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Anaerobic digestion is a technology that has been used by humans for centuries. Anaerobic digestion is considered to be a useful tool that can generate renewable energy and significant research interest has arisen recently. The underlying theory of anaerobic digestion has been established for decades; however, a great deal of current research is directed towards the optimization of anaerobic digestion under diverse digestion conditions. This review provides a summary of the processes underlying anaerobic digestion, commonly-utilized measurements of anaerobic sludge, operating parameters of anaerobic digesters, and methods of acceleration and optimization used to improve process efficiency. Recent developments in addition to older research are considered to provide a general but comprehensive summary of accumulated knowledge in the theory of anaerobic digestion, as well as considerations in the efficient operation of digesters. We have determined that the numerous factors pertinent to the design and operation of batch-based anaerobic digesters must each be considered to ensure the maximum efficiency and cost-effectiveness of a digester provided its respective operating conditions.

Cell therapies have emerged as a promising therapeutic modality with the potential to treat and even cure a diverse array of diseases. Cell therapies offer unique clinical and therapeutic advantages over conventional small molecules and the growing number of biologics. Particularly, living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot; cell therapies have expanded the spectrum of available therapeutic options to include key cellular functions and processes. As such, cell therapies are currently one of the most investigated therapeutic modalities in both preclinical and clinical settings, with many products having been approved and many more under active clinical investigation. Here, we highlight the diversity and key advantages of cell therapies and discuss their current clinical advances. In particular, we review 28 globally approved cell therapy products and their clinical use. We also analyze >1700 current active clinical trials of cell therapies, with an emphasis on discussing their therapeutic applications. Finally, we critically discuss the major biological, manufacturing, and regulatory challenges associated with the clinical translation of cell therapies.

As an intracellular pathogen, the reproduction of the hepatitis B virus (HBV) depends on the occupancy of host metabolism machinery. Here we test a hypothesis if HBV may govern intracellular biosynthesis to achieve a productive reproduction. To test this hypothesis, we set up an affinity purification screen for host factors that interact with large viral surface antigens (LHBS). This identified pyruvate kinase isoform M2 (PKM2), a key regulator of glucose metabolism, as a binding partner of viral surface antigens. We showed that the expression of viral LHBS affected oligomerization of PKM2 in hepatocytes, thereby increasing glucose consumption and lactate production, a phenomenon known as aerobic glycolysis. Reduction of PKM2 activity was also validated in several different models, including HBV-infected HepG2-NTCP-C4 cells, adenovirus mediated HBV gene transduction and transfection with a plasmid containing complete HBV genome on HuH-7 cells. We found the recovery of PKM2 activity in hepatocytes by chemical activators, TEPP-46 or DASA-58, reduced expressions of viral surface and core antigens. In addition, reduction of glycolysis by culturing in low-glucose condition or treatment with 2-deoxyglucose also decreased expressions of viral surface antigen, without affecting general host proteins. Finally, TEPP-46 largely suppressed proliferation of LHBS-positive cells on 3-dimensional agarose plates, but showed no effect on the traditional 2-dimensional cell culture. Taken together, these results indicate that HBV-induced metabolic switch may support its own translation in hepatocytes. In addition, aerobic glycolysis is likely essential for LHBS-mediated oncogenesis. Accordingly, restriction of glucose metabolism may be considered as a novel strategy to restrain viral protein synthesis and subsequent oncogenesis during chronic HBV infection.

Purpose: Understanding speech in complex realistic acoustic environments requires effort. In everyday listening situations, speech quality is often degraded due to adverse acoustics, such as excessive background noise level (BNL) and reverberation time (RT), or talker characteristics such as foreign accent (Mattys, Davis, Bradlow, & Scott, 2012). In addition to factors affecting the quality of the input acoustic signals, listeners' individual characteristics such as language abilities can also make it more difficult and effortful to understand speech. Based on the Framework for Understanding Effortful Listening (Pichora-Fuller et al., 2016), factors such as adverse acoustics, talker accent, and listener language abilities can all contribute to increasing listening effort. In this study, using both a dual-task paradigm and a self-report questionnaire, we seek to understand listening effort in a wide range of realistic classroom acoustic conditions as well as varying talker accent and listener English proficiency. Method: One hundred fifteen native and nonnative adult listeners with normal hearing were tested in a dual task of speech comprehension and adaptive pursuit rotor (APR) under 15 acoustic conditions from combinations of BNLs and RTs. Listeners provided responses on the NASA Task Load Index (TLX) questionnaire immediately after completing the dual task under each acoustic condition. The NASA TLX surveyed 6 dimensions of perceived listening effort: mental demand, physical demand, temporal demand, effort, frustration, and perceived performance. Fifty-six listeners were tested with speech produced by native American English talkers; the other 59 listeners, with speech from native Mandarin Chinese talkers. Based on their 1st language learned during childhood, 3 groups of listeners were recruited: listeners who were native English speakers, native Mandarin Chinese speakers, and native speakers of other languages (e.g., Hindu, Korean, and Portuguese). Results: Listening effort was measured objectively through the APR task performance and subjectively using the NASA TLX questionnaire. Performance on the APR task did not vary with changing acoustic conditions, but it did suggest increased listening effort for native listeners of other languages compared to the 2 other listener groups. From the NASA TLX, listeners reported feeling more frustrated and less successful in understanding Chinese-accented speech. Nonnative listeners reported more listening effort (i.e., physical demand, temporal demand, and effort) than native listeners in speech comprehension under adverse acoustics. When listeners' English proficiency was controlled, higher BNL was strongly related to a decrease in perceived performance, whereas such relationship with RT was much weaker. Nonnative listeners who shared the foreign talkers' accent reported no change in listening effort, whereas other listeners reported more difficulty in understanding the accented speech. Conclusions: Adverse acoustics required more effortful listening as measured subjectively with a self-report NASA TLX. This subjective scale was more sensitive than a dual task that involved speech comprehension, which was beyond sentence recall. It was better at capturing the negative impacts on listening effort from acoustic factors (i.e., both BNL and RT), talker accent, and listener language abilities.

RNA sequencing (RNA-seq) is the leading technology for genome-wide transcript quantification. However, publicly available RNA-seq data is currently provided mostly in raw form, a significant barrier for global and integrative retrospective analyses. ARCHS4 is a web resource that makes the majority of published RNA-seq data from human and mouse available at the gene and transcript levels. For developing ARCHS4, available FASTQ files from RNA-seq experiments from the Gene Expression Omnibus (GEO) were aligned using a cloud-based infrastructure. In total 187,946 samples are accessible through ARCHS4 with 103,083 mouse and 84,863 human. Additionally, the ARCHS4 web interface provides intuitive exploration of the processed data through querying tools, interactive visualization, and gene pages that provide average expression across cell lines and tissues, top co-expressed genes for each gene, and predicted biological functions and protein–protein interactions for each gene based on prior knowledge combined with co-expression. Publicly available RNA-seq data is provided mostly in raw form, resulting in a barrier for integrative analyses. Here, Lachmann et al. develop a high-throughput processing infrastructure and search database (ARCHS4) that provides processed RNA-seq data for 187,946 publicly available mouse and human samples to support exploration and reuse.

Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H 2 S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H 2 S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism. Low level of pyruvate kinase M2 (PKM2) activity in cancer cells is essential for the dependence on aerobic glycolysis. Here the authors show that PKM2 sulfhydration by hydrogen sulfide destabilizes the PKM2 tetramer, leading to reduced PKM2 enzyme activity and enhanced proliferation of breast cancer cells.

Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant myeloid function is often observed in MS plaques in the central nervous system (CNS), the role of myeloid cells in therapeutic intervention is currently overlooked. Here, we developed a myeloid cell-based strategy to reduce the disease burden in experimental autoimmune encephalomyelitis (EAE), a mouse model of progressive MS. We developed monocyte-adhered microparticles (“backpacks”) for activating myeloid cell phenotype to an anti-inflammatory state through localized interleukin-4 and dexamethasone signals. We demonstrate that backpack-laden monocytes infiltrated into the inflamed CNS and modulated both the local and systemic immune responses. Within the CNS, backpack-carrying monocytes regulated both the infiltrating and tissue-resident myeloid cell compartments in the spinal cord for functions related to antigen presentation and reactive species production. Treatment with backpack-monocytes also decreased the level of systemic pro-inflammatory cytokines. Additionally, backpack-laden monocytes induced modulatory effects on TH1 and TH17 populations in the spinal cord and blood, demonstrating cross talk between the myeloid and lymphoid arms of disease. Backpack-carrying monocytes conferred therapeutic benefit in EAE mice, as quantified by improved motor function. The use of backpack-laden monocytes offers an antigen-free, biomaterial-based approach to precisely tune cell phenotype in vivo, demonstrating the utility of myeloid cells as a therapeutic modality and target.

Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition. TNBCs subtypes include two basal-like (BL1, BL2), a mesenchymal (M) and a luminal androgen receptor (LAR) subtype. Through a comprehensive analysis of mutation, copy number, transcriptomic, epigenetic, proteomic, and phospho-proteomic patterns we describe the genomic landscape of TNBC subtypes. Mesenchymal subtype tumors display high mutation loads, genomic instability, absence of immune cells, low PD-L1 expression, decreased global DNA methylation, and transcriptional repression of antigen presentation genes. We demonstrate that major histocompatibility complex I (MHC-I) is transcriptionally suppressed by H3K27me3 modifications by the polycomb repressor complex 2 (PRC2). Pharmacological inhibition of PRC2 subunits EZH2 or EED restores MHC-I expression and enhances chemotherapy efficacy in murine tumor models, providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC. Triple negative breast cancer can be divided into additional subtypes. Here, using omics analyses, the authors show that in the mesenchymal subtype expression of MHC-1 is repressed and that this can be restored by using drugs that target subunits of the epigenetic modifier PRC2.

Cell therapies, such as immune cell and stem cell therapies, are being preclinically and clinically explored for the treatment of various diseases, but are often limited by low efficacy and safety concerns. Drug delivery systems at the nanoscale, microscale and macroscale can be designed to improve cell therapies by optimizing pharmacokinetics, cell function and cell viability, and by preventing cell exhaustion and immunogenicity. In this Review, we discuss the engineering of drug delivery systems at various scales to improve the biological functions of therapeutic cells, modulate tissue environments to promote the survival and efficacy of therapeutic cells, enable targeted delivery of therapeutic agents by transferred cells and provide protective barriers for cells in vivo. We further outline crucial milestones for the clinical translation of cell therapies integrated with drug delivery systems and highlight manufacturing challenges.Drug delivery systems can be integrated with cell therapies to improve the efficacy and safety of therapeutic cells. This Review discusses the design of nanoscale, microscale and macroscale drug delivery systems for precise cell modulation, targeted cell and cargo delivery and cell protection.

The annual cycle of extra-tropical surface air temperature is an important component of the Earth’s climate system. Over the past decades, a reduced amplitude of this mode has been observed in some regions. Although attributed to anthropogenic forcing, it remains unclear when dampening of the annual cycle started. Here we use a residual series of tree-ring width and maximum latewood density from the Tibetan Plateau >4,000 m asl to reconstruct changes in temperature seasonality over the past three centuries. The new proxy evidence suggests that the onset of a decrease in summer-to-winter temperature difference over the Tibetan Plateau occurred in the 1870s. Our results imply that the influence of anthropogenic forcing on temperature seasonality might have started in the late nineteenth century, and that future human influence may further contribute to a weakening of the annual temperature cycle, with subsequent effects on ecosystem functioning and productivity. Weakening of the Tibetan Plateau’s annual temperature cycle has been observed in recent decades, yet the long-term context remains unknown. Here, the authors reconstruct a 300-year temperature record from tree-ring width and maximum latewood density, which indicates the onset of weakening as early as the 1870s.