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Object-sensitive pointer analysis (denoted kobj under $k$k-limiting) for an object-oriented program can be accelerated if context-sensitivity can be selectively applied to only some precision-critical variables/objects in a program. Existing pre-analyses for making such selections, which are performed as whole-program analyses to a program, are developed based on two broad approaches. One approach preserves the precision of object-sensitive pointer analysis but achieves limited speedups by reasoning about all the possible value flows in the program conservatively, while the other approach achieves greater speedups but sacrifices precision (often unduly) by examining only some but not all the value flows in the program heuristically. In this paper, we introduce a new pre-analysis approach, Turner$^{\mathcal{m}}$m (where $\mathcal {m}$m stands for modularity), that represents a sweet spot between these two existing ones, as it is designed to enable kobj to run significantly faster than the former approach and achieve significantly better precision than the latter approach. Turner$^{\mathcal{m}}$m is simple, lightweight yet effective due to two novel aspects in its design. First, we exploit a key observation that some precision-uncritical objects in the program can be approximated based on the object-containment relationship pre-established (from Andersen's analysis). In practice, this approximation introduces only a small degree of imprecision into kobj. Second, leveraging this initial approximation, we apply a novel object reachability analysis to the program by pre-analyzing its methods according to a reverse topological order of its call graph. When pre-analyzing each method, we make use of a simple DFA (Deterministic Finite Automaton) to reason about object reachability intra-procedurally from its entry to its exit along all the possible value flows established by its statements to identify its precision-critical variables/objects. In practice, this new modular object reachability analysis, which runs linearly in terms of the number of statements in the program, introduces again only a small loss of precision into kobj. We have validated Turner$^{\mathcal{m}}$m with an open-source implementation in Soot (already publicly available) against the state of the art by using a set of 12 widely used Java benchmarks and applications.

Background/Objectives: The results linking body iron stores to the risk of gestational diabetes mellitus (GDM) are conflicting. We aimed to measure the serum ferritin level of women in early pregnancy and evaluate the risk of GDM in a Chinese urban population. Subjects/Methods: In total, 851 pregnant women between 10 and 20 weeks of gestation took part in the prospective, observational study conducted. The women were divided into four groups by quartiles of serum ferritin levels (Q1–4). Their blood samples were collected and assayed for several biochemical variables at the beginning of the study, and the women were followed up with a 75-g oral glucose tolerance test at 24–28 weeks of gestation. Results: The participants had an average serum ferritin concentration of 65.67 μg/L. GDM prevalence within each serum ferritin quartile was 9.4%, 14.6%, 18.8% and 19.3%, respectively, (P=0.016). The odds ratio for GDM in the ferritin Q2–4 was 1.64 (CI: 0.90–2.99), 2.23 (CI: 1.26–3.96) and 2.31 (CI: 1.30–4.10), compared with Q1, respectively. This association persisted after adjusting for potential confounders factors. In addition, in Q4, pregnant women with a pre-pregnancy body mass index ≥24 kg/m2, maternal age ≤35 years old or haemoglobin≥ 110 g/L did have an increased risk of developing GDM. Conclusions: Elevated serum ferritin concentrations in early gestation are associated with an increased risk of GDM, especially in pregnant women who have a high baseline iron storage status with no anaemia or who are overweight/obese. Individual iron supplementation should be considered to minimize the risk of GDM.

Aging is associated with an increased incidence of venous thromboembolism (VTE), resulting in significant morbidity and mortality in the elderly. Platelet hyperactivation is linked to aging-related VTE. However, the mechanisms through which aging enhances platelet activation and susceptibility to VTE are poorly understood. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) signaling is essential for aging-related platelet hyperactivation and VTE. mTORC1 was hyperactivated in platelets and megakaryocytes (MKs) from aged mice, accompanied by elevated mean platelet volume (MPV) and platelet activation. Inhibition of mTORC1 with rapamycin led to a significant reduction in susceptibility to experimental deep vein thrombosis (DVT) in aged mice (P < .01). To ascertain the specific role of platelet mTORC1 activation in DVT, we generated mice with conditional ablation of the mTORC1-specific component gene Raptor in MKs and platelets (Raptor knockout). These mice developed markedly smaller and lighter thrombi, compared with wild-type littermates (P < .01) in experimental DVT. Mechanistically, increased reactive oxygen species (ROS) production with aging induced activation of mTORC1 in MKs and platelets, which, in turn, enhanced bone marrow MK size, MPV, and platelet activation to promote aging-related VTE. ROS scavenger administration induced a significant decrease (P < .05) in MK size, MPV, and platelet activation in aged mice. Our findings collectively demonstrate that mTORC1 contributes to enhanced venous thrombotic susceptibility in aged mice via elevation of platelet size and activation.

Aging is associated with an increased incidence of venous thromboembolism (VTE), resulting in significant morbidity and mortality in the elderly. Platelet hyperactivation is linked to aging-related VTE. However, the mechanisms through which aging enhances platelet activation and susceptibility to VTE are poorly understood. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) signaling is essential for aging-related platelet hyperactivation and VTE. mTORC1 was hyperactivated in platelets and megakaryocytes (MKs) from aged mice, accompanied by elevated mean platelet volume (MPV) and platelet activation. Inhibition of mTORC1 with rapamycin led to a significant reduction in susceptibility to experimental deep vein thrombosis (DVT) in aged mice (P< .01). To ascertain the specific role of platelet mTORC1 activation in DVT, we generated mice with conditional ablation of the mTORC1-specific component gene Raptorin MKs and platelets (Raptor knockout). These mice developed markedly smaller and lighter thrombi, compared with wild-type littermates (P< .01) in experimental DVT. Mechanistically, increased reactive oxygen species (ROS) production with aging induced activation of mTORC1 in MKs and platelets, which, in turn, enhanced bone marrow MK size, MPV, and platelet activation to promote aging-related VTE. ROS scavenger administration induced a significant decrease (P< .05) in MK size, MPV, and platelet activation in aged mice. Our findings collectively demonstrate that mTORC1 contributes to enhanced venous thrombotic susceptibility in aged mice via elevation of platelet size and activation.

Abernethy malformation is a rare anomaly of the splanchnic venous system. We report a case of an unusual portosystemic shunt via a dilated inferior mesenteric vein. A 20-year-old woman was referred to our hospital with complains of nonspecific abdominal pain for almost 3 years and hematochezia since 15 months old. Computed tomography and further transhepatic splenoportography revealed a hypoplastic portal vein and a giant inferior mesenteric vein, via which part of the portal venous blood drained into the inferior vena cava. The patient underwent a surgical ligation of the portocaval shunt and recovered well. We believe that this is the first case of type II Abernethy malformation presenting as a portosystemic shunt via the giant inferior mesenteric vein.

Fructooligosaccharide (FOS) is one of the most important and well-known prebiotics that confers health benefits on the host. The effect of FOS is frequently associated with modulation of the abundance of gut microbes. However, the effect of FOS on gut microbes-mediated metabolism pathway remains largely undefined. This study aimed to explore the modulation effect of FOS on the metabolism pathway of tyrosine in gut microbes. Moreover, the effect of FOS on the production of p-cresol by gut microbes was studied, in which p-cresol is a uremic toxin precursor produced by tyrosine metabolism pathway. The results showed that FOS significantly prompted the anabolism pathway of tyrosine, which might promote the proliferation of gut microbes. Additionally, FOS significantly inhibited the catabolism pathway of tyrosine, therefore decreased p-cresol production in tyrosine oxidative catabolism pathway. Two mechanisms were proposed to explain the effect of FOS, one was to switch tyrosine catabolism from oxidative pathway to reductive pathway, the other was to directly inhibit the oxidative pathway in which p-cresol was produced. In conclusion, the present study suggested that as a well-known prebiotic, FOS inhibited the biosynthesis of p-cresol in gut microbes by regulating gut microbes-mediated tyrosine metabolism.

ABSTRACTUremic toxins are a class of toxins that accumulate in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a typical uremic toxin, is not efficiently removed by hemodialysis. Modulation of IS production in the gut microbiota may be a promising strategy for decreasing IS concentration, thus, delaying CKD progression. In the present study, we identified isoquercitrin (ISO) as a natural product that can perturb microbiota-mediated indole production without directly inhibiting the growth of microbes or the indole-synthesizing enzyme TnaA. ISO inhibits the establishment of H proton potential by regulating the gut bacteria electron transport chain, thereby inhibiting the transport of tryptophan and further reducing indole biosynthesis. This non-microbiocidal mechanism may enable ISO to be used as a therapeutic tool, specifically against pathologies triggered by the accumulation of the microbial-produced toxin IS, as in CKD. Herein, we have shown that it is possible to inhibit gut microbial indole production using natural components. Therefore, targeting the uremic toxin metabolic pathway in gut bacteria may be a promising strategy to control host uremic toxin production.