Highly reusable Bi2O3/electron-Cu-shuttle in-situ immobilized polyacrylonitrile fibrous mat for efficient photocatalytic degradation of methylene blue and rhodamine B dyes.

Organic semiconductor-based photocatalysts have been alluring due to their edge over inorganic photocatalysts. In this study, a reusable copper-bismuth oxide/polyacrylonitrile (Cu-Bi2O3/PAN) fibrous mat was prepared by fast-process flame spray pyrolysis and electrospinning for photocatalytic degradation of methylene blue (MB) and rhodamine B (RhB) dyes. The results confirmed a well-defined morphology of Cu-Bi2O3/PAN fibers and good coordination of flame-made Cu-Bi2O3 particles with the functional groups of PAN. The Cu-Bi2O3/PAN fibrous mat exhibits remarkable photocatalytic performance of 96.2% MB and 98.6% RhB degradation, with a reaction rate as high as about 4.5- and 10.2-times than that of flame-made Cu-Bi2O3 particles and PAN under neutral condition, even after 10 cycles. The Cu-Bi2O3/PAN exhibits complete degradation of MB and RhB in 90 and 150 min under alkaline and slightly acidic conditions, respectively. The synergistic effect of Cu-Bi2O3 and coordination bond between particles and functional groups of PAN promoted carrier migration, suppressed recombination of carriers and provided abundant radicals on the surface of the mat. Superoxide and hydroxyl radicals were the major active species involved in the degradation of RhB and MB, respectively. This work provides an insight into designing the Cu-metal-shuttle based photocatalysts to optimize fibrous mat application in water remediation.

Retention of methyl iodide on metal and TEDA impregnated activated carbon using indigenously developed setup.

Removal of methyl iodide (CH3I) from the air present within nuclear facilities is a critical issue. In case of any nuclear accident, there is a great need to mitigate the radioactive organic iodide immediately as it accumulates in human bodies, causing severe consequences. Current research focuses on removing organic iodides, for which the surface of activated carbon (AC) was modified by impregnating it with different metals individually, i.e. Ag, Ni, Zn, Cu and with the novel combination of these four metals (AZNC). After the impregnation of metals, triethylenediamine (TEDA) was coated on metal impregnated activated carbon (IAC) surface. The adsorption capacity of the combination of four metals IAC was found to be 276 mg/g as the maximum for the trapping of CH3I. Whereas TEDA-metal impregnation on ACs enhanced the removal efficiency of CH3I up to 352 mg/g. After impregnation, adsorption capacity of AZNC and AZNCT is significantly higher as compared to AC. According to the finding, t5% of AZNCT IAC is 46 min, which is considerably higher than the t5% of other tested adsorbents. According to isotherm fitting data, Langmuir isotherm was found superior for describing CH3I sorption onto AC and IACs. Kinetics study shows that pseudo second order model represented the sorption of CH3I more accurately than the pseudo first order. Thermodynamic studies gave negative value of ΔG which shows that the reaction is spontaneous in nature. Based on the findings, AZNCT IAC appears to have a great potential for air purification applications in order to obtain clean environment.

BiP inactivation due to loss of the deAMPylation function of FICD causes a motor neuron disease.

PURPOSE: The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP activity regulation. METHODS: Exome sequencing was performed to identify causative pathogenic variants associated with motor neuron diseases. Functional studies were conducted on fibroblasts from patients to explore the molecular mechanism of the disease. RESULTS: We identified biallelic variants in FICD causing a neurodegenerative disease of upper and lower motor neurons. Affected individuals harbor a specific missense variant, Arg374His, positioned in the catalytic motif of the enzyme and important for adenosine triphosphate binding. The mutated residue abolishes intramolecular interaction with the regulatory residue Glu234, essential to inhibit AMPylation and to promote de-AMPylation by FICD. Consequently, fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. CONCLUSION: Loss of BiP chaperone activity in patients likely results in a chronic impairment of the protein quality control system in the endoplasmic reticulum. These findings will guide the development of therapeutic strategies for motoneuron and related diseases linked to proteotoxic stress.

Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss.

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.

Assessment of arsenic exposure by drinking well water and associated carcinogenic risk in peri-urban areas of Vehari, Pakistan.

Arsenic (As) is a highly toxic and carcinogenic element. It has received considerable consideration worldwide in recent years due to its highest toxicity to human, and currently, high concentrations observed in the groundwater. Some recent media and research reports also highlighted possible As contamination of groundwater systems in Pakistan. However, there is a scarcity of data about As contents in groundwater in different areas/regions of the country. Consequently, the current study estimated the As concentration in the groundwater used for drinking purpose in 15 peri-urban sites of district Vehari, Pakistan. In total, 127 groundwater samples were collected and examined for As contents in addition to physicochemical characteristics such as temperature, electrical conductivity, pH, total soluble salts, chloride, carbonates, bicarbonates, sodium, potassium, lithium, calcium and barium. Results indicated that the groundwater samples were not fully fit for drinking purposes with several parameters, especially the alarming levels of As (mean As: 46.9 µg/L). It was found that 83% groundwater samples of peri-urban sites in district Vehari have As concentration greater than WHO lower permissible limit (10 µg/L). The risk assessment parameters (mean hazard quotient: 3.9 and mean cancer risk: 0.0018) also showed possible carcinogenic and non-carcinogenic risks associated with ingestion of As-contaminated groundwater at peri-urban sites. Based on the findings, it is anticipated that special monitoring and management of groundwater is necessary in the studied area in order to curtail the health risks associated with the use of As-contaminated drinking water. Moreover, appropriate remediation and removal of As from groundwater is also imperative for the study area before being used for drinking purpose to avoid As exposure and related risks to the local community.

Cadmium Partitioning, Physiological and Oxidative Stress Responses in Marigold (Calendula calypso) Grown on Contaminated Soil: Implications for Phytoremediation.

Marigold (Calendula calypso) is a multipurpose ornamental plant, but its cadmium (Cd) tolerance and phytoremediation potential is unknown. The proposed study was carried out to unravel Cd partitioning, physiological and oxidative stress responses of C. calypso grown under Cd stress. Plants were grown for four months in pots having different soil Cd levels: 0, 25, 50, 75, and 100 mg kg-1 soil. Plant growth, biomass, photosynthetic pigments, leaf water contents, stomatal conductance, and membrane stability index were not decreased at 25 mg kg-1 Cd. At higher levels of Cd stress, activities of antioxidant enzymes (SOD, APX, CAT, POD) increased to mitigate H2O2 and lipid peroxidation. Cadmium uptake in plants increased with increasing soil Cd levels, and roots accumulated a greater portion of Cd, followed by shoots and flowers, respectively. On the basis of Cd accumulation and its tolerance, it was determined that C. calypso can be successfully grown for phytostabilization of Cd contaminated soils.

Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss.

Auditory reception relies on the perception of mechanical stimuli by stereocilia and its conversion to electrochemical signal. Mechanosensory stereocilia are abundant in actin, which provides them with structural conformity necessary for perception of auditory stimuli. Out of three major classes of actin-bundling proteins, plastin 1 encoded by PLS1, is highly expressed in stereocilia and is necessary for their regular maintenance. A missense PLS1 variant associated with autosomal dominant hearing loss (HL) in a small family has recently been reported. Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non-syndromic HL confirming the causative role of PLS1 mutations in HL. We propose that HL due to the p.E269K variant is from the loss of a stable PLS1-ACTB interaction.

SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency.

Recessive mutations in the mitochondrial copper-binding protein SCO2, cytochrome c oxidase (COX) assembly protein, have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency. Significantly expanding the known phenotypic spectrum, we identified compound heterozygous variants in SCO2 in two unrelated patients with axonal polyneuropathy, also known as Charcot-Marie-Tooth disease type 4. Different from previously described cases, our patients developed predominantly motor neuropathy, they survived infancy, and they have not yet developed the cardiomyopathy that causes death in early infancy in reported patients. Both of our patients harbour missense mutations near the conserved copper-binding motif (CXXXC), including the common pathogenic variant E140K and a novel change D135G. In addition, each patient carries a second mutation located at the same loop region, resulting in compound heterozygote changes E140K/P169T and D135G/R171Q. Patient fibroblasts showed reduced levels of SCO2, decreased copper levels and COX deficiency. Given that another Charcot-Marie-Tooth disease gene, ATP7A, is a known copper transporter, our findings further underline the relevance of copper metabolism in Charcot-Marie-Tooth disease.

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice.

Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.

Effect of salinity on cadmium tolerance, ionic homeostasis and oxidative stress responses in conocarpus exposed to cadmium stress: Implications for phytoremediation.

Contamination of soil with salinity and Cd negatively affects growth and productivity of plants. The proposed study has been planned to explore the effects of salinity on Cd uptake, tolerance and phytoremediation potential of conocarpus (Conocarpus erectus L.). One-month-old uniform plants of conocarpus were exposed to 0, 8.9, 44.5, 89 and 178 µM Cd alone or in combination with 0, 100 and 200 mM NaCl in Hoagland's nutrient solution. Results revealed that shoot and root biomasses, leaf water content and pigment content decreased more in response to combination of Cd and salinity compared to Cd alone. The Na+ and Cl- concentrations in shoot and root were not affected by Cd alone, but increased in Cd + salinity treatments. The K+ concentration decreased by Cd alone as well as Cd combination with salinity. Plant Cd uptake increased in the presence of salinity but its translocation from root to shoot remained unaffected. Exposure of plants to Cd alone and Cd + salinity caused oxidative stress via overproduction of H2O2 and inducing lipid peroxidation. The activities of antioxidant enzymes such as SOD, CAT, POD and APX increased to mitigate this oxidative stress. It is concluded that the tolerance of conocarpus against Cd stress is decreased in the presence of salinity due to increased uptake of toxic ions and intensification of oxidative stress. Moreover, the Cd uptake behavior of this tree indicates its suitability for phytostabilization of Cd contaminated saline and non-saline soils.

Study of land cover/land use changes using RS and GIS: a case study of Multan district, Pakistan.

Water and land both are limited resources. Current management strategies are facing multiple challenges to meet food security of an increasing population in numerous South Asian countries, including Pakistan. The study of land cover/land use changes (LCLUC) and land surface temperature (LST) is important as both provide critical information for policymaking of natural resources. We spatially examined LCLU and LST changes in district Multan, Pakistan, and its impacts on vegetation cover and water during 1988 to 2017. The LCLUC indicate that rice and sugarcane had less volatility of change in comparison with both cotton and wheat. Producer's accuracy (PA) is the map accuracy (the producer of map), but user's accuracy (UA) is the accuracy from the point of view of a map user, not the map maker. Average overall producer's and user's accuracy for the region was 85.7% and 87.7% for Rabi (winter) and Kharif (summer) seasons, respectively. The results of this study showed that 'built-up area' increased with 7.2% of all the classes during 1988 to 2017 in the Multan district. Anthropogenic activities decreased the vegetation, leading to an increase in LST in study area. Changes on LCLU and LST during the last 30 years have shown that vegetation pattern has changed and temperature has increased in the Multan district.

A missense mutation in DCDC2 causes human recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation.

Hearing loss is the most common sensory deficit in humans. We show that a point mutation in DCDC2 (DCDC2a), a member of doublecortin domain-containing protein superfamily, causes non-syndromic recessive deafness DFNB66 in a Tunisian family. Using immunofluorescence on rat inner ear neuroepithelia, DCDC2a was found to localize to the kinocilia of sensory hair cells and the primary cilia of nonsensory supporting cells. DCDC2a fluorescence is distributed along the length of the kinocilium with increased density toward the tip. DCDC2a-GFP overexpression in non-polarized COS7 cells induces the formation of long microtubule-based cytosolic cables suggesting a role in microtubule formation and stabilization. Deafness mutant DCDC2a expression in hair cells and supporting cells causes cilium structural defects, such as cilium branching, and up to a 3-fold increase in length ratios. In zebrafish, the ortholog dcdc2b was found to be essential for hair cell development, survival and function. Our results reveal DCDC2a to be a deafness gene and a player in hair cell kinocilia and supporting cell primary cilia length regulation likely via its role in microtubule formation and stabilization.

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing.

In a large consanguineous Turkish kindred with recessive nonsyndromic, prelingual, profound hearing loss, we identified in the gene FAM65B (MIM611410) a splice site mutation (c.102-1G>A) that perfectly cosegregates with the phenotype in the family. The mutation leads to exon skipping and deletion of 52-amino acid residues of a PX membrane localization domain. FAM65B is known to be involved in myotube formation and in regulation of cell adhesion, polarization, and migration. We show that wild-type Fam65b is expressed during embryonic and postnatal development stages in murine cochlea, and that the protein localizes to the plasma membranes of the stereocilia of inner and outer hair cells of the inner ear. The wild-type protein targets the plasma membrane, whereas the mutant protein accumulates in cytoplasmic inclusion bodies and does not reach the membrane. In zebrafish, knockdown of fam65b leads to significant reduction of numbers of saccular hair cells and neuromasts and to hearing loss. We conclude that FAM65B is a plasma membrane-associated protein of hair cell stereocilia that is essential for hearing.

Helix 8 and the i3 loop of the muscarinic M3 receptor are crucial sites for its regulation by the Gß5-RGS7 complex.

The muscarinic M3 receptor (M3R) is a Gq-coupled receptor and is known to interact with many intracellular regulatory proteins. One of these molecules is Gß5-RGS7, the permanently associated heterodimer of G protein ß-subunit Gß5 and RGS7, a regulator of G protein signaling. Gß5-RGS7 can attenuate M3R-stimulated release of Ca(2+) from intracellular stores or enhance the influx of Ca(2+) across the plasma membrane. Here we show that deletion of amino acids 304-345 from the central portion of the i3 loop renders M3R insensitive to regulation by Gß5-RGS7. In addition to the i3 loop, interaction of M3R with Gß5-RGS7 requires helix 8. According to circular dichroism spectroscopy, the peptide corresponding to amino acids 548-567 in the C-terminus of M3R assumes an α-helical conformation. Substitution of Thr553 and Leu558 with Pro residues disrupts this α-helix and abolished binding to Gß5-RGS7. Introduction of the double Pro substitution into full-length M3R (M3R(TP/LP)) prevents trafficking of the receptor to the cell surface. Using atropine or other antagonists as pharmacologic chaperones, we were able to increase the level of surface expression of the TP/LP mutant to levels comparable to that of wild-type M3R. However, M3R-stimulated calcium signaling is still severely compromised. These results show that the interaction of M3R with Gß5-RGS7 requires helix 8 and the central portion of the i3 loop.

Novel mutations confirm that COL11A2 is responsible for autosomal recessive non-syndromic hearing loss DFNB53.

Hearing loss (HL) is a major public health issue. It is clinically and genetically heterogeneous.The identification of the causal mutation is important for early diagnosis, clinical follow-up, and genetic counseling. HL due to mutations in COL11A2, encoding collagen type XI alpha-2, can be non-syndromic autosomal-dominant or autosomal-recessive, and also syndromic as in Otospondylomegaepiphyseal Dysplasia, Stickler syndrome type III, and Weissenbacher-Zweymuller syndrome. However, thus far only one mutation co-segregating with autosomal recessive non-syndromic hearing loss (ARNSHL) in a single family has been reported. In this study, whole exome sequencing of two consanguineous families with ARNSHL from Tunisia and Turkey revealed two novel causative COL11A2 mutations, c.109G > T (p.Ala37Ser) and c.2662C > A (p.Pro888Thr). The variants identified co-segregated with deafness in both families. All homozygous individuals in those families had early onset profound hearing loss across all frequencies without syndromic findings. The variants are predicted to be damaging the protein function. The p.Pro888Thr mutation affects a -Gly-X-Y- triplet repeat motif. The novel p.Ala37Ser is the first missense mutation located in the NC4 domain of the COL11A2 protein. Structural model suggests that this mutation will likely obliterate, or at least partially compromise, the ability of NC4 domain to interact with its cognate ligands. In conclusion, we confirm that COL11A2 mutations cause ARNSHL and broaden the mutation spectrum that may shed new light on genotype-phenotype correlation for the associated phenotypes and clinical follow-up.

Allostery mediates ligand binding to WWOX tumor suppressor via a conformational switch.

While being devoid of the ability to recognize ligands itself, the WW2 domain is believed to aid ligand binding to the WW1 domain in the context of a WW1-WW2 tandem module of WW domain-containing oxidoreductase (WWOX) tumor suppressor. In an effort to test the generality of this hypothesis, we have undertaken here a detailed biophysical analysis of the binding of WW domains of WWOX alone and in the context of the WW1-WW2 tandem module to an array of putative proline-proline-x-tyrosine (PPXY) ligands. Our data show that while the WW1 domain of WWOX binds to all ligands in a physiologically relevant manner, the WW2 domain does not. Moreover, ligand binding to the WW1 domain in the context of the WW1-WW2 tandem module is two-to-three-fold stronger than when treated alone. We also provide evidence that the WW domains within the WW1-WW2 tandem module physically associate so as to adopt a fixed spatial orientation relative to each other. Of particular note is the observation that the physical association of the WW2 domain with WW1 blocks access to ligands. Consequently, ligand binding to the WW1 domain not only results in the displacement of the WW2 lid but also disrupts the physical association of WW domains in the liganded conformation. Taken together, our study underscores a key role of allosteric communication in the ability of the WW2 orphan domain to chaperone physiological action of the WW1 domain within the context of the WW1-WW2 tandem module of WWOX.

Effect of osmolytes on the binding of EGR1 transcription factor to DNA.

Osmolytes play a key role in maintaining protein stability and mediating macromolecular interactions within the intracellular environment of the cell. Herein, we show that osmolytes such as glycerol, sucrose, and polyethylene glycol 400 (PEG400) mitigate the binding of early growth response (protein) 1 (EGR1) transcription factor to DNA in a differential manner. Thus, while physiological concentrations of glycerol only moderately reduce the binding affinity, addition of sucrose and PEG400 is concomitant with a loss in the binding affinity by an order of magnitude. This salient observation suggests that EGR1 is most likely subject to conformational equilibrium and that the osmolytes exert their effect via favorable interactions with the unliganded conformation. Consistent with this notion, our analysis reveals that while EGR1 displays rather high structural stability in complex with DNA, the unliganded conformation becomes significantly destabilized in solution. In particular, while liganded EGR1 adopts a well-defined arc-like architecture, the unliganded protein samples a comparatively large conformational space between two distinct states that periodically interconvert between an elongated rod-like shape and an arc-like conformation on a submicrosecond time scale. Consequently, the ability of osmolytes to favorably interact with the unliganded conformation so as to stabilize it could account for the negative effect of osmotic stress on EGR1-DNA interaction observed here. Taken together, our study sheds new light on the role of osmolytes in modulating a key protein-DNA interaction.

PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.

Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot-Marie-Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.

Structures of YAP protein domains reveal promising targets for development of new cancer drugs.

YAP (Yes-associated protein) is a potent oncogene and a major effector of the mammalian Hippo tumor suppressor pathway. In this review, our emphasis is on the structural basis of how YAP recognizes its various cellular partners. In particular, we discuss the role of LATS kinase and AMOTL1 junction protein, two key cellular partners of YAP that bind to its WW domain, in mediating cytoplasmic localization of YAP and thereby playing a key role in the regulation of its transcriptional activity. Importantly, the crystal structure of an amino-terminal domain of YAP in complex with the carboxy-terminal domain of TEAD transcription factor was only recently solved at atomic resolution, while the structure of WW domain of YAP in complex with a peptide containing the PPxY motif has been available for more than a decade. We discuss how such structural information may be exploited for the rational development of novel anti-cancer therapeutics harboring greater efficacy coupled with low toxicity. We also embark on a brief discussion of how recent in silico studies led to identification of the cardiac glycoside digitoxin as a potential modulator of WW domain-ligand interactions. Conversely, dobutamine was identified in a screen of known drugs as a compound that promotes cytoplasmic localization of YAP, thereby resulting in growth suppressing activity. Finally, we discuss how a recent study on the dynamics of WW domain folding on a biologically critical time scale may provide a tool to generate repertoires of WW domain variants for regulation of the Hippo pathway toward desired, non-oncogenic outputs.

De novo ACTG2 mutations cause congenital distended bladder, microcolon, and intestinal hypoperistalsis.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by prenatal-onset distended urinary bladder with functional intestinal obstruction, requiring extensive surgical intervention for survival. While it is believed to be an autosomal recessive disorder, most cases are sporadic. Through whole-exome sequencing in a child with MMIHS, we identified a de novo mutation, p.R178L, in the gene encoding the smooth muscle gamma-2 actin, ACTG2. We subsequently detected another de novo ACTG2 mutation, p.R178C, in an additional child with MMIHS. Actg2 transcripts were primarily found in murine urinary bladder and intestinal tissues. Structural analysis and functional experiments suggested that both ACTG2 mutants interfere with proper polymerization of ACTG2 into thin filaments, leading to impaired contractility of the smooth muscle. In conclusion, our study suggests a pathogenic mechanism for MMIHS by identifying causative ACTG2 mutations.