Protease domains within toxins typically act as the primary effector domain within target cells. By contrast, the primary function of the cysteine protease domain (CPD) in Multifunctional Autoprocessing RTX-like (MARTX) and Clostridium sp. glucosylating toxin families is to proteolytically cleave the toxin and release its cognate effector domains. The CPD becomes activated upon binding to the eukaryotic-specific small molecule, inositol hexakisphosphate (InsP6), which is found abundantly in the eukaryotic cytosol. This property allows the CPD to spatially and temporally regulate toxin activation, making it a prime candidate for developing anti-toxin therapeutics. In this review, we summarize recent findings related to defining the regulation of toxin function by the CPD and the development of inhibitors to prevent CPD-mediated activation of bacterial toxins.
Many bacterial toxins whose targets are within host cells require proteolytic activation for their function. Whereas most toxins, such as cholera toxin and anthrax toxin, are cleaved by a eukaryotic cell protease, a subset of bacterial toxins is autoproteolytically activated by an internal cysteine protease domain (CPD). The CPD is found within two multidomain toxin families: the Multifunctional Autoprocessing RTX-like toxins (MARTX) toxins and the Clostridium sp. glucosylating toxins (GTs) (Figure 1a and b). Because the CPD is directly activated by the eukaryotic-specific small molecule inositol hexakisphosphate (InsP6), the CPD acts as a biosensor that appears to allow for temporal and spatial regulation of toxin activation. Once toxins translocate across eukaryotic cell membranes, the CPD binds to InsP6 within the cell (KD ~ 1-2 µM) [3,4,5] and induces toxin autoprocessing. Cleavage of the toxins by the CPD releases cognate effector domains and subsequently enhances toxin function [6,7,8,9]. Importantly, InsP6 is found at concentrations between 5-100 µM within the cytosol of mammalian cells, exhibits a long half-life in cells, and may be localized to cellular membranes and the nucleus [10,11,12].
The MARTX toxins are a newly discovered family of toxins that are encoded in the genomes of a number of Gram-negative bacteria . Although only a few toxin members have been studied to date, MARTX toxins have been shown to modulate the virulence of Vibrio cholerae, Vibrio vulnificus, and Vibrio anguillarum. The MARTX toxin of V. cholerae, the causative agent of cholera, is produced by nearly all clinical and environmental isolates of V. cholerae [15,16,17]. Although it is not cytotoxic, it induces cell rounding and enhances colonization in a mouse model of infection [18,19,20,21]. By contrast, MARTX toxins of the marine pathogens V. vulnificus and V. anguillarum are cytotoxic and function as key virulence factors [22,23,24].
MARTX toxins are some of the largest bacterial proteins identified to date, with molecular weights often in excess of 450 kDa . They are characterized by conserved N- and C-terminal repeat regions with similarity to RTX toxins that flank a central effector domain region (Figure 1a). These repeat regions have been proposed to form a pore that allows the central effector region to autotranslocate across host cell membranes . While the composition of the central region varies across MARTX toxin family members, the most C-terminal effector of MARTX toxins is always the InsP6-sensing cysteine protease domain (CPD). In V. cholerae MARTX toxin, the best characterized family member, the CPD cleaves the toxin at multiple sites to release discrete effector domains (Figure 1c) [9,25].
Aside from the CPD, the activities of most MARTX effector domains remain uncharacterized. The functions of only two other effector domain functions have been identified to date; both these domains are found within V. cholerae MARTX toxins and disrupt host cell actin dynamics. The actin crosslinking domain (ACD) has homology to ATP-dependent ligases and covalently crosslinks actin monomers together through an atypical glutamate-lysine crosslink [26,27,28,29]. As a result, the ACD prevents growth of actin filaments and depletes the monomeric actin pool, which leads to cell rounding due to destruction of the actin cytoskeleton. The Rho Inactivating Domain (RID) domain inhibits small Rho GTPase activity through an as yet undefined mechanism .
Figure 1. Autoproteolytic activation of MARTX and glucosylating toxin families by the CPD. (a) Domain organization of V. cholerae MARTX toxin. Conserved glycine-rich repeat regions in the N- and C-termini of MARTX toxins (MARTX conserved, red); actin crosslinking domain (ACD, orange); Rho-inactivating domain (RID, green); α/β hydrolase domain (α/β, purple), cysteine protease domain (CPD, pink). Cleavage sites are shown. (b) ABCD domain organization of C. difficile glucosylating toxins. A: Glucosyltransferase (Glc) "activity" domain; B: receptor "binding" domain; C: cysteine protease "cutting" domain; and D: hydrophobic translocation "delivery" domain. Cleavage site in TcdB is marked (c) Schematic model for CPD-mediated activation of V. cholerae MARTX toxin. Upon encountering a eukaryotic cell, the N- and C-terminal MARTXVc conserved regions insert into the plasma membrane and form a pore that permits translocation of the toxin central region across the cell membrane. Following toxin entry, the CPD binds inositol hexakisphosphate (InsP6, starburst), resulting in activation of its protease activity. The CPD first cleaves at Leu3441, the preferred autoprocessing site, then Leu2447, followed by Leu3099 (least preferred cleavage site) . Processing of MARTXVc by the CPD releases the RID and (α/β) domains into the cytosol, while the ACD and CPD remain tethered to the membrane. Cleavage of MARTXVc, particularly at Leu2447, activates the actin crosslinking activity of the ACD. (d) Schematic model for CPD-mediated activation of Clostridium sp. glucosylating toxins. Binding of the toxins to unidentified receptors results in their uptake by receptor-mediated endocytosis. Acidification of the early endosome triggers toxin translocation of the Glc domain (triangle). This is the only part of the protein released into the cytosol, presumably due to CPD-mediated autoproteolysis . Whether the CPD itself is translocated, and when and where it is activated by InsP6 (starburst) is unknown, although it likely occurs on the cytosolic face of the endosomal membrane.
Similar to MARTX toxins, Clostridium sp. glucosylating toxins are multidomain toxins that alter target cell cytoskeletal dynamics in a manner dependent on CPD-mediated toxin autoprocessing (Figure 1b and d). Glucosylating toxins are large (~250 kDa) proteins with an ABCD toxin structure (A, biological activity; B, binding; C, cutting; D, delivery) [7,31,32]. The "biological activity" (A) is conferred by the N-terminal glucosyltransferase (Glc) domain, which glucosylates Rho GTPases (such as RhoA and Ras) at a conserved Thr residue [33,34]. This covalent modification prevents Rho GTP-GDP exchange and irreversibly inhibits Rho GTPase function, leading to disruption of epithelial barrier junctions, inhibition of Rho-mediated signaling, and ultimately cell death and inflammation . The "binding activity" (B) of GTs is mediated by the C-terminal repeat region, which forms a solenoid structure that probably binds sugar moieties on cell surface receptors (the identity of which has not been determined). The toxins are then taken up by receptor-mediated endocytosis.
As "short-trip" toxins, acidification of the early endosomal compartment induces conformational changes in GTs that results in membrane insertion and toxin translocation. The central, hydrophobic region is thought to confer this "delivery activity" (D) . While the mechanism by which this occurs remains unclear, the central region likely mediates translocation of the Glc domain across the endosomal membrane into the target cell cytosol. The CPD domain presumably is also transferred, but this has not been directly tested. Nevertheless, binding of InsP6 to the CPD (either in the endosome or in the host cytosol) results in CPD activation and cleavage of GTs at the Glc domain-CPD junction [3,37,38]. This "cutting" (C) event releases the Glc domain from the endosome, an event that presumably improves access of the Glc domain to its Rho GTPase substrates at the membrane.
The glucosylating toxins (GTs) are produced by select Clostridium sp. pathogens, which are Gram-positive, anaerobic, spore-forming bacteria. Members of the GT family include TcdL and TcdH of C. sordellii, TcnA of C. novyi, and C. perfringens types B and C, but the prototypical members are TcdA and TcdB of C. difficile. This latter bacterium is of particular interest as it is the leading cause of nosocomial diarrhea worldwide and is associated with significant morbidity and cost in health care-associated settings [39,40]. The glucosylating toxins TcdA and TcdB are the primary causes of C. difficile infection (CDI), with TcdB being the more active of the two toxins and essential for virulence . The relevance of these toxins to disease is underscored by the observation that a strain that hyper-produces TcdA and TcdB causes more frequent and severe cases of CDIs [40,42]. Thus, the development of inhibitors that can inhibit TcdA and TcdB function or activation should have considerable therapeutic utility.
Although MARTX and GT toxin families differ in their activities and domain organization, they share a common cysteine protease domain (CPD) that proteolytically processes toxin family members. Despite differing in 60% of their amino acid residues, both MARTX and GT CPDs have a similar overall fold that resembles a canonical caspase-like fold (Figure 2a and b). As clan CD proteases (MEROPS classification) , both bacterial CPDs and caspases have a central β-sheet that is surrounded by α-helices . Unlike the caspases, however, bacterial CPDs contain an InsP6 binding site and a region termed the β-flap (described below). Structures of both MARTX and TcdB CPDs reveal that the InsP6 binding site is comprised of numerous positively charged residues that trap a single negatively-charged InsP6 molecule [4,25,45]. Interestingly, the mechanism of InsP6 binding differs slightly between Tcd and MARTX CPDs, with InsP6 lying flat on the surface of the protease in V. cholerae MARTX CPD, and InsP6 being wedged into the side of TcdA CPD (Figure 2c and d) . Both proteases, however, have similar low micromolar affinities for InsP6[4,5,37].
Figure 2. Structure of bacterial CPDs. Ribbon structure of (a)V. cholerae MARTX CPD (PDB ID: 3EEB) and (b)C. difficile TcdA CPD (PDB ID: 3HO6). Electrostatic surface potential of (c)V. cholerae MARTX CPD and (d) C. difficile TcdB CPD as viewed from above the InsP6 binding site. Blue denotes positively charged surface; red denotes negatively charged surface. InsP6 is shown in the binding site as a stick model. Note that the orientation of the InsP6 molecule differs between the two structures.
Notably, the InsP6 binding site is physically distinct from the active site, indicating that InsP6 likely functions as an allosteric activator of bacterial CPDs. Although a number of studies have shown that InsP6 binding improves access of the CPD to its substrates and inhibitors [3,4,25], the mechanism by which InsP6 binding is communicated to the active site has not been fully characterized. Current work suggests that the β-flap region - the second structural feature in which bacterial CPDs differ from other clan CD proteases - transduces the InsP6 binding to the active site. Mutation of key residues in the β-flap disrupt CPD function [4,5,37,45], and residues in this region have been shown to be resistant to limited proteolysis in the presence of InsP6 . This latter result suggests that InsP6 binding induces stabilization of the β-flap in the activated protease. Interestingly, the β-flap region of TcdA CPD is larger than that of V. cholerae CPD, with TcdA CPD containing an additional alpha-helix ; the functional significance of this addition is unknown.
This mechanism of allosteric regulation by a small metabolite is unique among proteases. Nevertheless, bacterial CPDs exhibit many similarities in substrate recognition to clan CD proteases. In particular, like the caspases, the substrate specificity of MARTX CPDs is governed by the P1 residue, the amino acid immediately N-terminal to the scissile bond [9,25,46,47,48]. Just as caspases cleave almost exclusively after P1 Asp residues, bacterial CPDs appear to cleave exclusively after P1 Leu residues: all known MARTX and GT toxin autoprocessing sites occur after Leu residues [3,9,25,49]. In addition, like the caspases, MARTX CPDs appear to exhibit a preference for a small amino acid in the P1' position, the residue immediately C-terminal to the scissile bond. A comparison of known and inferred cleavage sites within MARTX and GT toxins suggests that small residues in the P1' position are favored (Figure 3). Furthermore, the CPD has been shown to cleave more efficiently when the P1' residue is an Ala versus a Ser residue, while the presence of a bulky P1' Leu residue is sufficient to abrogate CPD-mediated processing .
Figure 3. Sequence logo representation of MARTX and GT CPD consensus cleavage site. The sequence logo was created using natural MARTX CPD cleavage sites mapped by intact mass spectrometry  and cleavage sites mapped and/or inferred in GT CPDs [38,49], see http://weblogo.berkeley.edu. The dashed line indicates the scissile bond.
The restraints on substrate specificity determined by cleavage site comparisons are also observed in studies with MARTX CPD inhibitors . Inhibitors of V. cholerae MARTX CPD processing were recently identified in a screen of a focused library of cysteine protease inhibitors. All CPD inhibitors derived from the screen contain a Leu in the P1 position, the residue immediately N-terminal to the scissile bond. They were also all functionalized with an aza-epoxide group, which reacts with the caspases . The screen produced a small structure-activity relationship (SAR) series that shows remarkable similarities to an SAR series previously performed on the caspases. In particular, the regio- and stereochemistry at the epoxide moiety influences inhibitor potency for both V. cholerae CPD and caspase-3, with S,S > trans > R,R [9,51].
The crystal structure of V. cholerae CPD bound to the most potent inhibitor from the screen (JCP598, Z-LL-azaL-EP, Figure 4a) provided the most convincing evidence that MARTX CPDs and caspases share similar mechanisms of substrate recognition and catalysis . In both the V. cholerae CPD and caspase-3 structures bound to aza-epoxide inhibitors, the catalytic Cys of V. cholerae CPD attacks on the C3 position of the expoxide rather than the C2. Furthermore, the catalytic residues of V. cholerae MARTX CPD and caspase-3 exhibit similar geometries around the P1-P1' peptide bond, and the S1 binding pockets (that recognize the P1 residue) are similarly aligned. Indeed, the S1 pocket of V. cholerae MARTX CPD forms a deep, hydrophobic cavity that perfectly accommodates a Leu residue (Figure 4b), and residues that form this S1 pocket are conserved across MARTX and GT CPDs. Notably, the structure of aza-epoxide inhibited V. cholerae MARTX CPD is essentially superimposable with the recently solved structure of the uncleaved form of the protease. This uncleaved form carries the native P1 Leu and non-native TEV protease cleavage site . The P1 Leu residues of both MARTX CPD structures are similarly aligned, while mutational analyses of the P2 site also support the conclusion that the primary substrate specificity determinant is a P1 Leu .
As observed with the natural cleavage substrates of MARTX toxins, the P2 and P3 positions of the inhibitors do not strongly contribute to substrate recognition . For example, no difference in inhibitor potency was observed between a Cbz-Leu-Leu-azaLeu (Z-LLaL-EP) epoxide inhibitor and Cbz-Asp-Ala-azaLeu (Z-EAaL-EP) epoxide inhibitor. Furthermore, the S2 and S3 sub-sites in the crystal structure of inhibitor-bound MARTX CPD do not make contacts with the P2 and P3 side chains of the inhibitor; rather, the protease interacts with the peptide backbone of the inhibitor. These conclusions are consistent with SAR series results, indicating that inhibitors carrying P2 and P3 residues were more potent than inhibitors with only a single P1 Leu.
The functional group of the P1 Leu inhibitors also affects inhibitor potency. Whereas inhibitors with a P1 Leu and acyloxymethylketone (AOMK) functional group, which reacts with caspases , block the activity of V. cholerae MARTX CPD, inhibitors with the same peptide sequence as JCP598 (but different reactive groups) do not inhibit CPD function . Specifically, MG132, a common proteasome inhibitor (Cbz-LLL-aldehyde) and Z-L3VS (Cbz-LLL-vinyl sulfone) do not block V. cholerae CPD autocleavage. The lack of inhibitory activity of Z-L3VS may reflect the preference of MARTX CPDs for small P1' residues in the consensus cleavage site sequence. Indeed, the S1' subsite (which interacts with the P1' residue) is flat and featureless and may not accommodate large constituents in the P1' position. Nevertheless, making contacts with the S1' subsite would appear to be important for inhibitor potency given the lack on inhibitor activity of MG132.
Although the aza-epoxide inhibitors identified in the screen are designed to covalently inhibit cysteine proteases, they failed to irreversibly react with V. cholerae MARTX CPD under standard assay conditions (A. Shen, unpublished data). The apparent slow reactivity of V. cholerae MARTX CPD with the aza-epoxide inhibitors may reflect the rapid rate with which InsP6 likely binds to and dissociates from the CPD relative to inhibitor binding. In contrast, when the aza-epoxide inhibitor was co-crystallized with V. cholerae CPD in the presence of InsP6, the inhibitor likely had sufficient time to react with the enzyme constrained in the crystal lattice. The lack of reactivity of the aza-epoxide inhibitors may also reflect the need for optimization of substrate binding or electrophile reactivity to V. cholerae CPD. To the latter point, functionalized alkylating agents have been shown to react with the sole catalytic Cys of V. cholerae CPD in a manner that is enhanced by the presence of InsP6[9,25].
Figure 4. Chemical inhibition of MARTX CPD activity. (a) Structures of the most potent MARTX CPD inhibitors. Navy blue indicates aza-linkage; purple highlights P1 Leu, and orange denotes electrophile warhead. (b) Surface topology of activated MARTXVc CPD bound to an aza-peptide epoxide inhibitor. Hydrophobic residues in the substrate binding cleft are in yellow. The aza-peptide epoxide inhibitor (JCP598) is shown as a stick model bound in the substrate binding pocket. The N-terminus is shown as a grey ribbon, terminating at Ile3437 and highlighting the threading of this region along the surface of the core domain.
Nevertheless, MARTX CPD inhibitors are capable of reducing CPD-mediated processing of MARTX toxin during growth of V. cholerae in broth culture . While the inhibitors are not effective at preventing CPD autocleavage in the native toxin, they do prevent processing of the toxin by the CPD at distal sites. Although they have limited potency on the native toxin, the CPD inhibitors were useful in determining the relative affinity of the CPD for its different cleavage sites, which correlated the relative affinities determined using in vitro cleavage reactions. Notably, the inhibitors were also capable of preventing MARTX toxin activity (specifically actin crosslinking activity) during intoxication of target cells. The aza-epoxide inhibitors were the most potent, since they were more cell permeable than the AOMK inhibitors; Cbz-LLaL-EP was the most cell permeable inhibitor. While the specificity of these inhibitors in complex mixtures still needs to be assessed, these results strongly suggest that CPD inhibitors can prevent the autoproteolytic activation of MARTX toxins inside target cells. Thus, the MARTX CPD inhibitors provide a starting point for the development of active site inhibitors of MARTX CPDs and potentially GT CPDs (given that S1 residues in MARTX and GT CPDs appear to be conserved).
Although CPD-mediated processing of V. cholerae MARTX and C. difficile Tcd toxins is necessary for optimal toxin function, it is not absolutely required. Toxins carrying mutations in the catalytic Cys of both V. cholerae MARTX and C. difficile TcdB CPDs can still exert cytopathic effects on cells, but the toxin activity is significantly decreased [3,4,6,8]. Why proteolytic cleavage enhances effector domain function has not been characterized. The known substrates of both V. cholerae MARTX and Tcd toxins are often localized to the host cell plasma membrane, so it has been hypothesized that CPD-mediated processing improves access of toxin effector domains to their substrates.
C. difficile glucosylating toxins are cleaved by the CPD after a single conserved Leu at the glucosyltransferase (Glc) domain-CPD junction [3,49]. This cleavage event releases the Glc domain from the endosomal membrane into the cytosol, while the remainder of the toxin remains membrane-associated (Figure 1b, [13,49]). This cleavage event likely enhances access of the Glc domain to its Rho GTPase substrates at the plasma membrane given that a membrane localization domain (MLD) was recently identified in its N-terminus . This MLD was recently shown to be sufficient to mediate plasma membrane localization, with enrichment observed at cell-cell junctions in particular. An analysis of the localization of the Glc domain and its activity in toxins carrying mutations of the CPD cleavage site and/or CPD catalytic residues will be important for determining the precise function of the CPD in regulating Clostridium sp. glucosylating toxin activation. Such analyses will be greatly facilitated with the advent of new tools for manipulating C. difficile genetically .
In contrast with the glucosylating toxins, the precise mechanism by which CPD-mediated processing increases effector domain activity in MARTX toxins is less apparent. Whereas the CPD cleaves Clostridium sp. glucosylating toxins at a single site, the CPD processes MARTX toxins at multiple sites. The cleavage sites all occur after a Leu residue and are found at interdomain boundaries predicted to be disordered . The identity of cleavage sites was confirmed by mutational analyses with both recombinant and native MARTX toxin. These analyses indicate that these three sites are the primary cleavage sites in the toxin, although a small amount of second site processing of these toxins can be observed in a mutant in which all three P1 Leu cleavage sites have been mutated to Ala residues . It should be noted that a fourth cleavage site was mapped by Prochazkova et al.  using N-terminal sequencing of in vitro cleavage reactions of recombinant V. cholerae MARTX toxin. However, extensive Western blot analyses of wildtype and cleavage site mutants indicate that this site is not physiologically relevant in the native toxin .
CPD-mediated processing separates the actin crosslinking domain (ACD), Rho-inactivating domain (RID), and α/β hydrolase domains (Figure 1a). While these cleavage events should liberate the RID and α/β hydrolase domains from the membrane, both the ACD and CPDs are predicted to remain tethered to the membrane. The membrane localization of these domains may be important to their function, perhaps by optimizing access of the ACD and CPD to their substrates. Indeed, the CPD is always found adjacent to the C-terminal MARTX conserved region, while the ACD in other MARTX toxins is always found just downstream of the N-terminal MARTX conserved region. Tethering of the CPD to the membrane likely facilitates processing of the toxin at distal sites, by keeping the substrates in close proximity. The dependence of the ACD domain on CPD-mediated processing remains less clear. Studies of V. cholerae cleavage site mutants indicate that processing of the ACD-RID junction is necessary for optimal ACD activity . Nevertheless, cleavage at any site would appear to stimulate ACD activity, although why this is observed is unknown. Further studies of the ACD and its interaction with its substrate will likely provide important insight into the functional requirements of this domain and the role of CPD-mediated processing in stimulating its activity.
The dependence of the remaining V. cholerae effector domains on CPD-mediated processing has not yet been tested. Further analysis of the biochemical functions of the RID and α/β hydrolase domains will likely provide insight into any role that the CPD may play in activating the function of these effector domains. These studies will require that a function for the α/β hydrolase domain be determined, since there is no information on the activity or localization of this domain. Likewise, a more thorough characterization of the function of the RID domain would contribute to an understanding of the role of proteolysis in activating RID function. Although the RID domain has been shown to disrupt Rho GTPase function , the mechanism by which this occurs is unknown. CPD-mediated processing should liberate the RID domain from MARTX toxin at the membrane. However, a recent study suggests that the RID should remain associated with the membrane through its N-terminal MLD domain , which preferentially localizes to cell-cell junctions and is necessary for optimal RID activity. If these sites are where the putative RID substrate is enriched, CPD-mediated cleavage may similarly enhance access of the RID domain to its substrates. Indeed, localization of the RID to the membrane has been shown to significantly increase its ability to induce cell rounding . Alternatively, CPD-mediated processing may function to produce free N- and C-termini that are necessary for optimal RID enzymatic activity.
Analyses of V. cholerae MARTX toxin will likely be transferable to other MARTX toxins, which typically contain RID, ACD, and/or α/β domains. Studies of other MARTX toxins will be greatly enhanced by mapping CPD cleavage sites, since these will define effector domain boundaries and contribute to a more global understanding of the role of this protease domain in toxin regulation. In general, the CPD appears to function analogously to viral polyprotein processing proteases such as those produced by picornaviruses (such as poliovirus and Hepatitis C). Viruses often use a conserved internal protease domain to proteolytically process the single polyprotein precursor into discrete functional domains that mediate viral replication and assembly . Notably, both viral and CPD autoprocessing proteases exhibit a high degree of sequence specificity but poor transcleavage activity . As a result, these proteases do not appear to cleave substrates in their target host cells. Consistent with this proposal, a MARTX toxin that carries only the CPD in the central translocated region does not overtly affect the morphology of target cells exposed to this mutant toxin (A. Shen, unpublished data), strongly suggesting that the CPD does not have many substrates within target cells aside from the MARTX toxins.
Nevertheless, just as viral polyprotein processing enzymes have been prime targets for therapeutic intervention , the CPDs of both MARTX and Clostridium sp. glucosylating toxins are excellent targets for drug design. The C. difficile glucosylating toxin CPDs are particularly good candidates because TcdA and TcdB toxins are the primary factors responsible for C. difficile-associated disease . Given that C. difficile infections are often promoted by antibiotic administration, targeting virulence rather than viability will likely be the most effective strategy for controlling C. difficile-associated disease. Likewise, given that MARTX toxins are comprised of multiple effector domains that vary among toxin family members , targeting the conserved CPD domain will likely be a more effective strategy at inhibiting MARTX toxin activation that developing inhibitors against each domain. MARTX CPD inhibitors would have particular applicability in aquaculture settings where infection by V. anguillarum and V. vulnificus infection of fish and bivalves is particularly costly to the seafood industry.
The identification of the first active site inhibitors of bacterial CPDs has provided an excellent starting point for the optimization of inhibitors with greater potency, selectivity, and stability, and the structure of inhibitor-bound CPD may serve as a platform for inhibitor modeling. An alternative strategy to targeting the active sites of these proteases may be to prevent the activation of bacterial CPDs by restraining their conformational mobility and thus allosteric activation . Thus, a better understanding of the mechanism of CPD activation will likely lead to more effective strategies for preventing toxin activation.
A.S. is funded by the National Institute of Health Awards K99 GM092934-01.


text:
Q: passing $_POST data to a PDO function It's more of a basic php issue than a pdo issue, but none the less I am getting error 'Notice: Undefined index: body in /home/downlowd/www/dev/launch.php on line 20'
I tried to pass $_POST in a few places, but just made things worse.
<?php
require_once('config.php');
$attrs = array(PDO::ATTR_PERSISTENT => true);
$pdo = new PDO("mysql:host=localhost;dbname=".$dbname, $db_username, $db_password, $attrs);
$pdo->setAttribute(PDO::ATTR_ERRMODE, PDO::ERRMODE_EXCEPTION);
$custlist = $pdo->prepare("SELECT * FROM customer_list");
$carrierlist = $pdo->prepare("SELECT * FROM carriers");
//$products = array();

$smsarrayobject = new ArrayObject($carrierlist);

if ($custlist->execute()) {
        while ($row = $custlist->fetch(PDO::FETCH_ASSOC)) {
                $prefix = $row['sms_num'];
                if ($carrierlist->execute()) {
                        while ($rows = $carrierlist->fetch(PDO::FETCH_ASSOC)) {
                                $from = 'admin@telecomm.com';
                                $to = $prefix.$rows['carrieraddr'];
                                $body = $_POST['body'];
                                mail($to, $from, $body);
                        }
                }
        }
}
$pdo = null;
?>
<form action="" method="POST">
        Your Message Body <input name="body" type="text" />
        <input type="submit">
</form>

A: You should check $_POST even before executing your code, this prevents to handle empty inputs, the best way is to check using isset() function:
if(isset($_POST['body']){
// your stuff

}

redpajama_set_name: RedPajamaStackExchange


From 11 to 13 April 2019, policymakers from across the world will gather at Emperors Palace at a forum hosted by the World Health Organization (WHO) and South African government that is asking: what is a fair price for a medicine?
Civil Society Organizations and activists, local and international, have organized a side event at the same venue to discuss the emerging issues in medicine pricing as well as strategies to ensure that people are not denied their right to health due to the ever-increasing cost of medicines. One of the focus areas is the excessive price of cancer medicines in South Africa, with a specific focus on lenalidomide, a drug used for the treatment of myeloma.
In South Africa, Celgene holds 32 secondary patents on lenalidomide that may block more affordable generics coming to market until 2028. Currently, it costs around ZAR 828,000 for a year's treatment course in the private sector and is not available in the public sector. It is excluded from prescribed minimum benefits of private medical schemes because of the cost. In India, a year's course of lenalidomide costs ZAR 28,476.
Cancer survivors and activists from South Africa and across the world will join the discussion to demand more affordable generic lenalidomide -- and more affordable medicines more broadly. They will be available for interviews on request.


text:
Johann Nepomuk von Kolb (* 14. Januar 1726; † 1799 in Wurzach) war ein deutscher römisch-katholischer Theologe, Stadtpfarrer von Wurzach und Dekan des Wurzacher Landkapitels.

Leben
Der promovierte Theologe Johann Nepomuk von Kolb war von 1748 bis 1750 Pfarrer in Wilflingen, ab 1750  Propst im Collegienstift zu Zeil. Später wurde er Fürstbischöflicher Constanzischer Geheimer Geistlicher Rat und wirkte ab 1756 als Kapitels- und Landdekan sowie Stadtpfarrer in der reichsgräflichen truchsessischen Stadt Wurzach.

Die angeblich aus dem Privatbesitz von Papst Innozenz XII. stammende und im Jahr 1764 aus dem Nachlass des Paulanerbruders Theophilus Maria Miller de Malkowitz (1699–1763) auf den Gottesberg gekommene Heiligblutreliquie, die sich zu dieser Zeit noch in einer goldenen Kapsel befand, die man um den Hals tragen konnte, ließ Johann Nepomuk von Kolb in eine vergoldete barocke Strahlenmonstranz einsetzen und erteilte mit ihr an den Fastenfreitagen und am Titularfest den Segen. Zur damaligen Zeit pilgerten daraufhin ganze Pfarreien mit ihren Wallfahrern nach Wurzach, um die durch diese Maßnahme eröffnete Gelegenheit zu nutzen, die Reliquie am Gottesdienstende des Heilig-Blut-Festes küssen zu können. Im Jahr 1774 ließ Johann Nepomuk von Kolb in Wurzach mit Mitteln aus seinem Privatvermögen die Seelenkapelle und in den Jahren von 1775 bis 1777 vom Wurzacher Baumeister und Bildhauer Johann Jakob Willibald Ruez (1728–1782) die römisch-katholische Pfarrkirche St. Verena errichten.

Am 21. September 1789 wurde Johann von Kolb mit dem akademischen Beinamen Eubulus III. unter der Matrikel-Nr. 894 als Mitglied in die Kaiserliche Leopoldinisch-Carolinische Akademie der Naturforscher aufgenommen.

Johann Nepomuk von Kolb wurde 1799 in der Gruft der Seelenkapelle in Wurzach bestattet.

Literatur
 Otto Beck: 250 Jahre Heilig-Blut-Reliquie in Bad Wurzach. In: HL Blutfest 2014 Bad Wurzach, Katholisches Pfarramt St. Verena, Bad Wurzach 2014, S. 3 (Digitalisat)
 August Friedrich Pauly: Beschreibung des Oberamts Leutkirch (= Beschreibung des Königreichs Württemberg. Band 18). Mit einer Karte des Oberamts, einer Ansicht von Wurzach und vier Tabellen. Cotta, Stuttgart/Tübingen 1843, , (Volltext in Wikisource).

Anmerkungen und Einzelnachweise

Römisch-katholischer Geistlicher (18. Jahrhundert)
Geistlicher Rat
Mitglied der Leopoldina (18. Jahrhundert)
Deutscher
Geboren 1726
Gestorben 1799
Mann

redpajama_set_name: RedPajamaWikipedia


Where you submit personal information for publication on our website, we will publish and otherwise use that information per the licence you grant to us.
Also, personal information that you submit for publication on the website will be published on the internet and may be available, via the internet, around the world. We cannot prevent the use or misuse of such information by others.
The data controller responsible in respect of the information collected on this website is I'm a Nurse Practitioner.


Diller Pickleball Paddle | Pickleball, Inc.
When we invented the game of pickleball back in 1965, we also created a variety of wood paddles. The Diller Paddles are a great way to experience the original feel of the game and are great for institutional or recreational play.
Weight: 10 - 11 oz.
Pickle-Ball Inc. stands by their products, they were very helpful, super friendly, and helped take care of my concern with one of my paddles. I would highly recommend buying their products :) I love my set!


text:
Periodogram – rodzaj dyskretnej transformaty Fouriera. Pojęcia periodogramu prawdopodobnie po raz pierwszy użył Arthur Schuster w 1898, opierając się na pracy Power Spectral Density estimation (z ang. "estymacja widmowej gęstości mocy") Fernanda Schlindweina.

Schuster definiował periodogram następująco: niech dla funkcji f(t) będzie

gdzie  dla wygody można wybrać jako równe całkowitej wielokrotności  biorąc  jako odcięte, a  jako rzędne, otrzymuje się krzywą, albo lepiej: obszar między tą krzywą a osią odciętych reprezentuje periodogram funkcji

Periodogram wykorzystywany jest jako estymator w analizie widmowej (np. analiza statystyczna danych, opis mocy sygnału i inne). Wyniki nierzadko obarczone są dużym błędem, jednak mimo tego jest dość często wykorzystywany. Skuteczny głównie dla funkcji wyraźnie okresowych. W periodogramie wartość przebiegu widma jest przybliżona jako suma fal sinusoidalnych. Częstotliwości tych fal są wielokrotnościami odwrotności czasu trwania analizowanej próbki.

Zobacz też
 transformacja Fouriera

Cyfrowe przetwarzanie sygnałów


Defendant law firm Plexus Law has secured a £15m investment from a private equity company that specialises in the services sector.
Origin Equity has taken a minority shareholding in the firm and its partners Gavin Loughrey and Olivia Roberts will join the Plexus board.
Plexus has obtained an alternative business structure from the Solicitors Regulation Authority to enable the investment. Origin's model is to invest £5m-20m in the services sector in the UK and Ireland.
It is Plexus's second go at private equity, having been a large part of the Parabis Group – the first law firm to be bought by a private equity business – before it was broken up in a pre-pack sale in November 2015. Plexus returned to the ownership of its founders.
The firm is headquartered in Leeds and has offices in London, Manchester, Edinburgh and Evesham, with over 1,000 employees, including 119 partners and 655 fee-earners. It is also opening offices in Chelmsford and Taunton.
It generated a £6m profit after payments to partners on £56m of revenues, with net operating assets of £29m for year ending 31 March 2018.
Plexus said that, since returning to independent ownership, is has "enjoyed sustained organic growth off the back of increased demand, particularly from London market and reinsurer clients, for claims handling and litigation expertise in areas such as financial lines, professional indemnity and liability work".
Chief executive Fiona Scott said: "We operate in a highly competitive market and in order to thrive, we need to grow. Origin's investment will accelerate our organic growth across the UK and Ireland, support our efforts to secure talent through lateral hires and enable us to further explore how we utilise and invest in technology.
"We are in a really strong position to take on this investment. Plexus is cash rich, overdraft free and has an impressive client roster.
"The decision to opt for private equity investment rather than looking at a merger, IPO or becoming highly leveraged with debt, was influenced by a number of factors, notably that this approach doesn't compromise management control.
"In addition, the fact that it is a cash equity purchase ensures that it does not expose the business and its partners to the risk that a highly leveraged, debt funded buy in or IPO might – particularly in the current economic and political climate.
Origin said it approached Plexus, having tracked the business, the market and its competitors for some time, and in doing so, identified a major opportunity to invest in and support the firm's growth and accelerate its existing strategy.
A spokeswoman said: "We believe we can help the firm's senior management team consolidate Plexus' position as the go-to independent defendant law firm.
"We can also help the team further exploit advances around data management, analytics and next generation case management processing, three areas in which they have already made great strides.
"Central to our approach is the idea of working closely with ambitious managers and with Plexus we see a huge opportunity for the firm to continue to evolve and innovate.


text:
Libya Business News
Tag Archives | Elections
Libya Parliamentary Campaigning Begins Amid Security Concerns
By editor on 18th June 2012 in Politics
Campaigning began today in Libya's first national parliamentary election since the overthrow of Muammar Qaddafi, with security in the North African nation a continuing issue. A total of more than 3,700 candidates are vying for seats in the 200-seat legislature, the election commission reported on its website. The commission said that 142 parties are running […]
Tags: Elections
Libya puts back election date by 18 days
Libya's first election in more than half a century will take place 18 days later than planned because of logistical challenges, the electoral commission has said . The election will now take place on 7 July. Nuri al-Abbar, head of the electoral commission, said crucial preparations for the election – including voter registration and vetting […]
Libya transitional council sees delay to elections
By editor on 29th May 2012 in Politics
The head of Libya's National Transitional Council said he expected an election for the national assembly would be delayed, holding up a landmark vote in the transformation of the country following the fall of Moammar Gadhafi. The election for an assembly that will draw up a new constitution was originally scheduled for June 19. Mustafa […]
Tags: Elections, Mustafa Abdul Jalil, NTC
Libyan Premier Says 2.5 Million Registered to Vote in Election
Libyan Prime Minister Abdurrahim el- Keib said that more than 2.5 million Libyans have already registered to vote in elections in June for a national legislature tasked with writing a new constitution. "Work is continuing in order to complete the final preparations so that the elections will be held on time," el- Keib said at […]
Tags: Abdel Rahim al-Keib, Elections, IMF
Libya elections commission says vote date not set
By editor on 22nd May 2012 in Politics
Libya's electoral commission said on Tuesday 4,000 candidates had registered for upcoming national assembly elections, but the commission head said he could not confirm the vote would be held on June 19 as set by the ruling National Transitional Council. "To announce the election date is linked to a number of issues including delivering election […]
Oil business waiting for Libyan elections to clear the air – Medserv
By editor on 18th May 2012 in Oil & Gas, Politics, Uncategorized
Oil companies which suspended their Libyan offshore oil exploration activities are awaiting the outcome of the June elections, oil industry services company Medserv has said in a statement. The company, which has a base in Malta and the Libyan port town of Misurata, said the first three months of 2012 had been notable for the […]
Tags: Elections, Malta, Medserv, Misurata
Libya's Belhadj quits military post for politics
Libyan Islamist commander Abdel Hakim Belhadj has resigned his military post in a bid to enter politics. Mr Belhadj, a key brigade leader in the 2011 toppling of Col Gaddafi, plans to run in elections next month. He is a former member of an Islamist insurgent group which sought to overthrow Gaddafi in the 1990s. […]
Tags: Abdel Hakim Belhadj, Elections
Election candidate murdered in south Libya
By editor on 14th May 2012 in Politics, Security
A candidate in the upcoming poll for a constituent assembly was murdered in Libya's southern desert on Sunday shortly after submitting his registration, a security official said. "Khaled Abu Saleh was murdered 30 kilometres (22 miles) from Ubari," in the south of Libya, Mohammed Saleh, deputy chairman of the High Security Commission, told AFP. "An […]
← Previous 1 … 8 9 10 11 Next →
LBN Newsletter FREE Weekly Subscription
What's Your Advice to Libya? 3rd September 2012
New Shipping Service from Italy, Slovenia, to Libya 24th September 2012
NOC to open US Office to support $20bn Spending Prog 21st November 2017
Unfreezing money: some action 17th December 2011
UN appoints Jan Kubis as Special Envoy on Libya 19th January 2021
Latest Oil Tenders 19th January 2021
New Career Opportunities in Libya 19th January 2021
Williams conducts Digital Dialogue with 1000 Libyans 17th January 2021
Ali Tirba: Dear Sir/ Madam Kindly let me have information, i...
Ali Elseid: Unification of Institutions including the Central...
addy taymore: Dear Sir/Madam, I am writing to enquire if you ...
NICHOLAS HADJITHEODOROU: CONGRATULATIONS FOR THIS EXCELLENT INITIATIVE. PLE...
Iran Business News
Iraq Business News
Libyan British Business Council
The Web Orchard
© 2021 Libya Business News. All Rights Reserved.
Website Designed by The Web Orchard

redpajama_set_name: RedPajamaCommonCrawl


Your organization has decided to start its transformation to become Lean. The Lean methodology and tools have been selected. Your Lean facilitator (either your Lean Manager or a Lean Consultant) has set the date and time for the event. The only real question is, How do we ensure this kaizen event gets measurable results?
Lets first understand what a kaizen event actually is. It is a team activity aimed at continuous improvement of an entire value stream or an individual process to create more value and reduce/eliminate waste. Now having said all that how do we do it?
There are several things to consider before the event takes place. The first is to have qualified production/distribution coverage and advanced production. Production output will decline during an event as operators direct their time to event activities and changes to floor layout. Planning for this reduction will ensure that overall productivity does not suffer while improvements become the standard.
Secondly, the employees chosen for the event will have a major impact on the improvements and sustaining the results. The team should be comprised of a broad cross-section of the company. Typically, you want at least one expert who performs the task under study. The remaining members will be made up from other areas of the process, as well as employees from the office. They will provide a fresh perspective, so the main thing is to get them INVOLVED! The team needs to take ownership of the event and the following implementation action items.
If you have never gone through a kaizen event before, you may want to use an outside professional to lead you. Once you are into the thick of making dramatic improvements, you will be glad for the expertise of someone who has been there. A consultants primary purpose is to be able to help you become skilled in running future events so that you can begin training others to lead events also. The role of upper management will be to support the Lean initiatives and to let the employees know that successful kaizen events and implementing Lean processes will not eliminate anyones job. This increase in productivity means increased capacity, which, in turn, will create the need for these employees.
You must communicate to the whole company about the kaizen event. An announcement from upper management will convey the serious support given to the event. Post information about the daily schedules and the agenda. Since there are going to be significant changes, it is best to lay the communication groundwork well in advance. This will provide for questions to be answered and for employees to understand the reason for the change.
The next thing to consider is what area of study you wish to improve. Typically, choose an area that will have an impact but not pose too many difficult problems in the beginning. It is all about building momentum. Each event will teach you things that will make the next event go more smoothly and easier to successfully run. You can choose several areas and decide the merits of each. Examples of prime areas are ones that experience excessive WIP, have significant bottlenecks or frequent stoppages, or produce large cycle times and have medium to high volume.
Then, you will want to investigate the problem itself. One of the first things that should be considered in any area or process is the completion of 5S+1 tool. This sets the table for improvement as it is the baseline for Lean improvement. If you complete the 5S+1 process first, you will not have to include it in every implementation plan in all the events. The focus is on eliminating waste and is the function of every kaizen event. So the decision must be made on its impact to eliminate waste in the area and/or process.
Once you have determined the area or process to be examined, you then need to obtain the necessary background information. This may include the event objectives and expectations. Use a background/problem statement to explain the reason this will be the area of study. Get current metrics for the area, in terms of productivity, quality, customer order volume (daily, weekly, monthly), flowchart of the area to be improved and safety records for the area. Time can be wasted searching for data in order to make decisions on takt time, process requirements and developing the current state.
Next, prepare the area and the training room where the Lean methodology will be taught. Make sure during the times of classroom training that the room is well-ventilated and well-lit and that all the training materials and supplies are in place. Provide pens, paper, flip charts, calculators and other relevant supplies. If audio/video projectors are used, make sure there is a spare bulb and fresh batteries. If the project runs through lunch and/or dinner, make sure that this is provided. Keep refreshments on hand as well, so the team is comfortable and focused on the event. In addition, maintenance personnel should also be notified and included in the event, as they will probably be summoned to aid the improvement strategies. Stick to the agenda for the hours and days of the event. Depending on the scale and scope, most kaizen events last approximately five days. Staying on course will keep the project productive and motivating.
Every kaizen event is different, and as you go through the process more, you will have greater returns. The preparation of the event can not be undervalued. If you follow the steps, your kaizen events will yield significant reduction in waste and non-value added activities.


text:
Yitzi G
The Future Belongs to The Passionate
Contemporary social media (i.e., TikTok), social e-com (i.e., Instagram, Etsy), Open learning platforms(Udemy, YouTube) have proven that...
You Missed the Most Important Detail in This Video
There is a hidden gem in this video. Pause at 0:10, and you'll see the command: npx sled-test-runner What the heck is this? To allow our...
© 2023 By Yitzi.


Be prepared in the event of an emergency.
Keep track of the service interruptions on the Web, through your mobile device or listen to your battery-powered radio, if the outage seems widespread. That's why it's so important to have a battery-powered radio in your emergency kit.
Call 1-800-434-1235 to report the outage immediately so that we can act as soon as possible.
If it has already been reported, our system will tell you what we know about the situation.
To avoid damage when service is restored, unplug computers, TVs, DVD players, cell phone chargers and any other electronic devices that may generate heat - except for the refrigerator and freezer.
If you're planning to use fuel-burning heaters, lights, generators or portable stoves designed for outdoor use, you should know that they can cause asphyxiation or poisoning if used inside, because they have no exhaust system to evacuate carbon monoxide.
We recommend that you do not use this equipment indoors.
If you notice any damage to your electrical installations, make sure to have them inspected by a master electrician.
Gradually turn electrical appliances back on, including heating appliances (e.g., baseboard heaters).
Wait until the temperature and humidity have returned to normal before turning electronic devices back on (TVs, stereo, computers, microwave oven, etc.).
Once the power is back on, see whether your electrical installation has been damaged. If you see sparks or broken or frayed wires, notice a smell or feel heat, turn off the power at the distribution panel (circuit breaker or fuse panel). Call a master electrician for advice, if necessary.
Don't walk through water to get to the distribution panel (circuit breaker or fuse panel).
Check the food left in the refrigerator and freezer during your absence and throw out any that has spoiled.
Restock your emergency kit and provisions.


Packard Bell has announced it's upgrading the dot s netbook - with the snappily monikered dot s2.
The new lap-warmer has a 10.1-inch screen, a 10-hour battery life, which PB is claiming means it's an ultra-portable, all-day netbook.
To be fair, the dimensions do show something pretty teeny, with 258mm width and 185 mm height, and a hair over 25mm in depth, and only 1.25kg in weight with the 6-cell, 10-hour battery.
There's an Intel Atom N450 processor powering things along under the hood, 250GB hard drive and both a five-in-one card reader and Adobe Photoshop Elements on board too.
The 10.1-inch screen is backlit by low power LEDs, and PB states that the keyboard and the multi-touch trackpad offer accurate typing and enhanced mouseless action - although we'll wait for the review to believe that.
Oh, and check out the colours on this puppy, in the words of Packard Bell: "The 'Cherry Red' means spontaneity, energy, passion; the 'NightSky Black' stands for classic elegance and standing; the 'Glacier White' tells a story of simplicity and perfection."
The Packard Bell dot s2 netbook has got a UK release date for later this month, and will cost £299.99 with Windows 7 Starter Edition.


List of boiler types, by manufacturer There have been a vast number of designs of steam boiler … circular in plan with a domed top and often a flat base.
Alfa Boilers Pvt Ltd is one of the leading & a reliable boiler manufacturer & contractor in India, with high reputation & satisfactory record of service.
Get a quote for all kinds of industrial boilers. We have listed the complete details for leading manufacturers, suppliers & companies. Click to contact!
Which Boiler is Best? Author: Alex Vasili. Published: Tuesday, 03 January 2017. Tweet. … Leading boiler manufacturers are: Brand Name Info. WORCESTER BOSCH.
1.Why choose ZG as leading boiler manufacturers manufacturer?
2.How much the price of leading boiler manufacturers ?
3.How about the quality of leading boiler manufacturers ?


Scangroup Limited is engaged in developing communication strategies, creating advertisements for products and services, planning and buying media, as well as providing marketing consultancy. The activities of the Company include media investment and management, brand / creative advertising, public relations, experiential marketing, integrated digital marketing, and field marketing. Its media planning and buying services are carried out through Media Initiative East Africa (MIEA), MEDIACOM and Universal McCann. The development of the communication strategy and advertising, and its implementation is carried out by advertising agencies. Public relations consultancy is carried out through Hill & Knowlton. Roundtrip, a subsidiary of the Company, carries out experiential marketing, field marketing and event management. Smollan East Africa Limited provides field marketing services, market intelligence and brand activation.
The stock of ScanGroup Limited (SCAN) is currently trading at 18.05 KES per share on the Nairobi Securities Exchange. SCAN began the year with a share price of 14.00 KES and has since gained 28.93% of that price valuation, ranking it 4th on the NSE in terms of year-to-date performance. Shareholders will be pleasantly optimistic about SCAN knowing that the stock has accrued 64.09% over the past four-week period alone. The table below details the last 10 trading days of activity of ScanGroup Limited on the Nairobi Securities Exchange.
ScanGroup Limited operates in the Consumer Services sector. Unfortunately, we do not have information on the company's board of directors and/or key executives at this time.
ScanGroup Limited, issuers of the SCAN stock on the Nairobi Securities Exchange, have a number of market competitors who are also engaged in the Consumer Services sector. The table below gives you an overview of the market standing of the top nine by year-to-date performance.


text:
Donald Trump calls Saudi King to discuss oil supplies
The pair also discussed issues of regional concern
Saudi Arabia's King Salman bin Abdulaziz Al Saud, at the inauguration of the Haramain Railway from Makkah and Madinah to Jeddah, on September 25, 2018, spoke to US President Donald Trump about regional issues. Reuters
Saudi Arabia's King Salman received a phone call from United States President Donald Trump on Saturday.
The pair discussed developing existing ties between the Kingdom and the US, according to the Saudi Press Agency.
The efforts to maintain oil supplies to ensure the stability of the energy market and the growth of the global economy were also reviewed during the call.
The White House said Mr Trump and the king spoke on "issues of regional concern".
Saudi Crown Prince arrives in Kuwait for talks with Qatar focus
Germany, Saudi Arabia agree to turn page on diplomatic dispute
Regime air raids kill 11 civilians in northwest Syria: monitor
Three former Lebanese prime ministers ask Saudi to up support
US official concerned Iran has seized UAE based tanker
Yemen's peace process advances but trust remains an obstacle, experts say
Russia repatriates 33 children of ISIS supporters from Iraq
The Middle East framed - today's best pictures
Iraqi-Saudi border crossing to reopen on October 15


text:
Lapara ist eine Gattung innerhalb der Schmetterlingsfamilie der Schwärmer (Sphingidae).

Merkmale
Die Falter sind mattgrau bis graubraun. Ihre Vorderflügel sind unterschiedlich stark schwarz, braun und weiß gefleckt. Die Hinterflügel tragen wie bei Lapara coniferarum keine Musterung oder sind maximal undeutlich gemustert wie bei den meisten Individuen von Lapara bombycoides. Der Hinterleib der Falter ist entweder weitgehend einfarbig oder trägt schräg verlaufende, dunkle Intersegmentalbänder. Der Saugrüssel ist kurz und sehr schwach, jedoch funktionsfähig.

Anders als bei allen anderen in Nordamerika vertretenen Schwärmerarten fehlt den Raupen von Lapara-Arten in allen Stadien das Analhorn. Ausgewachsen haben die Raupen eine grüne Grundfarbe und tragen vereinzelte Sekundärborsten. Auf ihrem Körper verlaufen auf jeder Seite je ein Längsstreifen am Rücken (dorsal), beidseits des Rückens (subdorsal) und unterhalb der Stigmen (subspiracular). Diese Streifen sind weiß bis gelblich und dienen der Tarnung, wenn die Raupen auf Nadeln der Nahrungspflanzen sitzen. Die Raupen tragen darüber hinaus am Rücken und entlang der subdorsalen Längsstreifen Flecken in unterschiedlichen rotbraunen Tönen. Die Farbe und deren Ausbreitung variiert nicht nur zwischen den Arten, sondern auch innerhalb einer Art zwischen den Individuen bzw. Populationen. Der Kopf jüngerer Raupen ist nach oben spitz zulaufend und trägt zahlreiche kleine Stacheln. Im letzten Raupenstadium ist die Kopfkapsel nur leicht dreieckförmig und hat eine glatte Oberfläche. Die Raupe zeigt eine verkehrte "V"-förmige, dunkelbraune Markierung auf dem Gesicht. Die Unterscheidung der Arten im Raupenstadium ist sehr schwierig.

Die Puppen können nicht voneinander unterschieden werden. Sie sind glatt, nahezu schwarz und langgestreckt. Der Kremaster ist breit und basal leicht tränenförmig, ist aber zu einem dünnen Schaft ausgezogen, der spitz endet.

Vorkommen und Lebensweise
Sämtliche Arten der Gattung treten in Kanada und den Vereinigten Staaten von Amerika auf. Die Raupen ernähren sich von Kiefern (Pinus).

Systematik
Es sind vier Arten der Gattung bekannt. Die taxonomische Stellung der Arten ist jedoch teilweise unklar. So betrachten Kitching & Cadiou (2000) Lapara halicarnie als eigenständige Art, wohingegen Tuttle dieser Auftrennung nicht folgt, sondern diese Tiere als größere und weniger gemusterte Individuen von Lapara coniferarum betrachtet.

 Lapara bombycoides Walker, 1856
 Lapara coniferarum (J. E. Smith, 1797)
 Lapara halicarnie (Strecker, 1880)
 Lapara phaeobrachycerous Brou, 1994

Belege

Einzelnachweise

Literatur
 James P. Tuttle: The Hawkmoths of North America, A Natural History Study of the Sphingidae of the United States and Canada. The Wedge Entomological Research Foundation, Washington, DC 2007, ISBN 978-0-9796633-0-7.

Weblinks

Schwärmer
Sphingidae


text:
Home/Biologics/BioRestorative Therapies Scientific Advisory Board Member and Clinical Director of Regenerative Disc/Spine Program, Dr. Wayne J. Olan, to Receive Prestigious Award
BiologicsSpine
BioRestorative Therapies Scientific Advisory Board Member and Clinical Director of Regenerative Disc/Spine Program, Dr. Wayne J. Olan, to Receive Prestigious Award
Mike Adams September 16, 2019
MELVILLE, N.Y., Sept. 16, 2019 (GLOBE NEWSWIRE) — BioRestorative Therapies, Inc. (the "Company") (OTC: BRTX), a life sciences company focused on stem cell-based therapies, today announced that a member of the Company's Scientific Advisory Board and its Clinical Director of Regenerative Disc/Spine Program, Wayne J. Olan, MD, has received the Distinguished Alumni Award for Achievement from the Chicago Medical School ("CMS"). The award is bestowed upon CMS alumni who have made a significant impact in the field of medicine and whose efforts have brought distinction to the Chicago Medical School. Dr. Olan's achievements will be celebrated at the CMS Alumni Dinner and Awards Ceremony on Saturday, October 5, 2019 as part of the CMS Reunion Weekend in Chicago.
Dr. Olan has been a member of the Company's Scientific Advisory Board since 2014 and its Disc Advisory Committee since its creation in early 2019. He has also served as Clinical Director of the Company's Regenerative Disc/Spine Program since 2018 and provides expertise and direction regarding regenerative medical technologies, autologous solutions for degenerative disorders, and minimally invasive treatment of spinal disorders, which substantially support the Company's Disc/Spine program and specifically, its lead product candidate, BRTX-100. Dr. Olan is extensively published and lectures globally on these subjects and others and is also involved in the development of many devices and technology in these areas.
Dr. Olan is board-certified in radiology and currently serves as the Director of Interventional and Endovascular Neurosurgery, Co-Director of the Endovascular Stroke Program and an Associate Professor of Neurosurgery and Radiology at the George Washington University School of Medicine & Health Sciences. He serves as a consulting physician to the National Institutes of Health and the United States Congress and is a member of the White House Medical Unit.
"We congratulate Dr. Olan on this outstanding achievement and his contributions to our disc program. He is a member of an advisory board comprised of accomplished and globally recognized persons who help direct the Company's efforts in the cell therapy space," said Mark Weinreb, CEO of BioRestorative.
About BioRestorative Therapies, Inc.
BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:
• Disc/Spine Program (brtxDISC™): Our lead cell therapy candidate, BRTX-100, is a product formulated from autologous (or a person's own) cultured mesenchymal stem cells collected from the patient's bone marrow. We intend that the product will be used for the non-surgical treatment of painful lumbosacral disc disorders. The BRTX-100 production process utilizes proprietary technology and involves collecting a patient's bone marrow, isolating and culturing stem cells from the bone marrow and cryopreserving the cells. In an outpatient procedure, BRTX-100 is to be injected by a physician into the patient's damaged disc. The treatment is intended for patients whose pain has not been alleviated by non-invasive procedures and who potentially face the prospect of surgery. We have received authorization from the Food and Drug Administration to commence a Phase 2 clinical trial using BRTX-100 to treat persistent lower back pain due to painful degenerative discs.
• Metabolic Program (ThermoStem®): We are developing a cell-based therapy to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue ("BAT"). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in the body may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.
This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, whether the Company will be able to consummate the private placement and the satisfaction of closing conditions related to the private placement and those set forth in the Company's Form 10-K filed with the Securities and Exchange Commission. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.
Email: ir@biorestorative.com
advisory board award BioRestorative Therapies Dr. Wayne J. Olan
Mike Adams is a medical device sales leader with extensive clinical experience in spine and biologics and a nationwide distribution network built over the last 10+ years in the industry. He has held various leadership positions in healthcare and device including Distributor Partner, Hospital COO and Spine VP of Sales. He currently leads the commercialization strategy for OrthoSpine Partners and is a Distributor Principal at Novel Medical. Because of his unique career path, Mike has the ability to see the healthcare business from multiple perspectives making him passionate about building strategic partnerships that help reduce overall costs, drive innovation, and cultivate growth for new markets.
AlloSource's ProChondrix CR, Cryopreserved Osteochondral Allograft, To Be Featured At The British Patellofemoral Society Meeting


text:
Alice donovan as Mrs. Willits Silhouette, 1928
Alice Donovan was featured as Mrs. Willits, mother of founder Anna Willets, in the 1928 HIstorical Pageant. This silhouette was featured on page 439 of The Key, October 1928.
Barbara Poore as "Chi" Silhouette, 1928
Barbara Poore was featured as "Chi" in the 1928 HIstorical Pageant. This silhouette was featured on page 439 of The Key, October 1928. It was also printed in a publicity article in the St. Paul and Minneapolis papers on July 15, 1928.
Information and Song Booklet, 1927
This booklet acts as an informational guide to the 1928 National Convention. It offers lists of fraternity presidents, previous conventions, Panhellenic fraternities, and songs sung at convention.
The Hootlet, June 25, 1928
The first page reports on the role delegates from Chi Chapter would play at the upcoming 1928 National Convention. The second page includes updates on convention arrangements.
The Hoot Vol. 5, No. 5, 1928
The first article in this publication introduces some of Kappa's early history and pioneering work. The second article tells of the travels of Tade Kuhns, previously Grand President. The second page includes a formal appreciation written by an anonymous undergraduate member, updates on Kappa leaders, and an article on the Blue and Blue Ball. Item is a photocopy.
The first article reports on the history of Gamma Sigma Chapter, and why the founding members decided to join the fraternity. The next article gives a short resume of Beta Zeta Chapter. The second page includes details for the Endowment Fund and the latest from Panhellenic House. The publication ends with athletic prizes awarded at convention. Item is a photocopy.
The Hoot Vol. 5, No. 2, c. 1928
The first article reports on the opening session at the 1928 National Convention, focusing on the speakers. The featured article tells a story about Father Hennepin, back in 1690. The rest of the publication focuses on the Panhellenic Conference. Item is a photocopy.
The first article is an extract from a radio talk by Edgar Zelle, president of the Alumni Association of the University of minnesota. The second article reports on the attention Kappa received from the nation's capital. The second page includes articles on the Rose McGill Fund, delegates from Boston, and a letter from founder Louise Bennett Boyd. The last page lists initiates from the first day of convention. Item is a photocopy.
The Iroquois Pulling into Harbor Photograph, June 25-July 3, 1928
The Iroquois pulls into harbor carrying a group of Kappas during the 1928 National Convention in Breezy Point, Minnesota. Other women, likely also Kappas, watch from the shore in the foreground.
Cleora Wheeler in Native American Headdress Photograph, June 25-July 3, 1928


text:
Уилтон () — тауншип в округе Уосика, Миннесота, США. На 2000 год его население составило 392 человека.

География
По данным Бюро переписи населения США площадь тауншипа составляет 93,5 км², из которых 92,4 км² занимает суша, а 1,1 км² — вода (1,22 %).

Демография
По данным переписи населения 2000 года здесь находились 392 человека, 137 домохозяйств и 99 семей.  Плотность населения —  4,2 чел./км².  На территории тауншипа расположено 143 постройки со средней плотностью 1,5 построек на один квадратный километр. Расовый состав населения: 97,96 % белых, 0,26 % азиатов, 1,79 % — других рас США. Испанцы или латиноамериканцы любой расы составляли 3,32 % от популяции тауншипа.

Из 137 домохозяйств в 35,8 % воспитывались дети до 18 лет, в 62,8 % проживали супружеские пары, в 3,6 % проживали незамужние женщины и в 27,7 % домохозяйств проживали несемейные люди. 23,4 % домохозяйств состояли из одного человека, при том 5,8 % из — одиноких пожилых людей старше 65 лет. Средний размер домохозяйства — 2,86, а семьи — 3,41 человека.

30,9 % населения — младше 18 лет, 8,2 % — в возрасте от 18 до 24 лет, 26,5 % — от 25 до 44, 23,0 % — от 45 до 64, и 11,5 % — старше 65 лет. Средний возраст — 36 лет. На каждые 100 женщин приходилось 110,8 мужчин.  На каждые 100 женщин старше 18 приходилось 106,9 мужчин.

Средний годовой доход домохозяйства составлял 40 313 долларов, а средний годовой доход семьи —  41 364 доллара. Средний доход мужчин —  28 393  доллара, в то время как у женщин — 26 250. Доход на душу населения составил 17 327 долларов. За чертой бедности находились 8,0 % семей и 8,8 % всего населения тауншипа, из которых 5,9 % младше 18 лет.

Примечания

Тауншипы округа Уосика


This is a twelve-week programme designed by you and your personal tutor. The course is intensive and requires full commitment.
In addition to 5 assignments and a diagnostic lesson, you will need to teach 6 lessons as part of Delta Module 2. It is important that you complete the tasks and assignments on time. Given the background work around each lesson, it is important that you space out lessons sensibly, so that you can devote enough time to each of them. This also allows you time for reflection and further development. You will need to put together a work plan at the beginning of the course.
Depending on your teaching situation you have the option of taking the course over 16 weeks (starting in February) or 9 months (starting in March and September).
It is recommended that a DELTA Module 2 candidate should EITHER be a graduate OR have a previous teaching qualification (e.g. CELTA), plus at least TWO years' full-time teaching experience (i.e. 1,200 hours) within the past five years. Ideally, this teaching experience should include a range of levels and contexts. It is also recommended that the candidate has sucessfully completed Delta Modules 1.
For Delta Module 2, you will need to complete 5 practical assignments.
An experimental practice assignment, in which you investigate an area of classroom practice that is new to you, teach a lesson (unobserved) to try out this practice, and reflect on what you learn from it.


text:
A hapless young Englishman (Joel Edgerton) inherits his father's failing shoe factory. Faced with laying off all his loyal employees, he casts about desperately for something to do and meets a flamboyant drag queen (Chiwetel Ejiofor) who wishes someone would make sexy high-heeled shoes that can bear a big man's weight. Written by Geoff Deane and Tim Firth and directed by Julian Jarrold, this allegedly fact-based comedy hits all the standard whimsy buttons for these British blue-collar-little-guy-makes-good films. It's not bad, but there's an excruciating familiarity to it all, and the performances, while creditable enough (especially Ejiofor, in a whopping departure from his work in Inside Man), don't always compensate. The climactic scene at a shoemaker's fashion show is hopelessly cornball.
Mrs. Palfrey at the Claremont


As your organization scales mobile management, find out how to make devices secure, manageable, and flexible with Android Enterprise and Android Enterprise Recommended from Google.
In both cases, Uber was only able to realise its global expansion by providing Android devices to its drivers. Uber also provided a driver-specific Uber app using Android Management tools that run on drivers' own Android phones. The app provides pickup locations; helps with routing and navigations; keeps the drivers connected, efficient and productive; and is an essential part of Uber's business.
The principal benefit in both cases was to drive substantial growth of Uber's business. A secondary benefit has been being able to choose the right devices for different use cases, with a single management framework across the fleet.
SAS Institute, a developer of analytics software, used Android Enterprise to standardize mobile device management and give employees more choice in devices while maintaining high levels of security and support. SAS Information Systems Engineer Jay Robinson said the goal for the company was to find a mobility solution to increase productivity and communications.
Today Android devices can even be built into appliances, reducing the costs compared to writing controller software from scratch and greatly increasing the utility of these "smart" appliances compared to legacy appliances. For example, Pitney Bowes transformed a postage meter into its new SendPro C-Series mailing, shipping, and tracking device for SMBs using an Android tablet with a custom Android read-only memory chip. The device not only weighs packages and prints postage, but it also helps users decide the best way to ship a package, and then tracks the package through the shipping process.
For more information about how Uber, SAS, and Pitney Bowes use Android Enterprise devices to help drive business growth, see this panel discussion from Cloud Next '18.


text:
Q: What kinds of type is better for get the path String? I want to get the String value about path.
I have two way about that.

*

*Using String.format()

String a = "/root"
String b = "Downloads"
String path = String.format("%s/%s",a,b)

*Using Paths.get()

String a = "/root"
String b = "Downloads"
String path = Path.get(a,b).toString();

Which one is better?
or
Do you have more better practice?

A: Paths.get verifies that you pass in syntactically valid file paths. For example, on Unix you get an exception from:
Paths.get("a", "b\000") // -> java.nio.file.InvalidPathException: Nul character not allowed

It also gets rid of extra directory separators:
Paths.get("a/", "/b") // -> a/b

If this behavior is what you want, use Paths.get.
If you just want to concatenate with no extra checks, use String.format.

A: Best util for path is:
import java.nio.file.*;
// Example 1
Path p = Paths.get("/articles/folder");
// Example 2
Path p2 = Paths.get("/articles", "folder");

For more info see Path Documentation


The pub is housed in a Grade II listed 17th-Century Georgian building which was once part of a market hall. The frontage is made up of a series of arches. Located in Warwick's Market Square, the pub has one light airy bar, but the layout and decor produce three distinct areas. The seating outside in the square on good weather days offers a relaxing continental feel and there is also a small courtyard to the rear. Real cider is available.


text:
Q: postgresql-client-13 : Depends: libpq5 (>= 13~beta2) but 12.3-1.pgdg18.04+1 is to be installed I want to try new PostgreSQL and follow this instruction. But installation fails:
$ sudo apt install postgresql-client-13
Reading package lists... Done
Building dependency tree
Reading state information... Done
Some packages could not be installed. This may mean that you have
requested an impossible situation or if you are using the unstable
distribution that some required packages have not yet been created
or been moved out of Incoming.
The following information may help to resolve the situation:

The following packages have unmet dependencies:
 postgresql-client-13 : Depends: libpq5 (>= 13~beta2) but 12.3-1.pgdg18.04+1 is to be installed
E: Unable to correct problems, you have held broken packages.

I also tried this instruction to resolve unmet dependencies
What did I wrong and how to install psql 13?
UPD
Content of my sources.list.d:
kes@kes-X751SA /etc/apt/sources.list.d $ cat pgdg.list
deb http://apt.postgresql.org/pub/repos/apt/ bionic-pgdg main

kes@kes-X751SA /etc/apt/sources.list.d $ cat pgdg-testing.list
deb http://apt.postgresql.org/pub/repos/apt/ bionic-pgdg-testing main 13

Also:
$ sudo apt-cache policy postgresql-13
postgresql-13:
  Installed: (none)
  Candidate: 13~beta2-1.pgdg18.04+1
  Version table:
     13~beta2-1.pgdg18.04+1 100
        100 http://apt.postgresql.org/pub/repos/apt bionic-pgdg-testing/13 amd64 Packages

A: try aptitude instead of apt-get
sudo apt-get install aptitude

sudo aptitude install <package-name>

https://askubuntu.com/a/1056378/1087086

A: Had the same problem.
in /etc/apt/sources.list.d/pgdg.list where you have
deb http://apt.postgresql.org/pub/repos/apt/ focal-pgdg main

change it to
deb http://apt.postgresql.org/pub/repos/apt/ focal-pgdg main 13

then run
sudo apt update

and then you can do
sudo apt install postgresql-13 postgresql-client-13

that worked on my machine.
Just FYI:

WARNING: The data format may change between beta releases. Be prepared
to pg_dump the database contents before you upgrade the package to a
newer beta or to a final release. Check the release notes before
upgrading.

A: Finally at my docker container I do next commands:
RUN yum -y install https://dl.fedoraproject.org/pub/epel/epel-release-latest-7.noarch.rpm
RUN yum -y install llvm5.0-devel
RUN yum -y install centos-release-scl-rh
RUN yum -y install llvm-toolset-7-clang
#RUN rpm -Uvh https://yum.postgresql.org/11/redhat/rhel-7-x86_64/pgdg-redhat-repo-latest.noarch.rpm --replacepkgs
#RUN yum-config-manager --enable pgdg13-updates-testing
RUN yum -y install https://download.postgresql.org/pub/repos/yum/reporpms/EL-7-x86_64/pgdg-redhat-repo-latest.noarch.rpm
RUN yum -y install postgresql13 postgresql13-devel

Commented out lines were for case before 13.1 was released


One of the most interesting trends in real estate market Kolkata is the entry of new players offering luxurious yet affordable properties for the homebuyers. A number of up-scale multistory projects have been launched all across the city and among these the Southern part of the city is witnessing huge growth. The social infrastructure is also well-developed here and more and more end-users in the city are willing to move to apartments. This has further increased the demand of real-estate properties here.
If you are among those homebuyers looking for lavish homes equipped with all the luxury features and amenities of global standards in Kolkata, then you must have a look at Mani Vista project located in Tollygunge. This is a high-end residential development offering the exotic living facilities and comfort that a modern homebuyer craves for. Besides this, one can also experience that taste of traditional heritage of the city when he will move to these homes.
Located at a premium location Tollygunge in Kolkata, the area offers quick and hassle-free connectivity to all the major locations in and around the city. The social infrastructure at this location is refined and the project is also located very close to several civic amenities including banks, colleges, ATMs, shopping centers, retail centers, hospitals and more. The transportation system is also well-developed and one can access anything quickly as all conveniences are easily available at your doorstep. Apart from this, the airport is also in located very close to the project location.
Mani Vista Tollygunge is an upcoming residential venture that will offer a beautiful mix of 3, 3.5 and 4 BHK luxury homes to the residents that will bring you all the amenities to make your living comfortable. These homes are designed with all the classy and ultra-modern features to elevate your lifestyle. This new housing segment offers 3-side open apartments that ensure maximum natural light and air to spread throughout. You will feel living close to nature while sitting in your balcony area watching to the central greens.
Life at Mani Vista Kolkata is peaceful as well as pollution-free with its beautiful landscaped gardens and open areas. The whole complex is planned brilliantly by the world-class designers and architects to elevate your living standard. The builder has thoughtfully designed the complex as per the expectations and requirements of modern homebuyers. Living here is truly amazing. The apartments are equipped with super-luxurious features like stylish interiors, superb flooring and best fittings. The area of apartments varies from 1795 sq. ft. to 2364 sq. ft., offering a luxurious space to enjoy the lovely moments with your beloved family.
There is a lavish banquet hall at the complex with an attached lawn and pre-function area where you can plan your gatherings and family functions. There are separate swimming pools for adults as well as kids along with several indoor and outdoor sports facilities. The project offers every facility and feature to make your living truly comfortable. If you are planning to invest in a property in Kolkata, investing in Vista project by Mani Group is really the best option. So, what are you waiting? Have a look at this property and make a wise investment decision.


text:
Home > Features > A publisher's needs in today's marketplace - The Noel D'Cunha Sunday Column A publisher's needs in today's marketplace - The N...
A publisher's needs in today's marketplace - The Noel D'Cunha Sunday Column
By Noel D'Cunha 09 Jun 2018
Publishers and printers came together to discuss the way forward in a closed-door roundtable discussion titled 'Anatomy of Bookmaking in India' on 8 June in New Delhi.
For a full day they confabulated about how to introduce a set of best practices and how to make book manufacturing and distribution more time- and cost-efficient. The discussion ranged from sustainability and safety on the shopfloor; plus how to re-look at management, distribution, print and fulfillment of book orders, and
Publishers and printers from across India came together to brainstorm on the course ahead during a closed-door roundtable discussion titled "Anatomy of Bookmaking in India". Organised by Henkel Adhesives Technologies India, Impel (Welbound), and PrintWeek India, the event took place at India Habitat Centre, New Delhi, on 8 June. The event was coordinated by Subhasis Ganguly, an independent publishing consultant.
S Sunil Kumar of Henkel, Sanjiv Gupta of Penguin Random House India, Ananth Padmanabhan of HarperCollins India
The takeaway from the discussions, which revolved around the challenges of book printing in India, was that of a positive outlook. As Ananth Padmanabhan, CEO, HarperCollins India explained, books are agnostic to economic and cultural changes. He gave the example of Raghuram Rajan's book which went on to become a bestseller. Again, contrary to the popular belief, he asserted that reading habit is not on the decline. Publishers are doing well, he insisted, adding that there are opportunities to do better.
Padmanabhan said the country now has the infrastructure and the wherewithal to print good looking quality books. At the same time, he argued that the stakeholders should not get complacent about what they have achieved and should work towards building a foolproof system, which is future-ready.
He said the industry is yet to tap the advantages of technology in their supply chain to make the entire process smoother and faster. He also expressed concerns about turnaround time, especially during reprints, the unchecked piracy and the publishers' inability to increase the cover price of books.
Sanjiv Gupta, COO, Penguin Random House India, echoed that since books are considered non-essential items, the market is highly cost-sensitive. This is one of the reasons for the proliferation of piracy. He also argued that reading habits, which were taken over by the electronic media, is set to return as there has been an increased focus on inculcating reading habit among schoolchildren. This will increase the readership for books.
Both Padmanabhan and Gupta spoke during the second half of the event, where they answered questions related to the business outlook of the industry.
The event started with S Sunil Kumar, business director – industrial adhesives, Henkel Adhesives Technologies India sharing the story about Henkel and Henkel's industry initiatives globally. This was followed by a presentation, where Munish Agarwal, MD, Edelman Group India, spoke about the processes he has implemented in the company, primarily, CAPA (corrective actions preventive actions methodology).
The roundtable then invited attendant printers and publishers to share their experience on a host of issues, including recyclability and how to leverage paper; safety at the workplace; saying no to the use of single-use plastic; minimising waste during production and quality standards, among others.
Ajay Joshi (holding the mic in the pic above) of Penguin Random House said the company had become the first trade publisher in India to move to FSC paper entirely. He also added that the company has now taken the initiative to recycle the excess unsold inventory to make stationery products for internal use.
On the issue of avoiding single-use plastic, the publishers were of different opinion. Some agreed that it's possible to forego lamination and opt for UV instead. They also urged printers to suggest a suitable paper for cover where lamination is not necessary. On the other hand, publishers of education books argued that lamination on a cover is important for their books as they are thicker.
On the usage of shrink film for the pack, Hachette does not deploy individual shrink wrap whereas Penguin does. And both publishing majors get their books multiple copy shrink-wrapped. All the members at the roundtable agreed that it is required to have a re-look at the packing specifications, especially monsoon-packaging.
On the publisher-printer partnership, Chander Shekhar of XSEED, an education publisher, explained how the company chose print partners across different geographies, closer to the company warehouse, to avoid logistics delays. He added that the ideal situation would be the one where the printers directly supply the books to the schools.
On wastage of paper, two important points came to the fore. One, as mills supply paper in roll form, the paper stock in the core is often wasted. Again, the system of paper handling remains primitive where hooks are used to unload the rolls. This adds to the waste.
Two, both the printers and the publishers agreed that often there is no consistency in the same category of paper supplied by the same mill. This invariably affects quality.
On ensuring quality, MN Pandey of Avantika highlighted the use of software and production maintenance. He also urged the stakeholders not to worry about cost control and instead focus on wastage control.
During the event, Ramu Ramanathan made a presentation on some leading book printers, including Lovely, Inndus, Kadam Digital, Pragati and Repro, to illustrate their endeavour towards saving cost and resources.
The full-day roundtable conversation concluded with a commitment by printers-publishers to help control, monetise, and secure their content while boosting revenues. Almost everyone agreed that "Publishing is going through a big change. A couple of years ago it was - print is dying or not relevant anymore, and we need to move everything to an eBook or online course material. However, that's not what the market wants, especially in India."
Book print is growing again, and publishers who were present sought a seamless system to keep print relevant but help them change how they print, what they print and where they print. Some things like best practices on sustainability, safety, and standardisation, the 3S, plus IPR can be easily implemented through mutual discussion.
Subhasis Ganguly said: "Publishers want tools to help them better monetise their content, which is technically their product. They want to be able to get more value out of that content and secure the content, and then they want to find ways to innovate that content, bridging between both print and digital."
Padmanabhan of HarperCollins India said it would be a boon to standardise the creation of a book. "One of the biggest hurdles is the creation of every single book that looks similar - from paper to format to grain direction. We need a system to make the process repeatable and easier."
Everyone agreed that the forum should be re-convened, soon, since this is the best way to offer solutions which can have a direct impact on the bottom line, improve profitability and efficiency.
What we need is a concerted effort to maintain the momentum so that in time we can arrive upon a set of best practices guidelines which are acceptable to all stakeholders, from publishers to paper manufacturers to printers. In time, the scope can be widened to include others, such as distributors and sellers, both physical and online, and even the literature festivals, big and small.
Perhaps the book print and publishing industry can borrow a leaf from other segments and lobby aggressively for its collective welfare.
Tags: Welbound Technical Services, Sunday Column
Post Script: Somya Bhargava
by Charmiane Alexander 15 Jan 2020
Jitendra Kalani: Screen print...
by PrintWeek Team 15 Jan 2020
/features/publishers-todays-marketplace-noel-dcunha-sunday-column-29856 A publisher's needs in today's marketplace - The Noel D'Cunha Sunday Column https://www.printweek.in/Utils/ImageResizer.ashx?n=http://img.haymarketsac.in/printweek//IMG/350/71350/attendees.jpg
Features 29856 29856 29848 29856,
Pamex 2020: DGM India bags eight orders News
Pamex 2020: Vijaya strikes two deals for Veenine 65 News
Pamex 2020: Vinsak announces Aarya Print Pack installation news News
Pamex 2020: Polykam Offset books its third Komori News
Pamex 2020: Rohan Cards installs Asia's first Heidelberg Speedmaster X... News
Pamex 2020: HP announces Xpress Labels' HP Indigo WS 6900 investment News
Pamex 2020: Konica Minolta highlights its AccurioPress series News
Pune's Star Copier invests in Versant 3100 News
Print Summit to sharpen focus and open minds News
Plastivision 2020 NEW!
Jan 16 - 20 Jan 2020
The All India Plastics Manufacturing Association (AIMPA)
Bombay Exhibition Center, Mumb...
Print Summit 2020 NEW!
The Bombay Master Printers' Association
NCPA, Tata Theatre, Mumbai
Five headlines emerged in the first ten days of the new year. Which of them will dominate 2020?
Anaswara winning AIFMP printer of the year
J&K print industry in a crisis
Pamex boosts animal spirits
Raw material crisis due to geopolitics
All eyes on Drupa
Tweets by printweekindia