[Shabelle] Mogadishu -- In a move signaling deepening political discord, Somalia's Deputy Minister of Ports and Maritime Transport, MP Saddam Mohamud Abdi, resigned on Tuesday, accusing the federal government of constitutional violations and politicizing development projects in his home region of Puntland.

[Shabelle] Mogadishu, Somalia -- Somalia's Minister of Defense, Abdiqadir Mohamed Noor, has been actively engaging with troop-contributing countries for the forthcoming African Union mission, set to start in 2025.

[Shabelle] Mogadishu, Somalia -- In its weekly session, Somalia's Council of Ministers, under the leadership of Prime Minister Hamsa Abdi Barre, delved into a comprehensive review of the nation's strategies and achievements in combating terrorism and financial crimes.

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Over the past few months, the escalation of gang violence and mass displacement in Haiti have been of great concern for humanitarian organizations. Severe levels of armed violence have resulted in significant instability, with food insecurity, sexual violence, civilian casualities, and restricted freedom of movement plaguing the nation. Displacement cases have risen sharply, to the […]

Keynote address by Masatsugu Asakawa, President, Asian Development Bank, at the 23rd Ministerial Conference of the Central Asia Regional Economic Cooperation Program, 8 November 2024

ADB has a vacancy for the position of Senior Administration and Communications Assistant in the Strategy, Policy and Partnerships Department. The deadline for submitting applications is on 26-NOV-2024.

KARACHI: The Federal Board of Revenue’s (FBR) decision to fix the minimum retail price (MRP) of tea at Rs1,200 per kg for levying sales tax would make the commodity more expensive, warned traders on Tuesday.

Pakistan Tea Association (PTA) Chairman Mohammad Altaf said the MRP at the import stage would have an adverse impact of Rs150-300 per kg on imported tea prices.

The flat MRP also ignores global tea prices hovering between 0.50 cents to over $3 per kg. Tea is imported in different packaging, with bulk shipments typically weighing more than 5kgs and around/approximately 80kgs. An 18 per cent general sales tax is already charged based on the imported tea.

He said before fixing the MRP for sales tax purposes, it is crucial to consider that the definition of “manufacturer” in Section 2(16) of the Sales Tax Act 1990, includes activities such as blending, mixing, processing, and packaging, as clarified in Circular No. 3(11) ST-L&P/2013-94433-R dated July 17, 2019. Based on this, tea imported for these processes qualifies as “raw material”.

Tea sellers warn FBR move will incentivise arrival of low-quality product via illegal channels

“According to judicial interpretations (e.g., CTO v. Rajasthan Taxchem Ltd., 2007) and definitions in Advanced Law Lexicon, “raw material” includes ingredients necessary for manufacturing. Tea used in blending and packaging clearly falls under this category, he added.

Accordingly, sales tax should be based on the import value, as per Subsection 46(f) of Section 2 of the Sales Tax Act, 1990, rather than the minimum retail price, Altaf said.

Tea retail prices vary significantly due to numerous factors, including the company, method of sale (open or packaged), product quality, and regional differences. The PTA chief said that the flat MRP rate per kg also does not reflect the prices charged by most traders, manufacturers, and sellers.

The imposition of a flat rate per kg would have severe negative consequences for a large portion of the tea trade, which may result in reduced business activity and ultimately lead to a loss of revenue for the national exchequer via misusing several exemptions.

Two-thirds of Pakista­nis purchase tea at Rs700-950 per kg, reflecting socio-economic and regional price variations.

He said that MRP cannot be applied at the import stage as the tea has to follow various value-addition procedures before it is made shelf-ready. “This MRP disrupts the supply chain and eradicates the role of wholesalers and distributors who play a vital role in the business, while MRP at the import stage also eradicates the basic right of commercial imports,” the PTA chief observed.

Tea is a part of our daily diet, a staple food item, not a drink.

Most people in rural and urban areas consume tea as per their earnings. Further fixing of MRP will incentivise unscrupulous elements to exploit the situation, and thus, import of low-priced teas will find its way through illegal channels, Altaf feared.

Published in Dawn, November 13th, 2024

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The neuronal nucleus houses a meticulously organized genome. Within this structure, genetic material is not simply compacted but arranged into a precise and functional 3D chromatin landscape essential for cellular regulation. This mini-review highlights the importance of this chromatin landscape in healthy neurodevelopment, as well as the diseases that occur with aberrant chromatin architecture. We discuss insights into the fundamental mechanistic relationship between histone modifications, DNA methylation, and genome organization. We then discuss findings that reveal how these epigenetic features change throughout normal neurodevelopment. Finally, we highlight single-gene neurodevelopmental disorders that illustrate the interdependence of epigenetic features, showing how disruptions in DNA methylation or genome architecture can ripple across the entire epigenome. As such, we emphasize the importance of measuring multiple chromatin architectural aspects, as the disruption of one mechanism can likely impact others in the intricate epigenetic network. This mini-review underscores the vast gaps in our understanding of chromatin structure in neurodevelopmental diseases and the substantial research needed to understand the interplay between chromatin features and neurodevelopment.

Over the past 20 years, quantitative proteomics has contributed a wealth of protein expression data, which are currently used for a variety of systems pharmacology applications, as a complement or a surrogate for activity of the corresponding proteins. A symposium at the 25th North American International Society for the Study of Xenobiotics meeting, in Boston, in September 2023, was held to explore current and emerging applications of quantitative proteomics in translational pharmacology and strategies for improved integration into model-informed drug development based on practical experience of each of the presenters. A summary of the talks and discussions is presented in this perspective alongside future outlook that was outlined for future meetings.

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy.

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures of CYP-sensitive substrates coadministered with cytokine modulators as reported in the University of Washington Drug Interaction Database were extracted and examined for each of the CYPs. Coadministration of cytochrome P450 family 3 subfamily A (CYP3A) (midazolam/simvastatin), cytochrome P450 subfamily 2C19 (omeprazole), or cytochrome P450 subfamily 1A2 (caffeine/tizanidine) substrates with anti-interleukin-6 and with anti-interleukin-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ –58% to ~35%; no significant trends were observed for cytochrome P450 subfamily 2D6 (dextromethorphan) and cytochrome P450 subfamily 2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when coadministered with tocilizumab, suggest a ~six- to sevenfold increase in midazolam clearance, suggesting potential implications of cytokine–CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of nonclinical and clinical assessments of cytokine–CYP drug interactions in drug discovery and development.

The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental, and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport, and pharmacokinetics is reviewed. Pharmacometabolomic approaches can help describe factors mediating drug disposition, efficacy, and toxicity. While important advancements in this area have been made, there remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy.

G protein–coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of α and β subunits, to convert extracellular signals into activation of intracellular signaling pathways. Canonically, GPCR-mediated activation results in the exchange of GDP for GTP on G protein α subunits (Gα) and the dissociation of Gα-GTP and G protein β subunits (Gβ), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by Gα returns the protein to Gα-GDP and allows reassociation with Gβ to reform the inactive heterotrimer. Naturally occurring mutations in Gα have been found at conserved glutamine and arginine amino acids that disrupt the canonical G protein cycle by inhibiting GTP hydrolysis, rendering these mutants constitutively active. Interestingly, these dysregulated Gα mutants are found in many different cancers due to their ability to sustain aberrant signaling without a need for activation by GPCRs. This review will highlight an increased recognition of the prevalence of such constitutively activating Gα mutations in cancers and the signaling pathways activated. In addition, we will discuss new knowledge regarding how these constitutively active Gα are regulated, how different mutations are biochemically distinct, and how mutationally activated Gα are unique compared with GPCR-activated Gα. Lastly, we will discuss recent progress in developing inhibitors directly targeting constitutively active Gα mutants.

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration–approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032–1.0 mg/kg), nalbuphine (0.32–10 mg/kg), buprenorphine (0.0032–0.032 mg/kg), methadone (0.32–1.0 mg/kg), or flumazenil (1–3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse–related behaviors.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB₁)-selective, cannabinoid receptor type 2 (CB₂)-selective, and CB₁/CB₂ mixed agonists in the cisplatin CIPN model, using both male and female mice. CB₁ selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB₂ agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB₁ selective agonism decreasing plasma estradiol while CB₂ selective agonism increased plasma estradiol. Chronic administration of a mixed CB₁/CB₂ agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB₂ acting compound while selective CB₁ agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa. The two most abundant cannabinoids (⁹-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC.

Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRAB_eCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

Optimal patient management protocols for metastatic castration-resistant prostate cancer (mCRPC) are poorly defined and even further complexified with new therapy approvals, such as radiopharmaceuticals. The prostate-specific membrane antigen (PSMA)–targeted agent ¹⁷⁷Lu vipivotide tetraxetan ([¹⁷⁷Lu]Lu-PSMA-617), approved after the phase III VISION study, presents physicians with additional aspects of patient management, including specific adverse event (AE) monitoring and management, as well as radiation safety. Drawing on our experience as VISION study investigators, here we provide guidance on best practices for delivering PSMA-targeted radiopharmaceutical therapy (RPT) to patients with mCRPC. After a comprehensive review of published evidence and guidelines on RPT management in prostate cancer, we identified educational gaps in managing the radiation safety and AEs associated with [¹⁷⁷Lu]Lu-PSMA-617. Our results showed that providing sufficient education on AEs (e.g., fatigue and dry mouth) and radiation safety principles is key to effective delivery and management of patient expectations. Patient counseling by health care professionals, across disciplines, is a cornerstone of optimal patient management during PSMA-targeted RPT. Multidisciplinary collaboration is crucial, and physicians must adhere to radiation safety protocols and counsel patients on radiation safety considerations. Treatment with [¹⁷⁷Lu]Lu-PSMA-617 is generally well tolerated; however, additional interventions may be required, such as dosing modification, medications, or transfusions. Urinary incontinence can be challenging in the context of radiation safety. Multidisciplinary collaboration between medical oncologists and nuclear medicine teams ensures that patients are monitored and managed safely and efficiently. In clinical practice, the benefit-to-risk ratio should always be evaluated on a case-by-case basis.

Watch President Donald Trump and the Greek prime minister’s joint news conference in the player above.

WASHINGTON — President Donald Trump says the U.S. stands with Greece as they recover from their economic crisis. He is speaking with Prime Minister Alexis Tsipras at the White House in a joint news conference.

The U.S. president says the two leaders have discussed defense, energy, commerce and trade.

Trump is praising Greece for its defense spending under NATO and is noting a potential sale to Greece to upgrade its F-16 aircraft, which he says would be worth up to $2.4 billion and generate thousands of U.S. jobs.

Tsipras says his country has made economic strides and is “leaving behind the economic model that led to the crisis.” He says Greece’s relationship with the U.S. is “more important than ever.”

The post WATCH: Trump and Greek prime minister hold joint news conference appeared first on PBS NewsHour.

Human rights campaigners are calling on SNP ministers to do all they can to “mitigate” Prevent, the UK Government's controversial anti-terror strategy.

Health Secretary Neil Gray will address concerns around his use of a ministerial car to attend football games at Hampden.

I didn't sleep last night for entirely self-inflicted reasons and my brain feels like that one accursed hoover bag you refuse to empty, because there is no way of doing so that won't turn the neighbourhood into Silent Hill. I need to avoid any complicated write-ups, or my brain will detonate similarly and paint north London grey.

Ah, a minigolf game! I think I can just about hack the concept of minigolf, on this most desperate of Mondays. It is golf but mini. Bonzai golf. Digestible! Intuitive! Why, I've managed to write 100 words without even looking at the Steam page. Let's do so now. Wait a minute, this isn't minigolf. It's Mini Mini Golf Golf. What is Mini Mini Golf Golf? "Destabilize the present and plunge into a neon psychohistory of a bizarre entity in distress," the Steam page explains. "This is not a game about minigolf." It is too late to flee.

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New research has revealed a growing mental phenomena sweeping the UK, which may only affect those with a certain income

Friday on the RealClearPolitics radio show -- weeknights at 6:00 p.m. on SiriusXM's POTUS Channel 124 and then on Apple, Spotify, and here on our website -- Tom Bevan, Andrew Walworth, and Carl Cannon look at the latest count to determine the final popular vote and House majority.

Robert F. Kennedy Jr. launched a "Nominees for the People" forum to crowdsource 4,000 positions in the Trump administration to Make America Healthy Again.

The Fox News Politics newsletter, with the latest updates on the Trump transition, exclusive interviews and more Fox News politics content.

Dispute risks damage to Canada's reputation as reliable trade partner, says Steven Mackinnon

First Mac mini redesign in almost 15 years highlights how good the insides are.

The State Department said Tuesday that the Biden-Harris administration would not cut off weapons supplies to Israel in reaction to what it said was a declining humanitarian situation in the Gaza Strip, due to Israeli mitigation efforts.

The post Biden-Harris Administration Decides Not to Cut Arms to Israel, After Threat appeared first on Breitbart.

President-elect Donald Trump has made many selections to lead his administration as his transition gets underway, ranging from chief of staff to head of the Environmental Protection Agency (EPA). At the same time, a number of crucial positions have yet to be filled just one week removed from the landslide election.

The post Donald Trump’s Administration Takes Shape After 15 Official or Expected Picks appeared first on Breitbart.