes in large cohorts. Applied to 5941 samples from 14 different cancer types, GSECA correctly identified the alteration of the PI3K/AKT signaling pathway driven by the somatic loss of PTEN and verified the emerging role of PTEN in modulating immune-related processes. In particular, we showed that, in prostate cancer, PTEN loss appears to establish an immunosuppressive tumor microenvironment through the activation of STAT3, and low PTEN expression levels have a detrimental impact on patient disease-free survival. GSECA is available at https://github.com/matteocereda/GSECA., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We evaluated the modifications induced by chronic treatment with an alpha 1-adrenolytic hybrid drug, urapidil, on the hemodynamic parameters in peripheral artery and left ventricle diastolic function. Fifteen mild to moderate essential hypertensive patients (13 men, 2 women; mean age 42 years, range 32-54 years) received urapidil (60 mg b.i.d.) for 6 months. Peripheral hemodynamic and cardiac parameters were evaluated by duplex scanner, coupled with a plethysmographic method, basally (T0) and after 6 weeks' (T1) and 6 months' treatment (T2). Mean blood pressure (BP) showed a reduction after 6 weeks of -9.07 mm Hg (confidence intervals [CI] 95%: -9.21; -8.92; P < 0.01), which was maintained after 6 months (-8.21 mm Hg, CI 95%: -8.97; -7.43; P < 0.01), while no significant change was seen in heart rate. Compliance showed highly significant changes after both 6 weeks (+1.073 dyn-1.cm4.10(-7), 95% CI: +0.965; +1.181, P < 0.001) and 6 months (+0.933 dyn-1.cm4. 10(-7), 95% CI: +0.903; +0.963, P < 0.001), as well as characteristic impedance (T1:-16.689 dyn.s.cm-5/10(2), 95% CI: -16.914; -16.463 P < 0.001; T2: -15.98 dyn.s.cm-5. 10(2), 95% CI: -18.186; -13.784; P < 0.001) and forearm resistances (T1: -26.153 mm Hg.ml-1.s, 95% CI: -34.553; -17.753, P < 0.01; T2: -43.587 mm Hg.ml-1.s, 95% CI: -52.711; -34.464, P < 0.01). Similarly, we have recorded a similar change in left ventricular end-diastolic posterior wall thickness (T1: -1.067 mm, 95% CI: -1.099; -1.035, P < 0.01; T2: -2.866 mm, 95% CI: -3.044; -2.688, P < 0.01), end-diastolic interventricular septum thickness (T1: -0.921 mm, 95% CI: -1.511; -0.289, P < 0.05; T2: -2.711 mm, 95% CI: -3.211; -2.199, P < 0.01), end-diastolic volume (T1: +6.4 ml, 95% CI: +6.343; +6.456, P < 0.01; T2: +19.867 ml, 95% CI: +18.564; +21.170, P < 0.01), and mass/volume index (T1: -0.11, 95% CI: -0.118; -0.101, P < 0.01; T2: -0.218, 95% CI: -0.221; -0.217, P < 0.01). Changes in arterial compliance have shown a statistically significant correlation with changes in mass/volume index (r = -0.468; P < 0.03), end diastolic volume (r = 0.501; P < 0.02), as well as left ventricle rapid filling phase (r = 0.426; P < 0.05) and left ventricle end diastolic posterior wall thickness (r = -0.478, P < 0.03). Our results suggest that the antihypertensive efficacy of urapidil coupled with the restoration of the dumping function of the large arteries, and the reduced activation of reflex sympathetic activation, may play a considerable role among the mechanisms allowing the regression of the functional modifications affecting the left ventricular diastole.

Objective: To evaluate the modifications induced by chronic treatment with a new formulation of nicardipine (slow release) on the hemodynamic parameters in peripheral artery and left ventricle diastolic function., Materials and Methods: Ten mild to moderate essential hypertensive male patients (mean age 42 years, range 32-54 years) received nicardipine slow release (40 mg b.i.d.) for six months. Peripheral hemodynamic and cardiac parameters were evaluated by duplex scanner, coupled with a plethysmographic method, basally (T0) and after 1 (T1) and 6 months' treatment (T2)., Results: Blood pressure showed a significant reduction after 1 month (mean blood pressure 109 +/- 2 vs 124 +/- 3 mmHg, M +/- SE, p < 0.001), which was maintained after 6 months (mean blood pressure 112 +/- 3 mmHg, p < 0.001), while heart rate showed only a slight, non-significant increase. There were highly significant changes in distensibility (0.29 +/- 0.02 vs 0.16 +/- 0.01 s2.cm-2, T2 vs T0, p < 0.001), characteristic impedance (55 +/- 3 vs 78 +/- 3 dyn.s.cm-5.10(2), T2 vs T0, p < 0.001) and local resistances (71 +/- 5 vs 118 +/- 4 mmHg.ml-1. s, T2 vs T0, p < 0.001) in the brachial artery, and also in left ventricle posterior wall diastolic thickness (10.2 +/- 0.4 vs 11.5 +/- 0.3 mm, T2 vs T0, p < 0.05), end diastolic volume (127 +/- 3 vs 109 +/- 3 ml, T2 vs T0, p < 0.01) and mass/volume index (1.21 +/- 0.03 vs 1.35 +/- 0.03, p < 0.05)., Conclusions: The antihypertensive efficacy of nicardipine slow release, with only two daily administrations, allows the restoration of the dumping function of the large arteries, and the regression of the functional modifications affecting the left ventricular diastole.

In a double-blind crossover study, 16 hypertensive patients (mean age, 41 years) were randomly assigned to receive placebo or 5 mg of an extended-release formulation of isradipine for 30 days. Blood pressure and heart rate were recorded by an automatic device and hemodynamics measured by a duplex scanner and plethysmography. After the first dose and after 30 days' treatment with isradipine, blood pressure was significantly reduced (mean arterial pressure 4 hours after the first dose, 106 +/- 3 vs 120 +/- 4 mmHg, P < 0.01; 22 hours after the last dose, 108 +/- 3 mmHg, P < 0.01) with no significant changes in heart rate. The compliance of the brachial artery was significantly increased (2.823 +/- 0.358 vs 1.204 +/- 0.156 dyn-1.cm4.10(-7), P < 0.002) and the characteristic impedence decreased (49 +/- 6 vs 91 +/- 12 dyn.s.cm-5.10(2), P < 0.05) as well as local resistances (71 +/- 5.6 vs 198 +/- 18 mmHg.ml-1.s, P < 0.001). After 30 days of isradipine treatment, 22 hours after the last dose, compliance was still increased (2.575 +/- 0.453 dyn-1.cm4.10(-7), P < 0.01) whereas impedance and forearm vascular resistances were reduced (59 +/- 8 dyn.s.cm-5.10(2), P < 0.05, and 97 +/- 14 mmHg.ml-1.s, P < 0.001, respectively). The results indicate that sustained-release isradipine ensures good blood pressure control up to the time of the following dose and restores the large artery dumping function against cyclic variations in intraluminal pressure.

We conducted a randomly allocated, double-blind study in 16 essential hypertensive patients, eight of whom were treated with nifedipine and eight with lacidipine. The antihypertensive efficacy was evaluated and any modifications to peripheral haemodynamic parameters were observed in the brachial artery by a mechanographic method and B-mode scanner with a 10-MHz probe. Statistically significant reductions in blood pressure from basal values were observed after 1 and 6 months' treatment. Enhanced compliance (P less than 0.005), reduced characteristic impedance (P less than 0.001) and lower peripheral resistances (P less than 0.01) were also noted. Variations in pulse wave velocity and mean blood pressure showed a statistically significant correlation as early as the first month of treatment (P less than 0.01). Our results suggest that therapy with nifedipine and lacidipine allows an improvement in peripheral haemodynamics in hypertensive patients. This response is maintained in chronic treatment, even just before the next dose administration at the end of the longest dose interval.

A noninvasive follow-up using duplex ultrasonography was conducted in 128 patients who had undergone carotid endarterectomy from January 1987 to December 1988. Repeated scans of the operated area revealed a distinct increase in thickened ultrasonographic features (32% vs 8%), and a stenosing lesion was detected in 8 patients. There was also a parallel increase in the number of subjects with thicknesses of the intima adjacent to the endarterectomy area exceeding 2.5 mm. In 7% of cases, dilatation was detected in the operated area and in 27% the margin of the area was raised. The study also dealt with the contralateral carotid artery, where a progression of atheromatous involvement was observed with an increased number of cases of hemodynamically significant stenosis and 3 cases of occlusion. Periodic duplex ultrasonography in endarterectomized patients proves useful for the early detection of hemodynamically significant stenoses or of structural features potentially capable of generating emboli.