Our data support further clinical evaluation of the combination of peposertib (M38814) and IR in cervical cancer.Drug treatments for middle ear diseases are currently delivered systemically, or locally after opening the impermeable tympanic membrane (TM). We previously used bacteriophage display to discover novel peptides that are actively transported across the intact TM, with a variety of transport rates. Peptide structures were analyzed for evidence regarding the mechanism for this unexpected transport, which was then tested by the application of chemical inhibitors. Primary sequences indicated that trans-TM peptides share one of two amino acid motifs. Secondary structures revealed that linear configurations associate with higher transport rates than coiled structures. Tertiary analysis indicated that the shared sequence motifs are prominently displayed at the free ends of rapidly transported peptide phage. The shared motifs were evaluated for similarity to known motifs. The highest probability matches were for protein motifs involved in transmembrane transport and exosomes. Overall, structural findings suggest that the shared motifs represent binding sequences. They also implicate transcytosis, a polarized cell transport mechanism consisting of endocytosis, transcellular transport, and exocytosis. Inhibitor studies indicated that macropinocytosis, retrograde transport through Golgi and exocytosis participate in transport across the TM, consistent with transcytosis. This process can be harnessed to noninvasively deliver therapeutics to the middle ear.The Strecker Synthesis of (a)chiral α-amino acids from simple organic compounds, such as ammonia (NH3), aldehydes (RCHO), and hydrogen cyanide (HCN) has been recognized as a viable route to amino acids on primordial earth. However, preparation and isolation of the simplest hemiaminal intermediate – the aminomethanol (NH2CH2OH)- formed in the Strecker Synthesis to even the simplest amino acid glycine (H2NCH2COOH) has been elusive. Here, we report the identification of aminomethanol prepared in low-temperature methylamine (CH3NH2) – oxygen (O2) ices upon exposure to energetic electrons. Isomer-selective photoionization time-of-flight mass spectrometry (PI-ReTOF-MS) facilitated the gas phase detection of aminomethanol during the temperature program desorption (TPD) phase of the reaction products. The preparation and observation of the key transient aminomethanol changes our perception of the synthetic pathways to amino acids and the unexpected kinetic stability in extreme environments.Risk genes for Mendelian (single-gene) disorders (SGDs) are consistent across populations, but pathogenic risk variants that cause SGDs are typically population-private. The goal was to develop „QChip1,” an inexpensive genotyping microarray to comprehensively screen newborns, couples, and patients for SGD risk variants in Qatar, a small nation on the Arabian Peninsula with a high degree of consanguinity. Over 108 variants in 8445 Qatari were identified for inclusion in a genotyping array containing 165,695 probes for 83,542 known and potentially pathogenic variants in 3438 SGDs. QChip1 had a concordance with whole-genome sequencing of 99.1%. Testing of QChip1 with 2707 Qatari genomes identified 32,674 risk variants, an average of 134 pathogenic alleles per Qatari genome. The most common pathogenic variants were those causing homocystinuria (1.12% risk allele frequency), and Stargardt disease (2.07%). The majority (85%) of Qatari SGD pathogenic variants were not present in Western populations such as European American, South Asian American, and African American in New York City and European and Afro-Caribbean in Puerto Rico; and only 50% were observed in a broad collection of data across the Greater Middle East including Kuwait, Iran, and United Arab Emirates. This study demonstrates the feasibility of developing accurate screening tools to identify SGD risk variants in understudied populations, and the need for ancestry-specific SGD screening tools.The microbiota in broiler chicken intestines affects the animals’ health, metabolism, and immunity both positively and negatively. Accordingly, it has a significant impact on animal productivity. Phages, host-specific parasites of bacterial cells, are a promising antimicrobial alternative that selectively target pathogens without disturbing the microbiota. The purpose of this study is to further characterize the commensal microbial community at production scale in broiler chickens treated with a Salmonella phage treatment. We evaluated the cecal microbiota of broilers reared in a commercial farming system where a phage cocktail against Salmonella, SalmoFree was supplied to animals. To do so, two field trials were conducted, incorporating three doses of phages in the broilers’ drinking water. Our results showed that the core microbiome (taxa that were present in more than 50% of samples) contained species that are key to microbiota adaptation in the last stage of the production cycle. Among these, there are some important degraders of complex polysaccharides and producers of short chain fatty acids (SCFA) such as Eisenbergiella and Lachnoclostridium. The phage cocktail did not affect the normal development of the microbiota’s structure. The addition of the phage cocktail resulted in a significant reduction in Campylobacter and an increase in Butyricimonas, Helicobacter and Rikenellaceae, which are common inhabitants in chicken gut with known negative and positive effects on their health and metabolism. Altogether, we consider that these results contribute valuable information to the implementation of large-scale phage therapy technologies.Topology optimization by optimally distributing materials in a given domain requires non-gradient optimizers to solve highly complicated problems. However, with hundreds of design variables or more involved, solving such problems would require millions of Finite Element Method (FEM) calculations whose computational cost is huge and impractical. Here we report Self-directed Online Learning Optimization (SOLO) which integrates Deep Neural Network (DNN) with FEM calculations. A DNN learns and substitutes the objective as a function of design variables. A small number of training data is generated dynamically based on the DNN’s prediction of the optimum. The DNN adapts to the new training data and gives better prediction in the region of interest until convergence. The optimum predicted by the DNN is proved to converge to the true global optimum through iterations. Our algorithm was tested by four types of problems including compliance minimization, fluid-structure optimization, heat transfer enhancement and truss optimization. It reduced the computational time by 2 ~ 5 orders of magnitude compared with directly using heuristic methods, and outperformed all state-of-the-art algorithms tested in our experiments. This approach enables solving large multi-dimensional optimization problems.Mapping cell types across a tissue is a central concern of spatial biology, but cell type abundance is difficult to extract from spatial gene expression data. We introduce SpatialDecon, an algorithm for quantifying cell populations defined by single cell sequencing within the regions of spatial gene expression studies. SpatialDecon incorporates several advancements in gene expression deconvolution. We propose an algorithm harnessing log-normal regression and modelling background, outperforming classical least-squares methods. We compile cell profile matrices for 75 tissue types. We identify genes whose minimal expression by cancer cells makes them suitable for immune deconvolution in tumors. Using lung tumors, we create a dataset for benchmarking deconvolution methods against marker proteins. SpatialDecon is a simple and flexible tool for mapping cell types in spatial gene expression studies. It obtains cell abundance estimates that are spatially resolved, granular, and paired with highly multiplexed gene expression data.Kerr-effect-induced changes of the polarization state of light are well known in pulsed laser systems. An example is nonlinear polarization rotation, which is critical to the operation of many types of mode-locked lasers. Here, we demonstrate that the Kerr effect in a high-finesse Fabry-Pérot resonator can be utilized to control the polarization of a continuous wave laser. It is shown that a linearly-polarized input field is converted into a left- or right-circularly-polarized field, controlled via the optical power. The observations are explained by Kerr-nonlinearity induced symmetry breaking, which splits the resonance frequencies of degenerate modes with opposite polarization handedness in an otherwise symmetric resonator. The all-optical polarization control is demonstrated at threshold powers down to 7 mW. The physical principle of such Kerr effect-based polarization controllers is generic to high-Q Kerr-nonlinear resonators and could also be implemented in photonic integrated circuits. Beyond polarization control, the spontaneous symmetry breaking of polarization states could be used for polarization filters or highly sensitive polarization sensors when operating close to the symmetry-breaking point.Bacterial type IV secretion systems (T4SSs) are largely responsible for the proliferation of multi-drug resistance. We solved the structure of the outer-membrane core complex (OMCCF) of a T4SS encoded by a conjugative F plasmid at less then 3.0 Å resolution by cryoelectron microscopy. The OMCCF consists of a 13-fold symmetrical outer ring complex (ORC) built from 26 copies of TraK and TraV C-terminal domains, and a 17-fold symmetrical central cone (CC) composed of 17 copies of TraB β-barrels. Domains of TraV and TraB also bind the CC and ORC substructures, establishing that these proteins undergo an intraprotein symmetry alteration to accommodate the C13C17 symmetry mismatch. We present evidence that other pED208-encoded factors stabilize the C13C17 architecture and define the importance of TraK, TraV and TraB domains to T4SSF function. This work identifies OMCCF structural motifs of proposed importance for structural transitions associated with F plasmid dissemination and F pilus biogenesis.The fate of hematopoietic stem cells (HSCs) can be directed by microenvironmental factors including extracellular calcium ion concentration ([Ca2+]e), but the local [Ca2+]e around individual HSCs in vivo remains unknown. Here we develop intravital ratiometric analyses to quantify the absolute pH and [Ca2+]e in the mouse calvarial bone marrow, taking into account the pH sensitivity of the calcium probe and the wavelength-dependent optical loss through bone. Unexpectedly, the mean [Ca2+]e in the bone marrow (1.0 ± 0.54 mM) is not significantly different from the blood serum, but the HSCs are found in locations with elevated local [Ca2+]e (1.5 ± 0.57 mM). With aging, a significant increase in [Ca2+]e is found in M-type cavities that exclusively support clonal expansion of activated HSCs. This work thus establishes a tool to investigate [Ca2+]e and pH in the HSC niche with high spatial resolution and can be broadly applied to other tissue types.α-adrenergic receptors (αARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential of αARs, however, is largely unexploited and hampered by the scarcity of subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to αARs or fail to interact with the desired subtype. Here, we report the crystal structure of human α1BAR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The α1BAR structure allows the identification of two unique secondary binding pockets. By structural comparison of α1BAR with α2ARs, and by constructing α1BAR-α2CAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of α1BAR-selective ligands and may guide the optimization of aminergic drugs to prevent off-target binding to αARs, or to elicit a selective interaction with the desired subtype.