Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Non-reciprocal and non-Newtonian mechanical metamaterials.

Non-Newtonian liquids are characterized by stress and velocity-dependent dynamical response. In elasticity, and in particular, in the field of phononics, reciprocity in the equations acts against obtaining a directional response for passive media. Active stimuli-responsive materials have been conceived to overcome it. Significantly, Milton and Willis have shown theoretically in 2007 that quasi-rigid bodies containing masses at resonance can display a very rich dynamical behavior, hence opening a route toward the design of non-reciprocal and non-Newtonian metamaterials. In this paper, we design a solid structure that displays unidirectional shock resistance, thus going beyond Newton's second law in analogy to non-Newtonian fluids. We design the mechanical metamaterial with finite element analysis and fabricate it using three-dimensional printing at the centimetric scale (with fused deposition modeling) and at the micrometric scale (with two-photon lithography). The non-Newtonian elastic response is measured via dynamical velocity-dependent experiments. Reversing the direction of the impact, we further highlight the intrinsic non-reciprocal response.

Micro-Scale Mechanical Metamaterial with a Controllable Transition in the Poisson's Ratio and Band Gap Formation.

The ability to significantly change the mechanical and wave propagation properties of a structure without rebuilding it is currently one of the main challenges in the field of mechanical metamaterials. This stems from the enormous appeal that such tunable behavior may offer from the perspective of applications ranging from biomedical to protective devices, particularly in the case of micro-scale systems. In this work, a novel micro-scale mechanical metamaterial is proposed that can undergo a transition from one type of configuration to another, with one configuration having a very negative Poisson's ratio, corresponding to strong auxeticity, and the other having a highly positive Poisson's ratio. The formation of phononic band gaps can also be controlled concurrently which can be very useful for the design of vibration dampers and sensors. Finally, it is experimentally shown that the reconfiguration process can be induced and controlled remotely through application of a magnetic field by using appropriately distributed magnetic inclusions.

3D Auxetic Metamaterials with Elastically-Stable Continuous Phase Transition.

In solid state physics, phase transitions can influence material functionality and alter their properties. In mechanical metamaterials, structural-phase transitions can be achieved through instability or buckling of certain structural elements. However, these fast transitions in one mechanical parameter typically affect significantly the remaining parameters, hence, limiting their applications. Here, this limitation is addressed by designing a novel 3D mechanical metamaterial that is capable of undergoing a phase transition from positive to negative Poisson's ratio under compression, without significant degradation of Young's modulus (i.e. the phase transition is elastically-stable). The metamaterial is fabricated by two-photon lithography at the micro-scale and its mechanical behavior is assessed experimentally. For another choice of structural parameters, it is then shown that the auxetic behavior of the considered 3D metamaterial class can be maintained over a wide range of applied compressive strain.

Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.

Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61ß-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.

Micro-Scale Auxetic Hierarchical Mechanical Metamaterials for Shape Morphing.

Shape morphing and the possibility of having control over mechanical properties via designed deformations have attracted a lot of attention in the materials community and led to a variety of applications with an emphasis on the space industry. However, current materials normally do not allow to have a full control over the deformation pattern and often fail to replicate such behavior at low scales which is essential in flexible electronics. Thus, in this paper, novel 2D and 3D microscopic hierarchical mechanical metamaterials using mutually-competing substructures within the system that are capable of exhibiting a broad range of the highly unusual auxetic behavior are proposed. Using experiments (3D microprinted polymers) supported by computer simulations, it is shown that such ability can be controlled through geometric design parameters. Finally it is demonstrated that the considered structure can form a composite capable of shape morphing allowing it to deform to a predefined shape.

Comparative Study of the Influence of Three-Dimensional Versus Two-Dimensional Urological Laparoscopy on Surgeons' Surgical Performance and Ergonomics: A Systematic Review and Meta-Analysis.

Objective: The objective of this study is to compare the use of three-dimensional (3D) vision systems with traditional two-dimensional systems in laparoscopic urological surgery, analyzing the benefits, limitations, and impact of introducing this medical technology with regard to surgical performance and the surgeon's ergonomics. Methods: A systematic review with a structured bibliographic search was conducted in the electronic libraries (PubMed and EMBASE) until August 2019 and with no language restrictions. Studies on 3D visualization technology in laparoscopic urologic surgery, randomized controlled trials, and observational comparative studies were included. Relevant data were extracted and analyzed. Results: A total of 25 articles were obtained, of which 4 were clinical studies with patients, 2 studies were carried out in experimental animal models, and the remaining 19 were conducted in simulated environments. Regarding the European training program in basic laparoscopic urological skills, the results showed no significant differences in execution time using either imaging system. Three-dimensional vision led to a significant reduction in surgery time in pyeloplasty and radical nephrectomy. In addition, there was a reported decrease in blood loss in adrenalectomy, nephron-sparing nephrectomy, radical nephrectomy, simple nephrectomy, and pyeloplasty using 3D vision. Regarding ergonomics, the studies generally described no differences in side effects (headache, nausea, eye strain) when comparing the two types of visualization systems. Surgeons reported reduced workloads and stress with 3D vision than with traditional laparoscopy. Conclusions: Three-dimensional laparoscopic systems essentially advance surgical performance in less-experienced laparoscopic surgeons. Three-dimensional laparoscopy leads to improvements in surgery time, which is important for specific surgical procedures involving intracorporeal ligatures and sutures. The results achieved on the surgeons' ergonomics showed better depth perception and decreased stress and workloads during 3D vision with no differences in potential side effects.

Highly Effective GeNi Alloy Contact Diffusion Barrier for BiSbTe Long-Term Thermal Exposure.

A GeNi alloy diffusion barrier for contacts on bismuth antimony telluride is proposed. Multiple gold contact diffusion barriers were tested at different thermal aging conditions in air and reducing atmospheres. Among all diffusion barriers, the GeNi alloy barrier shows the best performance for bulk samples with no substantial degradation of the contact resistance, no contact color change, and no change of thermoelectric properties. We observed D Au-GeNi = (9.8 ± 2.7) × 10-20 m2/s within the GeNi alloy barrier, which is 4 times smaller than D Au-BiSbTe. The presence of the initial Ge layer also proves to be effective in reducing nickel diffusion yielding D Ni-BiSbTe = (8.57 ± 0.49) × 10-19 m2/s. During GeNi alloy formation, Ge diffusion into BiSbTe produces GeTe, which apparently blocks the van der Waals gaps eliminating Au and Ni fast diffusion pathways. Thermal aging of BiSbTe nanowires shows that Au and Ni diffusion degrades the thermoelectric power factor, whereas the GeNi alloy barrier sample is mostly preserved. The GeNi alloy barrier is a reliable solution to long-term thermal applications of BiTe-based materials.

Enhanced thermoelectric transport in modulation-doped GaN/AlGaN core/shell nanowires.

The thermoelectric properties of unintentionally n-doped core GaN/AlGaN core/shell N-face nanowires are reported. We found that the temperature dependence of the electrical conductivity is consistent with thermally activated carriers with two distinctive donor energies. The Seebeck coefficient of GaN/AlGaN nanowires is more than twice as large as that for the GaN nanowires alone. However, an outer layer of GaN deposited onto the GaN/AlGaN core/shell nanowires decreases the Seebeck coefficient at room temperature, while the temperature dependence of the electrical conductivity remains the same. We attribute these observations to the formation of an electron gas channel within the heavily-doped GaN core of the GaN/AlGaN nanowires. The room-temperature thermoelectric power factor for the GaN/AlGaN nanowires can be four times higher than the GaN nanowires. Selective doping in bandgap engineered core/shell nanowires is proposed for enhancing the thermoelectric power.

Simultaneous Thermoelectric and Optoelectronic Characterization of Individual Nanowires.

Semiconducting nanowires have been explored for a number of applications in optoelectronics such as photodetectors and solar cells. Currently, there is ample interest in identifying the mechanisms that lead to photoresponse in nanowires in order to improve and optimize performance. However, distinguishing among the different mechanisms, including photovoltaic, photothermoelectric, photoemission, bolometric, and photoconductive, is often difficult using purely optoelectronic measurements. In this work, we present an approach for performing combined and simultaneous thermoelectric and optoelectronic measurements on the same individual nanowire. We apply the approach to GaN/AlGaN core/shell and GaN/AlGaN/GaN core/shell/shell nanowires and demonstrate the photothermoelectric nature of the photocurrent observed at the electrical contacts at zero bias, for above- and below-bandgap illumination. Furthermore, the approach allows for the experimental determination of the temperature rise due to laser illumination, which is often obtained indirectly through modeling. We also show that under bias, both above- and below-bandgap illumination leads to a photoresponse in the channel with signatures of persistent photoconductivity due to photogating. Finally, we reveal the concomitant presence of photothermoelectric and photogating phenomena at the contacts in scanning photocurrent microscopy under bias by using their different temporal response. Our approach is applicable to a broad range of nanomaterials to elucidate their fundamental optoelectronic and thermoelectric properties.

Complicaciones de la adenomectomía en el adulto mayor / Complications of the Adenomectomy in the Elderly

Se realizó un estudio descriptivo, con el objetivo de determinar las complicaciones más frecuentes de la adenomectomía en 209 pacientes, atendidos en la consulta de Urología del hospital “Somine Dolo” de la región de Mopti, República de Mali, a los cuales se les diagnosticó Hiperplasia Benigna de la Próstata a través del examen rectal y confirmado por ecografía transabdominal. Se les realizó, además, el chequeo preoperatorio, consistente en hemoglobina, hematocrito, creatinina y grupo y factor; fueron operados de la próstata a cielo abierto por la vía transvesical. Se les aplicó antibioticoterapia profiláctica con ciprofloxacina, a razón de 500 mg cada 12 horas, y metronidazol, a razón de 250 mg cada 8 horas, como es la usanza en ese país. Se mantuvo cubierta la herida quirúrgica con apósito y esparadrapo y se realizaron curas en días alternos. Las principales complicaciones encontradas fueron la infección y la dehiscencia de la herida quirúrgica. La hemorragia postoperatoria (1,4 por ciento) y la incontinencia urinaria postoperatoria (7,6 por ciento) fueron otras complicaciones producidas. Solo se ocasionaron dos decesos, lo cual representó el 0,9 por ciento y demuestra que la adenomectomía es una operación que puede ser practicada con seguridad en el adulto mayor, contribuyendo, por tanto, a mejorar su calidad de vida (AU)

A descriptive study was carried out with the objective to determine the most frequent complications of the adenomectomy in 209 patients assisted at the Department of Urology of “Somine Dolo” Hospital of Mopti region, in the Republic of Mali. The patients were diagnosed with benign prostatic hyperplasia by means of the rectal exam and confirmed with transabdominal echography. The preoperative check-up was also performed, consisting of haemoglobin, hematocrit, creatinine and group and factor. The patients had a prostate open operation through transvesical way. They were treated with prophylactic antibiotic therapy which included ciprofloxacin 500 mg every 12 hours and metronidazole 250 mg every 8 hours, as it is usual in that country. The surgical wounds were cover with dressing and adhesive tape and were cured on alternate days. The main complications were infection and dehiscence of the surgical wounds. Other complications were postoperative haemorrhage (1,4 por ciento) as well as the postoperative urinary incontinence (7,6 por ciento). Only two deaths occurred which represented a 0,9 por ciento. The study showed that the adenectomy is a safe operation for adults and therefore, it contributes to improve their quality of life (AU)

Varicocele e infertilidad: resultados del tratamiento quirúrgico / Varicocele and Infertility: results of the surgical treatment

Se realizó un estudio observacional analítico, con el objetivo de precisar los resultados del tratamiento quirúrgico en los pacientes con infertilidad causada por varicocele, en el Hospital General Docente Dr Ernesto Guevara de la Serna, de la provincia de Las Tunas; en el período de enero de 2011 hasta abril de 2012. Se revisaron las historias clínicas de 756 pacientes con varicocele e infertilidad, operados por la técnica de Lewis entre enero de 2008 y diciembre de 2011. Se observó la mayor incidencia en el grupo de edades de 26 a 35 años. La calidad del semen mejoró en el 73,3 por ciento después de la operación. El grupo de edades que tuvo mejores resultados en cuanto a calidad del semen y embarazos fue el de 26 a 35 años. Lograron el embarazo el 75 por ciento de los pacientes (AU)

An analytic and observational study was carried out with the objective of specifying the results of the surgical treatment in patients with infertility caused by varicocele in Dr Ernesto Guevara de la Serna General Hospital in Las Tunas, from January, 2011 to April, 2012. The clinical records of 756 patients with varicocele and infertility were checked, all of them operated by Lewis technique between January, 2008 and December, 2011. The main incidence was observed in the group of ages from 26 to 35 years old. The quality of semen improved in 73,3 percent after the operation. The group of ages that had better results regarding the quality of the semen and pregnancies was that of 26 to 35 years old; 75 percent of the patients achieved the pregnancy (AU)

Functional integration of membrane proteins with nanotube and nanowire transistor devices.

Biological molecules perform a sophisticated array of transport and signaling functions that rival anything that the modern electronics industry can create. Incorporating such building blocks into nanoelectronic devices could enable new generations of electronic circuits that use biomimetics to perform complicated tasks. Such types of circuits could ultimately blur the interface between living biological organisms and synthetic structures. Our laboratory has recently developed a versatile and flexible platform for integrating ion channels and pumps into single-walled carbon nanotube (SWNT) and silicon nanowire (SiNW) transistor devices, in which membrane proteins are embedded in a lipid bilayer shell covering the nanotube or nanowire component. In this chapter, we provide details for the fabrication of these devices and outline procedures for incorporating biological molecules into them. In addition, we also provide several examples of the use of these devices to couple biological transport to electronic signaling.

Carbon nanotube transistor controlled by a biological ion pump gate.

We report a hybrid bionanoelectronic transistor that has a local ATP-powered protein gate. ATP-dependent activity of a membrane ion pump, Na(+)/K(+)-ATPase, embedded in a lipid membrane covering the carbon nanotube, modulates the transistor output current by up to 40%. The ion pump gates the device by shifting the pH of the water layer between the lipid bilayer and nanotube surface. This transistor is a versatile bionanoelectronic platform that can incorporate other membrane proteins.

Valoraciones acerca de la incorporación curricular de la Medicina Tradicional al pregrado / Evaluations about the curricular incorporation of the Traditional Medicine to the undergraduate

La educación cubana contribuye a la formación de un hombre plenamente identificado con su nacionalidad y de sólida y profunda formación humanista, que responda a los valores positivos de la época, y entre una de sus funciones sociales se encuentra la de facilitar la apropiación de contenidos significativos que contribuyan a la formación científico­técnica, humanista y práctica acorde a las necesidades sociales, grupales e individuales y deben buscarse espacios para ello.

Bioelectronic silicon nanowire devices using functional membrane proteins.

Modern means of communication rely on electric fields and currents to carry the flow of information. In contrast, biological systems follow a different paradigm that uses ion gradients and currents, flows of small molecules, and membrane electric potentials. Living organisms use a sophisticated arsenal of membrane receptors, channels, and pumps to control signal transduction to a degree that is unmatched by manmade devices. Electronic circuits that use such biological components could achieve drastically increased functionality; however, this approach requires nearly seamless integration of biological and manmade structures. We present a versatile hybrid platform for such integration that uses shielded nanowires (NWs) that are coated with a continuous lipid bilayer. We show that when shielded silicon NW transistors incorporate transmembrane peptide pores gramicidin A and alamethicin in the lipid bilayer they can achieve ionic to electronic signal transduction by using voltage-gated or chemically gated ion transport through the membrane pores.

Highly efficient biocompatible single silicon nanowire electrodes with functional biological pore channels.

Nanoscale electrodes based on one-dimensional inorganic conductors could possess significant advantages for electrochemical measurements over their macroscopic counterparts in a variety of electrochemical applications. We show that the efficiency of the electrodes constructed of individual highly doped silicon nanowires greatly exceeds the efficiency of flat Si electrodes. Modification of the surfaces of the nanowire electrodes with phospholipid bilayers produces an efficient biocompatible barrier to transport of the solution redox species to the nanoelectrode surface. Incorporating functional alpha-hemolysin protein pores in the lipid bilayer results in a partial recovery of the Faradic current due to the specific transport through the protein pore. These assemblies represent a robust and versatile platform for building a new generation of highly specific biosensors and nano/bioelectronic devices.

Formation, stability, and mobility of one-dimensional lipid bilayers on polysilicon nanowires.

Curved lipid membranes are ubiquitous in living systems and play an important role in many biological processes. To understand how curvature and lipid composition affect membrane formation and fluidity, we have assembled and studied mixed 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) supported lipid bilayers on amorphous silicon nanowires grown around carbon nanotube cores with controlled wire diameters ranging from 20 to 200 nm. We found that lipid vesicles fused onto nanowire substrates and formed continuous bilayers for all DOPC-DOPE mixtures tested (with the DOPE content of up to 30%). Our measurements demonstrate that nanowire-supported bilayers are mobile, exhibit fast recovery after photobleaching, and have a low concentration of defects. Lipid diffusion coefficients in these high-curvature tubular membranes are comparable to the values reported for flat supported bilayers and increase slightly with decreasing nanowire diameter. A free space diffusion model adequately describes the effect of bilayer curvature on the lipid mobility for nanowire substrates with diameters greater than 50 nm, but shows significant deviations from the experimental values for smaller diameter nanowires.