China's growing influence in the global carrageenan industry and implications for Indonesia.

China has reconfigured the global value chains of a wide range of commodities. This includes carrageenan, a polysaccharide extracted from specific types of red seaweeds used as a gelling and thickening agent in a wide range of applications. In the past 20 years, China has moved to centre stage in the global carrageenan processing sector, with wide-ranging implications for seaweed producing nations and farmers. This is especially the case for Indonesia, a pivotal carrageenan seaweeds producer that exports almost all seaweed to China, cemented by large Chinese investments in processing in Indonesia. Despite the importance, there is a dearth of studies on the Chinese domestic industry and associated trade and investment flows. This study fills the gap by triangulating a range of detailed industry, statistical and interview data, in multiple language sources. It finds that Chinese trade and investment linkages is of net benefit to Indonesia but that Indonesian government agencies at both central and local levels can begin to introduce terms in their favour.

ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma.

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.

Evidence from a Choice Experiment in Consumer Preference towards Infant Milk Formula (IMF) in the Context of Dairy Revitalization and COVID-19 Pandemic.

China is the largest global consumer of infant milk formula (IMF). Chinese consumer preferences towards IMF have evolved over time but have also been rocked in recent years by COVID-19 with major implications for the IMF industry, globally and within China. This study is the first to document parents' preferences toward IMF since the outbreak. We used novel methods to do so, through an online choice experiment of 804 participants that included risk perceptions and socio-demographic variables. Our study finds that Chinese parents continue to prioritize quality and safety attributes of IMF represented by functional ingredients, organic labelling and traceability information. Notably, it also finds greatly increased confidence in Chinese domestically produced IMF and an underlying preference away from expensive products. This implies that the era of 'go for foreign' and 'go for the most expensive' in IMF purchasing may be coming to an end. The shift in sentiment is driven by the longer-term revitalization of the Chinese dairy industry, accelerated by COVID-19. Understanding these trends will be of major benefit to both Chinese producers and non-Chinese exporters of IMF.

The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of N-Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human.

Conjugation of oligonucleotide therapeutics, including small interfering RNAs (siRNAs) or antisense oligonucleotides, to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI (givosiran) for the treatment of acute hepatic porphyria, OXLUMO (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio (inclisiran) for the treatment of hypercholesterolemia, the technology has been well validated clinically. Although much knowledge has been gained over decades of development, there is a paucity of published literature on the drug metabolism and pharmacokinetic properties of GalNAc-siRNA. With this in mind, the goals of this minireview are to provide an aggregate analysis of these nonclinical absorption, distribution, metabolism, and excretion (ADME) data to build confidence on the translation of these properties to human. Upon subcutaneous administration, GalNAc-conjugated siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic (PK) properties that reflect rapid elimination through asialoglycoprotein receptor-mediated uptake from circulation into hepatocytes. These studies confirm that liver PK, including half-life and, most importantly, siRNA levels in RNA-induced silencing complex in hepatocytes, are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the ADME properties of GalNAc-conjugated siRNAs. These studies demonstrate that the PK/PD and ADME properties of GalNAc-conjugated siRNAs are highly conserved across species, are largely predictable, and can be accurately scaled to human, allowing us to identify efficacious and safe clinical dosing regimens in the absence of human liver PK profiles. SIGNIFICANCE STATEMENT: Several nonclinical ADME studies have been conducted in order to provide a comprehensive overview of the disposition and elimination of GalNAc-conjugated siRNAs and the pharmacokinetic/pharmacodynamic translation between species. These studies demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species, building confidence in the ability to extrapolate to human.

Reversal of siRNA-mediated gene silencing in vivo.

We report rapid, potent reversal of GalNAc-siRNA-mediated RNA interference (RNAi) activity in vivo with short, synthetic, high-affinity oligonucleotides complementary to the siRNA guide strand. We found that 9-mers with five locked nucleic acids (LNAs) have the highest potency across several targets. Our modular, sequence-specific approach, named REVERSIR, may enhance the therapeutic profile of any long-acting GalNAc-siRNA (short interfering RNA) conjugate by enabling control of RNAi pharmacology.

Homology Modeling Inspired Synthesis of 5-HT2A Receptor Inhibitors: A Diazepine Analogue of the Atypical Antipsychotic JL13.

BACKGROUND: The benzoxazepine JL13 is an analogue of the clozapine family of antipsychotic agents which target the 5-HT2A receptor, and has showed promise as an atypical antipsychotic agent. Based on the dearth of clinically effective anti-psychotic agents available, we sought to design and chemically synthesize additional analogues. METHODS: Structure function analysis was conducted using state of art computational methods, which were designed to highlight new candidates for chemical synthesis. Efficient syntheses were then conducted and the products screened for affinity to the receptor. RESULTS: Among many new analogues prepared, an aza analogue demonstrated seventeen times greater affinity for the receptor than JL13. CONCLUSION: An efficient synthetic route to an aza-analogue of JL13 was developed and will allow rapid modifications of the core and synthesis of related libraries.

Impact of Oligonucleotide Structure, Chemistry, and Delivery Method on In Vitro Cytotoxicity.

Single-stranded (ss) 2'-fluoro (2'-F)-modified oligonucleotides (ONs) with a full phosphorothioate (PS) backbone have been reported to be cytotoxic and cause DNA double-strand breaks (DSBs) when transfected into HeLa cells. However, the molecular determinants of these effects have not been fully explored. In this study, we investigated the impact of ON structure, chemistry, delivery method, and cell type on in vitro cytotoxicity and DSBs. We found that ss PS-ONs were more cytotoxic than double-stranded (ds) PS-ONs, irrespective of the 2'-ribose chemistry, inclusive of the 2'-F modification. Cytotoxicity of ss ONs was most affected by the total PS content, with an additional contribution of 2'-F substitutions in HeLa, but not HepG2, cells. The relatively mild cytotoxicity of ds ONs was most impacted by long contiguous PS stretches combined with 2'-F substitutions. None of the tested ds 2'-F-modified PS-ONs caused DSBs, while the previously reported DSBs caused by ss 2'-F-modified PS-ONs were PS dependent. HeLa cells were more sensitive to ON-mediated toxicity when transfected with Lipofectamine 2000 versus Lipofectamine RNAiMax. Importantly, asialoglycoprotein receptor-mediated uptake of N-acetylgalactosamine-conjugated ss or ds PS-ONs, even those with long PS stretches and high 2'-F content, was neither cytotoxic nor caused DSBs at transfection-equivalent exposures. These results suggest that in vitro cytotoxicity and DSBs associated with ONs are delivery method dependent and primarily determined by single-stranded nature and PS content of ONs.