Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: Insights into the phagosomal environment

Little is known about the biochemical environment in phagosomes harboring an infectious agent. To assess the state of this organelle we captured the transcriptional responses of Mycobacterium tuberculosis (MTB) in macrophages from wild-type and nitric oxide (NO) synthase 2–deficient mice before and after immunologic activation. The intraphagosomal transcriptome was compared with the transcriptome of MTB in standard broth culture and during growth in diverse conditions designed to simulate features of the phagosomal environment. Genes expressed differentially as a consequence of intraphagosomal residence included an interferon � – and NO-induced response that intensifies an iron-scavenging program, converts the microbe from aerobic to anaerobic respiration, and induces a dormancy regulon. Induction of genes involved in the activation and �-oxidation of fatty acids indicated that fatty acids furnish carbon and energy. Induction of �E-dependent, sodium dodecyl sulfate–regulated genes and genes involved in mycolic acid modification pointed to damage and repair of the cell envelope. Sentinel genes within the intraphagosomal transcriptome were induced similarly by MTB in the lungs of mice. The microbial transcriptome thus served as a bioprobe of the MTB phagosomal environment

Intrahistiocytic Storage of Clofazimine Crystals in a Cat

A 13-year-old castrated male Maine coon cat with a 5-year history of atypical mycobacteriosis was euthanized and submitted for necropsy. The cat had been kept in clinical remission since diagnosis using a combination of the antimycobacterial drug clofazimine and additional multimodal antimicrobial therapy. Grossly, tissues were diffusely discolored red-brown to yellow. Histologically, the myocardial interstitum was expanded by numerous, often multinucleated cells, which were distended by uniformly shaped acicular cytoplasmic spaces. These cells were immunopositive for CD18 and immunonegative for desmin, suggesting a histiocytic rather than muscular origin. Macrophages in other tissues contained similar acicular spaces. Ultrastructurally, the spaces were surrounded by 2 lipid membranes, resembling an autophagosome. Based on the clinical history and histologic, immunohistochemical, and ultrastructural data, we diagnosed clofazimine crystal storage. To our knowledge, this is the first report of clofazimine storage in a cat or within myocardial interstitial macrophages

Type 2 Diabetes Mellitus and Alcoholic Liver Disease: a literature review

Introduction Alcoholic liver disease (ALD) and type 2 diabetes mellitus (T2DM) are two important chronic diseases in Australia, both of which are emerging epidemics. As a result, patients presenting with both conditions may become increasingly more common. However, not much is known about how each affects the other in terms of clinical outcomes.   Methods Evidence from studies exploring the relationship between T2DM and ALD, including those pertaining to liver function tests (LFT) and hepatocellular carcinoma (HCC), was reviewed and summarised.   Results There are studies which show that high alcohol intake and chronic liver disease (CLD) are risk factors of developing T2DM. Conversely, having impaired glucose tolerance has been shown to promote progression of CLD. There is also some evidence of increased risk of HCC in patients with T2DM and who consume alcohol in the context of other liver disease. However, no studies that looked into how T2DM directly affects LFT results in ALD were found.   Discussion There seems to be a bidirectional relationship between T2DM and ALD, although it is not explicitly cause-and-effect in nature. Hence, there is a need for a comprehensive management plan that utilises a multidisciplinary approach to minimise the risk of complications for patients with either or both diseases. Currently, this is not available and both diseases are treated as separate entities. Therefore, further research must be done to elucidate the relationship between the two, so that effective strategies to manage co-existing T2DM and ALD can be developed

Under-five mortality: spatial-temporal clusters in Ifakara HDSS in South-eastern Tanzania.

BACKGROUND\ud \ud Childhood mortality remains an important subject, particularly in sub-Saharan Africa where levels are still unacceptably high. To achieve the set Millennium Development Goals 4, calls for comprehensive application of the proven cost-effective interventions. Understanding spatial clustering of childhood mortality can provide a guide in targeting the interventions in a more strategic approach to the population where mortality is highest and the interventions are most likely to make an impact.\ud \ud METHODS\ud \ud Annual child mortality rates were calculated for each village, using person-years observed as the denominator. Kulldorff's spatial scan statistic was used for the identification and testing of childhood mortality clusters. All under-five deaths that occurred within a 10-year period from 1997 to 2006 were included in the analysis. Villages were used as units of clusters; all 25 health and demographic surveillance sites (HDSS) villages in the Ifakara health and demographic surveillance area were included.\ud \ud RESULTS\ud \ud Of the 10 years of analysis, statistically significant spatial clustering was identified in only 2 years (1998 and 2001). In 1998, the statistically significant cluster (p < 0.01) was composed of nine villages. A total of 106 childhood deaths were observed against an expected 77.3. The other statistically significant cluster (p < 0.05) identified in 2001 was composed of only one village. In this cluster, 36 childhood deaths were observed compared to 20.3 expected. Purely temporal analysis indicated that the year 2003 was a significant cluster (p < 0.05). Total deaths were 393 and expected were 335.8. Spatial-temporal analysis showed that nine villages were identified as statistically significant clusters (p < 0.05) for the period covering January 1997-December 1998. Total observed deaths in this cluster were 205 while 150.7 were expected.\ud \ud CONCLUSION\ud \ud There is evidence of spatial clustering in childhood mortality within the Ifakara HDSS. Further investigations are needed to explore the source of clustering and identify strategies of reaching the cluster population with the existing effective interventions. However, that should happen alongside delivery of interventions to the broader population

Comments on scaling limits of 4d N=2 theories

We revisit the study of the maximally singular point in the Coulomb branch of 4d N=2 SU(N) gauge theory with N_f=2n flavors for N_f= 2, we find that the low-energy physics is described by two non-trivial superconformal field theories coupled to a magnetic SU(2) gauge group which is infrared free. (In the special case n=2, one of these theories is a theory of free hypermultiplets.) This observation removes a possible counter example to a conjectured a-theorem.Comment: 13 page

The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels.

Hypoxia Inducible transcription Factors (HIFs) are principally regulated by the 2-oxoglutarate and Iron(II) prolyl hydroxylase (PHD) enzymes, which hydroxylate the HIFα subunit, facilitating its proteasome-mediated degradation. Observations that HIFα hydroxylation can be impaired even when oxygen is sufficient emphasise the importance of understanding the complex nature of PHD regulation. Here, we use an unbiased genome-wide genetic screen in near-haploid human cells to uncover cellular processes that regulate HIF1α. We identify that genetic disruption of the Vacuolar H+ ATPase (V-ATPase), the key proton pump for endo-lysosomal acidification, and two previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115, stabilise HIF1α in aerobic conditions. Rather than preventing the lysosomal degradation of HIF1α, disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation. Iron supplementation directly restores PHD catalytic activity following V-ATPase inhibition, revealing important links between the V-ATPase, iron metabolism and HIFs.This work was supported by a Wellcome Trust Senior Clinical Research Fellowship to JAN (102770/Z/13/Z), and an MRC Award to ALM (MR/K50127X/1). The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140)

Author Correction: A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis (Nature Communications, (2023), 14, 1, (4816), 10.1038/s41467-023-40541-1)

\ua9 The Author(s) 2024.The original version of this Article contained errors in Figs. 2, 3, and 5. In the original Fig. 2e, the flow cytometry panel on the right (labelled “StD (24 hr) followed by 1% O2 (~16 hr)”), was inadvertently duplicated from the panel on the left (labelled “Concurrent StD and 1% O2 (~24 hr)”). In the original Fig. 3a, the flow cytometry panel on the right (labelled “Roxadustat”), was inadvertently duplicated from the panel on the left (labelled “DMOG”). In the original Fig. 5c, the labels did not properly communicate that both panels come from the same experiment and have the same controls. The following sentence has been added to the end of the legend for Fig. 5c: “The data depicted in the left and right panels originated from the same experiment and as such the control plots are the same in both.” Figures 2, 3, and 5 have been corrected in both the PDF and HTML versions of the Article. The original version of the Supplementary Information associated with this Article contained an error in Supplementary Fig. 5. In the original Supplementary Fig. 5a, the labels did not properly communicate that all three panels come from the same experiment and have the same control. The following sentence has been added to the end of the legend for Supplementary Fig. 5a: “The data depicted in the three panels originated from the same experiment and as such the control plot is the same in all panels”. The HTML has been updated to include a corrected version of the Supplementary Information

A Decision Analysis Evaluating Screening for Kidney Cancer Using Focused Renal Ultrasound

Background Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value. Objective To determine (1) whether current evidence suggests that screening is potentially cost effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps. Design, setting, and participants A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted. Intervention A single focused renal ultrasound scan compared with standard of care (no screening). Outcome measurements and statistical analysis Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum. Results and limitations Given a prevalence of RCC of 0.34% (0.18–0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08–0.25%), screening 60-yr-old women resulted in an ICER of £37 327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was <£30 000/QALY as long as the prevalence of RCC was ≥0.25% for men and ≥0.2% for women at age 60 yr. Given the willingness to pay a threshold of £30 000/QALY (€37 878/QALY), the population-expected values of perfect information were £194 million (€244 million) and £97 million (€123 million) for 60-yr-old men and women, respectively. The expected value of perfect parameter information suggests that the prevalence of RCC and stage shift associated with screening are key research priorities. Conclusions Current evidence suggests that one-off screening of 60-yr-old men is potentially cost effective and that further research into this topic would be of value to society. Patient summary Economic modelling suggests that screening 60-yr-old men for kidney cancer using ultrasound may be a good use of resources and that further research on this topic should be performed