Defective Transport Research Articles

Resistive Switching of Perovskite‐Type Oxides Using the Hebb–Wagner Polarization Method

Resistive switching, the change between a high‐resistive OFF state and a low‐resistive ON state, is well known for thin film oxides sandwiched between two ion‐blocking electrodes. Herein, the possibility for resistive switching in perovskite‐type oxides using the Hebb–Wagner polarization setup that uses an ion‐blocking and a reversible electrode is investigated. The resistive switching behavior is simulated numerically in terms of a defect chemical and transport model that describes the polarization of the model system SrTiO3 between two different electrodes by applying an ac voltage. Corresponding experiments are also performed and the experimental results are compared with the simulation results. It is shown that the Hebb–Wagner setup allows the bulk resistive state to change not only for thin films but also for large sample thicknesses using low maximum voltage values, without the need for initially high voltages to form filaments. The effect of other parameters and phenomena on the switching behavior, like maximum voltage, surface exchange coefficient, sample thickness, and a Schottky contact between an electrode and the semiconducting oxide, is also determined. The experimental results show a high agreement with the numerical simulations, demonstrating that the Hebb–Wagner polarization setup enables bulk resistive switching of perovskite‐type oxides.

Microstructure-electrochemical behavior relationship in post processed AISI316L stainless steel parts fabricated by laser powder bed fusion

AISI316L stainless steel components produced via additive manufacturing techniques have quickly found new applications across several industrial sectors. However, parts manufactured through this method generally exhibit poor surface quality and performance in the as-built state. This work addresses the influence of laser polishing and water jet assisted recirculating shot peening on the surface quality, microstructure and electrochemical properties of AISI316L samples produced by the laser powder bed fusion method. To do so, surface roughness analysis, residual stress measurement, scanning electron microscope and electron backscatter diffraction analysis were employed along with electrochemical tests, including cyclic potentiodynamic polarization, electrochemical impedance spectroscopy and Mott-Schottky analysis. Laser polished samples exhibited a smooth surface with high tensile residual stress on the surface, which led to the reduction of pitting potential and formation of passive layers, including more crystal defects. Microscopical analysis evidenced that the higher density of lattice defects and local microstrain on the surface of the shot peened samples promoted surface hardness and induced compressive residual stress. Therfore, the shot peened samples exhibited a wider passive range in cyclic potentiodynamic polarization measurements, higher polarization resistance in electrochemical impedance spectroscopy measurements, and less defective passive film in Mott-Schottky analysis. Moreover, it was calculated that the passive film thickness of the shot peened sample was slightly larger than the other samples. Low surface roughness, high crystal defect density, and compressive residual stresses enhanced the passive layer's resistance to defect transport, lowered the point defect concentration in the passive film, and improved the pitting resistance of the samples.

Huntingtin polyglutamine expansions impair the transport of signalling and degradative cargoes.

Huntingtin scaffolds motor proteins and adaptors to vesicular cargoes. Through interactions with kinesin, dynein, and myosin-VI, huntingtin regulates the direction of transport along microtubules and switching between microtubules and actin filaments. Huntington's disease (HD) is caused by polyglutamine (polyQhtt) expansion of length >35Q at Huntington's N-terminus, with longer repeats leading to more severe neurodegeneration. Defects in transport of brain-derived neurotrophic factor (BDNF) and lysosomes have been reported in cells expressing polyQhtt. We track signalling BDNF vesicles and degradative lysosomes in induced neurons from isogenic human stem cell lines with repeat lengths of 18, 30, 45, 65, and 81Q to understand how transport of signalling and degradative cargoes are affected in HD. Preliminary data indicate that lysosomes have lower processivity and similar run lengths with pathological polyQhtt. Interestingly, the 45Q cells have lower processivity and run length compared to all other conditions, indicating divergent mechanisms might contribute to mild and severe disease phenotypes. Lysosomes are typically transported towards the soma. However, with polyQhtt we observe increased outward motility, suggesting huntingtin's ability to regulate transport direction is impaired. To examine how polyQ huntingtin alters the activity of kinesin and dynein, we use optical tweezers to measure the forces exerted on endocytosed BDNF-coated nanodiamonds in control compared to 81Q neurons. BDNF-coated nanodiamonds (∼100 nm) are readily endocytosed by neurons and enable reliable force measurements due to their high refractive index. In parallel, we developed methods to isolate BDNF-phagosomes from neurons and reconstitute their motility along microtubules. Together, live-cell imaging, optical trapping, and in vitro reconstitution reveal how HD mutations impact the transport of signalling and degradative cargoes by misregulating the recruitment and activity of kinesin and dynein.

Failure to Thrive: Impaired BDNF Transport along the Cortical–Striatal Axis in Mouse Q140 Neurons of Huntington’s Disease

Boosting trophic support to striatal neurons by increasing levels of brain-derived neurotrophic factor (BDNF) has been considered as a target for therapeutic intervention for several neurodegenerative diseases, including Huntington's disease (HD). To aid in the implementation of such a strategy, a thorough understanding of BDNF cortical-striatal transport is critical to help guide its strategic delivery. In this manuscript, we investigate the dynamic behavior of BDNF transport along the cortical-striatal axis in Q140 primary neurons, a mouse model for HD. We examine this by using single-molecule labeling of BDNF conjugated with quantum dots (QD-BDNF) to follow the transport along the cortical-striatal axis in a microfluidic chamber system specifically designed for the co-culture of cortical and striatal primary neurons. Using this approach, we observe a defect of QD-BDNF transport in Q140 neurons. Our study demonstrates that QD-BDNF transport along the cortical-striatal axis involves the impairment of anterograde transport within axons of cortical neurons, and of retrograde transport within dendrites of striatal neurons. One prominent feature we observe is the extended pause time of QD-BDNF retrograde transport within Q140 striatal dendrites. Taken together, these finding support the hypothesis that delinquent spatiotemporal trophic support of BDNF to striatal neurons, driven by impaired transport, may contribute to the pathogenesis of HD, providing us with insight into how a BDNF supplementation therapeutic strategy may best be applied for HD.

Repeat-associated non-AUG translation induces cytoplasmic aggregation of CAG repeat-containing RNAs

CAG trinucleotide repeat expansions cause several neurodegenerative diseases, including Huntington's disease and spinocerebellar ataxia. RNAs with expanded CAG repeats contribute to disease in two unusual ways. First, these repeat-containing RNAs may agglomerate in the nucleus as foci that sequester several RNA-binding proteins. Second, these RNAs may undergo aberrant repeat-associated non-AUG (RAN) translation in multiple frames and produce aggregation-prone proteins. The relationship between RAN translation and RNA foci, and their relative contributions to cellular dysfunction, are unclear. Here, we show that CAG repeat-containing RNAs that undergo RAN translation first accumulate at nuclear foci and, over time, are exported to the cytoplasm. In the cytoplasm, these RNAs are initially dispersed but, upon RAN translation, aggregate with the RAN translation products. These RNA-RAN protein agglomerates sequester various RNA-binding proteins and are associated with the disruption of nucleocytoplasmic transport and cell death. In contrast, RNA accumulation at nuclear foci alone does not produce discernable defects in nucleocytoplasmic transport or cell viability. Inhibition of RAN translation prevents cytoplasmic RNA aggregation and alleviates cell toxicity. Our findings demonstrate that RAN translation-induced RNA-protein aggregation correlates with the key pathological hallmarks observed in disease and suggest that cytoplasmic RNA aggregation may be an underappreciated phenomenon in CAG trinucleotide repeat expansion disorders.

Insight on hydrogen injection and GdOx/Co interface chemistry from in operando neutron reflectometry and secondary ion mass spectrometry

Ionic and redox control of magnetism can produce large changes to a variety of magnetic properties using a relatively small voltage. A model structure that continues to be of interest is Pt/Co/GdOxHy/Au, where the Co magnetic layer oxidation state and perpendicular magnetic anisotropy can be toggled using voltage control of proton transport through the GdOxHy electrolyte layer. The hydration of the oxide layer to form a hydroxide phase is the key to improve the speed of these magneto-ionic devices, but there is insufficient understanding of protonic defect incorporation and transport during hydration and electrical gating. In this work, we use polarized neutron reflectometry (PNR) to observe the effects of hydration and electrical gating by scanning in an as-grown state, a hydrated state, and in operando during electrical gating. We directly measure the depth profile of hydrogen and confirm the transformation from oxide (Gd2O3) to hydroxide [Gd(OH)3]. We observe the accumulation of H in the Co magnetic layer and the effects of gating on the structure and hydrogen content of the other layers in the device stack. Using PNR and secondary ion mass spectrometry, we find evidence for much more complex chemistry at the Co/GdOxHy interface than was previously assumed, including evidence for persistent CoO phases and CoOxHy phases. We offer insight on using PNR to observe relatively fast proton dynamics in the system and fitting a rather complex set of parameters to achieve a physical result for the fit spectrum and scattering length density profiles.

Senescent melanocytes driven by glycolytic changes are characterized by melanosome transport dysfunction.

Rationale: Senescent melanocytes accumulate in photoaged skin and are closely related to skin aging. A better understanding of the molecular characteristics of senescent melanocytes may be the key to controlling skin aging. Methods: We have developed an in vitro model of senescence in melanocytes using UV irradiation and investigated the functional characteristics and molecular mechanisms underlying senescence in UV-irradiated melanocytes. Results: We have highlighted that in vitro senescent melanocytes are characterized by melanosome transport dysfunction resulting in melanin accumulation. The defective melanosome transport was confirmed with the ultrastructural characterization of both in vitro UV-induced senescent melanocytes and in vivo melanocytes of hypopigmented aging skin. A single-cell transcriptomic analysis revealed that the glycolytic metabolism pathway appeared to be significantly upregulated in most senescent phenotypes. Furthermore, the inhibition of glycolysis by pharmacological compounds mitigates the pro-aging effects of melanocytes senescence, suggesting that alterations in cellular glucose metabolism act as a driving force for senescence in melanocytes. Conclusion: These results demonstrate that senescent melanocytes are characterized by glycolytic metabolism changes and a defective melanosome transport process, which may be related to impaired mitochondrial function, highlighting the importance of metabolic reprogramming in regulating melanocyte senescence.

Theoretical approaches to defect mechanisms and transport properties of compounds used for electrodes and solid-state electrolytes in alkali-ion batteries.

The transition from fossil fuels to cleaner energies employing different renewable sources constitutes one of the primary worldwide challenges. The search for appropriate solutions is becoming more urgent in view of the severe consequences of climate change. As for a perspective, stationary energy storage, alkali-ion batteries and hybrid supercapacitors are, among others, considered as efficient and affordable solutions. Alkali-ion batteries have proved to be the most investigated products in the past decade including optimizations for cost, energy density and safety. In this Perspective, a computational approach and its applicability in the inverse material design are presented. This approach includes density functional theory calculations, force field-based determinations and both static and molecular dynamics simulations. As for an illustration, the main properties of a selected series of battery materials, including oxides and sulfides Li2SiO3, Li2SnO3, SrSnO3, and A2B6X13 (A = Li+, Na+, K+; B = Ti4+, Sn4+; X = O2-, S2-), and mixed halide antiperovskite A3OX (A = Li+, Na+; X = Cl-, Br-) are explored in depth using these theoretical approaches. Doping strategies, new dopant incorporation mechanism, treatment with alkali insertion/de-insertion cycle in electrodes, transport properties, as well as thermodynamic stability, are discussed. Theoretical approaches reveal that the oxygen-sulfur exchange in alkali hexatitanates and hexastannates induces remarkable improvement of the required properties for electrode and electrolyte materials. In addition, doping of Li2SiO3 with low Na-concentration enhances the room temperature Li-diffusivity by a reduction of the activation energy. The effects of transition-metal and divalent dopants on the defect chemistry and transport properties of Li2SnO3 are also disclosed. The interstitial trivalent doping mechanism is a friendly synthesis strategy to improve the large-scale diffusion in Li2SnO3. The potential of SrSnO3 as an anode in alkali-ion batteries, and the influence of a particular grain boundary in nanocrystalline antiperovskite A3OX are also revealed by using advanced atomistic simulations. The computational approaches described here provide us with a convenient tool for the determination of the properties of battery materials with high accuracy and for the prediction of characteristics of a new generation of alkali battery materials that could be used in improved technologies.

Skin as a Window to Diagnose Inborn Errors of Metabolism

Skin serves as a window to diagnose many systemic diseases, including inborn errors of metabolism (IEM). IEM occur due to disturbance in the metabolism of carbohydrates, proteins, fats, and other micronutrients. Amino acid disorders, organic acidurias, transport defects, urea cycle diseases, storage disorders, and micronutrient defects are some of them which are included under this spectrum. As timely intervention can improve the outcome in some of these conditions, it is prudent to be aware of their clinical presentation. Dermatologist can play a crucial role in the diagnosis of these conditions as many of them can have skin, hair, and mucosal findings that serve as markers for unrecognized IEM. The aim of this review is to give a succinct outline of the cutaneous features seen in commonly encountered IEMs.

Axonal Transport Defects in Retinal Ganglion Cell Diseases.

For the survival and maintenance of retinal ganglion cells (RGCs), axonal transportation is fundamental. Axonal transportation defects can cause severe neuropathies leading to neuronal loss. Axonal transport defects usually precede axonal degeneration and RGC loss in disease models. To date, the main causes of axonal transport defects have not been fully understood. Therefore, elucidation of the mechanisms that lead to transport defects will help us to develop novel therapeutic targets and early diagnostic tools. In this review, we provide an overview of optic neuropathies and axonal degeneration with a focus on axonal transport.

Methods to Study Mitochondria: Techniques Used to Study the Effects of Age-Related Diseases Including Alzheimer's.

Various laboratories across the world have developed methods to study mitochondrial proteins/markers through extraction of mitochondrial RNA and protein to assess mitophagy/autophagy in Alzheimer's disease and other age-related diseases. Techniques outlined in this article include qRT-PCR, immunoblotting, immunofluorescence, transmission electron microscopy, Seahorse bioanalysis, staining for mitochondrial membrane potential, detection of mitophagy, and mitochondrial functional assays. Most of these techniques have been performed in vitro (in human and mouse neuronal cell lines transfected with mutant amyloid precursor protein or tau protein cDNAs) and in vivo (in brain tissues from different mouse models of Alzheimer's and other neurological diseases). Mitochondrial abnormalities in Alzheimer's disease have taken various forms, including excessive reactive oxygen species production, mitochondrial calcium dyshomeostasis, loss of ATP, defects in mitochondrial dynamics and transport, and mitophagy. Mitochondrial dysfunction is largely involved in aging; age-related diseases such as cancer, diabetes, and obesity; and neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others. The goal of this article is to make protocols/methods available to students, scholars, and researchers of mitochondria in order to facilitate future mitochondrial studies. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Analyzing mitochondrial gene expression in mouse brain tissue and HT22 cells by qRT-PCR Basic Protocol 2: Analyzing protein expression in mouse brain tissue and HT22 cells by immunoblotting Basic Protocol 3: Immunofluorescence staining of cells and tissue sections Basic Protocol 4: Staining for mitochondrial membrane potential Basic Protocol 5: Assessing mitochondrial structure by transmission electron microscopy Basic Protocol 6: Methods for detecting mitophagy Basic Protocol 7: Bioenergetics assay via Seahorse Basic Protocol 8: Assays for mitochondrial function.

Low-dimensional antimony selenosulfide as an emerging material for solar cell applications

Antimony chalcogenides (Sb2X3), including Sb2S3, Sb2Se3, and the alloy-type Sb2(S,Se)3, have been considered as a promising absorber materials for photovoltaic applications. Owing to its unique quasi-one-dimensional crystal structure, it displays distinct defect and carrier transport properties and requires special material synthesis strategy compared with the traditional three-dimensional crystal structure semiconductor materials. Recent studies on this class of materials have generated new understandings in film fabrication, defect characteristics and passivation, interfacial engineering, and efficiency improvement. With these efforts, the power conversion efficiency of the solar cell device has been increased from below 3% to 10.7% over the past 10 years. This efficiency achievement suggests that Sb2X3 possesses great potential for practical applications with further efficiency enhancement. This perspective article presents the critical development in the Sb2X3 materials and solar cells in recent years, including the unique crystal structure for solar cells, the preparation method for obtaining high-quality Sb2X3 films, and the discovery and passivation of unusual and complex defects. Finally, we propose several strategies for future efficiency improvement.

Abstract 1231: Deletion of Mdm1 induces retinal degeneration due to intraflagellar transport defects of photoreceptor cells

Abstract 1231: Deletion of Mdm1 induces retinal degeneration due to intraflagellar transport defects of photoreceptor cells

Rare primary intrahepatic lithiasis in a young patient

Introduction. Intrahepatic lithiasis (IHL) is a disease that occurs in middle-aged and elderly people. Presentations of IHL in the young are rare, and considerations in the differential diagnosis include primary sclerosing cholangitis, recurrent pyogenic cholangitis, bile acid transporter defect, Caroli?s disease, and other known genetic diseases. Treatment is often complex, all in order to prevent complications. In this report, we describe the diagnosis and treatment, with the application of a flexible ureteroscope of 4 Fr, of a younger patient with intra-hepatic lithiasis. Case report. A 25-year-old man appeared with a known diagnosis of IHL and a recurrent attack of abdominal pain that required medical treatment. Magnetic resonance imaging of the abdomen showed segmental stenosis of the left bile duct and segmental bile duct for the lateral section with intraductal calculi and its proximal dilatation and mild dilatation of the bile ducts for liver segments II and III. During surgery, a cholangiography and ultrasonography of the liver were performed. Through choledochotomy, the bile ducts were flushed, and extirpation of the several calculi was performed. The bile ducts were examined with a chole-dochscope, and the remaining concrements were removed with a flexible ureteroscope. Conclusion. Segmental liver bile ducts may be explored with a flexible ureteroscope without bile duct injury or trauma. In selected cases, with isolated lithiasis in one liver lobe and the absence of concomitant diseases, IHL can be treated surgically without liver resection. This case is unique because we did not perform liver resection but duct stone extraction, which was an appropriate treatment since there was no recurrence during the two-year follow-ups.

Short range order in disordered spinels and the impact on cation vacancy transport

Spinels can exhibit high levels of cation disorder under irradiation. We show that short range order in spinels manifests as chains of nearest neighbor coordinated antisites, which modifies defect transport depending on the spinel chemistry and degree of disorder.

Fatal congenital copper transport defect caused by a homozygous likely pathogenic variant of SLC31A1.

Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans.

Prise en charge des biopsies duodénales dans la période néonatale et chez le petit enfant

AbstractDuodenal biopsies in neonates and young children are often sampled in the context of early onset protracted diarrhea and require a multidisciplinary strategy (clinical, pathological, biological and genetic) in order to reach the diagnosis and apply the right treatment. For the pediatric pathologist to describe and classify the lesions into the different types of pediatric enteropathies (congenital transport or enzymatic defects, congenital epithelial differenciation defects, auto-immune enteropathies, inborn errors of Immunity, other), an optimal technical workup is needed for these – most of the time – very small samples.

Mutant and non-mutant neoantigen-based cancer vaccines: recent advances and future promises.

Major advances in cancer treatment have emerged with the introduction of immunotherapies using blocking antibodies that target T-cell inhibitory receptors, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), known as immune checkpoints. However, most cancer patients do not respond to immune checkpoint blockade (ICB) therapies, suggesting the development of resistance mechanisms associated with either an insufficient number of preexisting tumor-specific T-cell precursors and/or inappropriate T-cell reactivation. To broaden clinical benefit, anti-PD-1/PD-1 ligand (PD-L1) neutralizing antibodies have been combined with therapeutic cancer vaccines based on non-mutant and/or mutant tumor antigens, to stimulate and expand tumor-specific T lymphocytes. Although these combination treatments achieve the expected goal in some patients, relapse linked to alterations in antigen presentation machinery (APM) of cancer cells often occurs leading to tumor escape from CD8 T-cell immunity. Remarkably, an alternative antigenic peptide repertoire, referred to as T-cell epitopes associated with impaired peptide processing (TEIPP), arises on these malignant cells with altered APM. TEIPP are derived from ubiquitous non-mutant self-proteins and represent a unique resource to target immune-edited tumors that have acquired resistance to cytotoxic T lymphocytes (CTLs) related to defects in transporter associated with antigen processing (TAP) and possibly also to ICB. The present review discusses tumor-associated antigens (TAAs) and mutant neoantigens and their use as targets in peptide- and RNA-based therapeutic cancer vaccines. Finally, this paper highlights TEIPP as a promising immunogenic non-mutant neoantigen candidates for active cancer immunotherapy and combination with TAA and mutant neoantigens. Combining these polyepitope cancer vaccines with ICB would broaden T-cell specificity and reinvigorate exhausted antitumor CTL, resulting in the eradication of all types of neoplastic cells, including immune-escaped subtypes.

Kinesin-1 autoinhibition facilitates the initiation of dynein cargo transport.

The functional significance of Kinesin-1 autoinhibition has been unclear. Kinesin-1 transports multiple cargoes including cytoplasmic dynein to microtubule plus ends. From a genetic screen for Aspergillus mutants defective in dynein-mediated early endosome transport, we identified a kinesin-1 mutation kinAK895* at the C-terminal IAK motif involved in autoinhibition. The kinA∆IAK and kinAK895E mutants exhibited a similar defect in dynein-mediated early endosome transport, verifying the importance of kinesin-1 autoinhibition in dynein-mediated transport. Kinesin-1 autoinhibition is not critical for dynein accumulation at microtubule plus ends or for the secretory vesicle cargoes of kinesin-1 to reach the hyphal tip. However, it facilitates dynein to initiate early endosome transport. This is unrelated to a direct competition between dynein and kinesin-1 on early endosomes because kinesin-3 rather than kinesin-1 drives the plus-end-directed early endosome movement. This effect of kinesin-1 autoinhibition on dynein-mediated early endosome transport is related to cargo adapter-mediated dynein activation but at a step beyond the switching of dynein from its autoinhibited conformation.

Immunodeficiency associated with a novel functionally defective variant of SLC19A1 benefits from folinic acid treatment.

Insufficient dietary folate intake, hereditary malabsorption, or defects in folate transport may lead to combined immunodeficiency (CID). Although loss of function mutations in the major intestinal folate transporter PCFT/SLC46A1 was shown to be associated with CID, the evidence for pathogenic variants of RFC/SLC19A1 resulting in immunodeficiency was lacking. We report two cousins carrying a homozygous pathogenic variant c.1042 G > A, resulting in p.G348R substitution who showed symptoms of immunodeficiency associated with defects of folate transport. SLC19A1 expression by peripheral blood mononuclear cells (PBMC) was quantified by real-time qPCR and immunostaining. T cell proliferation, methotrexate resistance, NK cell cytotoxicity, Treg cells and cytokine production by T cells were examined by flow cytometric assays. Patients were treated with and benefited from folinic acid. Studies revealed normal NK cell cytotoxicity, Treg cell counts, and naive-memory T cell percentages. Although SLC19A1 mRNA and protein expression were unaltered, remarkably, mitogen induced-T cell proliferation was significantly reduced at suboptimal folic acid and supraoptimal folinic acid concentrations. In addition, patients' PBMCs were resistant to methotrexate-induced apoptosis supporting a functionally defective SLC19A1. This study presents the second pathogenic SLC19A1 variant in the literature, providing the first experimental evidence that functionally defective variants of SLC19A1 may present with symptoms of immunodeficiency.