Miracle-dz/UniFAR-FTUs huggingface dataset:
Memory B cell heterogeneity: Remembrance of things past

B cells that persist for long periods of time after antigen encounter exist as either antibody‐producing plasma cells (long‐lived plasma cells, LLPCs) that reside primarily in the bone marrow or rapidly responsive memory B cells (MBCs) that reside in the spleen and circulation. Although LLPCs are thought to be non‐responsive to a secondary infection, MBCs respond to subsequent infection through the production of antibody‐secreting cells, formation of new germinal centers (GCs), and repopulation of the memory pool. Dogma suggests that MBCs express class‐switched, somatically hypermutated BCRs after undergoing a GC reaction. Yet this narrow view of MBCs has been challenged over the years and it is now well recognized that diverse MBC subsets exist in both rodents and humans. Here, we review current thoughts on the phenotypic and functional characteristics of MBCs, focusing on a population of somatically hypermutated, high affinity IgM+ MBCs that are rapidly responsive to a secondary malaria infection.
Forensic Biology Evidence Screening Past and Present

ABSTRACT Although forensic laboratories worldwide have been continually investing resources in the development of new DNA profiling technologies, the technological advancements in the field of forensic body fluid identification have not experienced the same priority or enhancements. It is important for forensic scientists to use the most effective biological screening processes to ensure the best evidence is processed first in order to optimize the use of new DNA analysis technologies and provide information in a timely manner. It is surprising to learn that the majority of biological body fluid identification technologies were initially discovered in the past centuries and further enhanced many years ago. This has resulted in a body fluid identification process which often has less specificity and sensitivity compared to the subsequent DNA analysis methods in current use. Our study serves to briefly review the evolution of common forensic body fluid screening technologies and document their use in 47 laboratories worldwide. The intent of this paper is to revisit the past in an effort to improve our future use of DNA technologies for forensic science applications.
Female-biased reproductive strategies in a Hungarian Gypsy population

Hungarian Gypsy populations invest more heavily in daughters than in sons compared to co–resident Hungarians, in conformity with the predictions of the Trivers–Willard hypothesis. These effects are shown for four different measures of parental investment (sex ratio at birth, frequency of abortion, duration of breast–feeding and length of education). Opportunities for hypergamy into the wealthier Hungarian population appears to be one factor causing Gypsies to prefer daughters over sons. We show that differential investment by sex of offspring is directly related to the fitness pay–offs that accrue for each population through both sexes of offspring.
The Risk of α‐Thalassaemia in Offspring of β‐Thalassaemia Carriers in Hong Kong

Couples in whom one is heterozygous for α‐thalassaemia‐1 and the other is heterozygous for β‐thalassaemia are assumed not to be at risk of having offspring with homozygous α‐thalassaemia‐1 or homozygous β‐thalassaemia. We retrospectively reviewed the genetic outcome of 189 pregnancies of 178 couples in whom the partners were diagnosed to be discordant heterozygotes of α‐thalassaemia and β‐thalassaemia on haematological tests. ζ gene mapping was performed on 158 β‐thalassaemia carriers to diagnose the presence of co‐existing α‐thalassaemia‐1. Eleven patients (7 per cent) were found to be compound α‐ and β‐thalassaemia heterozygotes. They accounted for 16 pregnancies, of which five were diagnosed to be affected by homozygous α‐thalassaemia‐1. Our results show that couples presumed to be discordant heterozygotes of α‐ and β‐thalassaemia on haematological testing are at risk of having offspring with homozygous α‐thalassaemia‐1 if the ζ gene mapping of the heterozygous β‐thalassaemia partner shows co‐inheritance of α‐thalassaemia‐1. Prenatal diagnosis of homozygous α‐thalassaemia‐1 should be performed on these at‐risk pregnancies. © John Wiley & Sons, Ltd.
The development of advanced practice roles in ophthalmic nursing

Advanced practice roles in ophthalmic settings have enabled the delivery of the policy agenda with high quality outcomes. This paper reports on a study undertaken to provide a ‘snapshot’ of such roles. It was found that while roles are diverse and continue to respond to service need, ophthalmologists, rather than nurses, control many of the parameters of the role and undertake much of the training and assessment. All nurses in this study undertook in-house training rather than education for their roles and none was able to be supernumerary which, in some cases, delayed service development. It is suggested that nursing administration must recognise the need for education as well as training and advocate for it in order that roles may be developed effectively and systematically. Copyright © 2006 John Wiley & Sons, Ltd.
Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA

Mephedrone (4‐methylmethcathinone) is a β‐ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re‐uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine‐induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4‐methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine‐induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co‐abused with it, leading to heightened neurotoxicity.
CHF5074 restores visual memory ability and pre‐synaptic cortical acetylcholine release in pre‐plaque Tg2576 mice

CHF5074, a new microglial modulator, attenuates memory deficit in Alzheimer's disease transgenic mice. In this study, the effect of an acute or subacute CHF5074 treatment on in vivo novel object recognition test and on [3H]Acetylcholine (ACh) and GABA release in pre‐plaque (7‐month‐old) Tg2576 mice have been compared with those induced by the γ‐secretase inhibitor LY450139 (semagacestat). Vehicle‐treated Tg2576 mice displayed an impairment of recognition memory compared with wild‐type animals. This impairment was recovered in transgenic animals acutely treated with CHF5074 (30 mg/kg), while LY450139 (1, 3, 10 mg/kg) was ineffective. In frontal cortex synaptosomes from vehicle‐treated Tg2576 mice, K+‐evoked [3H]ACh release was lower than that measured in wild‐type mice. This reduction was absent in transgenic animals subacutely treated with CHF5074 (30 mg/kg daily for 8 days), while it was slightly, not significantly, amplified by LY450139 (3 mg/kg daily for 8 days). There were no differences between the groups on spontaneous [3H]ACh release as well as spontaneous and K+‐evoked GABA release. These results suggest that CHF5074 has beneficial effects on visual memory and cortical cholinergic dysfunctions in pre‐plaque Tg2576 mice. Together with previous findings, these data suggest that CHF5074 could be a possible candidate for early Alzheimer's disease therapeutic regimens.
A Comprehensive and Comparative Review of Adolescent Substance Abuse Treatment Outcome

There are relatively few studies on adolescent substance abuse treatment. The ones that exist tend to be methodologically weak. Methodologically stronger studies have usually found most adolescents receiving treatment to have significant reductions in substance use and problems in other life areas in the year following treatment. Average rate of sustained abstinence after treatment is 38% (range, 30–55) at 6 months and 32% at 12 months (range, 14–47). Variables most consistently related to successful outcome are treatment completion, low pretreatment substance use, and peer/ parent social support/nonuse of substances. There is evidence that treatment is superior to no treatment, but insufficient evidence to compare the effectiveness of treatment types. The exception to this is that outpatient family therapy appears superior to other forms of outpatient treatment.
Neuroprotection conferred by post‐ischemia ethanol therapy in experimental stroke: an inhibitory effect on hyperglycolysis and NADPH oxidase activation

Ethanol provides neuroprotection following ischemia/reperfusion. This study assessed ethanol's effect on hyperglycolysis and NADPH oxidase (NOX) activation. Adult, male Sprague–Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Three sets of experiments were conducted to determine ethanol's effect on (i) conferring neuroprotection by measuring infarct volume and neurological deficits 24 h post reperfusion; (ii) cerebral glucose metabolism and lactic acidosis by measuring brain and blood glucose concentrations and protein expression of glucose transporter 1 and 3 (GLUT1, GLUT3), phosphofructokinase (PFK), as well as lactic acidosis by measuring lactate dehydrogenase (LDH), and lactate; and (iii) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation by detecting enzymatic activity and subunit expression at 3 h after reperfusion. When administered upon reperfusion, ethanol (1.5 g/kg) reduced infarct volume by 40% (p < 0.01) and neurological deficits by 48% at 24 h post reperfusion while reducing (p < 0.01) elevations in glycolytic protein expression and lactate levels during early reperfusion (3 h). Ethanol increased the reductions in cerebral glucose concentration at 3 h post reperfusion by 64% (p < 0.01) while enhancing (p < 0.01) post stroke blood glucose concentration, suggesting a reduced cellular glucose uptake and utilization. Ethanol decreased (p < 0.01) stroke‐induced NOX activation by reducing enzymatic activity and gp91phox expression by 45% and 38%, respectively. Post‐ischemia ethanol treatment exerts neuroprotection through attenuation of hyperglycolysis and associated NOX activation. Because of the lack of associated hypoglycemia and selectivity toward decreasing cerebral metabolism, further investigation of ethanol's use as a post‐stroke therapy, especially in the context of hyperglycemia, seems warranted.
Harnessing the power of yeast to unravel the molecular basis of neurodegeneration

Several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or prion diseases, are known for their intimate association with protein misfolding and aggregation. These disorders are characterized by the loss of specific neuronal populations in the brain and are highly associated with aging, suggesting a decline in proteostasis capacity may contribute to pathogenesis. Nevertheless, the precise molecular mechanisms that lead to the selective demise of neurons remain poorly understood. As a consequence, appropriate therapeutic approaches and effective treatments are largely lacking. The development of cellular and animal models that faithfully reproduce central aspects of neurodegeneration has been crucial for advancing our understanding of these diseases. Approaches involving the sequential use of different model systems, starting with simpler cellular models and ending with validation in more complex animal models, resulted in the discovery of promising therapeutic targets and small molecules with therapeutic potential. Within this framework, the simple and well‐characterized eukaryote Saccharomyces cerevisiae, also known as budding yeast, is being increasingly used to study the molecular basis of several neurodegenerative disorders. Yeast provides an unprecedented toolbox for the dissection of complex biological processes and pathways. Here, we summarize how yeast models are adding to our current understanding of several neurodegenerative disorders.
A blind two-stage receiver for MIMO-CDMA systems

A blind two-stage multiple-input multiple-output (MIMO) receiver is proposed for code-division multiple access (CDMA) systems utilizing space-time block coding (STBC) over a multipath fading channel. Specifically, in the first stage, a signal-blocked (SB) interference-blocked (IB) detector is first constructed for collection of the desired signals and suppression of multiple access interference (MAI). In the second-stage, a decision-directed scheme is developed to alleviate desired signal cancellation. Computer simulations demonstrate that the proposed blind receiver can achieve a reliable output signal-to-interference-plus-noise ratio (SINR) performance approximating that of the optimal minimum mean squared error (MMSE) receiver and can exhibit the robustness against the finite data sample effect.
Quetiapine and Gabapentin Dramatically Improve Treatment-resistant Schizoaffective Disorder in a Patient With a Long History of Cocaine Abuse

Objective:To describe the successful use of quetiapine and gabapentin in a patient with treatment-resistant schizoaffective disorder and comorbid crack cocaine addiction. Case Report:This case report describes a 34-year-old man with a history of schizoaffective disorder, depression, and cocaine addiction. After numerous suicide attempts, repeated hospitalizations, and treatment with various conventional and atypical antipsychotics over a 10-year period, the patient showed dramatic improvement on a combination of quetiapine 800 mg/d and gabapentin 1200 mg/d. Over a 5-month period, his mood stabilized; he became less paranoid; he was able to cope better with his auditory hallucinations; and he had no cravings for crack cocaine. In addition, the concomitant administration of quetiapine and gabapentin in this patient caused no adverse events. Conclusion:The concomitant use of quetiapine and gabapentin may have beneficial effects in patients with schizo-affective disorder and comorbid cocaine addiction refractory to other medications. Controlled clinical trials are needed to confirm these findings.
Nesfatin‐1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats

Nesfatin‐1, a peptide whose receptor is yet to be identified, has been involved in the modulation of feeding, stress, and metabolic responses. More recently, increasing evidence supports a modulatory role for nesfatin‐1 in autonomic and cardiovascular activity. This study was undertaken to test if the expression of nesfatin‐1 in the nucleus ambiguus, a key site for parasympathetic cardiac control, may be correlated with a functional role. As we have previously demonstrated that nesfatin‐1 elicits Ca2+ signaling in hypothalamic neurons, we first assessed the effect of this peptide on cytosolic Ca2+ in cardiac pre‐ganglionic neurons of nucleus ambiguus. We provide evidence that nesfatin‐1 increases cytosolic Ca2+ concentration via a Gi/o‐coupled mechanism. The nesfatin‐1‐induced Ca2+ rise is critically dependent on Ca2+ influx via P/Q‐type voltage‐activated Ca2+ channels. Repeated administration of nesfatin‐1 leads to tachyphylaxis. Furthermore, nesfatin‐1 produces a dose‐dependent depolarization of cardiac vagal neurons via a Gi/o‐coupled mechanism. In vivo studies, using telemetric and tail‐cuff monitoring of heart rate and blood pressure, indicate that microinjection of nesfatin‐1 into the nucleus ambiguus produces bradycardia not accompanied by a change in blood pressure in conscious rats. Taken together, our results identify for the first time that nesfatin‐1 decreases heart rate by activating cardiac vagal neurons of nucleus ambiguus.
Unesterified docosahexaenoic acid is protective in neuroinflammation

Docosahexaenoic acid (22:6n‐3) is the major brain n‐3 polyunsaturated fatty acid and it is possible that docosahexaenoic acid is anti‐inflammatory in the brain as it is known to be in other tissues. Using a combination of models including the fat‐1 transgenic mouse, chronic dietary n‐3 polyunsaturated fatty acid modulation in transgenic and wild‐type mice, and acute direct brain infusion, we demonstrated that unesterified docosahexaenoic acid attenuates neuroinflammation initiated by intracerebroventricular lipopolysaccharide. Hippocampal neuroinflammation was assessed by gene expression and immunohistochemistry. Furthermore, docosahexaenoic acid protected against lipopolysaccharide‐induced neuronal loss. Acute intracerebroventricular infusion of unesterified docosahexaenoic acid or its 12/15‐lipoxygenase product and precursor to protectins and resolvins, 17S‐hydroperoxy‐docosahexaenoic acid, mimics anti‐neuroinflammatory aspects of chronically increased unesterified docosahexaenoic acid. LC‐MS/MS revealed that neuroprotectin D1 and several other docosahexaenoic acid‐derived specialized pro‐resolving mediators are present in the hippocampus. Acute intracerebroventricular infusion of 17S‐hydroperoxy‐docosahexaenoic acid increases hippocampal neuroprotectin D1 levels concomitant to attenuating neuroinflammation. These results show that unesterified docosahexaenoic acid is protective in a lipopolysaccharide‐initiated mouse model of acute neuroinflammation, at least in part, via its conversion to specialized pro‐resolving mediators; these docosahexaenoic acid stores may provide novel targets for the prevention and treatment(s) of neurological disorders with a neuroinflammatory component.
Klassische systemische Therapie der Psoriasis

Zur Therapie von schweren Psoriasis-Formen und der Psoriasisarthritis stehen eine Reihe klassischer Systemtherapeutika zur Verfugung, darunter Fumarsaure, Acitretin, Methotrexat und Ciclosporin. Daneben ist Leflunomid in Deutschland fur die Psoriasisarthritis zugelassen; kasuistisch und im Rahmen kleinerer Studien wurde auch Mycophenolat-Mofetil erfolgreich eingesetzt. Nach Einfuhrung der Biologicals wird zunehmend eine Neubewertung der klassischen Antipsoriatika und ihres Stellenwerts in der Psoriasistherapie gefordert. Diese Arbeit gibt einen Uberblick uber Einsatzmoglichkeiten, Effektivitat und Sicherheitsprofil der klassischen Systemtherapeutika der Psoriasis und moglicher Kombinationen. Da die Psoriasis eine oft uber mehrere Jahrzehnte chronisch verlaufende Erkrankung ist, bedarf es eines langfristigen Therapiekonzepts unter Berucksichtigung der Langzeit-Risiken und kumulativen Toxizitaten. Zur Reduktion solcher Risiken bietet sich oftmals der sequenzielle oder rotierende Einsatz der verschiedenen Systemtherapeutika an. In diesem Zusammenhang werden die Biologicals in Zukunft noch starker als heute eine Rolle spielen; ob sie die klassischen Antipsoriatika ersetzen konnen werden, ist heute noch nicht absehbar. For therapy of severe psoriasis and psoriatic arthritis, a number of classical systemic therapeutics are available that include fumaric acid, acitretin, MTX and cyclosporine. In addition, leflunomide has been approved for the treatment of psoriatic arthritis. Moreover, casuistically and in the context of small studies, mycophenolate mofetil has been applied successfully. After the introduction of biologicals, there is an increasing demand for re-evaluating the classical systemic antipsoriatics and reappraising their value for psoriasis therapy. This article gives a survey of their efficiency, their safety profile and possible combinations. As psoriasis is a chronic disease often affecting the patients over many decades, a long-term therapy concept considering long-run risks and cumulative toxicities is required. To reduce such risks, a sequential or rotating application of the diverse systemic medications often appears suitable. In this context, biologicals will gain a greater role in the future than today, but presumably will not completely replace the classical antipsoriatics.
Blocking the apolipoprotein E/Amyloid β interaction in triple transgenic mice ameliorates Alzheimer's disease related amyloid β and tau pathology

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late‐onset Alzheimer's disease (AD). Studies have shown that the binding between apoE and amyloid‐β (Aβ) peptides occurs at residues 244–272 of apoE and residues 12–28 of Aβ. ApoE4 has been implicated in promoting Aβ deposition and impairing clearance of Aβ. We hypothesized that blocking the apoE/Aβ interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Aβ12‐28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy. In the present study, we investigated whether the Aβ12‐28P elicits a therapeutic effect on tau‐related pathology in addition to amyloid pathology using old triple transgenic AD mice (3xTg, with PS1M146V, APPSwe and tauP30IL transgenes) with established pathology from the ages of 21 to 26 months. We show that treatment with Aβ12‐28P substantially reduces tau pathology both immunohistochemically and biochemically, as well as reducing the amyloid burden and suppressing the activation of astrocytes and microglia. These affects correlate with a behavioral amelioration in the treated Tg mice.
Thalamic synaptic transmission of sensory information modulated by synergistic interaction of adenosine and serotonin

The thalamic synapses relay peripheral sensory information to the cortex, and constitute an important part of the thalamocortical network that generates oscillatory activities responsible for different vigilance (sleep and wakefulness) states. However, the modulation of thalamic synaptic transmission by potential sleep regulators, especially by combination of regulators in physiological scenarios, is not fully characterized. We found that somnogen adenosine itself acts similar to wake‐promoting serotonin, both decreasing synaptic strength as well as short‐term depression, at the retinothalamic synapse. We then combined the two modulators considering the coexistence of them in the hypnagogic (sleep‐onset) state. Adenosine plus serotonin results in robust synergistic inhibition of synaptic strength and dramatic transformation of short‐term synaptic depression to facilitation. These synaptic effects are not achievable with a single modulator, and are consistent with a high signal‐to‐noise ratio but a low level of signal transmission through the thalamus appropriate for slow‐wave sleep. This study for the first time demonstrates that the sleep‐regulatory modulators may work differently when present in combination than present singly in terms of shaping information flow in the thalamocortical network. The major synaptic characters such as the strength and short‐term plasticity can be profoundly altered by combination of modulators based on physiological considerations.