Simple high-precision diode laser system with digital control.

A simple wavelength tunable diode laser system has been designed and fabricated for laboratory use. Both the current and temperature controllers are based on an AVR microcontroller, and the experimental controls have been implemented with the help of daemon programs running in a message passing interface environment, which allows the users to run the control server and client programs on separate computers. The stability of the controllers has been tested using a distributed feedback (DFB) diode laser with a central wavelength of 852.3 nm. A noise spectral analysis of the current controller with and without the use of the diode laser as the active load has been demonstrated. The absorption spectra of 6S 1/2→6P 3/2 transition of 133 C s, as recorded by using the DFB laser system developed, are also presented.

Signatures of Nontrivial Pairing in the Quantum Walk of Two-Component Bosons.

Nearest neighbor bosons possessing only on-site interactions do not form on-site bound pairs in their quantum walk due to fermionization. We obtain signatures of nontrivial on-site pairing in the quantum walk of strongly interacting two component bosons in a one dimensional lattice. By considering an initial state with particles from different components located at the nearest-neighbor sites in the central region of the lattice, we show that in the dynamical evolution of the system, competing intra- and intercomponent on-site repulsion leads to the formation of on-site intercomponent bound states. We find that when the total number of particles is three, an intercomponent pair is favored in the limit of equal intra- and intercomponent interaction strengths. However, when two bosons from each species are considered, intercomponent pairs and trimer are favored depending on the ratios of the intra- and intercomponent interactions. In both cases, we find that the quantum walks exhibit a reentrant behavior as a function of intercomponent interaction.

Optical See-Through Cancer Vision Goggles Enable Direct Patient Visualization and Real-Time Fluorescence-Guided Oncologic Surgery.

BACKGROUND: The inability to visualize the patient and surgical site directly, limits the use of current near infrared fluorescence-guided surgery systems for real-time sentinel lymph node biopsy and tumor margin assessment. METHODS: We evaluated an optical see-through goggle augmented imaging and navigation system (GAINS) for near-infrared, fluorescence-guided surgery. Tumor-bearing mice injected with a near infrared cancer-targeting agent underwent fluorescence-guided, tumor resection. Female Yorkshire pigs received hind leg intradermal indocyanine green injection and underwent fluorescence-guided, popliteal lymph node resection. Four breast cancer patients received 99mTc-sulfur colloid and indocyanine green retroareolarly before undergoing sentinel lymph node biopsy using radioactive tracking and fluorescence imaging. Three other breast cancer patients received indocyanine green retroareolarly before undergoing standard-of-care partial mastectomy, followed by fluorescence imaging of resected tumor and tumor cavity for margin assessment. RESULTS: Using near-infrared fluorescence from the dyes, the optical see-through GAINS accurately identified all mouse tumors, pig lymphatics, and four pig popliteal lymph nodes with high signal-to-background ratio. In 4 human breast cancer patients, 11 sentinel lymph nodes were identified with a detection sensitivity of 86.67 ± 0.27% for radioactive tracking and 100% for GAINS. Tumor margin status was accurately predicted by GAINS in all three patients, including clear margins in patients 1 and 2 and positive margins in patient 3 as confirmed by paraffin-embedded section histopathology. CONCLUSIONS: The optical see-through GAINS prototype enhances near infrared fluorescence-guided surgery for sentinel lymph node biopsy and tumor margin assessment in breast cancer patients without disrupting the surgical workflow in the operating room.

Antibody quantum dot conjugates developed via copper-free click chemistry for rapid analysis of biological samples using a microfluidic microsphere array system.

Antibody-based proteomics is an enabling technology that has significant implications for cancer biomarker discovery, diagnostic screening, prognostic and pharmacodynamic evaluation of disease state, and targeted therapeutics. Quantum dot based fluoro-immunoconjugates possess promising features toward realization of this goal such as high photostability, brightness, and multispectral tunability. However, current strategies to generate such conjugates are riddled with complications such as improper orientation of antigen binding sites of the antibody, aggregation, and stability issues. We report a facile yet effective strategy to conjugate anti-epidermal growth factor receptor (EGFR) antibody to quantum dots using copper-free click reaction, and compared them to similar constructs prepared using traditional strategies such as succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and biotin-streptavidin schemes. The Fc and Fab regions of the conjugates retain their binding potential, compared to those generated through the traditional schemes. We further applied the conjugates in testing a novel microsphere array device designed to carry out sensitive detection of cancer biomarkers through fluoroimmunoassays. Using purified EGFR, we determined the limit of detection of the microscopy centric system to be 12.5 ng/mL. The biological assay, in silico, was successfully tested and validated by using tumor cell lysates, as well as human serum from breast cancer patients, and the results were compared to normal serum. A pattern consistent with established clinical data was observed, which further validates the effectiveness of the developed conjugates and its successful implementation both in vitro as well as in silico fluoroimmunoassays. The results suggest the potential development of a high throughput in silico paradigm for predicting the class of patient cancer based on EGFR expression levels relative to normal reference levels in blood.

Dual-mode optical imaging system for fluorescence image-guided surgery.

In this Letter, we present a novel imaging concept that a single imaging system can image different spectral bands with different aperture sizes. It is achieved by using a filter with different transmitted spectral bands in different annular rings as the aperture stop. This concept will enable more efficient system configurations and practical clinical applications. We have demonstrated this concept with a dual-mode near-infrared fluorescence image guided surgical system.

Enhanced many-body localization in a kinetically constrained model.

In the study of the thermalization of closed quantum systems, the role of kinetic constraints on the temporal dynamics and the eventual thermalization is attracting significant interest. Kinetic constraints typically lead to long-lived metastable states depending on initial conditions. We consider a model of interacting hardcore bosons with an additional kinetic constraint that was originally devised to capture glassy dynamics at high densities. As a main result, we demonstrate that the system is highly prone to localization in the presence of uncorrelated disorder. Adding disorder quickly triggers long-lived dynamics as evidenced in the time evolution of density autocorrelations. Moreover, the kinetic constraint favors localization also in the eigenstates, where a finite-size transition to a many-body localized phase occurs for much lower disorder strengths than for the same model without a kinetic constraint. Our work sheds light on the intricate interplay of kinetic constraints and localization and may provide additional control over many-body localized phases in the time domain.

Machine learning for the advancement of genome-scale metabolic modeling.

Constraint-based modeling (CBM) has evolved as the core systems biology tool to map the interrelations between genotype, phenotype, and external environment. The recent advancement of high-throughput experimental approaches and multi-omics strategies has generated a plethora of new and precise information from wide-ranging biological domains. On the other hand, the continuously growing field of machine learning (ML) and its specialized branch of deep learning (DL) provide essential computational architectures for decoding complex and heterogeneous biological data. In recent years, both multi-omics and ML have assisted in the escalation of CBM. Condition-specific omics data, such as transcriptomics and proteomics, helped contextualize the model prediction while analyzing a particular phenotypic signature. At the same time, the advanced ML tools have eased the model reconstruction and analysis to increase the accuracy and prediction power. However, the development of these multi-disciplinary methodological frameworks mainly occurs independently, which limits the concatenation of biological knowledge from different domains. Hence, we have reviewed the potential of integrating multi-disciplinary tools and strategies from various fields, such as synthetic biology, CBM, omics, and ML, to explore the biochemical phenomenon beyond the conventional biological dogma. How the integrative knowledge of these intersected domains has improved bioengineering and biomedical applications has also been highlighted. We categorically explained the conventional genome-scale metabolic model (GEM) reconstruction tools and their improvement strategies through ML paradigms. Further, the crucial role of ML and DL in omics data restructuring for GEM development has also been briefly discussed. Finally, the case-study-based assessment of the state-of-the-art method for improving biomedical and metabolic engineering strategies has been elaborated. Therefore, this review demonstrates how integrating experimental and in silico strategies can help map the ever-expanding knowledge of biological systems driven by condition-specific cellular information. This multiview approach will elevate the application of ML-based CBM in the biomedical and bioengineering fields for the betterment of society and the environment.

Intraoperative detection of liver tumors aided by a fluorescence goggle system and multimodal imaging.

Real-time image guidance in the operating room is needed to improve instantaneous surgical decisions. Toward this goal, we utilized a new fluorescence goggle system and a near-infrared fluorescent dye approved for human use, indocyanine green, to demonstrate the feasibility of detecting liver tumors intraoperatively. The fluorescence goggle provided successful imaging of multifocal breast cancer metastases in mouse liver. Diffused tumor deposits as small as 0.8 mm in diameter were detected, which were not obvious without the fluorescence goggle. A combination of surface-weighted fluorescence imaging and deep tissue-sensitive ultrasound imaging allowed comprehensive image guidance with the fluorescence goggle system for tumor resection in a rabbit VX2 liver metastasis model. This multimodal detection and guided surgical intervention strategy using ultrasonic imaging and real-time intraoperative fluorescence guidance is a promising and innovative technology platform for improving surgical outcome of human patients with primary or metastatic liver cancer.

Self-organized criticality of magnetic avalanches in disordered ferrimagnetic material.

We observe multiple steplike jumps in a Dy-Fe-Ga-based ferrimagnetic alloy in its magnetic hysteresis curve at 2 K. The observed jumps are found to have a stochastic character with respect to their magnitude and the field position, and the jumps do not correlate with the duration of the field. The distribution of jump size follows a power law variation indicating the scale invariance nature of the jumps. We have invoked a simple two-dimensional random bond Ising-type spin system to model the dynamics. Our computational model can qualitatively reproduce the jumps and their scale-invariant character. It also elucidates that the flipping of antiferromagnetically coupled Dy and Fe clusters is responsible for the observed jumps in the hysteresis loop. These features are described in terms of the self-organized criticality.

In Situ Assembled Polynuclear Zinc Oxo Clusters Using Modified Schiff Bases as Ligands.

A series of different cores and nuclearity zinc metal clusters 1-5 have been synthesized using Zn(ClO4)2·6H2O, Schiff-base primary ligands, and dibenzoyl methane (DBM) or monoethanolamine (MEA) as co-ligand in a room-temperature reaction. The structure of the complexes is characterized using single-crystal X-ray diffraction. Among them, (1) [Zn(L1)(DBM)] is mononuclear; (2) [Zn4(L2)2(DBM)4], (3) [Zn4(L2)4(H2O)2(ClO4)2]·2CH2Cl2, and (4) [Zn4(L3)2(DBM)4] have a cubane core; and (5) [Zn4(L4)4(MEA)2(ClO4)2] has a ladderlike core structure. Compounds 1-5 have also been characterized using UV-vis absorption and emission spectroscopies. For an in-depth understanding of the absorption spectra of 1 and 3, density functional theory (DFT) calculations have been performed, which suggest that the transitions correspond to the π → π* intraligand charge transfer (ILCT) transitions.

Bacterial species metabolic interaction network for deciphering the lignocellulolytic system in fungal cultivating termite gut microbiota.

Fungus-cultivating termite Odontotermes badius developed a mutualistic association with Termitomyces fungi for the plant material decomposition and providing a food source for the host survival. The mutualistic relationship sifted the microbiome composition of the termite gut and Termitomyces fungal comb. Symbiotic bacterial communities in the O. badius gut and fungal comb have been studied extensively to identify abundant bacteria and their lignocellulose degradation capabilities. Despite several metagenomic studies, the species-wide metabolic interaction patterns of bacterial communities in termite gut and fungal comb remains unclear. The bacterial species metabolic interaction network (BSMIN) has been constructed with 230 bacteria identified from the O. badius gut and fungal comb microbiota. The network portrayed the metabolic map of the entire microbiota and highlighted several inter-species biochemical interactions like cross-feeding, metabolic interdependency, and competition. Further, the reconstruction and analysis of the bacterial influence network (BIN) quantified the positive and negative pairwise influences in the termite gut and fungal comb microbial communities. Several key macromolecule degraders and fermentative microbial entities have been identified by analyzing the BIN. The mechanistic interplay between these influential microbial groups and the crucial glycoside hydrolases (GH) enzymes produced by the macromolecule degraders execute the community-wide functionality of lignocellulose degradation and subsequent fermentation. The metabolic interaction pattern between the nine influential microbial species has been determined by considering them growing in a synthetic microbial community. Competition (30%), parasitism (47%), and mutualism (17%) were predicted to be the major mode of metabolic interaction in this synthetic microbial community. Further, the antagonistic metabolic effect was found to be very high in the metabolic-deprived condition, which may disrupt the community functionality. Thus, metabolic interactions of the crucial bacterial species and their GH enzyme cocktail identified from the O. badius gut and fungal comb microbiota may provide essential knowledge for developing a synthetic microcosm with efficient lignocellulolytic machinery.

Quantitative tumor depth determination using dual wavelength excitation fluorescence.

Quantifying solid tumor margins with fluorescence-guided surgery approaches is a challenge, particularly when using near infrared (NIR) wavelengths due to increased penetration depths. An NIR dual wavelength excitation fluorescence (DWEF) approach was developed that capitalizes on the wavelength-dependent attenuation of light in tissue to determine fluorophore depth. A portable dual wavelength excitation fluorescence imaging system was built and tested in parallel with an NIR tumor-targeting fluorophore in tissue mimicking phantoms, chicken tissue, and in vivo mouse models of breast cancer. The system showed high accuracy in all experiments. The low cost and simplicity of this approach make it ideal for clinical use.

Two component quantum walk in one-dimensional lattice with hopping imbalance.

We investigate the two-component quantum walk in one-dimensional lattice. We show that the inter-component interaction strength together with the hopping imbalance between the components exhibit distinct features in the quantum walk for different initial states. When the walkers are initially on the same site, both the slow and fast particles perform independent particle quantum walks when the interaction between them is weak. However, stronger inter-particle interactions result in quantum walks by the repulsively bound pair formed between the two particles. For different initial states when the walkers are on different sites initially, the quantum walk performed by the slow particle is almost independent of that of the fast particle, which exhibits reflected and transmitted components across the particle with large hopping strength for weak interactions. Beyond a critical value of the interaction strength, the wave function of the fast particle ceases to penetrate through the slow particle signalling a spatial phase separation. However, when the two particles are initially at the two opposite edges of the lattice, then the interaction facilitates the complete reflection of both of them from each other. We analyze the above mentioned features by examining various physical quantities such as the on-site density evolution, two-particle correlation functions and transmission coefficients.

Competing magnetic interactions and magnetocaloric effect in Ho5Sn3.

The rare-earth intermetallic compound Ho5Sn3demonstrates fascinating magnetic properties, which include temperature-driven multiple magnetic transitions and field-driven metamagnetism. We address the magnetic character of this exciting compound through a combined experimental and theoretical studies. Ho5Sn3orders antiferromagnetically below 28 K, and shows further spin reorientation transitions at 16 K and 12 K. We observe a sizable amount of low-temperature magnetocaloric effect (MEC) in Ho5Sn3with a maximum value of entropy change ΔS= -9.5 J Kg-1 K-1for an applied field ofH= 50 kOe at around 30 K. The field hysteresis is almost zero above 15 K where the MEC is important. Interestingly, ΔSis found to change its sign from positive to negative as the temperature is increased above about 8 K, which can be linked to the multiple spin reorientation transitions. The signature of the metamagnetism is visible in the ΔSversusHplot. The magnetic ground state, obtained from the density functional theory based calculation, is susceptible to the effective Coulomb interaction (Ueff) between electrons. Depending upon the value ofUeff, the ground state can be ferromagnetic or antiferromagnetic. The compound shows large relaxation (14% change in magnetisation in 60 min) in the field cooled state with a logarithmic time variation, which may be connected to the competing magnetic correlations observed in our theoretical calculations. The competing magnetic ground states are equally evident from the small value of the paramagnetic Curie-Weiss temperature.

Repurposing Molecular Imaging and Sensing for Cancer Image-Guided Surgery.

Gone are the days when medical imaging was used primarily to visualize anatomic structures. The emergence of molecular imaging (MI), championed by radiolabeled 18F-FDG PET, has expanded the information content derived from imaging to include pathophysiologic and molecular processes. Cancer imaging, in particular, has leveraged advances in MI agents and technology to improve the accuracy of tumor detection, interrogate tumor heterogeneity, monitor treatment response, focus surgical resection, and enable image-guided biopsy. Surgeons are actively latching on to the incredible opportunities provided by medical imaging for preoperative planning, intraoperative guidance, and postoperative monitoring. From label-free techniques to enabling cancer-selective imaging agents, image-guided surgery provides surgical oncologists and interventional radiologists both macroscopic and microscopic views of cancer in the operating room. This review highlights the current state of MI and sensing approaches available for surgical guidance. Salient features of nuclear, optical, and multimodal approaches will be discussed, including their strengths, limitations, and clinical applications. To address the increasing complexity and diversity of methods available today, this review provides a framework to identify a contrast mechanism, suitable modality, and device. Emerging low-cost, portable, and user-friendly imaging systems make the case for adopting some of these technologies as the global standard of care in surgical practice.

Differential flexibility leading to crucial microelastic properties of asymmetric lipid vesicles for cellular transfection: A combined spectroscopic and atomic force microscopy studies.

The role of microscopic elasticity of nano-carriers in cellular uptake is an important aspect in biomedical research. Herein we have used AFM nano-indentation force spectroscopy and Förster resonance energy transfer (FRET) measurements to probe microelastic properties of three novel cationic liposomes based on di-alkyl dihydroxy ethyl ammonium chloride based lipids having asymmetry in their hydrophobic chains (Lip1818, Lip1814 and Lip1810). AFM data reveals that symmetry in hydrophobic chains of a cationic lipid (Lip1818) imparts higher rigidity to the resulting liposomes than those based on asymmetric lipids (Lip1814 and Lip1810). The stiffness of the cationic liposomes is found to decrease with increasing asymmetry in the hydrophobic lipid chains in the order of Lip1818 > Lip1814 > lip1810. FRET measurements between Coumarin 500 (Donor) and Merocyanine 540 (Acceptor) have revealed that full width at half-maxima (hw) of the probability distribution (P(r)) of donor-acceptor distance (r), increases in an order Lip1818 < Lip1814 < Lip1810 with increasing asymmetry of the hydrophobic lipid chains. This increase in width (hw) of the donor-acceptor distance distributions is reflective of increasing flexibility of the liposomes with increasing asymmetry of their constituent lipids. Thus, the results from AFM and FRET studies are complementary to each other and indicates that an increase in asymmetry of the hydrophobic lipid chains increases elasticity and or flexibility of the corresponding liposomes. Cell biology experiments confirm that liposomal flexibility or rigidity directly influences their cellular transfection efficiency, where Lip1814 is found to be superior than the other two liposomes manifesting that a critical balance between flexibility and rigidity of the cationic liposomes is key to efficient cellular uptake. Taken together, our studies reveal how asymmetry in the molecular architecture of the hydrophobic lipid chains influences the microelastic properties of the liposomes, and hence, their cellular uptake efficiency.

Focal dynamic thermal imaging for label-free high-resolution characterization of materials and tissue heterogeneity.

Evolution from static to dynamic label-free thermal imaging has improved bulk tissue characterization, but fails to capture subtle thermal properties in heterogeneous systems. Here, we report a label-free, high speed, and high-resolution platform technology, focal dynamic thermal imaging (FDTI), for delineating material patterns and tissue heterogeneity. Stimulation of focal regions of thermally responsive systems with a narrow beam, low power, and low cost 405 nm laser perturbs the thermal equilibrium. Capturing the dynamic response of 3D printed phantoms, ex vivo biological tissue, and in vivo mouse and rat models of cancer with a thermal camera reveals material heterogeneity and delineates diseased from healthy tissue. The intuitive and non-contact FDTI method allows for rapid interrogation of suspicious lesions and longitudinal changes in tissue heterogeneity with high-resolution and large field of view. Portable FDTI holds promise as a clinical tool for capturing subtle differences in heterogeneity between malignant, benign, and inflamed tissue.

Selective imaging of solid tumours via the calcium-dependent high-affinity binding of a cyclic octapeptide to phosphorylated Annexin A2.

The heterogeneity and continuous genetic adaptation of tumours complicate their detection and treatment via the targeting of genetic mutations. However, hallmarks of cancer such as aberrant protein phosphorylation and calcium-mediated cell signalling provide broadly conserved molecular targets. Here, we show that, for a range of solid tumours, a cyclic octapeptide labelled with a near-infrared dye selectively binds to phosphorylated Annexin A2 (pANXA2), with high affinity at high levels of calcium. Because of cancer-cell-induced pANXA2 expression in tumour-associated stromal cells, the octapeptide preferentially binds to the invasive edges of tumours and then traffics within macrophages to the tumour's necrotic core. As proof-of-concept applications, we used the octapeptide to detect tumour xenografts and metastatic lesions, and to perform fluorescence-guided surgical tumour resection, in mice. Our findings suggest that high levels of pANXA2 in association with elevated calcium are present in the microenvironment of most solid cancers. The octapeptide might be broadly useful for selective tumour imaging and for delivering drugs to the edges and to the core of solid tumours.

Bio-inspired imager improves sensitivity in near-infrared fluorescence image-guided surgery.

Image-guided surgery can enhance cancer treatment by decreasing, and ideally eliminating, positive tumor margins and iatrogenic damage to healthy tissue. Current state-of-the-art near-infrared fluorescence imaging systems are bulky and costly, lack sensitivity under surgical illumination, and lack co-registration accuracy between multimodal images. As a result, an overwhelming majority of physicians still rely on their unaided eyes and palpation as the primary sensing modalities for distinguishing cancerous from healthy tissue. Here we introduce an innovative design, comprising an artificial multispectral sensor inspired by the Morpho butterfly's compound eye, which can significantly improve image-guided surgery. By monolithically integrating spectral tapetal filters with photodetectors, we have realized a single-chip multispectral imager with 1000 × higher sensitivity and 7 × better spatial co-registration accuracy compared to clinical imaging systems in current use. Preclinical and clinical data demonstrate that this technology seamlessly integrates into the surgical workflow while providing surgeons with real-time information on the location of cancerous tissue and sentinel lymph nodes. Due to its low manufacturing cost, our bio-inspired sensor will provide resource-limited hospitals with much-needed technology to enable more accurate value-based health care.

Image overlay solution based on threshold detection for a compact near infrared fluorescence goggle system.

Near infrared (NIR) fluorescence imaging has shown great potential for various clinical procedures, including intraoperative image guidance. However, existing NIR fluorescence imaging systems either have a large footprint or are handheld, which limits their usage in intraoperative applications. We present a compact NIR fluorescence imaging system (NFIS) with an image overlay solution based on threshold detection, which can be easily integrated with a goggle display system for intraoperative guidance. The proposed NFIS achieves compactness, light weight, hands-free operation, high-precision superimposition, and a real-time frame rate. In addition, the miniature and ultra-lightweight light-emitting diode tracking pod is easy to incorporate with NIR fluorescence imaging. Based on experimental evaluation, the proposed NFIS solution has a lower detection limit of 25 nM of indocyanine green at 27 fps and realizes a highly precise image overlay of NIR and visible images of mice in vivo. The overlay error is limited within a 2-mm scale at a 65-cm working distance, which is highly reliable for clinical study and surgical use.