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Poor understanding of the basic biology of Mycobacterium tuberculosis (MTB), the etiological agent of tuberculosis, hampers development of much-needed drugs, vaccines, and diagnostic tests. Better experimental tools are needed to expedite investigations of this pathogen at the systems level. Here, we present a functional MTB proteome microarray covering most of the proteome and an ORFome library. We demonstrate the broad applicability of the microarray by investigating global protein-protein interactions, small-molecule-protein binding, and serum biomarker discovery, identifying 59 PknG-interacting proteins, 30 bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) binding proteins, and 14 MTB proteins that together differentiate between tuberculosis (TB) patients with active disease and recovered individuals. Results suggest that the MTB rhamnose pathway is likely regulated by both the serine/threonine kinase PknG and c-di-GMP. This resource has the potential to generate a greater understanding of key biological processes in the pathogenesis of tuberculosis, possibly leading to more effective therapies for the treatment of this ancient disease.

Flexible and stretchable optoelectronics, built-in inorganic semiconductor materials, offer a wide range of unprecedented opportunities and will redefine the conventional rigid optoelectronics in biological application and medical measurement. However, a significant bottleneck lies in the brittleness nature of rigid semiconductor materials and the performance's extreme sensitivity to the light intensity variation due to human skin deformation while measuring physical parameters. In this study, the authors demonstrate a systematic strategy to design an epidermal inorganic optoelectronic device by using specific strain-isolation design, nanodiamond thinning, and hybrid transfer printing. The authors propose all-in-one suspension structure to achieve the stretchability and conformability for surrounding environment, and they propose a two-step transfer printing method for hybrid integrating III-V group emitting elements, Si-based photodetector, and interconnects. Owing to the excellent flexibility and stretchability, such device is totally conformal to skin and keeps the constant light transmission between emitting element and photodetector as well as the signal stability due to skin deformation. This method opens a route for traditional inorganic optoelectronics to achieve flexibility and stretchability and improve the performance of optoelectronics for biomedical application.

Metal–organic frameworks (MOFs) with well‐defined porous structures and tailored functionalities have been widely used in chemical sensing. However, the integration of MOFs with flexible electronic devices for wearable sensing is challenging because of their low electrical conductivity and fragile mechanical properties. Herein, a wearable sweat sensor for metabolite detection is presented by integrating an electrically conductive Ni‐MOF with a flexible nanocellulose substrate. The MOF‐based layered film sensor with inherent conductivity, highly porous structure, and active catalytic properties enables the selective and accurate detection of vitamin C and uric acid. More importantly, the lightweight sensor can conformably self‐adhere to sweaty skin and exhibits high water‐vapor permeability. Furthermore, a wireless epidermal nutrition tracking system for the in situ monitoring of the dynamics of sweat vitamin C is demonstrated, the results of which are comparable to those tested by high‐performance liquid chromatography. This study opens a new avenue for integrating MOFs as the active layer in wearable electronic devices and holds promise for the future development of high‐performance electronics with enhanced sensing, energy production, and catalytic capabilities through the implementation of multifunctional MOFs.

According to the statistics of the World Health Organization, an estimated 17.9 million people die from cardiovascular diseases each year, representing 31% of all global deaths. Continuous non-invasive arterial pressure (CNAP) is essential for the management of cardiovascular diseases. However, it is difficult to achieve long-term CNAP monitoring with the daily use of current devices due to irritation of the skin as well as the lack of motion artifacts suppression. Here, we report a high-performance skin-like optoelectronic system integrated with ultra-thin flexible circuits to monitor CNAP. We introduce a theoretical model via the virtual work principle for predicting the precise blood pressure and suppressing motion artifacts, and propose optical difference in the frequency domain for stable optical measurements in terms of skin-like devices. We compare the results with the blood pressure acquired by invasive (intra-arterial) blood pressure monitoring for >1500 min in total on 44 subjects in an intensive care unit. The maximum absolute errors of diastolic and systolic blood pressure were ±7/±10 mm Hg, respectively, in immobilized, and ±10/±14 mm Hg, respectively, in walking scenarios. These strategies provide advanced blood pressure monitoring techniques, which would directly address an unmet clinical need or daily use for a highly vulnerable population.

This report investigates the sequence specificity requirements for homeodomain structure and DNA binding activity by the design and synthesis of a "minimAl" homeodomain (for mimalist design and alanine sning mutagenesis) which contain the consensus residues and in which all nonconsensus residues have been replaced with alanin. The murine homeodomain Msx served as the prototype for the minimAl homeodomain, Ala-Msx. We show that Ala-Msx binds to DNA specifically, albeit with lower affinity than Msn. A derivative of the minimAl homeodomain, AlaMsx(NT), which contain a native rather than an alaninesubstituted N-terminal arm, has similar DNA binding affinity as Mnx. We show that the native N-terminal arm sbiizes the tertiary structure of the minimAl homeodomain. Although Ala-Mn resembles a molten-globule protein, the structure of Ala-Mnx(NT) is similar to Mn. The requirement for an intact N-terminal arm is not unique to the minimA homeodomain, since the N-ternl arm also promotes hih-affinity binding activit and appropriate tertiary structure of Mn. Therefore, the homeodomain "scaffold" consists of consensus residues, which are s t for DNA recognition, and nonconsensus residues in the N-terminal arm, which are required for optimal DNA binding affinity and appropriate tertiary structure. MinImAM design provides a powerful strategy to probe homeodomain structure and function. This approach should be of general utility to study the sequence specfcit requirements for structure and function of other DNA-bining domains.The homeodomain, a conserved DNA-binding domain, was originally described as a sequence motif shared among Drosophila homeotic proteins and was subsequently shown to be ubiquitous among developmental regulatory proteins from nematodes to humans (1-5). A high degree of conservation is evident in primary sequence (3, 5), tertiary structure (5-7), and mode of interaction with DNA (5-7). The sequence corresponds to 60 amino acid residues that assemble into three a-helices and an extended N-terminal arm (Fig. 1). Several residues are invariant or highly conserved among a majority of homeodomain proteins (Fig. 2). These constitute a consensus sequence that promotes tertiary structure and mediates DNA binding activity (3,5,7). Consensus residues in helices I-HI furnish the hydrophobic core and preserve the amphipathic nature of the a-helices, whereas other consensus residues in helix III and in the N-terminal arm contact DNA. Despite extensive conservation, the homeodomain also promotes the selective functions that are characteristic of homeodomain-containing proteins (e.g., refs. 10 and 11).One explanation for this paradox is that the consensus residues form a "scaffold" that provides DNA site recognition, whereas the nonconsensus residues allow functional diversity by promoting selective protein-protein and protein-DNA interactions.To characterize the contribution of consensus and nonconsensus residues toward homeodomain structure and function, we have designed and synthesized a "minimAl" homeodomain which...

We have developed an automatic approach for homology modeling using restrained molecular dynamics and simulated annealing procedures, together with conformational search algorithms available in the molecular mechanics program CONGEN (Bruccoleri RE, Karplus M, 1987, Biopolymers 26137-168). The accuracy of the method is validated by "predicting" structures of two homeodomain proteins with known three-dimensional structures, and then applied to predict the three-dimensional structure of the homeodomain of the murine Msx-1 transcription factor. Regions of the unknown protein structure that are highly homologous to the known template structure are constrained by "homology distance constraints," whereas the conformations of nonhomologous regions of the unknown protein are defined only by the potential energy function. A full energy function (excluding explicit solvent) is employed to ensure that the calculated structures have good conformational energies and are physically reasonable. As in NMR structure determinations, information on the consistency of the structure prediction is obtained by superposition of the resulting family of protein structures. In this paper, our homology modeling algorithm is described and compared with related homology modeling methods using spatial constraints derived from the structures of homologous proteins. The software is then used to predict the DNA-bound structures of three homeodomain proteins from the X-ray crystal structure of the engrailed homeodomain protein (Kissinger CR et al., 1990, Cell 63:579-590). The resulting backbone and side-chain conformations of the modeled yeast MatcY2 and D. melunogaster Antennapedia homeodomains are excellent matches to the corresponding published X-ray crystal (Wolberger C et al., 1991, Cell 67517-528) and NMR , J Mol Biol234:1084-1097) structures, respectively. Examination of these structures of Msx-1 reveals a network of highly conserved surface salt bridges that are proposed to play a role in regulating protein-protein interactions of homeodomains in transcription complexes. Abbreviations: Antp, homeodomain of the D. melanogusrer Antennapedia protein; DG, distance geometry calculations using metric-mauix embedding methods; Conf. E., total conformational energy including electrostatic effects, computed from the CHARMM potential function; Mata2, homeodomain of the yeast M a t d protein; Msx-1, homeodomain of the murine Msx-1 protein; pdf, probability density function; RMSD, R M S deviation; SARMD, simulated annealing with restrained molecular dynamics; VDW E., van der Waals energy computed from the Lennard-Jones portion of the CHARMM potential function. Keywords 956Homology modeling of homeodomain Msx-1 with CONGEN 957The homeodomain is a highly conserved sequence-specific DNAbinding domain that has been found in many transcription factors. First discovered in Drosophila melanogaster, homeodomains have been found in almost every organism from nematodes to humans (Kessel & Gruss, 1990; Wang et al., 1993), and have been found to play a fu...

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