Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhamm-null mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context–dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor–regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration.

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.

Kindlins are focal adhesion proteins that regulate integrin activation and outside-in signaling. The kindlin family consists of three members, kindlin-1, -2, and -3. Kindlin-2 is widely expressed in multiple cell types, except those from the hematopoietic lineage. A previous study has reported that the Drosophila Fit1 protein (an ortholog of kindlin-2) prevents abnormal spindle assembly; however, the mechanism remains unknown. Here, we show that kindlin-2 maintains spindle integrity in mitotic human cells. The human neuroblastoma SH-SY5Y cell line expresses only kindlin-2, and we found that when SH-SY5Y cells are depleted of kindlin-2, they exhibit pronounced spindle abnormalities and delayed mitosis. Of note, acetylation of α-tubulin, which maintains microtubule flexibility and stability, was diminished in the kindlin-2–depleted cells. Mechanistically, we found that kindlin-2 maintains α-tubulin acetylation by inhibiting the microtubule-associated deacetylase histone deacetylase 6 (HDAC6) via a signaling pathway involving AKT Ser/Thr kinase (AKT)/glycogen synthase kinase 3β (GSK3β) or paxillin. We also provide evidence that prolonged hypoxia down-regulates kindlin-2 expression, leading to spindle abnormalities not only in the SH-SY5Y cell line, but also cell lines derived from colon and breast tissues. The findings of our study highlight that kindlin-2 regulates mitotic spindle assembly and that this process is perturbed in cancer cells in a hypoxic environment.

Barbara H. Braffett
May 1, 2020; 69:1000-1010
Complications

Patrice D. Cani
Jun 1, 2008; 57:1470-1481
Metabolism

Mary C. Gannon
Sep 1, 2004; 53:2375-2382
Pathophysiology

1 October 2008 , Number 11

Nuclear, biological or chemical weapons and acts of terror may make the headlines, but it is conventional arms that take the lives in large numbers; maybe around a thousand a day. This month, a United Nations committee will try to find a way to limit the arms trade with a new treaty. For those facing the barrel of a gun, it cannot come a moment too soon.

MOSCOW (AP): United States (US) President Donald Trump and Russian President Vladimir Putin discussed progress in combating the coronavirus pandemic, along with arms-control issues and oil prices, in a phone call Thursday, the White House and the...

The Diabetes Control and Complications Trial Research Group
Feb 1, 1997; 46:271-286
Original Article

The Diabetes Control and Complications Trial Research Group
Aug 1, 1995; 44:968-983
Original Article

Patrice D. Cani
Jun 1, 2008; 57:1470-1481
Metabolism

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and diabetes.

Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, with the expectation of correlations with the impairment of large-fiber function. Sixty-one patients with type 2 diabetes (48 with and 13 without DPN) and 12 control subjects were enrolled and underwent MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aβ fibers) and mechanical pain (A fibers) but not in thermal pain and thermal detection clusters (C fibers) among the groups. Lesion load correlated with lower Aα-, Aβ-, and A-fiber but not with C-fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN.

Optimal immune-based therapies for type 1 diabetes (T1D) should restore self-tolerance without inducing chronic immunosuppression. CD4⁺Foxp3⁺ regulatory T cells (T_regs) are a key cell population capable of facilitating durable immune tolerance. However, clinical trials with expanded T_regs in T1D and solid-organ transplant recipients are limited by poor T_reg engraftment without host manipulation. We showed that T_reg engraftment and therapeutic benefit in nonautoimmune models required ablative host conditioning. Here, we evaluated T_reg engraftment and therapeutic efficacy in the nonobese diabetic (NOD) mouse model of autoimmune diabetes using nonablative, combinatorial regimens involving the anti-CD3 (αCD3), cyclophosphamide (CyP), and IAC (IL-2/JES6–1) antibody complex. We demonstrate that αCD3 alone induced substantial T-cell depletion, impacting both conventional T cells (T_conv) and T_regs, subsequently followed by more rapid rebound of T_regs. Despite robust depletion of host T_conv and host T_regs, donor T_regs failed to engraft even with interleukin-2 (IL-2) support. A single dose of CyP after αCD3 depleted rebounding host T_regs and resulted in a 43-fold increase in donor T_reg engraftment, yet polyclonal donor T_regs failed to reverse diabetes. However, infusion of autoantigen-specific T_regs after αCD3 alone resulted in robust T_reg engraftment within the islets and induced remission in all mice. This novel combinatorial therapy promotes engraftment of autoantigen-specific donor T_regs and controls islet autoimmunity without long-term immunosuppression.

Experts on this Spanish language webinar examine the operation of today’s interior immigration enforcement system and how state and local governments, civil society, and consulates are responding.    

A Spanish language webinar examining the operation of today’s interior enforcement system and how state and local governments, civil society, and consulates are responding.    

OBJECTIVE

Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.

OBJECTIVE

This study aimed to understand the longitudinal relationship between financial, psychosocial, and neighborhood social determinants and glycemic control (HbA_1c) in older adults with diabetes.

OBJECTIVE

To analyze the differences in health care costs according to glycemic control in people with type 2 diabetes.

OBJECTIVE

Self-management education and support are essential for improved diabetes control. A 1-year randomized telephonic diabetes self-management intervention (Bronx A1C) among a predominantly Latino and African American population in New York City was found effective in improving blood glucose control. To further those findings, this current study assessed the intervention’s impact in reducing health care utilization and costs over 4 years.

How did the U.S. border enforcement picture go in the span of two years from the lowest levels of illegal immigration since 1971 to a spiraling border security and humanitarian crisis? This report draws on enforcement and other data as well as analysis of changing migration trends and policies to tell this story. The authors outline key elements for a new strategy that can succeed over the long term.

Ian H. de Boer
Jan 1, 2014; 37:24-30
DCCT/EDIC 30th Anniversary Summary Findings

Kasia J. Lipska
Apr 1, 2017; 40:468-475
Emerging Science and Concepts for Management of Diabetes and Aging

Hannele Yki-Järvinen
Dec 1, 2014; 37:3235-3243
Emerging Technologies and Therapeutics

Muh Geot Wong
May 1, 2016; 39:694-700
Cardiovascular Disease and Diabetes

Boris P. Kovatchev
Jul 1, 2013; 36:1851-1858
Diabetes Care Symposium

Roy W. Beck
Aug 1, 2017; 40:994-999
Perspectives in Care

Robert R. Henry
Mar 1, 2015; 38:412-419
Evolving Tactics With Inhibition of Sodium-Glucose Cotransporters

Hans-Ulrich Häring
Jun 1, 2014; 37:1650-1659
Emerging Technologies and Therapeutics

John M. Lachin
Jan 1, 2014; 37:39-43
DCCT/EDIC 30th Anniversary Summary Findings

Matthew C. Riddle
Oct 1, 2014; 37:2755-2762
Emerging Technologies and Therapeutics

Gary F Lewis
Apr 1, 1996; 19:390-393
Symposium On Insulin Resistance

Catherine L. Martin
Jan 1, 2014; 37:31-38
DCCT/EDIC 30th Anniversary Summary Findings

Tina Vilsbøll
Jun 1, 2007; 30:1608-1610
BR Emerging Treatments and Technologies

Bruce A. Perkins
May 1, 2014; 37:1480-1483
Novel Communications in Diabetes

Saila B. Koivusalo
Jan 1, 2016; 39:24-30
Considerations in the Management of Gestational Diabetes Mellitus

Dorothee Deiss
Dec 1, 2006; 29:2730-2732
BR Emerging Treatments and Technologies

David M. Nathan
Jan 1, 2014; 37:9-16
DCCT/EDIC 30th Anniversary Summary Findings

Jennifer M. Yamamoto
Jul 1, 2018; 41:1346-1361
Reconsidering Pregnancy With Diabetes

Khalid A. Jadoon
Oct 1, 2016; 39:1777-1786
Emerging Technologies and Therapeutics

Kirstine J. Bell
Jun 1, 2015; 38:1008-1015
Type 1 Diabetes at a Crossroads

David M. Nathan
Jan 1, 2014; 37:9-16
DCCT/EDIC 30th Anniversary Summary Findings

Dror Dicker
May 1, 2011; 34:S276-S278
Diabetes Treatments

W. Timothy Garvey
May 1, 2020; 43:1085-1093
Emerging Therapies: Drugs and Regimens

Helena W. Rodbard
Dec 1, 2019; 42:2272-2281
Emerging Therapies: Drugs and Regimens

Rob M. van Dam
Dec 1, 2004; 27:2990-2992
Brief Reports

OBJECTIVE

Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone.

The ADA is sharing with members the CDC guidelines on the use of personal protective equipment on its website dedicated to COVID-19.