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From late 1926 to early 1934, the Nicaraguan nationalist leader General Augusto C. Sandino (1895—1934) sought to bridge a historical cultural boundary by bringing his social revolutionary project from the region of Las Segovias in Western Nicaragua to the country's Atlantic Coast region. This article examines these efforts and the reception of the peoples of the Atlantic Coast (Costeños) to Sandino's rebellion against US intervention in Nicaragua and Latin America. Intervening in a series of debates stretching back to the 1980s and before, the author consults a wide range of primary sources to argue that a critical mass of Costeños rejected Sandino's brand of Nicaraguan nationalism in favor of their own forms of historically rooted struggle meant to enhance their communities' autonomy, independence, power, and dignity in the face of multiple internal and external threats and opportunities. The responses of Miskitu Indians and Spanish-speaking wage laborers receive special attention, as do regional variations in political economies and sociocultural geographies. The essay builds on recent scholarship emphasizing the cultural and historical agency of Costeños in shaping their own history and is published in tandem with an online documentary and interpretive annex offering open access to over 2,000 digital images of nearly 1,000 primary documents from archives and repositories in the United States, Nicaragua, and Great Britain, at www.Sandino Rebellion.com.

Responds to Wolfgang Gabbert's \"Pluralizing the Costenos -- Reflections on Michael Schroeder's Cultural geographies of grievance and war: Nicaragua's Atlantic Coast region in the first Sandinista revolution, 1927 -- 1934\" and Jeffrey Gould's \"Notes on Costeno cultural politics\" (same journal issue). Adapted from the source document.

Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive. A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1. We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems. Not applicable. Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.

This article examines the politics of naming Sandinistas in Nicaragua during two periods of intense political and military struggle: the era of the Sandinista Revolution and Contra War (1979 - 90) and the era of the Sandino rebellion against the US Marines and Nicaraguan National Guard (1927 - 36). Focusing principally on the rhetorical and narrative strategies used by the USA and its Nicaraguan allies, the article explores the delegitimising master narratives concocted by these dominant groups and the efforts of two generations of Sandinistas and their allies to challenge these narratives. It argues that the politics of naming was embedded within a larger politics of storytelling, and that effective challenges to dominant groups' epithets must be grounded in historically informed challenges to the larger narratives from which they spring.

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease‐associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype‐specific morphological features. Here, we aimed at enhancing the understanding of these subtype‐specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot–Marie‐Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non‐myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle. To enhance the understanding of subtype‐specific features and pathophysiological aspects of hereditary neuropathies due to mutations in the myelin protein zero (MPZ), we performed neuropathological analyses of archival nerve and muscle biopsies as well as autopsy material and present them along with clinical and genetic data. We confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating Charcot‐Marie‐Tooth (CMT) 1 compared to CMT2/CMTi and observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. Furthermore, we found prominent neuromatous hyperinnervation of the spinal meninges in the autopsy case and marked structural mitochondrial abnormalities in skeletal muscle, the latter suggesting a peculiar association of MPZ mutations with mitochondrial alterations.

A growing number of hereditary neuropathies have been assigned to causative gene defects in recent years. The study of human nerve biopsy samples has contributed substantially to the discovery of many of these neuropathy genes. Genotype–phenotype correlations based on peripheral nerve pathology have provided a comprehensive picture of the consequences of these mutations. Intriguingly, several gene defects lead to distinguishable lesion patterns that can be studied in nerve biopsies. These characteristic features include the loss of certain nerve fiber populations and a large spectrum of distinct structural changes of axons, Schwann cells and other components of peripheral nerves. In several instances the lesion patterns are directly or indirectly linked to the known functions of the mutated gene. The present review is designed to provide an overview on these characteristic patterns. It also considers other aspects important for the manifestation and pathology of hereditary neuropathies including the role of inflammation, effects of chemotherapeutic agents and alterations detectable in skin biopsies.

We report missense mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) in seven large pedigrees affected with Charcot-Marie-Tooth neuropathy type 2A (CMT2A). Although a mutation in kinesin family member 1B-β ( KIF1B ) was associated with CMT2A in a single Japanese family, we found no mutations in KIF1B in these seven families. Because these families include all published pedigrees with CMT2A and are ethnically diverse, we conclude that the primary gene mutated in CMT2A is MFN2 .

Marinesco–Sjögren syndrome (MSS) features cerebellar ataxia, mental retardation, cataracts, and progressive vacuolar myopathy with peculiar myonuclear alterations. Most MSS patients carry homozygous or compound heterozygous SIL1 mutations. SIL1 is a nucleotide exchange factor for the endoplasmic reticulum resident chaperone BiP which controls a plethora of essential processes in the endoplasmic reticulum. In this study we made use of the spontaneous Sil1 mouse mutant woozy to explore pathomechanisms leading to Sil1 deficiency-related skeletal muscle pathology. We found severe, progressive myopathy characterized by alterations of the sarcoplasmic reticulum, accumulation of autophagic vacuoles, mitochondrial changes, and prominent myonuclear pathology including nuclear envelope and nuclear lamina alterations. These abnormalities were remarkably similar to the myopathy in human patients with MSS. In particular, the presence of perinuclear membranous structures which have been reported as an ultrastructural hallmark of MSS-related myopathy could be confirmed in woozy muscles. We found that these structures are derived from the nuclear envelope and nuclear lamina and associate with proliferations of the sarcoplasmic reticulum. In line with impaired function of BiP secondary to loss of its nucleotide exchange factor Sil1, we observed activation of the unfolded protein response and the endoplasmic-reticulum-associated protein degradation-pathway. Despite initiation of the autophagy–lysosomal system, autophagic clearance was found ineffective which is in agreement with the formation of autophagic vacuoles. This report identifies woozy muscle as a faithful phenocopy of the MSS myopathy. Moreover, we provide a link between two well-established disease mechanisms in skeletal muscle, dysfunction of chaperones and nuclear envelope pathology.

Neurofibromatosis type 2 (NF2) is caused by inactivation of the NF2 gene, which encodes merlin. NF2 patients develop peripheral neuropathies. The authors show that NF2 inactivation decreases axonal integrity in mice and NF2 patient tissue. Their data suggest that merlin activates RhoA and promotes neurofilament heavy chain phosphorylation to maintain axonal integrity. The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin-iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2–dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2–deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons.