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Protein tyrosine phosphatase 1B (PTP1B) plays important roles in cellular homeostasis and is a highly validated therapeutic target for multiple human ailments, including diabetes, obesity and breast cancer. However, much remains to be learned about how conformational changes may convey information through the structure of PTP1B to enable allosteric regulation by ligands or functional responses to mutations. High-resolution X-ray crystallography can offer unique windows into protein conformational ensembles, but comparison of even high-resolution structures is often complicated by differences between data sets, including non-isomorphism. Here, the highest resolution crystal structure of apo wild-type (WT) PTP1B to date is presented out of a total of ∼350 PTP1B structures in the PDB. This structure is in a crystal form that is rare for PTP1B, with two unique copies of the protein that exhibit distinct patterns of conformational heterogeneity, allowing a controlled comparison of local disorder across the two chains within the same asymmetric unit. The conformational differences between these chains are interrogated in the apo structure and between several recently reported high-resolution ligand-bound structures. Electron-density maps in a high-resolution structure of a recently reported activating double mutant are also examined, and unmodeled alternate conformations in the mutant structure are discovered that coincide with regions of enhanced conformational heterogeneity in the new WT structure. These results validate the notion that these mutations operate by enhancing local dynamics, and suggest a latent susceptibility to such changes in the WT enzyme. Together, these new data and analysis provide a detailed view of the conformational ensemble of PTP1B and highlight the utility of high-resolution crystallography for elucidating conformational heterogeneity with potential relevance for function.

We explain analysis of RIXS, HERFD and XR-HERFD data to discover new physical processes in manganese and manganese-containing materials, by applying our new technique XR-HERFD, developed from high resolution RIXS and HERFD.

In X-ray diffraction measurements, the angular resolution has a detection limit due to the receiving size of the detector. In many cases this detection limit is too large and must be breached to obtain the desired information. A novel method is proposed here by making the detector simultaneously measuring and moving. Using the deconvolution algorithm to remove the convolution effect, the pixel size limitation is finally broken. The algorithm used is not a common one, and suppresses signals at high frequencies, ensuring the reliability of the peak shape after restoration. The feasibility of this method is verified by successfully measuring the crystal truncation rod signal of SrTiO3 single crystal, and the resolution is nearly ten times higher than that of a single pixel. Moreover, this method greatly reduces the noise and improves the signal-to-noise ratio.

In the realm of X-ray ptychography experiments, a considerable amount of ptychography scans are typically performed within a field of view encompassing the target sample. While it is crucial to obtain overlapping scans in small increments over the region of interest for achieving high-resolution sample reconstruction, a significant number of these scans often redundantly measure the empty background within the wide field of view. To address this inefficiency, an innovative algorithm is proposed that introduces automatic guidance for data acquisition. The algorithm first directs the scan point to actively search for the object of interest within the field of view. Subsequently, it intelligently scans along the perimeter of the sample, strategically acquiring measurements exclusively within the boundary of the region of interest. By employing this approach, a reduction in the number of measurements required to obtain high-resolution reconstruction images is demonstrated, as compared with conventional raster scanning methods. Furthermore, the automatic guidance provided by the algorithm offers the added advantage of saving valuable time during the reconstruction process. Through practical implementation on real experiments, these findings showcase the efficacy of the proposed algorithm in enhancing the efficiency and accuracy of X-ray ptychography experiments. This novel approach holds immense potential for advancing sample analysis and imaging techniques in various scientific disciplines.

High energy resolution fluorescence detected X-ray absorption spectroscopy is a powerful method for probing the electronic structure of functional materials. The X-ray penetration depth and photon-in/photon-out nature of the method allow operando experiments to be performed, in particular in electrochemical cells. Here, operando high-resolution X-ray absorption measurements of a BiVO4 photoanode are reported, simultaneously probing the local electronic states of both cations. Small but significant variations of the spectral lineshapes induced by the applied potential were observed and an explanation in terms of the occupation of electronic states at or near the band edges is proposed.

Despite the increased brilliance of the new generation synchrotron sources, there is still a challenge with high-resolution scanning of very thick and absorbing samples, such as a whole mouse brain stained with heavy elements, and, extending further, brains of primates. Samples are typically cut into smaller parts, to ensure a sufficient X-ray transmission, and scanned separately. Compared with the standard tomography setup where the sample would be cut into many pillars, the laminographic geometry operates with slab-shaped sections significantly reducing the number of sample parts to be prepared, the cutting damage and data stitching problems. In this work, a laminography pipeline for imaging large samples (>1 cm) at micrometre resolution is presented. The implementation includes a low-cost instrument setup installed at the 2-BM micro-CT beamline of the Advanced Photon Source. Additionally, sample mounting, scanning techniques, data stitching procedures, a fast reconstruction algorithm with low computational complexity, and accelerated reconstruction on multi-GPU systems for processing large-scale datasets are presented. The applicability of the whole laminography pipeline was demonstrated by imaging four sequential slabs throughout an entire mouse brain sample stained with osmium, in total generating approximately 12 TB of raw data for reconstruction.

The demand for powder X-ray diffraction analysis continues to increase in a variety of scientific fields, as the excellent beam quality of high-brightness synchrotron light sources enables the acquisition of high-quality measurement data with high intensity and angular resolution. Synchrotron powder diffraction has enabled the rapid measurement of many samples and various in situ/operando experiments in nonambient sample environments. To meet the demands for even higher throughput measurements using high-energy X-rays at SPring-8, a high-throughput and high-resolution powder diffraction system has been developed. This system is combined with six sets of two-dimensional (2D) CdTe detectors for high-energy X-rays, and various automation systems, including a system for automatic switching among large sample environmental equipment, have been developed in the third experimental hutch of the insertion device beamline BL13XU at SPring-8. In this diffractometer system, high-brilliance and high-energy X-rays ranging from 16 to 72 keV are available. The powder diffraction data measured under ambient and various nonambient conditions can be analysed using Rietveld refinement and the pair distribution function. Using the 2D CdTe detectors with variable sample-to-detector distance, three types of scan modes have been established: standard, single-step and high-resolution. A major feature is the ability to measure a whole powder pattern with millisecond resolution. Equally important, this system can measure powder diffraction data with high Q exceeding 30 Å−1 within several tens of seconds. This capability is expected to contribute significantly to new research avenues using machine learning and artificial intelligence by utilizing the large amount of data obtained from high-throughput measurements.

Signal-to-noise ratio and spatial resolution are quantitatively analysed in the context of in-line (propagation based) X-ray phase-contrast imaging. It is known that free-space propagation of a coherent X-ray beam from the imaged object to the detector plane, followed by phase retrieval in accordance with Paganin's method, can increase the signal-to-noise in the resultant images without deteriorating the spatial resolution. This results in violation of the noise-resolution uncertainty principle and demonstrates `unreasonable' effectiveness of the method. On the other hand, when the process of free-space propagation is performed in software, using the detected intensity distribution in the object plane, it cannot reproduce the same effectiveness, due to the amplification of photon shot noise. Here, it is shown that the performance of Paganin's method is determined by just two dimensionless parameters: the Fresnel number and the ratio of the real decrement to the imaginary part of the refractive index of the imaged object. The relevant theoretical analysis is performed first, followed by computer simulations and then by a brief test using experimental images collected at a synchrotron beamline. More extensive experimental tests will be presented in the second part of this paper.

The crystal structure of a new 1:1 cocrystal of carbamazepine and S-naproxen (C15H12N2O·C14H14O3) was solved from powder X-ray diffraction (PXRD). The PXRD pattern was measured at the high-resolution beamline CRISTAL at synchrotron SOLEIL (France). The structure was solved using Monte Carlo simulated annealing, then refined with Rietveld refinement. The positions of the H atoms were obtained from density functional theory (DFT) ground-state calculations. The symmetry is ortho­rhom­bic with the space group P212121 (No. 19) and the following lattice parameters: a = 33.5486 (9), b = 26.4223 (6), c = 5.3651 (10) Å and V = 4755.83 (19) Å3.

3D electron diffraction (3D ED), or microcrystal electron diffraction (MicroED), has become an alternative technique for determining the high-resolution crystal structures of compounds from sub-micron-sized crystals. Here, we considered l-alanine, α-glycine and urea, which are known to form good-quality crystals, and collected high-resolution 3D ED data on our in-house TEM instrument. In this study, we present a comparison of independent atom model (IAM) and transferable aspherical atom model (TAAM) kinematical refinement against experimental and simulated data. TAAM refinement on both experimental and simulated data clearly improves the model fitting statistics (R factors and residual electrostatic potential) compared to IAM refinement. This shows that TAAM better represents the experimental electrostatic potential of organic crystals than IAM. Furthermore, we compared the geometrical parameters and atomic displacement parameters (ADPs) resulting from the experimental refinements with the simulated refinements, with the periodic density functional theory (DFT) calculations and with published X-ray and neutron crystal structures. The TAAM refinements on the 3D ED data did not improve the accuracy of the bond lengths between the non-H atoms. The experimental 3D ED data provided more accurate H-atom positions than the IAM refinements on the X-ray diffraction data. The IAM refinements against 3D ED data had a tendency to lead to slightly longer X—H bond lengths than TAAM, but the difference was statistically insignificant. Atomic displacement parameters were too large by tens of percent for l-alanine and α-glycine. Most probably, other unmodelled effects were causing this behaviour, such as radiation damage or dynamical scattering.

The activation of C—C bonds by transition-metal com­plexes is of continuing inter­est and aceto­nitrile (MeCN) has attracted attention as a cyanide source with com­paratively low toxicity for organic cyanation reactions. A di­iron end-on μ-η1:η1-CN-bridged com­plex was obtained from a crystallization experiment of an open-chain iron–NHC com­plex, namely, μ-cyanido-κ2C:N-bis­{[(aceto­nitrile-κN)[3,3'-bis­(pyridin-2-yl)-1,1'-(methyl­idene)bis­(benzimidazol-2-yl­idene)]iron(II)} tris­(hexa­fluoro­phos­phate), [Fe2(CN)(C2H3N)2(C25H18N6)2](PF6)3. The cyanide appears to originate from the MeCN solvent by C—C bond cleavage or through carbon–hy­dro­gen oxidation.

The determination of the atomic resolution structure of biomacromolecules is essential for understanding details of their function. Traditionally, such a structure determination has been performed with crystallographic or nuclear resonance methods, but during the last decade, cryogenic transmission electron microscopy (cryo-TEM) has become an equally important tool. As the blotting and flash-freezing of the samples can induce conformational changes, external validation tools are required to ensure that the vitrified samples are representative of the solution. Although many validation tools have already been developed, most of them rely on fully resolved atomic models, which prevents early screening of the cryo-TEM maps. Here, a novel and automated method for performing such a validation utilizing small-angle X-ray scattering measurements, publicly available through the new software package AUSAXS, is introduced and implemented. The method has been tested on both simulated and experimental data, where it was shown to work remarkably well as a validation tool. The method provides a dummy atomic model derived from the EM map which best represents the solution structure.

Fatty acid-derivative prodrugs have been utilized extensively to improve the physicochemical, biopharmaceutical and pharmacokinetic properties of active pharmaceutical ingredients. However, to our knowledge, the crystallization behavior of prodrugs modified with different fatty acids has not been explored. In the present work, a series of paliperidone aliphatic prodrugs with alkyl chain lengths ranging from C4 to C16 was investigated with respect to crystal structure, crystal morphology and crystallization kinetics. The paliperidone derivatives exhibited isostructural crystal packing, despite the different alkyl chain lengths, and crystallized with the dominant (100) face in both melt and solution. The rate of crystallization for paliperidone derivatives in the melt increases with alkyl chain length owing to greater molecular mobility. In contrast, the longer chains prolong the nucleation induction time and reduce the crystal growth kinetics in solution. The results show a correlation between difficulty of nucleation in solution and the interfacial energy. This work provides insight into the crystallization behavior of paliperidone aliphatic prodrugs and reveals that the role of alkyl chain length in the crystallization behavior has a strong dependence on the crystallization method.

Serial electron diffraction (SerialED), which applies a snapshot data acquisition strategy for each crystal, was introduced to tackle the problem of radiation damage in the structure determination of beam-sensitive materials by three-dimensional electron diffraction (3DED). The snapshot data acquisition in SerialED can be realized using both transmission and scanning transmission electron microscopes (TEM/STEM). However, the current SerialED workflow based on STEM setups requires special external devices and software, which limits broader adoption. Here, we present a simplified experimental implementation of STEM-based SerialED on Thermo Fisher Scientific STEMs using common proprietary software interfaced through Python scripts to automate data collection. Specifically, we utilize TEM Imaging and Analysis (TIA) scripting and TEM scripting to access the STEM functionalities of the microscope, and DigitalMicrograph scripting to control the camera for snapshot data acquisition. Data analysis adapts the existing workflow using the software CrystFEL, which was developed for serial X-ray crystallography. Our workflow for STEM SerialED can be used on any Gatan or Thermo Fisher Scientific camera. We apply this workflow to collect high-resolution STEM SerialED data from two aluminosilicate zeolites, zeolite Y and ZSM-25. We demonstrate, for the first time, ab initio structure determination through direct methods using STEM SerialED data. Zeolite Y is relatively stable under the electron beam, and STEM SerialED data extend to 0.60 Å. We show that the structural model obtained using STEM SerialED data merged from 358 crystals is nearly identical to that using continuous rotation electron diffraction data from one crystal. This demonstrates that accurate structures can be obtained from STEM SerialED. Zeolite ZSM-25 is very beam-sensitive and has a complex structure. We show that STEM SerialED greatly improves the data resolution of ZSM-25, compared with serial rotation electron diffraction (SerialRED), from 1.50 to 0.90 Å. This allows, for the first time, the use of standard phasing methods, such as direct methods, for the ab initio structure determination of ZSM-25.

Appreciating that the role of the solute–solvent and other outer-sphere interactions is essential for understanding chemistry and chemical dynamics in solution, experimental approaches are needed to address the structural consequences of these interactions, complementing condensed-matter simulations and coarse-grained theories. High-energy X-ray scattering (HEXS) combined with pair distribution function analysis presents the opportunity to probe these structures directly and to develop quantitative, atomistic models of molecular systems in situ in the solution phase. However, at concentrations relevant to solution-phase chemistry, the total scattering signal is dominated by the bulk solvent, prompting researchers to adopt a differential approach to eliminate this unwanted background. Though similar approaches are well established in quantitative structural studies of macromolecules in solution by small- and wide-angle X-ray scattering (SAXS/WAXS), analogous studies in the HEXS regime—where sub-ångström spatial resolution is achieved—remain underdeveloped, in part due to the lack of a rigorous theoretical description of the experiment. To address this, herein we develop a framework for differential solution scattering experiments conducted at high energies, which includes concepts of the solvent-excluded volume introduced to describe SAXS/WAXS data, as well as concepts from the time-resolved X-ray scattering community. Our theory is supported by numerical simulations and experiment and paves the way for establishing quantitative methods to determine the atomic structures of small molecules in solution with resolution approaching that of crystallography.

In this work, regenerated cellulose textile fibers, Ioncell-F, dry-wet spun with different draw ratios, have been investigated by scanning wide-angle X-ray scattering (WAXS) using a mesoscopic X-ray beam. The fibers were found to be homogeneous on the 500 nm length scale. Analysis of the azimuthal angular dependence of a crystalline Bragg spot intensity revealed a radial dependence of the degree of orientation of crystallites that was found to increase with the distance from the center of the fiber. We attribute this to radial velocity gradients during the extrusion of the spin dope and the early stage of drawing. On the other hand, the fiber crystallinity was found to be essentially homogeneous over the fiber cross section.

Single-particle cryo-electron microscopy (cryo-EM) has become an essential structural determination technique with recent hardware developments making it possible to reach atomic resolution, at which individual atoms, including hydrogen atoms, can be resolved. In this study, we used the enzyme involved in the penultimate step of riboflavin biosynthesis as a test specimen to benchmark a recently installed microscope and determine if other protein complexes could reach a resolution of 1.5 Å or better, which so far has only been achieved for the iron carrier ferritin. Using state-of-the-art microscope and detector hardware as well as the latest software techniques to overcome microscope and sample limitations, a 1.42 Å map of Aquifex aeolicus lumazine synthase (AaLS) was obtained from a 48 h microscope session. In addition to water molecules and ligands involved in the function of AaLS, we can observe positive density for ∼50% of the hydrogen atoms. A small improvement in the resolution was achieved by Ewald sphere correction which was expected to limit the resolution to ∼1.5 Å for a molecule of this diameter. Our study confirms that other protein complexes can be solved to near-atomic resolution. Future improvements in specimen preparation and protein complex stabilization may allow more flexible macromolecules to reach this level of resolution and should become a priority of study in the field.

Ultrahigh-resolution structures provide unprecedented details about protein dynamics, hydrogen bonding and solvent networks. The reported 0.70 Å, room-temperature crystal structure of crambin is the highest-resolution ambient-temperature structure of a protein achieved to date. Sufficient data were collected to enable unrestrained refinement of the protein and associated solvent networks using SHELXL. Dynamic solvent networks resulting from alternative side-chain conformations and shifts in water positions are revealed, demonstrating that polypeptide flexibility and formation of clathrate-type structures at hydro­phobic surfaces are the key features endowing crambin crystals with extraordinary diffraction power.

3D electron diffraction (3DED) is increasingly employed to determine molec­ular and crystal structures from micro-crystals. Indomethacin is a well known, marketed, small-molecule non-steroidal anti-inflammatory drug with eight known polymorphic forms, of which four structures have been elucidated to date. Using 3DED, we determined the structure of a new ninth polymorph, σ, found within an amorphous solid dispersion, a product formulation sometimes used for active pharmaceutical ingredients with poor aqueous solubility. Subsequently, we found that σ indomethacin can be produced from direct solvent evaporation using di­chloro­methane. These results demonstrate the relevance of 3DED within drug development to directly probe product formulations.

The NaZr2P3O12 family of materials have shown low and tailorable thermal expansion properties. In this study, SrZr4P6O24 (SrO·4ZrO2·3P2O5), CaZr4P6O24 (CaO·4ZrO2·3P2O5), MgZr4P6O24 (MgO·4ZrO2·3P2O5), NaTi2P3O12 [½(Na2O·4TiO2·3P2O5)], NaZr2P3O12 [½(Na2O·4ZrO2·3P2O5)], and related solid solutions were synthesized using the organic–inorganic steric entrapment method. The samples were characterized by in-situ high-temperature X-ray diffraction from 25 to 1500°C at the Advanced Photon Source and National Synchrotron Light Source II. The average linear thermal expansion of SrZr4P6O24 and CaZr4P6O24 was between −1 × 10−6 per °C and 6 × 10−6 per °C from 25 to 1500°C. The crystal structures of the high-temperature polymorphs of CaZr4P6O24 and SrZr4P6O24 with R3c symmetry were solved by Fourier difference mapping and Rietveld refinement. This polymorph is present above ∼1250°C. This work measured thermal expansion coefficients to 1500°C for all samples and investigated the differences in thermal expansion mechanisms between polymorphs and between compositions.

This study introduces bis­[hexa­kis­(nitrato-κ2O,O')lanthanum(III)] tris­[hexa­aqua­nickel(II)] hexa­hydrate, [La(NO3)6]2[Ni(H2O)6]3·6H2O, with a structure refined in the hexa­gonal space group Roverline{3}. The salt com­prises [La(NO3)6]3− icosa­hedra and [Ni(H2O)6]2+ octa­hedra, thus forming an intricate network of inter­penetrating honeycomb lattices arranged in layers. This arrangement is stabilized through strong hydrogen bonds. Two successive layers are connected via the second [Ni(H2O)6]2+ octa­hedra, forming sheets which are stacked perpendicular to the c axis and held in the crystal by van der Waals forces. The synthesis of [La(NO3)6]2[Ni(H2O)6]3·6H2O involves dissolving lanthanum(III) and nickel(II) oxides in nitric acid, followed by slow evaporation, yielding green hexa­gonal plate-like crystals.

Rietveld refinements are widely used for many purposes in the physical sciences. Conducting a Rietveld refinement typically requires expert input because correct results may require that parameters be added to the fit in the proper order. This order will depend on the nature of the data and the initial parameter values. A mechanism for computing the next parameter to add to the refinement is shown. The fitting function is evaluated with the current parameter value set and each parameter incremented and decremented by a small offset. This provides the partial derivatives with respect to each parameter, along with information to discriminate meaningful values from numerical computational errors. The implementation of this mechanism in the open-source GSAS-II program is discussed. This new method is discussed as an important step towards the development of automated Rietveld refinement technology.

In addressing the challenges faced by laboratories and universities with limited (or no) cryo-electron microscopy (cryo-EM) infrastructure, the ESRF, in collaboration with the Grenoble Institute for Structural Biology (IBS), has implemented the cryo-EM Solution-to-Structure (SOS) pipeline. This inclusive process, spanning grid preparation to high-resolution data collection, covers single-particle analysis and cryo-electron tomography (cryo-ET). Accessible through a rolling access route, proposals undergo scientific merit and technical feasibility evaluations. Stringent feasibility criteria demand robust evidence of sample homogeneity. Two distinct entry points are offered: users can either submit purified protein samples for comprehensive processing or initiate the pipeline with already vitrified cryo-EM grids. The SOS pipeline integrates negative stain imaging (exclusive to protein samples) as a first quality step, followed by cryo-EM grid preparation, grid screening and preliminary data collection for single-particle analysis, or only the first two steps for cryo-ET. In both cases, if the screening steps are successfully completed, high-resolution data collection will be carried out using a Titan Krios microscope equipped with a latest-generation direct electron counting detector coupled to an energy filter. The SOS pipeline thus emerges as a comprehensive and efficient solution, further democratizing access to cryo-EM research.

Neutron spectroscopy uniquely and non-destructively accesses diffusive dynamics in soft and biological matter, including for instance proteins in hydrated powders or in solution, and more generally dynamic properties of condensed matter on the molecular level. Given the limited neutron flux resulting in long counting times, it is important to optimize data acquisition for the specific question, in particular for time-resolved (kinetic) studies. The required acquisition time was recently significantly reduced by measurements of discrete energy transfers rather than quasi-continuous neutron scattering spectra on neutron backscattering spectrometers. Besides this reduction in acquisition times, smaller amounts of samples can be measured with better statistics, and most importantly, kinetically changing samples, such as aggregating or crystallizing samples, can be followed. However, given the small number of discrete energy transfers probed in this mode, established analysis frameworks for full spectra can break down. Presented here are new approaches to analyze measurements of diffusive dynamics recorded within fixed windows in energy transfer, and these are compared with the analysis of full spectra. The new approaches are tested by both modeled scattering functions and a comparative analysis of fixed energy window data and full spectra on well understood reference samples. This new approach can be employed successfully for kinetic studies of the dynamics focusing on the short-time apparent center-of-mass diffusion.

The Q resolution in Bonse–Hart double-crystal diffractometers is determined for a given Bragg angle by the value of the crystallographic structure factor. To date, the reflections Si 220 or Si 111 have been used exclusively in neutron scattering, which provide resolutions for triple-bounce crystals of about 2 × 10−5 Å−1 (FWHM). The Darwin width of the GaAs 200 reflection is about a factor of 10 smaller, offering the possibility of a Q resolution of 2 × 10−6 Å−1 provided crystals of sufficient quality are available. This article reports a feasibility study with single-bounce GaAs 200, yielding a Q resolution of 4.6 × 10−6 Å−1, six times superior in comparison with a Si 220 setup.

Here, a morphologically based approach is used for the in situ characterization of 3D growth rates of facetted crystals from the solution phase. Crystal images of single crystals of the β-form of l-glutamic acid are captured in situ during their growth at a relative supersaturation of 1.05 using transmission optical microscopy. The crystal growth rates estimated for both the {101} capping and {021} prismatic faces through image processing are consistent with those determined using reflection light mode [Jiang, Ma, Hazlehurst, Ilett, Jackson, Hogg & Roberts (2024). Cryst. Growth Des. 24, 3277–3288]. The growth rate in the {010} face is, for the first time, estimated from the shadow widths of the {021} prismatic faces and found to be typically about half that of the {021} prismatic faces. Analysis of the 3D shape during growth reveals that the initial needle-like crystal morphology develops during the growth process to become more tabular, associated with the Zingg factor evolving from 2.9 to 1.7 (>1). The change in relative solution supersaturation during the growth process is estimated from calculations of the crystal volume, offering an alternative approach to determine this dynamically from visual observations.

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Source: Rob Goff 11/11/2024

Volatus Aerospace Inc. (TSXV:FLT; OTCQX:TAKOF:ABBA.F) secured CA$2.8 million (CA$2.8M) through a private placement after having recently completed a financing package for CA$15M, reported Ventum Capital Markets analyst Rob Goff in a Nov. 6 research note. Volatus provides aerial intelligence solutions using drones and other aircraft systems, including inspections, surveillance, design, and sales.

"We believe the two financing rounds should be positively rewarded by investors for the financial flexibility they bring to Volatus, while the commitment of the two debt partners represents a strong validation," Goff wrote.

192% Return Implied

Goff reiterated Ventum's target price on the Canadian aircraft solutions provider of CA$0.38 per share. In comparison, it was trading at the time of the report at CA$0.13 per share. From this price, the return to target is 192%.

Volatus is a Buy.

Plans for Using the Funds

Goff discussed the private placement and Volatus' intended uses of it. For the offering, a total of 19,766,000 units was sold at CA$0.14 apiece. Each unit consists of one common Volatus voting share and one common Volatus voting share purchase warrant. With each warrant, the holder may purchase one Volatus common share for CA$0.20 per warrant share during the 24 months after the close of the raise.

"We believe the equity and debt financing will allow Volatus to invest in working capital to support higher equipment sales," an advantage its smaller peers do not have, Goff wrote.

The company expects to fund about CA$9–12M in unmet equipment sales demand, so Goff forecasts it will designate CA$3–4M to this purpose, to purchase working capital. Other uses of the proceeds are for research and development, capital expenditures and inventory.

Goff reported that Volatus wants to leverage every incremental CA$1M of invested working capital into about CA$3–4M of incremental equipment sales annually, aiming for gross profit margins of about 25% and modest incremental operating costs.

Volatus plans to use proceeds from the debt raise to back pay the outstanding CA$6M senior loan it has with a major Canadian bank. The company also intends to open a new secured line of credit to support anticipated growth. Current debt related to its fleet financing is about CA$5M.

Opportunities for Growth

With more balance sheet flexibility, Goff wrote, Volatus may pursue longer-term contracts with utilities and pipelines for inspection services using unmanned and manned fleets. This would position the company to become a leader in this specific market.

Volatus can monetize its portfolio of drones and landing stations. The U.S.' initiatives and intention to reduce use of Chinese-manufactured products could help drive this expansion. The company has third-party manufacturing capabilities to significantly boost its equipment sales.

"We anticipate that Volatus will leverage its unique software, network, and equipment capabilities, stewarded by an experienced and commercially focused leadership team," Goff wrote.

Future Financial Expectations

Goff discussed forecasts for merger synergies, EBITDA, and revenue. As for initial efficiencies achieved from Volatus' merger with Drone Delivery Canada, they should be seen in Volatus' Q4/24 and Q1/25 financial results, Goff wrote. Already, the company has exceeded CA$2.6M in cost synergies and expects to surpass CA$3M in the near term. By 2026, the company estimates revenue synergies will be about CA$5M-plus and will include initial traction gained from business-to-business cargo delivery.

Looking to 2025, Ventum expects Volatus to turn EBITDA break even in Q2/25 and produce CA$5.7M in positive EBITDA in 2025 versus Volatus' estimate of CA$10M-plus, Goff reported. Ventum estimates that Volatus will generate CA$60.3M in revenue in full-year 2025, less than Volatus' guidance of CA$70M+.

"We anticipate that Volatus will leverage its unique software, network, and equipment capabilities, stewarded by an experienced and commercially focused leadership team," wrote Goff.

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1. Doresa Banning wrote this article for Streetwise Reports LLC and provides services to Streetwise Reports as an independent contractor.
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Disclosures for Ventum Capital Markets, Volatus Aerospace Inc., November 6, 2024

Analyst Certification I, Rob Goff, hereby certify that all of the views expressed in this report accurately reflect my personal views about the subject securities or issuers. I also certify that no part of my compensation was, is, or will be, directly or indirectly related to the specific recommendations or views expressed in this report. I am the research analyst primarily responsible for preparing this report.

Research Disclosures

1. Ventum Financial Corp. and its affiliates’ holdings in the subject company’s securities, in aggregate exceeds 1% of each company’s issued and outstanding securities.
2. Ventum Financial Corp. and/or its affiliates have received compensation for investment banking services for the subject company over the preceding 12- month period.
3. Ventum Financial Corp. and/or its affiliates expect to receive or intend to seek compensation for investment banking services from the subject company.
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( Companies Mentioned: TSXV:FLT;OTCQX:TAKOF:ABBA.F), )

Emirates NBD and...

Source: Streetwise Reports 10/28/2024

Sernova Corp. (SVA:TSX.V; SEOVF:OTCQB; PSH:XERTA) and its Cell Pouch technology could be the solution to existing challenges involving the delivery of medical treatments to patients, such as the ones described here.

Diabetic patients in resource-limited settings are having to revert back to one of the less favored, alternative ways to take insulin, via syringes or glass vials, because Danish pharmaceutical company, Novo Nordisk A/S (NVO:NYSE), will stop making its insulin pens, The Guardian reported. Patients generally prefer this method for dosing themselves with insulin, as shown in a 2024 survey, because it is more convenient and more accurate.

Type 1 diabetic patients already are being impacted as Novo stopped supplying its insulin pens to certain regions, South Africa for instance. Patients there have switched back to using glass vials.

In a second situation, Novo Nordisk is working to bring stem cell-based therapies to patients more efficiently and, in seeking a solution, formed a partnership with Evotec SE (EVO:NASDAQ) to develop technologies that will achieve this, noted Evotec is a Germany-based global biotech firm with its own cell therapy and partnered cell types all in preclinical development for various indications, including diabetes, oncology, cardiology, and ophthalmology.

Per the agreement, Novo Nordisk is to provide research and development funding and potentially monetary incentives to Evotec, and Evotec is to develop the desired new technologies. Novo has the option to obtain exclusive rights to use, in a predefined medical indication, the product(s) born out of this collaboration agreement. Novo's areas of focus, along with diabetes, are cardiovascular diseases, rare diseases, growth hormone-related diseases, hemophilia, nonalcoholic steatohepatitis, and weight management.

Safe, Effective Therapeutic Cell Delivery

Sernova Corp.'s Cell Pouch is a vehicle for delivering various types of therapeutic cells to patients, such as donor islet cells to insulin-dependent diabetics.

When used, the Cell Pouch's containment channels are filled with the appropriate therapeutic cells, and then the device is implanted in the patient. In situ, the cells release therapeutic proteins or hormones the patient's body completely or partially lacks. The device creates a vascularized, organ-like environment that protects the therapeutic cells from immune system attacks, keeping them alive and functioning.

"The Cell Pouch is the most advanced encapsulation device in development," Ventum Capital Markets Analyst Stefan Quenneville wrote in a Sept. 12 research report.

Sernova is testing its Cell Pouch in the clinic, specifically in Type 1 diabetes. In its ongoing Phase 1/2 study, the Canadian company is evaluating the treatment of insulin-dependent diabetes with donor islets implanted via the Cell Pouch, with added immunosuppression therapy. Study data so far have shown the Cell Pouch to be safe and well tolerated and the treatment, effective, reported Dr. Joseph Pantginis, analyst at H.C. Wainwright & Co., in a Sept. 12 research report.

Seven patients, all six of Cohort A and one in Cohort B, achieved sustained insulin independence, between 5.5 and 50 months in duration, free of hypoglycemic episodes. Their blood sugar levels were controlled in the nondiabetic range (i.e.,) HbA1c less than 6.5%.

"The Cell Pouch is the most advanced encapsulation device in development," Ventum Capital Markets Analyst Stefan Quenneville wrote.

A Cell Pouch removed from one of the study patients showed it still contained functioning insulin, glucagon, and somatostatin-producing cells. No evidence was seen of detrimental fibrotic tissue, too many T-cells, material degradation, or changes in the device architecture.

"We believe the impressive response rates and observed durability support Sernova's strategy and justify further investigation while positioning the technology for potential commercial success," noted Pantginis.

The results add to an expanding collection of evidence that the Cell Pouch is functioning as it should. The data also support the "impressive" results already reported from this study and help derisk future related trials.

"If Sernova is successful in bringing its functional cure for insulin-dependent diabetes to the stage where it can go into commercial production, the global market for it will be massive," wrote Technical Analyst Clive Maund in a Sept. 16 note.

In another of its programs, Sernova, in collaboration with Evotec, is developing an implantable off-the-shelf, induced pluripotent stem cell (iPSC)-based islet replacement therapy, Maund reported.

"This partnership provides Sernova a potentially unlimited supply of insulin-producing cells to treat millions of patients with insulin-dependent diabetes (Type 1 and Type 2)," he added.

This partnership was announced on May 17, 2022. You can read more about it in the press release here.

Market Growth Predicted to 2030

The global live cell encapsulation market, encompassing drug delivery, regenerative medicine and cell transplantation, is expected to continue growing through at least 2030, according to Grand View Research. The market's value, US$210.7 million in 2022, is forecasted to increase at a 3.97% compound annual growth rate between that year and 2030.

"If Sernova is successful in bringing its functional cure for insulin-dependent diabetes to the stage where it can go into commercial production, the global market for it will be massive," wrote Technical Analyst Clive Maund.

Along with diabetes, live cell encapsulation is being used to treat neurological disorders like Parkinson's disease, The market research firm noted. Further, it has been proven to be a suitable way to deliver treatment for other types of diseases, including cancer, anemia, heart failure and more.

Several factors are expected to keep driving market growth during the forecast period, Grand View noted. A significant one is the increasing use of live cell encapsulation in regenerative medicine to replace disease or damaged tissues. A related contributor is rising public and private funding and investments in cell and gene therapies.

The advantages of live cell encapsulation in controlled drug delivery are boosting the market, too. They include enhanced therapeutic effects, lowered drug dose, reduced cytotoxicity, improved patient convenience and better patient compliance.

Novel new products and technological advancements are expected to add value to the market as well.

The Catalysts: Progress With Programs

Various potential stock-moving events are slated for Sernova, according to its September 2024 Corporate Presentation.

Two catalysts are expected by Sernova in 2025, related to the company's ongoing Phase 1/2 clinical trial in Type 1 diabetes. One is results for the remaining Cohort B patients. The other is commencement of Cohort C, who will receive, along with the islet cells, an optimized immune suppression regimen.

Several analysts are bullish on Sernova. One of them is Loe, who rates it as a Speculative Buy. His price target on the life sciences firm implies a 455% return from its current share price.

Next year, Sernova plans to start a Phase 1/2 trial of the regeneratively produced islet cells to result from its partnership with Evotec, delivered via the Cell Pouch to Type 1 diabetes patients.

Other catalysts are expected to come as a result of Sernova advancing its preclinical programs. One is a personalized treatment with patient corrected cells via Cell Pouch for hypothyroidism. Another is a Cell Pouch-delivered, ex vivo lentiviral factor VIII gene therapy for hemophilia, being developed in partnership with the European Haemacure Consortium.

Also, through partnerships, Sernova is developing technologies that would eliminate the need for concurrent immunosuppression during Cell Pouch-delivered cell treatment, a "blue sky objective," Douglas Loe, a Leede Financial Inc. analyst, noted in a Sept. 12 research report.

"Any advances in this regard could be incorporated into future Cell Pouch studies," he wrote. "We do not consider the need for such therapy to be relevant to Cell Pouch function itself."

Analyst: Company is "Very Undervalued"

Several analysts are bullish on Sernova. One of them is Loe, who rates it as a Speculative Buy. His price target on the life sciences firm implies a 455% return from its current share price.

According to H.C. Wainwright's Pantginis, the deepening responses of Type 1 diabetes patients in its Phase 1/2 trial continue to "crystallize Sernova stock's possible upside." The upside reflected in Pantginis' price target is 2,122%. The analyst recommends the company as a Buy.

Ventum's Quenneville also has a Buy on Sernova, and his target price reflects an 826% return on investment. In his report, the analyst highlighted the impressive efficacy and tolerability of the Cell Pouch up to five years post-implantation, as shown in the Phase 1/2 clinical trial data.

"This represents the longest-lasting implanted encapsulation device containing functioning islets without fibrosis," Quenneville wrote.

According to Technical Analyst Maund, Sernova is "very undervalued here given its huge potential" in the Type 1 diabetes market, as indicated on the stock charts. The fundamental outlook for the company is improving, and evidence is strong that a reversal to the upside may be happening. SVA may appreciate significantly soon. [OWNERSHIP_CHART-4790]

"Sernova is therefore viewed as a good stock to accumulate in this area, between the current price and recent lows," Maund wrote on Sept. 16. At that time, Sernova's share price was about the same as it is now.

Ownership and Share Structure

According to Refinitiv, about 12.96% of the company is held by insiders and management, and 0.05% by institutions. The rest is retail.

Top shareholders include Tomas Angel with 4.91%, Director Steven Sangha with 4.27%, Betty Anne Millar with 1.32%, Brett Alexander Whalen with 0.87%, and Garry Deol with 0.77%.

Its market cap is CA$83 M. Its 52-week range is CA$0.20−0.82 per share.

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Important Disclosures:

1. Sernova Corp. has a consulting relationship with Street Smart an affiliate of Streetwise Reports. Street Smart Clients pay a monthly consulting fee between US$8,000 and US$20,000.
2. As of the date of this article, officers and/or employees of Streetwise Reports LLC (including members of their household) own securities of Sernova Corp.
3. Doresa Banning wrote this article for Streetwise Reports LLC and provides services to Streetwise Reports as an independent contractor.
4. Streetwise Reports does not render general or specific investment advice and the information on Streetwise Reports should not be considered a recommendation to buy or sell any security. Each reader is encouraged to consult with his or her personal financial adviser and perform their own comprehensive investment research. By opening this page, each reader accepts and agrees to Streetwise Reports' terms of use and full legal disclaimer. Streetwise Reports does not endorse or recommend the business, products, services or securities of any company.
5. This article does not constitute medical advice. Officers, employees and contributors to Streetwise Reports are not licensed medical professionals. Readers should always contact their healthcare professionals for medical advice.

For additional disclosures, please click here.

( Companies Mentioned: SVA:TSX.V;SEOVF:OTCQB;PSH:XERTA, )

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