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Critics of virtue reliabilism allege that the view cannot account for testimonial knowledge, as the acquisition of such knowledge is creditable to the testifier, not the recipient's cognitive abilities. I defend virtue reliabilism by attending to empirical work concerning human abilities to detect sincerity, certainty, and seriousness through bodily cues and properties of utterances. Then, I consider forms of testimony involving books, newspapers, and online social networks. I argue that, while discriminatory abilities directed at bodily cues and properties of utterances are impotent in the face of such testimony, alternative abilities facilitate the acquisition of knowledge from these sources.

Knowledge intellectualism is the view that knowledge-how requires propositional knowledge. Knowledge intellectualism has a Gettier problem, or so many of its critics allege. The essence of this problem is that knowledge-how is compatible with epistemic luck in a way that ordinary propositional knowledge is not. Hence, knowledge-how can allegedly be had in the absence of knowledge-that, a fact inconsistent with knowledge intellectualism. This paper develops two responses to this challenge to knowledge intellectualism. First, it is not clear that propositional knowledge is incompatible with the forms of epistemic luck with which knowledge-how is allegedly compatible. Second, existing cases intended to serve as counterexamples to knowledge intellectualism are flawed, and revised versions of these cases no longer elicit the judgments necessary to challenge knowledge intellectualism.

This paper describes the ways in which trolls and bots impede the acquisition of knowledge online. I distinguish between three ways in which trolls and bots can impede knowledge acquisition, namely, by deceiving, by encouraging misplaced skepticism, and by interfering with the acquisition of warrant concerning persons and content encountered online. I argue that these threats are difficult to resist simultaneously. I argue, further, that the threat that trolls and bots pose to knowledge acquisition goes beyond the mere threat of online misinformation, or the more familiar threat posed by liars offline. Trolls and bots are, in effect, fake persons. Consequently, trolls and bots can systemically interfere with knowledge acquisition by manipulating the signals whereby individuals acquire knowledge from one another online. I conclude with a brief discussion of some possible remedies for the problem of fake persons.

Renal autoregulation maintains renal blood flow and glomerular filtration rate (GFR) in a wide range of renal perfusion pressure (RPP). This mechanism is impaired in diabetes and chronic kidney disease (CKD), such that even modest increases in arterial pressure (AP) are transmitted to glomerular capillaries resulting in glomerular injury. Elevated RPP drives renal immune cell infiltration ( Hypertens. 76: 849-858, 2020). We showed that hypertensive mechanical stretch and T cell cytokine interleukin (IL)-17A synergistically promote vascular fibrosis ( Wu, Circ. Res. 114: 616-625, 2014). However, the mechanisms by which hemodynamic and inflammatory stimuli cause CKD remain poorly understood. We sought to investigate the contributions of glomerular hyperfiltration (GHF) and inflammation on glomerular damage in a mouse CKD model induced by reduced kidney mass (RKM). This model is characterized by impaired autoregulation, early onset hypertension and subsequent lymphocytic inflammation, albuminuria and glomerulosclerosis. We hypothesize that the initial rise in AP post RKM surgery promotes kidney injury through both GHF and renal inflammation. Eight-week old male 129/S6 mice were implanted with radiotelemeters. After a 10-day recovery, mice underwent sham surgery or RKM which involved uninephrectomy and partial renal artery ligation in the remaining kidney, such that the functional renal mass is reduced by ~ 2/3. AP, urine albumin, and transcutaneous GFR were measured at baseline, day (D) 3, D7, D14, D21, D28, and D56 after RKM.Immediately after RKM, GFR dropped to 30% of sham levels (Mean ± SEM in μL/min/100 g: RKM 279 ± 59 vs Sham 913 ± 61, n = 4 – 6, p < 0.05, two-way ANOVA RM), consistent with the extent of renal mass ablation. The mean AP of RKM mice was identical to sham controls at baseline (115 ± 2 vs 116 ± 2 mmHg) but increased by 29 mmHg by D5 (144 ± 8 vs 112 ± 2 mmHg, p < 0.05), and remained significantly elevated through D56, albeit a declining trend. Compared to GFR of sham mice (100%), the GFR of RKM mice gradually increased to 36% at D3, 43% at D7 and 69% at D14. By D21 post surgery, the GFR of RKM mice rose to 71% of sham (800 ± 106 vs 1121 ± 47 μL/min/100 g, p > 0.05) and plateaued through day 28 (69% of sham), suggesting that the early rise in AP and impaired autoregulation may have caused GHF in the RKM mice. The adaptive increase in GFR post RKM surgery was associated with a trend towards increased renal leukocytes, monocyte/macrophages, CD3 T cells and CD4/CD8 subsets at D14 and significantly elevated albuminuria at D28 (832 ± 227 vs 341 ± 15 μg/day, p < 0.05), implying hyperfiltration-induced renal inflammation and glomerular damage. Importantly, the GFR declined to 57% of sham levels by day 56 (597 ± 86 vs 1047 ± 80 μL/min/100 g, p < 0.05), suggesting progressive glomerular injury. We conclude that impaired autoregulation exposes the kidney to both inflammation and GHF, causing glomerular injury, albuminuria, and CKD progression. This work is supported by a NIDDK K01 DK126792 and a University of Rochester Environmental Health Science Center Pilot award (as part of a NIEHS P30ES001247) to JW. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Study Objective: Understand the response to acute water load in mice lacking the insulin-regulated aminopeptidase (IRAP). Hypothesis: IRAP degrades vasopressin in vivo, therefore, mice lacking IRAP would have impaired ability to dilute urine and to excrete water. Methods: Age matched 8–10-week-old IRAP WT and KO male mice were used for all experiments. Immunofluorescence and immunoblotting were performed on kidneys at baseline and after 1-hr acute water load (2ml sterile water/IP). Urine/serum electrolytes and urine osmolality were measured before and after water load. Urine was collected from IRAP WT and KO mice before and after 1-hr administration of OPC 31260 (10mg/kg/IP) and furosemide (2.5mg/ml/IP) for urine osmolality and electrolyte measurements. Results: IRAP is expressed in the glomerulus, thick ascending loop of Henle, distal tubule, connecting and collecting ducts. At baseline, IRAP WT and KO mice have similar systolic blood pressure (122 ± 6.6 vs 128 ± 1.9 mmHg), glomerular filtration rate (251 ± 20 vs 254 ± 16 uL/min), and serum Na+ levels (142 ± 1.9 vs 143 ± 2.6 mmol/L), but KO mice have reduced proteinuria (3.3 ± 0.57 vs 4.5 ± 1.6 mg/mg). At baseline, IRAP KO have elevated serum copeptin levels (111 ± 43 vs 53 ± 31 pg/mL) and urine osmolality compared to respective IRAP WT (2506 ± 310 vs 1007 ± 212 mOsm/L). Urine osmolality decreased in IRAP KO after administration of vasopressin type 2 receptor antagonist, OPC 31260 (473 ± 341 vs 2479 ± 215 mOsm/L) and loop diuretic, furosemide (517 ± 96 vs 2750 ± 414 mOsm/L). After an acute water load, IRAP KO have lower serum Na+ levels (127 ± 3.8 vs 134 ±3.1 mmol/L) and increased urine osmolality compared to IRAP WT (2741 ± 400 vs 577 ± 274 mOsm/L). Additionally, after an acute water load, IRAP KO mice also have higher protein abundance of the Na+/K+/2Cl- (NKCC2) co-transporter (0.36 ± 0.04 vs 0.20 ± 0.03 AU) and phosphorylation of water channel, AQP2 (0.032 ± 0.005 vs 0.025 ± 0.003 AU). Conclusions: IRAP is required to dilute urine and to increase water excretion in response to an acute water load due to persistent activation of NKCC2 and AQP2. Funding Sources: Harold Amos Medical Faculty Development Award - Robert Wood Johnson Foundation; Vanderbilt Center for Kidney Disease This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

We previously reported that global deletion of angiotensin II (Ang II) AT1a receptors significantly lowered basal blood pressure and impaired urine concentration in mice. As we also demonstrated that renomedullary interstitial cells (RMICs) of the kidney expressed a high level of AT1 (AT1a) receptors, we hypothesized that AT1a receptors in RMICs may play an important physiological role in maintaining basal blood pressure and urine concentration homeostasis. To test the hypothesis, we generated a novel mouse model with deletion of AT1a receptors selectively in the RMICs of the kidney medulla using inducible Tenascin-C-CreER2/Agtr1af/f recombination approach (RMIC- Agtr1a-/- ) in the present study. Adult male wildtype (WT) and RMIC- Agtr1a-/- mice (n=10-18 per group) were phenotyped under basal conditions and treated with or without a slow pressor dose of Ang II infusion via an osmotic minipump (~500 μg/kg/day, i.p.) for 2 weeks to determine the roles of AT1a receptors in RMICs in maintaining basal blood pressure and urine concentration homeostasis and in the development of Ang II-induced hypertension. Under basal conditions, telemetry systolic blood pressure was significantly lower in adult male RMIC- Agtr1a-/- than WT mice (WT: 122 ± 4 mmHg vs. RMIC-Agtr1a-/-: 102 ± 3 mmHg, P-/- mice was associated with significant decreases in 24 h urine output (WT: 1.56 ± 0.15 mL/24 h vs. RMIC- Agtr1a-/- : 0.98 ± 0.13 mL/24 h, P-/- : 145.2 ± 5.4 μmol/24 h, P-/- mice even though 24 h urine output was lowered (WT: 1724 ± 335 mOsm/Kg H2O vs. RMIC- Agtr1a-/- : 1128 ± 102 mOsm/Kg H2O, P-/- mice ( P-/- mice (1226 ± 110 mOsm/Kg H2O, n.s.). In conclusion, we demonstrated for the 1st time that AT1a receptors in RMICs of the kidney medulla play a key role in physiologically maintaining basal blood pressure homeostasis and urine concentration, as well as in the development of Ang II-induced hypertension. R01DK123144, R01DK067299, R01DK102429 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Heteromeric Kir4.1/Kir5.1 (KCNJ10/KCNJ16) inward rectifier potassium (Kir) channels play key roles in the brain and kidney, but pharmacological tools for probing their physiology and therapeutic potential have not been developed. Here, we report the discovery, in a high-throughput screening of 80,475 compounds, of the moderately potent and selective inhibitor VU0493690, which we selected for characterization and chemical optimization. VU0493690 concentration-dependently inhibits Kir4.1/5.1 with an IC(50) of 0.96 μM and exhibits at least 10-fold selectivity over Kir4.1 and ten other Kir channels. Multidimensional chemical optimization of VU0493690 led to the development of VU6036720, the most potent (IC(50) = 0.24 μM) and selective (>40-fold over Kir4.1) Kir4.1/5.1 inhibitor reported to date. Cell-attached patch single-channel recordings revealed that VU6036720 inhibits Kir4.1/5.1 activity through a reduction of channel open-state probability and single-channel current amplitude. Elevating extracellular potassium ion by 20 mM shifted the IC(50) 6.8-fold, suggesting that VU6036720 is a pore blocker that binds in the ion-conduction pathway. Mutation of the “rectification controller” asparagine 161 to glutamate (N161E), which is equivalent to small-molecule binding sites in other Kir channels, led to a strong reduction of inhibition by VU6036720. Renal clearance studies in mice failed to show a diuretic response that would be consistent with inhibition of Kir4.1/5.1 in the renal tubule. Drug metabolism and pharmacokinetics profiling revealed that high VU6036720 clearance and plasma protein binding may prevent target engagement in vivo. In conclusion, VU6036720 represents the current state-of-the-art Kir4.1/5.1 inhibitor that should be useful for probing the functions of Kir4.1/5.1 in vitro and ex vivo. SIGNIFICANCE STATEMENT: Heteromeric inward rectifier potassium (Kir) channels comprising Kir4.1 and Kir5.1 subunits play important roles in renal and neural physiology and may represent inhibitory drug targets for hypertension and edema. Herein, we employ high-throughput compound library screening, patch clamp electrophysiology, and medicinal chemistry to develop and characterize the first potent and specific in vitro inhibitor of Kir4.1/5.1, VU6036720, which provides proof-of-concept that drug-like inhibitors of this channel may be developed.

Particularists maintain that conspiracy theories are to be assessed individually, while generalists hold that conspiracy theories may be assessed as a class. This paper seeks to clarify the nature and importance of the debate between particularism and generalism, while offering an argument for a version of generalism. I begin by considering three approaches to the definition of conspiracy theory, and offer reason to prefer an approach that defines conspiracy theories in opposition to the claims of epistemic authorities. I argue that particularists rely on an untenably broad definition of conspiracy theory. Then, I argue that particularism and its counterpart are best understood as constellations of theses, rather than a pair of incompatible theses. While some particularist theses are highly plausible, I argue that one important particularist thesis is false. The argument for this conclusion draws on the history of false conspiracy theories. I then defend this conclusion against a pair of potential objections.

The Human BioMolecular Atlas Program (HuBMAP) provides an opportunity to contextualize findings across cellular to organ systems levels. Constructing an atlas target is the primary endpoint for generalizing anatomical information across scales and populations. An initial target of HuBMAP is the kidney organ and arterial phase contrast-enhanced computed tomography (CT) provides distinctive appearance and anatomical context on the internal substructure of kidney organs such as renal context, medulla, and pelvicalyceal system. With the confounding effects of demographics and morphological characteristics of the kidney across large-scale imaging surveys, substantial variation is demonstrated with the internal substructure morphometry and the intensity contrast due to the variance of imaging protocols. Such variability increases the level of difficulty to localize the anatomical features of the kidney substructure in a well-defined spatial reference for clinical analysis. In order to stabilize the localization of kidney substructures in the context of this variability, we propose a high-resolution CT kidney substructure atlas template. Briefly, we introduce a deep learning preprocessing technique to extract the volumetric interest of the abdominal regions and further perform a deep supervised registration pipeline to stably adapt the anatomical context of the kidney internal substructure. To generate and evaluate the atlas template, arterial phase CT scans of 500 control subjects are de-identified and registered to the atlas template with a complete end-to-end pipeline. With stable registration to the abdominal wall and kidney organs, the internal substructure of both left and right kidneys are substantially localized in the high-resolution atlas space. The atlas average template successfully demonstrated the contextual details of the internal structure and was applicable to generalize the morphological variation of internal substructure across patients.