Miracle-dz/UniFAR-FTUs huggingface dataset:
Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity

Radiation and immunotherapy reduce tumor-induced erythroid progenitor cells, revealing possible targets for potentiating cancer therapies. “Ter”-ning a corner on cancer therapy Tumor cells exploit numerous signaling pathways to promote malignant progression. One such pathway is mediated by the neurotrophic peptide ARTN. ARTN is secreted by a population of erythroid progenitor cells called Ter cells and is thought to mediate both metastasis and survival. In this study, Hou et al. found that both radiotherapy and immunotherapy are able to deplete Ter cells, subsequently reducing ARTN production and tumor progression. Ter cell depletion was dependent on an intact adaptive immune response and mediated by interferon γ. Combinations of Ter cell depletion, blockade of ARTN signaling, radiotherapy, and immunotherapy led to enhanced control of tumor burden in mice. Thus, targeting Ter cells through combination therapy is an attractive option for cancer treatment. Tumor-induced CD45−Ter119+CD71+ erythroid progenitor cells, termed “Ter cells,” promote tumor progression by secreting artemin (ARTN), a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrate that both local tumor ionizing radiation (IR) and anti–programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter cell abundance in the mouse spleen and ARTN secretion outside the irradiation field in an interferon- and CD8+ T cell–dependent manner. Recombinant erythropoietin promoted resistance to radiotherapy or anti–PD-L1 therapies by restoring Ter cell numbers and serum ARTN concentration. Blockade of ARTN or potential ARTN signaling partners, or depletion of Ter cells augmented the antitumor effects of both IR and anti–PD-L1 therapies in mice. Analysis of samples from patients who received radioimmunotherapy demonstrated that IR-mediated reduction of Ter cells, ARTN, and GFRα3, an ARTN signaling partner, were each associated with tumor regression. Patients with melanoma who received immunotherapy exhibited favorable outcomes associated with decreased expression of GFRα3. These findings demonstrate an out-of-field, or “abscopal,” effect mediated by adaptive immunity, which is induced during local tumor irradiation. This effect, in turn, governs the therapeutic effects of radiation and immunotherapy. Therefore, our results identify multiple targets to potentially improve outcomes after radiotherapy and immunotherapy.
Light Capture, Skeletal Morphology, and the Biomass of Corals’ Boring Endoliths

Microbial communities living inside the skeletons of living corals play a variety of important roles within the coral meta-organism, both symbiotic and parasitic. Properly contextualizing the contribution of these enigmatic microbes to the life history of coral reefs requires knowledge of how these endolithic biofilms vary between coral species. ABSTRACT There is a growing interest in the endolithic microbial biofilms inhabiting skeletons of living corals because of their contribution to coral reef bioerosion and the reputed benefits they provide to live coral hosts. Here, we sought to identify possible correlations between coral interspecific patterns in skeletal morphology and variability in the biomass of, and chlorophyll concentrations within, the endolithic biofilm. We measured five morphological characteristics of five coral species and the biomasses/chlorophyll concentrations of their endolithic microbiome, and we compare interspecific patterns in these variables. We propose that the specific density of a coral’s skeleton and its capacity for capturing and scattering incident light are the main correlates of endolithic microbial biomass. Our data suggest that the correlation between light capture and endolithic biomass is likely influenced by how the green microalgae (obligatory microborers) respond to skeletal variability. These results demonstrate that coral species differ significantly in their endolithic microbial biomass and that their skeletal structure could be used to predict these interspecific differences. Further exploring how and why the endolithic microbiome varies between coral species is vital in defining the role of these microbes on coral reefs, both now and in the future. IMPORTANCE Microbial communities living inside the skeletons of living corals play a variety of important roles within the coral meta-organism, both symbiotic and parasitic. Properly contextualizing the contribution of these enigmatic microbes to the life history of coral reefs requires knowledge of how these endolithic biofilms vary between coral species. To this effect, we measured differences in the morphology of five coral species and correlate these with variability in the biomass of the skeletal biofilms. We found that the density of the skeleton and its capacity to trap incoming light, as opposed to scattering it back into the surrounding water, both significantly correlated with skeletal microbial biomass. These patterns are likely driven by how dominant green microalgae in the endolithic niche, such as Ostreobium spp. , are responding to the skeletal morphology. This study highlights that the structure of a coral’s skeleton could be used to predict the biomass of its resident endolithic biofilm.
Mechanism and reversal of drug-induced nephrotoxicity on a chip

Sensor-embedded spheroids-on-a-chip reveal the mechanisms of cisplatin- and cyclosporine-induced nephrotoxicity and identify a potential therapeutic. Chipping away at nephrotoxicity Tissue-on-a-chip technology can help elucidate mechanisms of drug-induced toxicity. Here, Cohen et al. used vascularized human kidney spheroids-on-a-chip and embedded sensors to monitor cellular metabolism in response to drug treatments. They found that proximal tubule polarity was disrupted and toxicity resulted from glucose accumulation upon exposure to cyclosporine and cisplatin, which could be prevented by inhibiting glucose reabsorption. Glomerular filtration rates were higher and markers of kidney damage were lower in patients treated with cyclosporine or cisplatin in combination with a sodium-glucose cotransporter-2 inhibitor. This study demonstrates the utility of kidney spheroid-on-a-chip technology to study mechanisms of drug-induced nephrotoxicity. The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (P < 0.001) improvement of kidney function, as well as reduction in creatinine and uric acid, markers of kidney damage. These results demonstrate the potential of sensor-integrated kidney-on-chip platforms to elucidate mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures.
Avenues of reef-building coral acclimatization in response to rapid environmental change

ABSTRACT The swiftly changing climate presents a challenge to organismal fitness by creating a mismatch between the current environment and phenotypes adapted to historic conditions. Acclimatory mechanisms may be especially crucial for sessile benthic marine taxa, such as reef-building corals, where climate change factors including ocean acidification and increasing temperature elicit strong negative physiological responses such as bleaching, disease and mortality. Here, within the context of multiple stressors threatening marine organisms, I describe the wealth of metaorganism response mechanisms to rapid ocean change and the ontogenetic shifts in organism interactions with the environment that can generate plasticity. I then highlight the need to consider the interactions of rapid and evolutionary responses in an adaptive (epi)genetic continuum. Building on the definitions of these mechanisms and continuum, I also present how the interplay of the microbiome, epigenetics and parental effects creates additional avenues for rapid acclimatization. To consider under what conditions epigenetic inheritance has a more substantial role, I propose investigation into the offset of timing of gametogenesis leading to different environmental integration times between eggs and sperm and the consequences of this for gamete epigenetic compatibility. Collectively, non-genetic, yet heritable phenotypic plasticity will have significant ecological and evolutionary implications for sessile marine organism persistence under rapid climate change. As such, reef-building corals present ideal and time-sensitive models for further development of our understanding of adaptive feedback loops in a multi-player (epi)genetic continuum. Summary: Reef-building corals are under threat from anthropogenic impacts. The partners of the coral holobiont and coral developmental process provide symbiotic, epigenetic and genetic mechanisms for acclimatization and adaptation to climate change.
Outer Membrane Structural Defects in Salmonella enterica Serovar Typhimurium Affect Neutrophil Chemokinesis but Not Chemotaxis

Neutrophils are the first responders to invading pathogens; thus, understanding their migratory response to live pathogens is crucial. We developed a microfluidic assay that separates bacteria from phagocytic neutrophils while maintaining chemical communication between the two populations. ABSTRACT Neutrophils, the first line of defense against pathogens, are critical in the host response to acute and chronic infections. In Gram-negative pathogens, the bacterial outer membrane (OM) is a key mediator of pathogen detection; nonetheless, the effects of variations in its molecular structure on the neutrophil migratory response to bacteria remain largely unknown. Here, we developed a quantitative microfluidic assay that precludes physical contact between bacteria and neutrophils while maintaining chemical communication, thus allowing investigation of both transient and steady-state responses of neutrophils to a library of Salmonella enterica serovar Typhimurium OM-related mutants at single-cell resolution. Using single-cell quantitative metrics, we found that transient neutrophil chemokinesis is highly gradated based upon OM structure, while transient and steady-state chemotaxis responses differ little between mutants. Based on our finding of a lack of correlation between chemokinesis and chemotaxis, we define “stimulation score” as a metric that comprehensively describes the neutrophil response to pathogens. Complemented with a killing assay, our results provide insight into how OM modifications affect neutrophil recruitment and pathogen survival. Altogether, our platform enables the discovery of transient and steady-state migratory responses and provides a new path for quantitative interrogation of cell decision-making processes in a variety of host-pathogen interactions. IMPORTANCE Our findings provide insights into the previously unexplored effects of Salmonella envelope defects on fundamental innate immune cell behavior, which advance the knowledge in pathogen-host cell biology and potentially inspire the rational design of attenuated strains for vaccines or immunotherapeutic strains for cancer therapy. Furthermore, the microfluidic assay platform and analytical tools reported herein enable high-throughput, sensitive, and quantitative screening of microbial strains' immunogenicity in vitro. This approach could be particularly beneficial for rapid in vitro screening of engineered microbial strains (e.g., vaccine candidates) as the quantitative ranking of the overall strength of the neutrophil response, reported by “stimulation score,” agrees with in vivo cytokine response trends reported in the literature.
A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis

A mutation in CD100, identified in a family with inherited primary sclerosing cholangitis, leads to dysfunctional T cells and cholangitis development. CD100 mutation primes PSC Primary sclerosing cholangitis (PSC) is an inflammatory liver disease without effective treatments. Although genetic factors are thought to predispose to PSC, no causative mutation has yet been identified. Jiang et al. performed whole-exome sequencing on a family with autosomal dominant inheritance of PSC and identified a germline mutation in SEMA4D, encoding CD100. The mutation resulted in T cell functional defects, including impaired interferon-γ production. Mutation knock-in mice were more prone to develop severe cholangitis after toxin exposure, and adoptive transfer of wild-type T cells into knock-in mice resulted in less severe disease. This protective role of T cells in PSC might be exploited therapeutically. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease without clear etiology or effective treatment. Genetic factors contribute to PSC pathogenesis, but so far, no causative mutation has been found. We performed whole-exome sequencing in a family with autosomal dominant inheritance of PSC and identified a heterozygous germline missense mutation in SEMA4D, encoding a K849T variant of CD100. The mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. It was found to alter the function of CD100-expressing cells with a bias toward the T cell compartment that caused increased proliferation and impaired interferon-γ (IFN-γ) production after stimulation. Homologous mutation knock-in mice developed similar IFN-γ impairment in T cells and were more prone to develop severe cholangitis when exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Transfer of wild-type T cells to knock-in mice before and during DDC exposure attenuated cholangitis. Taken together, we identified an inherited mutation in the disordered cytosolic region of CD100 resulting in T cell functional defects. Our findings suggest a protective role for T cells in PSC that might be used therapeutically.
Process Tracing the Term Limit Struggle in Malawi: The Role of International Democracy Promotion in Muluzi’s Bid for a Third Term

Attempts to circumvent presidential term limits in African countries show a puzzling variation of success or failure. This variation is due to both international and domestic factors. However, how these interact is not yet well understood. This article analyses how international donors and organisations intervened in the attempted term limit circumvention in Malawi from 1999 to 2003. It differentiates between different types of instruments used by donors in democracy promotion, and, by doing so, contributes to the question whether donors in term limit struggles can contribute to genuine democratic consolidation. It employs deductive process-tracing based on an analysis of primary media sources and interviews conducted during field research. The results show that erosion of party support as a proximate and a strong civil society response as a mediate factor were important in saving Malawi’s term limit. Aid conditionality and democracy promotion by donors and international organisations exerted influence on both factors.
Enhancement of the Shear Strength of Wastewater Residuals Using Industrial Waste By-Products

The engineering properties of wastewater residuals (biosolids) can be improved by using waste by-products from local industries. Dewatered biosolids from a wastewater-treatment plant in New Zealand were mixed, on the basis of the dry weight of biosolids, with 30%, 40%, and 50% of fly ash, lime kiln dust (LKD), and two slags [kontinous oxygen blast maxite (KOBM) and work debris (WD)], respectively, together with 0%, 10%, or 20% lime. Changes in the shear strength, measured by using a shear vane and triaxial tests, were obtained after 2 and 8 weeks of curing time. The pH of solids was measured and X-ray diffraction and X-ray fluorescence analyses were performed to determine the mineral and elemental composition of the material. The strain-rate dependency of the strength of biosolids was investigated by performing triaxial tests at different strain rates. The test results yield a logarithmic relation between strain rate and shear strength. Vane strengths of biosolids were found to be a factor of 1.8 higher t.
PHYSIOCHEMICAL INFLUENCE OF SOIL MINERALS ON THE ORGANIC REDUCTION OF SOIL CHROMIUM

The physiochemical influence of soil minerals (Bentonite, Kaolinite, Diatomite, Rutile and Ferrihydrite) on the organic reduction of chromium (VI) has been investigated with Oxalic acid as the organic reductant. The effect of pH and particle sizes of the soil minerals were also investigated. Results showed that with 0.1mol/dm 3 concentration of Oxalic acid, the concentration of chromium(VI) remaining was 0.28, 0.34, 0.38, 0.46 and 0.52mg/kg for Bentonite, Rutile, Diatomite, Kaolinite and Ferrihydrite respectively whereas at 0.5 mol/dm 3 of oxalic acid, the concentration of chromium reduced to 0.20, 0.26, 0.30, 0.38, and 0.44mg/kg for Bentonite, Rutile, Diatomite, Kaolinite and Ferrihydrite. Increased concentration of oxalic acid increased the reduction of chromium(VI) to chromium(III). At pH 5.0, the concentration of chromium(VI) left was 0.28, 0.34, 0.38, 0.46 and 0.52mg/kg for Bentonite, Rutile, Diatomite, Kaolinite and Ferrihydrite while at pH 2.5, concentration was 0.16, 0.22, 0.26, 0.34 and 0.43mg/kg respectively. At particle size of 47-42 microns, concentration of chromium(VI) was 0.28, 0.34, 0.38, 0.46, 0.52mg/kg for the same order of the soil minerals. At micron sizes of 33-29 and 28-25 ranges the concentration of chromium(VI) left was 0.23, 0.29, 0.33, 0.41 and 0.47mg/kg for both micron sizes and corresponding minerals as well. These results showed that above 33-29 micron sizes, the influence of particle size was negligible.
Astrocytes, Noradrenaline, α1-Adrenoreceptors, and Neuromodulation: Evidence and Unanswered Questions

Noradrenaline is a major neuromodulator in the central nervous system (CNS). It is released from varicosities on neuronal efferents, which originate principally from the main noradrenergic nuclei of the brain – the locus coeruleus – and spread throughout the parenchyma. Noradrenaline is released in response to various stimuli and has complex physiological effects, in large part due to the wide diversity of noradrenergic receptors expressed in the brain, which trigger diverse signaling pathways. In general, however, its main effect on CNS function appears to be to increase arousal state. Although the effects of noradrenaline have been researched extensively, the majority of studies have assumed that noradrenaline exerts its effects by acting directly on neurons. However, neurons are not the only cells in the CNS expressing noradrenaline receptors. Astrocytes are responsive to a range of neuromodulators – including noradrenaline. In fact, noradrenaline evokes robust calcium transients in astrocytes across brain regions, through activation of α1-adrenoreceptors. Crucially, astrocytes ensheath neurons at synapses and are known to modulate synaptic activity. Hence, astrocytes are in a key position to relay, or amplify, the effects of noradrenaline on neurons, most notably by modulating inhibitory transmission. Based on a critical appraisal of the current literature, we use this review to argue that a better understanding of astrocyte-mediated noradrenaline signaling is therefore essential, if we are ever to fully understand CNS function. We discuss the emerging concept of astrocyte heterogeneity and speculate on how this might impact the noradrenergic modulation of neuronal circuits. Finally, we outline possible experimental strategies to clearly delineate the role(s) of astrocytes in noradrenergic signaling, and neuromodulation in general, highlighting the urgent need for more specific and flexible experimental tools.
Prognostic Model to Predict Overall Survival for Metastatic Non-Small Cell Lung Cancer Patients Treated With Chemotherapy Combined With Concurrent Radiation Therapy to the Primary Tumor: Analysis From Two Prospective Studies

Purpose The role of radiotherapy, in addition to chemotherapy, has not been thoroughly determined in metastatic non-small cell lung cancer (NSCLC). The purpose of the study was to investigate the prognostic factors and to establish a model for the prediction of overall survival (OS) in metastatic NSCLC patients who received chemotherapy combined with the radiation therapy to the primary tumor. Methods The study retrospectively reviewed 243 patients with metastatic NSCLC in two prospective studies. A prognostic model was established based on the results of the Cox regression analysis. Results Multivariate analysis showed that being male, Karnofsky Performance Status score < 80, the number of chemotherapy cycles <4, hemoglobin level ≤120 g/L, the count of neutrophils greater than 5.8 ×109/L, and the count of platelets greater than 220 ×109/L independently predicted worse OS. According to the number of risk factors, patients were further divided into one of three risk groups: those having ≤ 2 risk factors were scored as the low-risk group, those having 3 risk factors were scored as the moderate-risk group, and those having ≥ 4 risk factors were scored as the high-risk group. In the low-risk group, 1-year OS is 67.7%, 2-year OS is 32.1%, and 3-year OS is 19.3%; in the moderate-risk group, 1-year OS is 59.6%, 2-year OS is 18.0%, and 3-year OS is 7.9%; the corresponding OS rates for the high-risk group were 26.2%, 7.9%, and 0% (P<0.001) respectively. Conclusion Metastatic NSCLC patients treated with chemotherapy in combination with thoracic radiation may be classified as low-risk, moderate-risk, or high-risk group using six independent prognostic factors. This prognostic model may help design the study and develop the plans of individualized treatment.