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The sustainable production of chemicals from non-petrochemical sources is one of the greatest challenges of our time. CO2 release from industrial activity is not environmentally friendly yet provides an inexpensive feedstock for chemical production. One means of addressing this problem is using acetogenic bacteria to produce chemicals from CO2, waste streams, or renewable resources. Acetogens are attractive hosts for chemical production for many reasons: they can utilize a variety of feedstocks that are renewable or currently waste streams, can capture waste carbon sources and covert them to products, and can produce a variety of chemicals with greater carbon efficiency over traditional fermentation technologies. Here we investigated the metabolism of Clostridium ljungdahlii, a model acetogen, to probe carbon and electron partitioning and understand what mechanisms drive product formation in this organism. We utilized CRISPR/Cas9 and an inducible riboswitch to target enzymes involved in fermentation product formation. We focused on the genes encoding phosphotransacetylase (pta), aldehyde ferredoxin oxidoreductases (aor1 and aor2), and bifunctional alcohol/aldehyde dehydrogenases (adhE1 and adhE2) and performed growth studies under a variety of conditions to probe the role of those enzymes in the metabolism. Finally, we demonstrated a switch from acetogenic to ethanologenic metabolism by these manipulations, providing an engineered bacterium with greater application potential in biorefinery industry.

Abstract Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson’s disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans. Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.

PURPOSESurgery provides vital services to diagnose, treat, and palliate patients suffering from malignancies. However, despite its importance, there is little information on the delivery of surgical oncology services in Tanzania.METHODSOperative logbooks were reviewed at all national referral hospitals that offer surgery, all zonal referral hospitals in Mainland Tanganyika and Zanzibar, and a convenience sampling of regional referral hospitals in 2022. Cancer cases were identified by postoperative diagnosis and deidentified data were abstracted for each cancer surgery. The proportion of the procedures conducted for patients with cancer and the total number of cancer surgeries done within the public sector were calculated and compared with a previously published estimate of the surgical oncology need for the country.RESULTSIn total, 69,195 operations were reviewed at 10 hospitals, including two national referral hospitals, five zonal referral hospitals, and three regional referral hospitals. Of the cases reviewed, 4,248 (6.1%) were for the treatment of cancer. We estimate that 4,938 cancer surgeries occurred in the public sector in Tanzania accounting for operations conducted at hospitals not included in our study. Prostate, breast, head and neck, esophageal, and bladder cancers were the five most common diagnoses. Although 387 (83%) of all breast cancer procedures were done with curative intent, 506 (87%) of patients with prostate and 273 (81%) of patients with esophageal cancer underwent palliative surgery.CONCLUSIONIn this comprehensive assessment of surgical oncology service delivery in Tanzania, we identified 4,248 cancer surgeries and estimate that 4,938 likely occurred in 2022. This represents only 25% of the estimated 19,726 cancer surgeries that are annually needed in Tanzania. These results highlight the need to identify strategies for increasing surgical oncology capacity in the country.

Betel leaves are widely used as herbal medicine in Asia due to their antimicrobial properties. These properties have been attributed to the phenolic compound eugenol and its derivative, hydroxychavicol. Hydroxychavicol has also been shown to inhibit cancer cell proliferation. The main objective of this study was to investigate which structural components of hydroxychavicol are responsible for the antiproliferative property of this compound. Jurkat-E6 cells (JE6) were treated with increasing concentrations (5, 15, and 45 µM) of hydroxychavicol and structural variants of it for 48 h. The results of this study demonstrate that the catechol structure in hydroxychavicol is the structural component that exhibits the highest antiproliferative effect. More specifically, the data show that the six-carbon ring must be aromatic with the two hydroxyl groups attached in an ortho position. Furthermore, this study establishes that the oxygen in the hydroxyl groups has a vital role in the antiproliferative properties of catechol and hydroxychavicol.

Abstract Background Despite the clinically apparent congenital urethra anomalies being one of the common causes of admission in pediatric urology, yet little is known about its associated factors, especially in third world countries. Understanding associated factors of clinically apparent congenital urethra anomalies is important in prevention and in genetic counseling that may help in reducing the incidence of their occurrence. Methods Hospital-based cross-sectional prospective study conducted among pediatric patients admitted to pediatric surgery unit at Muhimbili National Hospital from July 2021 to March 2022. Socio-demographic and clinical characteristics were collected from participant’s parent or guardian. Patients were examined thoroughly for clinically apparent congenital urethra anomalies and associated genital-urinary tract anomalies. Analysis was done using SPPS version 23 with descriptive statistics for categorical variables and univariate and multivariate logistic regression for association between presence of clinically apparent urethra anomaly and associated factors at 95% CI. A p-value of

We consider a system made up of a uniformly charged disk and a uniformly charged ring that are coplanar with each other. The disk and ring have arbitrary radii and contain arbitrary amounts of net charge that is spread uniformly over area and length, respectively. This study is seen as the first necessary step towards a classical model treatment of a two-dimensional system of electrons in a weak perpendicular magnetic field. In this scenario, the uniformly charged disk represents the neutralizing background in a jellium approximation while a uniformly charged ring is viewed as a classical approximation to the cyclotron motion of the electron in presence of a uniform perpendicular magnetic field. In this work, we obtain an exact integral expression for the interaction potential energy of the system as a function of the separation distance between the centers of the two bodies and discuss various emerging features of this model.

Objective: Mitochondrial “retrograde” signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated. Methods: We performed transcriptomics, quantitative proteomics and lifespan assays to identify pathways that are mechanistically linked to mitochondrial network expansion and homeostasis in Caenorhabditis elegans lacking the mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To support our findings, we carried out biochemical and image analyses in mammalian cells and mouse-derived tissues. Results: We report that micu-1(null) mutations impair the OXPHOS system and promote C. elegans longevity through a transcriptional program that is independent of the mitochondrial calcium uniporter MCU-1/MCU and the essential MCU regulator EMRE-1/EMRE. We identify sphingosine phosphate lyase SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit VPS-39/VPS39 as critical lifespan modulators of micu-1(null) mutant animals. Cross-species investigation indicates that SGPL1 upregulation stimulates VPS39 recruitment to the mitochondria, thereby enhancing mitochondria-lysosome contacts. Consistently, VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1 deficient cells. In mouse-derived muscles, we show that VPS39 recruitment to the mitochondria may represent a common signature associated with altered OXPHOS system. Conclusions: Our findings reveal a previously unrecognized SGPL1/VPS39 axis that stimulates intracellular organelle interactions and sustains autophagy and mitochondrial homeostasis in OXPHOS deficient cells.

Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.

Summary: Mitochondria sustain the energy demand of the cell. The composition and functional state of the mitochondrial oxidative phosphorylation system are informative indicators of organelle bioenergetic capacity. Here, we describe a highly sensitive and reproducible method for a single-cell quantification of mitochondrial CI- and CIV-containing respiratory supercomplexes (CI∗CIV-SCs) as an alternative means of assessing mitochondrial respiratory chain integrity. We apply a proximity ligation assay (PLA) and stain CI∗CIV-SCs in fixed human and mouse brains, tumorigenic cells, induced pluripotent stem cells (iPSCs) and iPSC-derived neural precursor cells (NPCs), and neurons. Spatial visualization of CI∗CIV-SCs enables the detection of mitochondrial lesions in various experimental models, including complex tissues undergoing degenerative processes. We report that comparative assessments of CI∗CIV-SCs facilitate the quantitative profiling of even subtle mitochondrial variations by overcoming the confounding effects that mixed cell populations have on other measurements. Together, our PLA-based analysis of CI∗CIV-SCs is a sensitive and complementary technique for detecting cell-type-specific mitochondrial perturbations in fixed materials. Motivation: The detection of mitochondrial lesions in patient-derived tissues represents a powerful diagnostic tool. However, in complex organs, such as the brain, neurodegenerative processes often alter the cell composition of the tissue, with extensive microgliosis influencing population-based analyses of mitochondrial bioenergetics. To detect cell-type-specific mitochondrial lesions in tissues, we developed a PLA-based method in which complex I, complex IV-containing mitochondrial supercomplexes (CI∗CIV-SCs) can be visualized as dot-like structures. This assay may be an alternative and complementary approach for the detection of mitochondrial perturbation in fixed materials.

NSAID-induced analgesia is typically induced by inhibition of COX enzymes. Here the authors show instead that fenamate NSAIDs inhibit the Nlrp3 inflammasome via an effect on volume-regulated anion channel function and also repurpose these drugs for therapeutic effect in rodent models of Alzheimer disease.

Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators.