Alternative pathways for hydrogen sink originated from the ruminal fermentation of carbohydrates: Which microorganisms are involved in lowering methane emission?

Agriculture is responsible for a great share of the anthropogenic sources of greenhouse gases that, by warming the earth, threaten its biodiversity. Among greenhouse gas emissions, enteric CH4 from livestock is an important target to slow down climate changes. The CH4 is originated from rumen fermentation and its concentration is affected by several factors, including genetics and nutrition. Ruminants have an extraordinary symbiosis with microorganisms (bacteria, fungi, and protozoa) that ferment otherwise indigestible carbohydrates, from which they obtain energy to grow and continue actively producing, among other products, volatile fatty acids, CO2 and H2. Detrimental ruminal accumulation of H2 is avoided by methanogenesis carried out by Archaea methanogens. Importantly, methanogenesis is not the only H2 sink pathway. In fact, other bacteria can reduce substrates using metabolic hydrogen formed during carbohydrate fermentation, namely propionate production and reductive acetogenesis, thus lowering the CH4 produced. Although the complexity of rumen poses challenges to mitigate CH4 production, the emergence of sequencing techniques that allow the study of microbial communities, gene expression, and metabolome are largely contributing to unravel pathways and key players in the rumen. Indeed, it is now recognized that in vivo emissions of CH4 are correlated to microbial communities, and particularly with the abundance of methanogens, several bacterial groups, and their genes. The goal of CH4 mitigation is to work in favor of the natural processes, without compromising rumen function, animal health, and productivity. Notwithstanding, the major challenge continues to be the feasibility and affordability of the proposed solutions.

Conserved meiotic mechanisms in the cnidarian Clytia hemisphaerica revealed by Spo11 knockout

During meiosis, each duplicated chromosome pairs and recombines with its unique homolog to ensure the shuffling of genetic information across generations. Functional studies in classical model organisms have revealed a surprising diversity in the chronology and interdependency of the earliest meiotic steps such as chromosome movements, pairing, association via Synaptonemal Complex formation (synapsis), recombination and the formation of chiasmata. A key player is Spo11, an evolutionarily conserved topoisomerase-related transesterase that initiates meiotic recombination via the catalysis of programmed DNA double stranded breaks (DSBs). While DSBs are required for pairing and synapsis in budding yeast and mouse, alternative pathways are employed during female meiosis of the fruit fly and nematode Caenorhabditis elegans. Here, to provide a comparative perspective on meiotic regulation from a distinct animal clade, we chart gametogenesis in Clytia hemisphaerica jellyfish and examine the role of Spo11 using CRISPR-Cas9 mutants, generated clonally from F0 polyp colonies. Spo11 mutant females fail to assemble synaptonemal complexes and chiasmata, such that homologous chromosome pairs disperse during oocyte growth. Subsequent meiotic divisions are abnormal but produce viable progeny. Clytia thus shares an ancient eukaryotic dependence of synapsis and chromosome segregation on Spo11-generated DSBs. It provides a valuable additional experimental model for dissecting meiotic mechanisms during animal gametogenesis, and for building a comparative framework for distinguishing evolutionarily conserved versus flexible features of meiosis.

Modulation of Human Hydrogen Sulfide Metabolism by Micronutrients, Preliminary Data

Background: Hydrogen sulfide (H2S) is a pivotal gasotransmitter networking with nitric oxide (NO) and carbon monoxide (CO) to regulate basic homeostatic functions. It is released by the alternative pathways of transulfuration by the enzymes Cystathionine Beta Synthase (CBS) and Cystathionine Gamma Lyase (CSE), and by Cysteine AminoTransferase (CAT)/ 3-Mercaptopyruvate Sulfur Transferase (3MPST). A non-enzymatic, intravascular release is also in place. We retrospectively investigated the possibility to modulate the endogenous H2S release and signaling in humans by a dietary manipulation with supplemented micronutrients (L-cystine, Taurine and pyridoxal 5-phopsphate/P5P). Methods: Patients referring for antiaging purposes underwent a 10-day supplementation. Blood was collected at baseline and after treatment and the metabolome was investigated by mass spectrometry to monitor the changes in the metabolites reporting on H2S metabolism and related pathways. Results: Data were available from 6 middle aged subjects (2 women). Micronutrients increased 3-mercaptopyruvate ( P = .03), reporting on the activity of CAT that provides the substrate for H2S release within mitochondria by 3MPST, decreased lanthionine ( P = .024), reporting the release of H2S from CBS, and had no significant effect of H2S release from CSE. This is compatible with a homeostatic balancing. We also recorded a strong increase of reporters of H2S-induced pathways including 5-MethylTHF ( P = .001) and SAME ( P = .022), reporting on methylation capacity, and of BH4 ( P = .021) and BH2 ( P = .028) reporting on nitric oxide metabolism. These activations may be explained by the concomitant induction of non-enzymatic release of H2S. Conclusions: Although the current evidences are weak and will need to be confirmed, the effect of micronutrients was compatible with an increase of the H2S endogenous release and signaling within the control of homeostatic mechanisms, further endorsing the role of feeding in health and disease. These effects might result in a H2S boosting effect in case of defective activity of pathologic origin, which should be checked in duly designed clinical trials.

Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum.

Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer

Breast cancer is the most common cancer affecting women and is the second leading cause of cancer related death worldwide. Angiogenesis, the process of new blood vessel development from pre-existing vasculature, has been implicated in the growth, progression, and metastasis of cancer. Tumor angiogenesis has been explored as a key therapeutic target for decades, as the blockade of this process holds the potential to reduce the oxygen and nutrient supplies that are required for tumor growth. However, many existing anti-angiogenic approaches, such as those targeting Vascular Endothelial Growth Factor, Notch, and Angiopoietin signaling, have been associated with severe side-effects, limited survival advantage, and enhanced cancer regrowth rates. To address these setbacks, alternative pathways involved in the regulation of tumor angiogenesis are being explored, including those involving Bone Morphogenetic Protein-9 signaling, the Sonic Hedgehog pathway, Cyclooxygenase-2, p38-mitogen-activated protein kinase, and Chemokine Ligand 18. This review article will introduce the concept of tumor angiogenesis in the context of breast cancer, followed by an overview of current anti-angiogenic therapies, associated resistance mechanisms and novel therapeutic targets.

Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

Double membrane vesicles (DMVs) serve as replication organelles of plus-strand RNA viruses such as hepatitis C virus (HCV) and SARS-CoV-2. Viral DMVs are morphologically analogous to DMVs formed during autophagy, but lipids driving their biogenesis are largely unknown. Here we show that production of the lipid phosphatidic acid (PA) by acylglycerolphosphate acyltransferase (AGPAT) 1 and 2 in the ER is important for DMV biogenesis in viral replication and autophagy. Using DMVs in HCV-replicating cells as model, we found that AGPATs are recruited to and critically contribute to HCV and SARS-CoV-2 replication and proper DMV formation. An intracellular PA sensor accumulated at viral DMV formation sites, consistent with elevated levels of PA in fractions of purified DMVs analyzed by lipidomics. Apart from AGPATs, PA is generated by alternative pathways and their pharmacological inhibition also impaired HCV and SARS-CoV-2 replication as well as formation of autophagosome-like DMVs. These data identify PA as host cell lipid involved in proper replication organelle formation by HCV and SARS-CoV-2, two phylogenetically disparate viruses causing very different diseases, i.e. chronic liver disease and COVID-19, respectively. Host-targeting therapy aiming at PA synthesis pathways might be suitable to attenuate replication of these viruses.

Alternative Pathways: The Use Of Field-Specific Micro-Credentials in Aging Services

The rise of formal academic programs in gerontology at colleges and universities has been well documented over the last fifty years. Organizations such as AGHE and AGEC have been established to provide guidance, foster consistency, and advance formal gerontology education programs. Broadly, the purpose of these programs has been to develop a pipeline of trained gerontologists for the aging services workforce. What has been less documented is the rise of alternative pathways to gerontology and gerontological competence, including micro-credentialing. Micro-credentials are intended to provide quick-to-complete competency-based education around specific topics to demonstrate relevant skills to employers. To date, little is known about the prevalence of micro-credentialing in gerontology. Still, it may be that micro-credentials are sought in place of formal academic preparation due to their reduced cost, ease of completion, recognizability, and opportunity to quickly train employees in specific skills. To address this gap, we conducted a review of existing gerontological micro-credentialing opportunities. We identified a total of 51 micro-credentials with an explicit aging-focus and searched for associated competencies for these micro-credentials. In this poster, we describe findings on the emphases of micro-credentials, including dementia and care coordination, and review the programs' scope and nature of competencies. We argue that micro-credentialing can offer value for employees unable or unwilling to pursue formal academic training but should be differentiated from such training. Moving forward, it is critical to ensure alignment between gerontological micro-credentials and established gerontological competencies and standards and to differentiate micro-credentials from formal academic programs.

And they slept happily ever after: Online interpretive repertoires on the use of benzodiazepines and z-drugs

Drawing on a critical social-psychological framework for discourse analysis, data from a popular forum for people over 50 were analysed to study how the habitual use of benzodiazepines and Z-drugs (BZD/Z) is discursively negotiated by Flemish older adults. We present five different repertoires (risk and addiction; alternative pathways; suffering; rationalisation; cessation) that illustrate how a pharmaceutical imaginary of these medications is constructed online and how posters act as reflexive users taking on a health role. Most repertoires emerge from a tacit norm on the undesirability of medication use for sleeping problems. In the alternative pathways and cessation repertoires this norm is implicitly accepted by focussing on how to either prevent or overcome chronic use with various alternative solutions or through tapering off, while the risk and addiction repertoire is used to more openly defend and discursively magnify the idea that medication has to be avoided at all cost. We discuss how this reflects a prevailing imperative of health and ethos of healthicisation of sleep. The rationalisation and suffering repertoires on the other hand challenge this norm by defending medication use. We further explore how these repertoires are used to self-position as either ‘noble non-user’, ‘deserving and/or compliant patient’ or ‘rational user’, reflecting previously found moral positions in offline settings. Our data add another position that has thus far not been discussed extensively with regard to prescription medication use, namely that of a ‘recovered user’. As such, this study shows how this particular online community is a site for contestation of health promotion and medical/pharmaceuticalised discourses on sleep by users and non-users alike and offers a unique insight into how people in the age group that is known to use most BZD/Z discursively negotiate the use of these medications in pseudonymised online interactions.

The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vector

Adiponectin-mediated pathways contribute to mammalian homeostasis; however, little is known about adiponectin and adiponectin receptor signaling in arthropods. In this study, we demonstrate that Ixodes scapularis ticks have an adiponectin receptor-like protein (ISARL) but lack adiponectin - suggesting activation by alternative pathways. ISARL expression is significantly upregulated in the tick gut after Borrelia burgdorferi infection suggesting that ISARL-signaling may be co-opted by the Lyme disease agent. Consistent with this, RNA interference (RNAi)-mediated silencing of ISARL significantly reduced the B. burgdorferi burden in the tick. RNA-seq-based transcriptomics and RNAi assays demonstrate that ISARL-mediated phospholipid metabolism by phosphatidylserine synthase I is associated with B. burgdorferi survival. Furthermore, the tick complement C1q-like protein 3 interacts with ISARL, and B. burgdorferi facilitates this process. This study identifies a new tick metabolic pathway that is connected to the life cycle of the Lyme disease spirochete.