Here’s a very welcome surprise before the end of the year: Leos Carax’s stunning cine-memoir It’s Not Me is getting a release this December. Sideshow and Janus Films announced today that the Cannes and NYFF selection will hit theaters in NY and LA as well as arrive on the Criterion Channel and VOD platforms on […]

The post Leos Carax’s It’s Not Me Coming to Theaters and Criterion Channel on December 10 first appeared on The Film Stage.

Procedures for establishing communication between two multiprotocol audiovisual terminals using digital channels at a multiple of 64 or 56 kbit/s

Transmission of start-stop characters over synchronous bearer channels

[Premium Times] The cleric commended the government for ensuring that the scope of intervention of TETFund expanded from building infrastructure to carrying out research programmes.

Special Technology Report: Warehouse Management Systems (WMS) and Voice-directed Picking.

Contributors include VDC Research, Gartner, Panorama Consulting, Frost & Sullivan, Cap Gemini, Aberdeen Strategy & Research, Manhattan Associates, Dakota Integrated Solutions, Ehrhardt Partner Group, Indigo Software, Renovotec.

Manhattan Associates has announced the findings of its 2024 ‘State of Warehouse Operations’ research in association with Vanson Bourne, highlighting the current challenges and key opportunities ahead for the sector. 

Celona reacts to the growing maturity of its channel by moving from a single-tier organization to a more diverse three tiered one, while complementing the channel announcement with new Aerloc security improvements for industrial IoT.

Location: Electronic Resource- 

In the first released video, the Duchess of Cambridge adorably corrects her husband's pronunciation when he spoke the Irish language for their 2021 St. Patrick's Day greeting.

In the first released video, the Duchess of Cambridge adorably corrects her husband's pronunciation when he spoke the Irish language for their 2021 St. Patrick's Day greeting.

Manos Nikolakis, GM, BIC Cello, said, "While e-commerce is growing significantly across the country, the landscape of the Indian market is still heavily reliant on traditional trade. Accordingly, this remains our main sales driver. The lack of digital penetration in semi-urban and rural areas can sometimes create a challenge in the e-commerce space, which means that e-commerce is mostly relevant in bigger cities with a more mature infrastructure."

He's the guy behind the Radio Disney versions of metal songs we all love.

Trey Songz performs an Usher classic.

Bermuda Hockey Federation’s men’s and women’s teams traveled to Jersey, Channel Islands to compete in the Easter Weekend Hockey Festival. In the opener the Bermuda women’s team defeated Jersey’s women’s team 2 – 0, the Bermuda men’s team then defeated the Jersey men’s team 3 – 2. There were two mixed matches as well, with […]

Concacaf has embraced the new WhatsApp Channels service launched by Meta, engaging over 1.6 million fans and providing a private way for followers to access the latest updates and content related to football in North America, Central America, and the Caribbean. A spokesperson said, “Concacaf has upped its digital engagement game with the governing body […]

The PLP has launched a new WhatsApp Channel which they said will send out “press releases, party statements, party events and highly informative social media content.” A spokesperson said, “In an effort to keep the public updated we have created a Progressive Labour Party WhatsApp Channel. “This WhatsApp Channel will allow persons to receive our […]

Nowadays many shoppers don’t even remember how they learned about an eCommerce brand in the first place. If you ask them, the most popular answer is “I found it somewhere on the Internet”. Commercial information is all over the place, so nobody cares about the “channel” they use to find it anymore.

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease.

The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.

Connexin (Cx) protein forms hemichannels and gap junctional channels, which play diverse and profound roles in human physiology and diseases. Gap junctions are arrays of intercellular channels formed by the docking of two hemichannels from adjacent cells. Each hexameric hemichannel contains the same or different Cx isoform. Although homomeric Cxs forms have been largely described functionally and structurally, the stoichiometry and arrangement of heteromeric Cx channels remain unknown. The latter, however, are widely expressed in human tissues and variation might have important implications on channel function. Investigating properties of heteromeric Cx channels is challenging considering the high number of potential subunit arrangements and stoichiometries, even when only combining two Cx isoforms. To tackle this problem, we engineered an HA tag onto Cx26 or Cx30 subunits and imaged hemichannels that were liganded by Fab-epitope antibody fragments via atomic force microscopy. For Cx26-HA/Cx30 or Cx30-HA/Cx26 heteromeric channels, the Fab-HA binding distribution was binomial with a maximum of three Fab-HA bound. Furthermore, imaged Cx26/Cx30-HA triple liganded by Fab-HA showed multiple arrangements that can be derived from the law of total probabilities. Atomic force microscopy imaging of ringlike structures of Cx26/Cx30-HA hemichannels confirmed these findings and also detected a polydisperse distribution of stoichiometries. Our results indicate a dominant subunit stoichiometry of 3Cx26:3Cx30 with the most abundant subunit arrangement of Cx26-Cx26-Cx30-Cx26-Cx30-Cx30. To our knowledge, this is the first time that the molecular architecture of heteromeric Cx channels has been revealed, thus providing the basis to explore the functional effect of these channels in biology.

Transient receptor potential vanilloid 1 (TRPV1) channel is a multimodal receptor that is responsible for nociceptive, thermal, and mechanical sensations. However, which biomolecular partners specifically interact with TRPV1 remains to be elucidated. Here, we used cDNA library screening of genes from mouse dorsal root ganglia combined with patch-clamp electrophysiology to identify the voltage-gated potassium channel auxiliary subunit Kvβ1 physically interacting with TRPV1 channel and regulating its function. The interaction was validated in situ using endogenous dorsal root ganglia neurons, as well as a recombinant expression model in HEK 293T cells. The presence of Kvβ1 enhanced the expression stability of TRPV1 channels on the plasma membrane and the nociceptive current density. Surprisingly, Kvβ1 interaction also shifted the temperature threshold for TRPV1 thermal activation. Using site-specific mapping, we further revealed that Kvβ1 interacted with the membrane-distal domain and membrane-proximal domain of TRPV1 to regulate its membrane expression and temperature-activation threshold, respectively. Our data therefore suggest that Kvβ1 is a key element in the TRPV1 signaling complex and exerts dual regulatory effects in a site-specific manner.

Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In the brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ∼80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5' end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in the brain.

S-Acylation, a reversible post-translational lipid modification of proteins, controls the properties and function of various proteins, including ion channels. Large conductance Ca2+-activated potassium (BK) channels are S-acylated at two sites that impart distinct functional effects. Whereas the enzymes that attach lipid groups are known, the enzymes mediating lipid removal (i.e. deacylation) are largely unknown. Here, McClafferty et al. identify two enzymes, ABHD17a and ABHD17c, that excise BK channel lipid groups with remarkable precision. These findings lend insights into mechanisms that orchestrate the (de)acylation that fine-tunes ion channel function in physiology and disease.

S-Acylation, the reversible post-translational lipid modification of proteins, is an important mechanism to control the properties and function of ion channels and other polytopic transmembrane proteins. However, although increasing evidence reveals the role of diverse acyl protein transferases (zDHHC) in controlling ion channel S-acylation, the acyl protein thioesterases that control ion channel deacylation are very poorly defined. Here we show that ABHD17a (α/β-hydrolase domain-containing protein 17a) deacylates the stress-regulated exon domain of large conductance voltage- and calcium-activated potassium (BK) channels inhibiting channel activity independently of effects on channel surface expression. Importantly, ABHD17a deacylates BK channels in a site-specific manner because it has no effect on the S-acylated S0–S1 domain conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases revealing mechanisms for generating both specificity and diversity for these important enzymes to control the properties and functions of ion channels.

Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.

The dominant role of CaV2 voltage-gated calcium channels for driving neurotransmitter release is broadly conserved. Given the overlapping functional properties of CaV2 and CaV1 channels, and less so CaV3 channels, it is unclear why there have not been major shifts toward dependence on other CaV channels for synaptic transmission. Here, we provide a structural and functional profile of the CaV2 channel cloned from the early-diverging animal Trichoplax adhaerens, which lacks a nervous system but possesses single gene homologues for CaV1–CaV3 channels. Remarkably, the highly divergent channel possesses similar features as human CaV2.1 and other CaV2 channels, including high voltage–activated currents that are larger in external Ba2+ than in Ca2+; voltage-dependent kinetics of activation, inactivation, and deactivation; and bimodal recovery from inactivation. Altogether, the functional profile of Trichoplax CaV2 suggests that the core features of presynaptic CaV2 channels were established early during animal evolution, after CaV1 and CaV2 channels emerged via proposed gene duplication from an ancestral CaV1/2 type channel. The Trichoplax channel was relatively insensitive to mammalian CaV2 channel blockers ω-agatoxin-IVA and ω-conotoxin-GVIA and to metal cation blockers Cd2+ and Ni2+. Also absent was the capacity for voltage-dependent G-protein inhibition by co-expressed Trichoplax Gβγ subunits, which nevertheless inhibited the human CaV2.1 channel, suggesting that this modulatory capacity evolved via changes in channel sequence/structure, and not G proteins. Last, the Trichoplax channel was immunolocalized in cells that express an endomorphin-like peptide implicated in cell signaling and locomotive behavior and other likely secretory cells, suggesting contributions to regulated exocytosis.

Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.

Alabama basketball is on the hunt for win No. 3 of the 2024-25 season.

LSU women's basketball hosts Charleston Southern on Tuesday morning for a nonconference game. Here's how to watch.

The precise regulation of Ca²⁺ signals plays a crucial role in the physiological functions of neurons. Here, we investigated the rapid effect of glucocorticoids on Ca²⁺ signals in cultured hippocampal neurons from both female and male rats. In cultured hippocampal neurons, glucocorticoids inhibited the spontaneous somatic Ca²⁺ spikes generated by Kv2.1-organized Ca²⁺ microdomains. Furthermore, glucocorticoids rapidly reduced the cell surface expressions of Kv2.1 and Ca_V1.2 channels in hippocampal neurons. In HEK293 cells transfected with Kv2.1 alone, glucocorticoids significantly reduced the surface expression of Kv2.1 with little effect on K⁺ currents. In HEK293 cells transfected with Ca_V1.2 alone, glucocorticoids inhibited Ca_V1.2 currents but had no effect on the cell surface expression of Ca_V1.2. Notably, in the presence of wild-type Kv2.1, glucocorticoids caused a decrease in the surface expression of Ca_V1.2 channels in HEK293 cells. However, this effect was not observed in the presence of nonclustering Kv2.1S586A mutant channels. Live-cell imaging showed that glucocorticoids rapidly decreased Kv2.1 clusters on the plasma membrane. Correspondingly, Western blot results indicated a significant increase in the cytoplasmic level of Kv2.1, suggesting the endocytosis of Kv2.1 clusters. Glucocorticoids rapidly decreased the intracellular cAMP concentration and the phosphorylation level of PKA in hippocampal neurons. The PKA inhibitor H89 mimicked the effect of glucocorticoids on Kv2.1, while the PKA agonist forskolin abrogated the effect. In conclusion, glucocorticoids rapidly suppress Ca_V1.2-mediated Ca²⁺ signals in hippocampal neurons by promoting the endocytosis of Kv2.1 channel clusters through reducing PKA activity.

Aerial America: Wilderness premieres Sunday, Sept. 7 at 9PM ET/PT

Dominic April fell in love with forging after his career in the military came to an end in 2015. Now operating a blacksmith studio near Quebec City, he hopes to help other veterans dealing with PTSD find creativity and purpose.

‘To design, I use my favorite tool, SOLIDWORKS’

For the first time, the training "Churches, Channels of Hope" on HIV and AIDS was given in Spanish, 2-8 of May, 2011 in Costa Rica.

Bharat Sanchar Nigam Limited (BSNL) has announced the launch of the first fibre-based intranet TV service in select regions in India. This service, dubbed IFTV, was first introduced last month alongside the unveiling of the state-owned telecommunications provider’s new logo and six other new facilities.

NDTV Profit, the business news channel of the New Delhi Television Ltd, is set to resume regular operations from December.

Record 56 people have so far died on the France-Britain route across the Channel in 2024.

Wild River Technology (WRT), the leading supplier of signal integrity measurement and optimization test fixtures for high-speed channels at data rates of up to 224G, has announced the availability of a new advanced channel modeling solution that helps achieve extreme signal integrity design to 70GHz. Read the press release. The CMP-70 program continues the industry-first simulation-to-measurement collaboration with Cadence that was initially established with the CMP-50. Significant resources were dedicated to the development of the CMP-70 by Cadence and WRT over almost three years. The CMP-70 will be on display at DesignCon 2025 , January 28-30, in Cadence booth 827 to benchmark the Cadence Clarity 3D Solver . “I am not a fan of hype-based programs that simply get attention,” remarked Alfred P. Neves, WRT’s co-founder and chief technical officer. “Both Cadence and Wild River brought substantial skills to the table in this project as we continued our industry-first simulation-to-measurement collaboration. The result is a proven, robust and accurate platform that brings extreme signal integrity to 70GHz designs. This application package has also been instrumental in demonstrating the robust 3D EM simulation capability of the Cadence Clarity solver.” “We’re delighted to continue the joint development and validation program with WRT that started with the CMP-50,” said Gary Lytle, product management director at Cadence. “The skilled and experienced signal integrity technologists that both companies bring to the program results in a superior signal integrity solution for our mutual customers.” CMP-70 Solution Features The solution is available both in a standard configuration and as a custom solution for customer-specific stackups and fabrication. The primary target application is to support a 3D EM solver analysis modeling versus the time- and frequency-domain measurement methodologies. The solution features include: The CMP-70 platform, assembled and 100% TDR NIST traceable tested, with custom stands Material Identification overview web-based meeting including anisotropic 3D material identification A cross-section PCB report and structures for using as-fabricated geometries Measured S-parameters, pre-tested for quality (passivity/causality and resampled for time domain simulations) A host of novel crosstalk structures suited for 112G HD level project analysis PCB layout design files (NDA required) An EDA starter library including loss models with industry-first accurate surface roughness models Comprehensive training available for 3D EM analysis – correspondence, material ID in X-Y and Z axis for a host of EDA tools Industry-First Hausdorff Technique The WRT application package also includes an industry-first modified Hausdorff (MHD) technique , included as MATLAB code. This algorithmic approach provides an accurate way to compare two sets of measurements in multi-dimensional space to determine how well they match. The technique is used to compare the results simulated by the Clarity solver with those measured on the CMP-70 platform. The methodology and initial results are shown in the figure below, where the figure of merit (FOM) is calculated from 10, 35, and finally to 50GHz. The MHD algorithm requires a MATLAB license, but WRT also accommodates customer data as another option, where WRT provides the comparison between measured and simulated data. Additional Resources If you are attending DesignCon 2025 , be sure to stop by Cadence booth 827 to see WRT’s CMP-70 advanced channel modeling solution in action with the Clarity 3D Solver. Check out our on-demand webinar, " Validating Clarity 3D Solver Accuracy Through Measurement Correlation ." Learn more about the CMP-70 solution and the Clarity 3D Solver . For more information about Cadence’s full suite of integrated multiphysics simulation solutions, download our Multiphysics System Analysis Solutions Portfolio .

At least two TV channels in a northern Afghan province stopped showing images of living beings during their broadcasts, journalists told AFP on Tuesday, in line with orders from morality police.

Russia started mass supplying its military with Zicron missiles to attempt to boost its nuclear forces.

Russian warship armed with hypersonic missiles trains in English Channel, state media reports

The orexigenic gut peptide ghrelin is an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHSR1a). Systemic ghrelin administration has previously been shown to increase gastric motility and emptying. While these effects are known to be mediated by the vagus nerve, the cellular mechanism underlying these effects remains unclear. Therefore, the purpose of the present study was to investigate the signaling mechanism by which GHSR1a inhibits voltage-gated Ca²⁺ channels in isolated rat gastric vagal afferent neurons using whole-cell patch-clamp electrophysiology. The ghrelin pharmacological profile indicated that Ca²⁺ currents were inhibited with a log (Ic₅₀) = –2.10 ± 0.44 and a maximal inhibition of 42.8 ± 5.0%. Exposure to the GHSR1a receptor antagonist (D-Lys3)-GHRP-6 reduced ghrelin-mediated Ca²⁺ channel inhibition (29.4 ± 16.7% vs. 1.9 ± 2.5%, n = 6, P = 0.0064). Interestingly, we observed that activation of GHSR1a inhibited Ca²⁺ currents through both voltage-dependent and voltage-independent pathways. We also treated the gastric neurons with either pertussis toxin (PTX) or YM-254890 to examine whether the Ca²⁺ current inhibition was mediated by the Gα_i/o or Gα_q/11 family of subunits. Treatment with both PTX (Ca²⁺ current inhibition = 15.7 ± 10.6%, n = 8, P = 0.0327) and YM-254890 (15.2 ± 11.9%, n = 8, P = 0.0269) blocked ghrelin’s effects on Ca²⁺ currents, as compared with control neurons (34.3 ± 18.9%, n = 8). These results indicate GHSR1a can couple to both Gα_i/o and Gα_q/11 in gastric vagal afferent neurons. Overall, our findings suggest GHSR1a-mediated inhibition of Ca²⁺ currents occurs through two distinct pathways, offering necessary insights into the cellular mechanisms underlying ghrelin’s regulation of gastric vagal afferents.

ABSTRACTIntroduction:Emergency contraceptive pills (ECPs) are effective and can be used safely at any age repeatedly within the same cycle. They are often favored by youth yet are underutilized. Private facilities can increase ECP access but present barriers including cost. Identifying effective public-sector ECP distribution models can help ensure equitable access. The Malawi Ministry of Health developed a strategy to improve ECP access in 2020. We documented ECP provision through select public, youth-serving channels recommended by the strategy: general and youth-specific outreach, paid and unpaid community health workers (CHWs), and youth clubs.Methods:We conducted this mixed methods study from November 2022–March 2023 in 2 rural districts (Mchinji and Phalombe) implementing the strategy. We conducted qualitative interviews with 10 national stakeholders, 46 providers, and 24 clients aged 15–24 years about ECP service delivery. Additionally, 25 providers collected quantitative tally data about clients seeking ECPs. We analyzed qualitative data using grounded theory and quantitative data descriptively.Results:Stakeholders and providers reported ECP uptake increased in geographies where the strategy was implemented, especially among youth. Providers documented 3,988 client visits for ECPs over 3 months. Of these visits, 26% were from male clients, 36% were from clients aged younger than 20 years, and 64% received ECPs for the first time. Across channels, youth club leaders and unpaid CHWs reported the most client visits per provider and served the youngest clients. However, no ECPs were dispensed during 29% of visits due to stock-outs. While many providers were supportive of youth accessing ECPs, most held unfavorable attitudes toward repeat use.Conclusion:ECP access should be expanded through provision in the studied channels, especially youth clubs and CHWs. However, to meet demand, the supply chain must be strengthened. We recommend addressing providers’ attitudes about repeat use to ensure informed method choice.

Is Jessie available to babysit again?

Promising to be inspiring, ‘Vijay 69’ turns out like a mildly entertaining episode in Anupam Kher’s popular play, ‘Kucch Bhi Ho Sakta Hai’