The rise of organic bioelectronics efficiently bridges the gap between semiconductor devices and biological systems, leading to flexible, lightweight, and lowcost organic bioelectronic devices suitable for health or body signal monitoring. The introduction of organic semiconductors in the devices can soften the boundaries between microelectronic systems and dynamically active cells and tissues. Therefore, organic bioelectronics has attracted much attention recently due to the unique properties and promising applications. Organic thin film transistors (OTFTs), owing to their inherent capability of amplifying received signals, have emerged as one of the state-of-the-art biosensing platforms. The advantages of organic semiconductors in terms of synthetic freedom, low temperature solution processing, biocompatibility, and mechanical flexibility render OTFTs ideal transducers for wearable electronics, e-skin, and implantable devices. How to realize highly sensitive, selective, rapid, and efficient signal capture and extraction of biological recognition events is the major challenge in the design of biosensors. OTFTs are prone to converting the presence or change of target analytes into specific electrical signals even in complex biological systems. More importantly, OTFT sensors can be conveniently functionalized with chemical or biological modifications and exhibit substantially improved device sensitivity and selectivity as well as other analytical figure of merits, including calibration range, linearity, and accuracy. However, the stability and reproducibility of the organic devices need to be further improved. In this Account, we first introduce the unique features of OTFTs for bioelectronic applications. Two typical OTFT configurations, including organic electrochemical transistor (OECT) and electrolyte gated organic field effect transistor (EGOFET), are highlighted in their sensing applications mainly due to the operation of the devices in electrolytes and the combination of ionic and electronic charge transports in the devices. These devices are potentiometric transducers with low working voltages (<1 V) and high sensitivity, and are thus suitable for wearable applications with low power consumption. Second, the functionalization strategies on channel materials, electrolytes, and gate electrodes based on various modification methods and sensing mechanisms are discussed in sequence. In an OECT-or EGOFET-based biosensor, the device performance is particularly sensitive to the physical properties of the two interfaces, including channel/electrolyte and gate/ electrolyte interfaces. Any change in the potential drop or capacitance of either interface can influence the channel current substantially. Therefore, the functionalization of the interfaces is critical to the sensing performance. In particular, when an electrochemically active material is modified on the interfaces, the reaction of the analyte catalyzed by the modified material can influence the interface potential and lead to a channel current response much...

Flexible fabric biosensors can find promising applications in wearable electronics. However, high-performance fabric biosensors have been rarely reported due to many special requirements in device fabrication. Here, the preparation of organic electrochemical transistors (OECTs) on Nylon fibers is reported. By introducing metal/conductive polymer multilayer electrodes on the fibers, the OECTs show very stable performance during bending tests. The devices with functionalized gates are successfully used as various biosensors with high sensitivity and selectivity. The fiber-based OECTs are woven together with cotton yarns successfully by using a conventional weaving machine, resulting in flexible and stretchable fabric biosensors with high performance. The fabric sensors show much more stable signals in the analysis of moving aqueous solutions than planar devices due to a capillary effect in fabrics. The fabric devices are integrated in a diaper and remotely operated by using a mobile phone, offering a unique platform for convenient wearable healthcare monitoring.

The analysis of protein biomarkers is of great importance in the diagnosis of diseases. Although many convenient and low-cost electrochemical approaches have been extensively investigated, they are not sensitive enough in the detection of protein biomarkers with low concentrations in physiological environments. Here, this study reports a novel organic-electrochemical-transistor-based biosensor that can successfully detect cancer protein biomarkers with ultrahigh sensitivity. The devices are operated by detecting electrochemical activity on gate electrodes, which is dependent on the concentrations of proteins labeled with catalytic nanoprobes. The protein sensors can specifically detect a cancer biomarker, human epidermal growth factor receptor 2, down to the concentration of 10 g mL , which is several orders of magnitude lower than the detection limits of previously reported electrochemical approaches. Moreover, the devices can successfully differentiate breast cancer cells from normal cells at various concentrations. The ultrahigh sensitivity of the protein sensors is attributed to the inherent amplification function of the organic electrochemical transistors. This work paves a way for developing highly sensitive and low-cost biosensors for the detection of various protein biomarkers in clinical analysis in the future.

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Rationale Delivery of connexin 43 (Cx43) to the intercalated disc is a continuous and rapid process critical for intercellular coupling. By a pathway of targeted delivery involving microtubule highways, vesicles of Cx43 hemichannels are efficiently trafficked to adherens junctions at intercalated discs. It has also been identified that actin provides rest stops for Cx43 forward trafficking, and that Cx43 has a 20kDa internally translated small C-terminus isoform (GJA1-20k) which is required for full-length Cx43 trafficking, but by an unknown mechanism. Objective We explored the mechanism by which the GJA1-20k isoform is required for full-length Cx43 forward trafficking to intercalated discs. Methods and Results Using an in-vivo AAV9-mediated gene transfer system, we confirmed in whole animal that GJA1-20k markedly increases endogenous myocardial Cx43 gap junction plaque size at the intercalated discs. In micropatterned cell pairing systems, we found that exogenous GJA1-20k expression stabilizes filamentous actin (F-actin) without affecting actin protein expression, and that GJA1-20k complexes with both actin and tubulin. We also found that F-actin regulates microtubule organization as inhibition of actin polymerization with a low dose of latrunculin A (LatA) disrupts the targeting of microtubules to cell-cell junctions. GJA1-20k protects actin filament from LatA disruption, preserving microtubule trajectory to the cell-cell border. For therapeutic implications, we found that prior in vivo AAV9-mediated gene delivery of GJA1-20k to the heart protects Cx43 localization to the intercalated discs against acute ischemic injury. Conclusions The internally translated GJA1-20k isoform stabilizes actin filaments which guides growth trajectories of the Cx43 microtubule trafficking machinery, increasing delivery of Cx43 hemichannels to cardiac intercalated discs. Exogenous GJA1-20k helps to maintain cell-cell coupling in instances of anticipated myocardial ischemia.

Because of the fast expansion of artificial intelligence, development and applications of neuromorphic systems attract extensive interest. In this paper, a highly interconnected neuromorphic architecture (HINA) based on flexible self-supported multiterminal organic transistors is proposed. Au electrodes, poly(3-hexylthiophene) active channels, and ion-conducting membranes were combined to fabricate organic neuromorphic devices. Especially, freestanding ion-conducting membranes were used as gate dielectrics as well as support substrates. Basic neuromorphic behavior and four forms of spike-timing-dependent plasticity were emulated. The fabricated neuromorphic device showed excellent electrical stability and mechanical flexibility after 1000 bends. Most importantly, the device structure is interconnected in a way similar to the neural architecture of the human brain and realizes not only the structure of the multigate but also characteristics of the global gate. Dynamic processes of memorizing and forgetting were incorporated into the global gate matrix simulation. Pavlov's learning rule was also simulated by taking advantage of the multigate array. Realization of HINAs would open a new path for flexible and sophisticated neural networks.

L-type calcium currents conducted by Ca V 1.2 channels initiate excitation-contraction coupling in cardiac and vascular smooth muscle. In the heart, the distal portion of the C terminus (DCT) is proteolytically processed in vivo and serves as a noncovalently associated autoinhibitor of Ca V 1.2 channel activity. This autoinhibitory complex, with A-kinase anchoring protein-15 (AKAP15) bound to the DCT, is hypothesized to serve as the substrate for ␤-adrenergic regulation in the fight-or-flight response. Mice expressing Ca V 1.2 channels with the distal C terminus deleted (DCT ) current in cardiomyocytes, where Ca 2ϩ enters through the channel and initiates excitation-contraction coupling via Ca 2ϩ -induced Ca 2ϩ release (1). Normal expression of Ca V 1.2 channels is required for cardiac contractile function and for survival beyond embryonic day 14 (2). Lack of the Ca V 1.2 channel also abolishes the development of myogenic tone and disrupts hormonal regulation of blood pressure (3). In contrast, deletion of Ca V 1.3, which also conducts L-type Ca 2ϩ currents, causes sinoatrial nodal dysfunction and cardiac arrhythmias but does not impair contractility or cause premature death (4). Overall, these gene deletion studies illustrate that L-type Ca 2ϩ currents are essential for normal cardiovascular function and for normal development.Ca V 1 channels are multisubunit complexes composed of a pore-forming ␣1 subunit and auxiliary ␤, ␣2␦, and in some cases ␥ subunits (5-7). They are a primary target for regulation by numerous hormones, protein kinases, and phosphoprotein phosphatases (5-7). In the "fight-or-flight" response, increased force of contraction is achieved largely through regulation of Ca V 1.2 channels in the heart by the sympathetic nervous system through activation of ␤-adrenergic receptors, adenylyl cyclase, and cyclic AMP-dependent protein kinase (PKA) and resulting phosphorylation of Ca V 1.2 channels (1,5,6,8). ␤-Adrenergic regulation of Ca V 1.2 channels requires A-kinase anchoring protein 15 (AKAP15), 2 which anchors the kinase to the distal C terminus of Ca V 1.2 via a modified leucine zipper (LZ) motif (9 -11).The C terminus of Ca V 1 channels undergoes proteolytic processing in vivo in skeletal and cardiac muscle (12-15). In cardiac muscle, the ␣1 subunit of Ca V 1.2 channels is present in two size forms of ϳ240 and 210 kDa, which differ by truncation of the distal C terminus (DCT) (15). This truncation leads to enhanced activity of Ca V 1.2 channels expressed in Xenopus oocytes and mammalian cell lines (16,17). Single channel conductance, modulation by ␤ and ␣2␦ subunits, and sensitivity to Ca 2ϩ channel agonists such as Bay K8644 remain unchanged (16, 17). The proteolytically cleaved DCT binds to the truncated channel and acts as potent autoinhibitor (18). Mutations of key charged residues at the interface between distal and proximal C-terminal domains of Ca V 1.2 relieves autoinhibition (18). Moreover, recent studies indicate that regulation of Ca V 1.2 channels can be reconstituted in transfect...

The undersigned authors wish to note, "The KefFC system of E. coli is maintained in an inactive state by the binding of glutathione (GSH) and is activated by the formation of GSH adducts (GSX), particularly those with bulky substituents. We described two crystal structures with density present in the ligand-binding domain that we interpreted as GSH and GSX. Recently, an independent, experienced crystallographer, who had viewed the structures from our study in a different context, made representations to us that cast doubt on position of the succinimido ring of GSX. We have further reviewed the density maps with the aid of an experienced crystallographer. As a consequence, we believe it is important to draw this altered interpretation of the crystal structures to the attention of readers. In both structures, the density for the backbone of GSH is clear and allows unequivocal assignment of the position of the tripeptide. In PDB coordinate set 3L9X, the density for the succinimido ring is very weak, making interpretation very speculative and the assignment rests on the identity of the ligand added to the crystallization mixture, for which there are two diastereomers in the solutiona possibility that provides some basis for weakening the density. However, in 3L9W there are two anomalies that affect the interpretation of the bound ligand. First, there is no density for the carbon atom attached to the sulfur of GSH and second, there is extra density adjacent to the position of sulfur that could be modelled as a constrained succinimido ring. However, this density could also be water or any other molecule that is trapped in the structure. Thus, while there is good evidence for the peptide, the evidence that it is in the GSH form is uncertain."There are no new data on either the structures or on the gating mechanism. However, we believe that we should be cautious in interpreting the structural data and that the field in general should be made aware of the alternative views of the electron density data. Note that the mutagenesis and spectroscopic data that were presented in the original manuscript are not affected by this alternative interpretation." Tarmo P. The authors note that the following grant should be added to the Acknowledgments: "NIH Grant AG002132." The authors note "The method used for exogenous expression of Ca V 1.2 channels in ref. 32 was incorrectly described as 'viral transduction' in the text. In fact, Yang et al. created transgenic mice with inducible, cardiomyocyte-specific expression of exogenous Ca V 1.2 channels regulated by a tetracycline-inducible promoter. When crossed with a transgenic mouse line expressing doxycycline-regulated reverse transcriptional activator under control of the α-myosin heavy chain protomer, the resulting double transgenic offspring expressed exogenous Ca V 1.2 channels in their cardiac myocytes after treatment with doxycycline. The authors regret the error in describing these methods."www.pnas.org/cgi