02020-02-07: Badain Jaran Desert

Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive. We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons in mice. Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons. Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but absent in NPY/AgRP neurons. To study the role of Prdm12 in vivo, we developed and characterized a floxed Prdm12 allele. Selective ablation of Prdm12 in embryonic POMC neurons led to significantly reduced Pomc expression as well as early-onset obesity in mice of either sex that recapitulates symptoms of human POMC deficiency. Interestingly, however, specific deletion of Prdm12 in adult POMC neurons showed that it is no longer required for Pomc expression or energy balance. Collectively, these findings establish a critical role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis. Finally, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the hypothalamus whose neurodevelopment remains poorly studied.

SIGNIFICANCE STATEMENT POMC and NPY/AgRP neurons are derived from the same hypothalamic progenitors but have opposing effects on food intake. We profiled the transcriptomes of genetically labeled POMC and NPY/AgRP neurons in the developing mouse hypothalamus to decipher the transcriptional codes behind the versus orexigenic neuron identity. Our analyses revealed 29 transcription regulators that are selectively enriched in one of the two populations. We generated new mouse genetic models to selective ablate one of POMC-neuron enriched transcription factors Prdm12 in developing and adult POMC neurons. Our studies establish a previously unrecognized role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis.

Pattern separation and completion are fundamental hippocampal computations supporting memory encoding and retrieval. However, despite extensive exploration of these processes, it remains unclear whether and how top-down processes adaptively modulate the dynamics between these computations. Here we examine the role of expectation in shifting the hippocampus to perform pattern separation. In a behavioral task, 29 participants (7 males) learned a cue-object category contingency. Then, at encoding, one-third of the cues preceding the to-be-memorized objects, violated the studied rule. At test, participants performed a recognition task with old objects (targets) and a set of parametrically manipulated (very similar to dissimilar) foils for each object. Accuracy was found to be better for foils of high similarity to targets that were contextually unexpected at encoding compared with expected ones. Critically, there were no expectation-driven differences for targets and low similarity foils. To further explore these effects, we implemented a computational model of the hippocampus, performing the same task as the human participants. We used representational similarity analysis to examine how top-down expectation interacts with bottom-up perceptual input, in each layer. All subfields showed more dissimilar representations for unexpected items, with dentate gyrus (DG) and CA3 being more sensitive to expectation violation than CA1. Again, representational differences between expected and unexpected inputs were prominent for moderate to high levels of input similarity. This effect diminished when inputs from DG and CA3 into CA1 were lesioned. Overall, these novel findings strongly suggest that pattern separation in DG/CA3 underlies the effect that violation of expectation exerts on memory.

SIGNIFICANCE STATEMENT What makes some events more memorable than others is a key question in cognitive neuroscience. Violation of expectation often leads to better memory performance, but the neural mechanism underlying this benefit remains elusive. In a behavioral study, we found that memory accuracy is enhanced selectively for unexpected highly similar foils, suggesting expectation violation does not enhance memory indiscriminately, but specifically aids the disambiguation of overlapping inputs. This is further supported by our subsequent investigation using a hippocampal computational model, revealing increased representational dissimilarity for unexpected highly similar foils in DG and CA3. These convergent results provide the first evidence that pattern separation plays an explicit role in supporting memory for unexpected information.

The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to lateral parabrachial (LPB) neurons from the CeA in animals of either sex. Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges, responses that far outlast the stimulus, compared with controls. LPB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that, in both rats and mice, LPB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin, and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naive animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.

SIGNIFICANCE STATEMENT We describe a novel pathway, consisting of inhibition by dynorphin, somatostatin, and corticotropin-releasing hormone-expressing neurons in the CeA that project to the parabrachial nucleus. We show that this pathway regulates the activity of pain-related neurons in parabrachial nucleus, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABA_A receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca²⁺ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABA_ARs synapses through a GABA receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.

SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca²⁺-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABA_A receptor synapses via Ca²⁺/calmodulin-dependent protein kinase II. Although Ca²⁺ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.

Theoretical models and experimental evidence have suggested that connections from the dentate gyrus (DG) to CA3 play important roles in representing orthogonal information (i.e., pattern separation) in the hippocampus. However, the effects of eliminating the DG on neural firing patterns in the CA3 have rarely been tested in a goal-directed memory task that requires both the DG and CA3. In this study, selective lesions in the DG were made using colchicine in male Long–Evans rats, and single units from the CA3 were recorded as the rats performed visual scene memory tasks. The original scenes used in training were altered during testing by blurring to varying degrees or by using visual masks, resulting in maximal recruitment of the DG–CA3 circuits. Compared with controls, the performance of rats with DG lesions was particularly impaired when blurred scenes were used in the task. In addition, the firing rate modulation associated with visual scenes in these rats was significantly reduced in the single units recorded from the CA3 when ambiguous scenes were presented, largely because DG-deprived CA3 cells did not show stepwise, categorical rate changes across varying degrees of scene ambiguity compared with controls. These findings suggest that the DG plays key roles not only during the acquisition of scene memories but also during retrieval when modified visual scenes are processed in conjunction with the CA3 by making the CA3 network respond orthogonally to ambiguous scenes.

SIGNIFICANCE STATEMENT Despite the behavioral evidence supporting the role of the dentate gyrus in pattern separation in the hippocampus, the underlying neural mechanisms are largely unknown. By recording single units from the CA3 in DG-lesioned rats performing a visual scene memory task, we report that the scene-related modulation of neural firing was significantly reduced in the DG-lesion rats compared with controls, especially when the original scene stimuli were ambiguously altered. Our findings suggest that the dentate gyrus plays an essential role during memory retrieval and performs a critical computation to make categorical rate modulation occur in the CA3 between different scenes, especially when ambiguity is present in the environment.

Autism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, reflected in exaggerated and variable responses to sensory stimuli. Attentional engagement is known to be regulated by the locus ceruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether, under different attentional task demands, individuals with ASD exhibit a different profile of LC activity compared with typically developing controls. Males and females with ASD and age- and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses, an established correlate for LC activity, were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared with controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed specifically in response to task-relevant events, providing confirmation that the group differences most likely were specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.

SIGNIFICANCE STATEMENT Individuals with autism spectrum disorder (ASD) exhibit atypical attentional behaviors, including altered sensory responses and atypical fixedness, but the neural mechanism underlying these behaviors remains elusive. One candidate mechanism is atypical locus ceruleus (LC) activity, as the LC plays a critical role in attentional modulation. Specifically, LC activity is involved in regulating the trade-off between environmental exploration and focused attention. This study shows that, under tightly controlled conditions, task-evoked pupil responses, an LC activity proxy, are lower in individuals with ASD than in controls, but only in the presence of task-irrelevant stimuli. This suggests that individuals with ASD evince atypical modulation of LC activity in accordance with changes in attentional demands, offering a mechanistic account for attentional atypicalities in ASD.

Did you know that cash transfer (CT) programmes in countries of the sub-Saharan Africa actually have a significant impact? In Malawi, these programmes helped families invest in agricultural equipment and livestock to produce their own food and reduce levels of negative coping strategies, like begging and school drop-outs. In Kenya, secondary school attendance rose by 9 percent and access to [...]

Autumn Ray's goal: 59 national parks before she turns 40 in four years

The worms are 283-times more abundant than they were in the 1970s, which might be a sign of healthy marine ecosystems

The story of two bored art lovers who found a way to "a-mouse" themselves

Mary Pearson, who was briefly engaged to the writer's brother, may be the real-life counterpart of Lydia Bennet from "Pride and Prejudice"

With many zoos and aquariums closed to the public, keepers let animals roam empty hallways to meet their neighbors

An online exhibition from the National WWI Museum and Memorial features recipes detailed in 1918 cookbook

Buyers can ask for a mix of their favorite genre or seek booksellers’ recommendations

The quarantined felines of the world are coming for your screens

Do some armchair traveling and see the breathtaking vistas of all 50 states while learning about their histories

The Nunavut government says there is no set limit on how much money it is prepared to spend on hotels for residents required to isolate before they return home.

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This rapid and efficient method to prepare highly purified recombinant adeno-associated viruses (rAAVs) is based on binding of negatively charged rAAV capsids to an anion-exchange resin that is pH dependent.

Plasmid DNA is prepared from the recombinant shuttle vector pLD53.SCAB/A-B created by cloning of the A and B homology arms for two-step bacterial artificial chromosome (BAC) engineering. To confirm that the A-box and B-box arms have been successfully incorporated into pLD53.SCAB, the pattern of enzyme digestion of the modified plasmid is compared with that of the unmodified pLD53.SCAB. Once the shuttle vector is shown to carry the proper sequences, it is ready for transfer into the BAC host.

The 700-bp A homology arm (A-box) and the 700-bp B homology arm (B-box) are amplified by polymerase chain reaction (PCR) using purified bacterial artificial chromosome (BAC) DNA as template for two-step BAC engineering. The resulting A-box PCR product contains an AscI site at its 5' end (the 5' primer incorporates an AscI site, and the 3' primer does not incorporate any restriction sites). The B-box PCR product contains an XmaI site at its 3' end (the 5' primer does not incorporate any restriction sites, and the 3' primer incorporates an XmaI site). The amplification products are then digested with the appropriate restriction endonucleases to render them suitable for cloning into the shuttle vector.

In two-step bacterial artificial chromosome (BAC) engineering, a single plasmid is introduced into the BAC-carrying cell lines. The shuttle vector pLD53.SCAB (or pLD53.SCAEB) carries the recA gene and the R6K origin, which requires the protein to replicate. PIR2 cells, expressing , are typically used for the amplification of the vector and maintain about 15 copies/cell of the donor vector, which is relatively stable in this host.

For close to 15 years, Reema Singh has been baking and selling cakes from her tiny shop on Parc Avenue in Montreal's Mile End. Cocoa Locale has been open throughout the pandemic because — well, it turns out that cake is essential.

Long-term interest rates have remained low despite a surge in the issuance of sovereign debt to mitigate the economic impact of the pandemic.

Canadian figure skater Scott Moir posted a video on Instagram and Twitter on Thursday, explaining that he and fiancee Jackie Mascarin are currently stationed in Tampa, Fla., because Mascarin works as a physician's assistant in the respiratory unit of a local hospital.

1. Bharat Biotech to lead human monoclonal antibodies project  The Hindu
2. Bharat Biotech leads CSIR project to develop antibodies against Covid-19  Times of India
3. Bharat Biotech To Lead CSIR’s Project To Develop Human Monoclonal Antibodies For Covid-19 Therapy  Swarajya
4. Bharat Biotech to develop human antibodies for COVID-19 therapy  Telangana Today
5. Bharat Biotech vows human monoclonal antibodies to neutralise COVID-19 in 6 months  Mumbai Mirror
6. View Full coverage on Google News

1. Coronavirus Outbreak Updates: Maharashtra reports 1,089 new COVID-19 cases across state, 748 in Mumbai; total infections at 19,063  Firstpost
2. Migrant workers | Maharashtra train accident victims were battling hunger  The Hindu
3. Maharashtra: They thought no trains were running, loco driver spotted them too late to stop  The Indian Express
4. ‘Stay where you are’: Shivraj Chouhan appeals to migrants after train tragedy  Hindustan Times
5. MP Ministers Ask Shivraj to Probe Tenure of Kamal Nath to ‘Expose Massive Corruption’  News18
6. View Full coverage on Google News

Hobbies during quarantine: How they can help us in a pandemic  Today.com

Karina LeBlanc was returning home from her second hospital visit after giving birth to her first child, only this time she would have to spend 14 days in self-isolation after doctors feared she contracted COVID-19 during her stay.

The Vancouver Whitecaps said it has ordered two player to self-quarantine for 14 days after they violated club and league orders to abide by physical distancing guidelines in B.C.

As part of the province's approach to curbing the COVID-19 pandemic, there are a number of rules in place that people have to follow. Kitchener and Waterloo bylaw officials offer some insight on what's allowed and what's not.

Living on a 10-acre plot of land 100 kilometres outside Toronto, David Stevens thought he and his family were well prepared to ride out the COVID-19 quarantine. But after a call from his mother, he learned that even the best laid plans can go wrong.

A normal draft year would see NHL scouts and executives spend the spring crisscrossing Europe and North America collecting information. The circumstances surrounding a 2020 draft and the COVID-19 pandemic, however, aren't anything resembling normal.

Former Montreal Canadiens enforcer Georges Laraque's biggest challenge is trying to breathe clearly as he fights COVID-19 at a Montreal hospital. "The nights are the worst. I have fevers a couple times a night. I have to get up and take pills."

Prime Minister Justin Trudeau said Sunday that NHL players would — at a minimum — need to follow quarantine protocols if they were to arrive in Canada while the border remains closed due to the pandemic.

A Toronto law firm has filed to launch a class action lawsuit against a Niagara Falls long-term care home where 18 residents have died from COVID-19, saying the home had a pub night in the midst of the pandemic.

Sofina Foods plants in Burlington and Mississauga have each had an employee test positive.

FSI Briefs No 5, April 2020. In response to the Covid-19 pandemic, governments have launched guarantee programmes to support bank lending to companies, especially small and medium-sized enterprises. This is essential to avoid a sharp contraction in bank credit that would exacerbate the pandemic's adverse impact. The design of such programmes needs to strike a difficult balance between responding promptly to the pandemic and maintaining a sufficient level of prudence. Key features of a sample of programmes (eg target beneficiaries, coverage of the guarantee, loan terms, length of the programme) reflect this tension. Incentives were created for the banks to join these programmes by exploiting flexibility in existing prudential requirements, while central banks have often provided liquidity support. Programmes are, however, subject to operational challenges and, ultimately, fiscal capacity limits.

Long-term interest rates have remained low despite a surge in the issuance of sovereign debt to mitigate the economic impact of the pandemic.

Frankly, Trump doesn’t give a damn.

CME will be updating liquidity parameters for Interest Rate Swap contracts denominated in BRL and MXN. These changes only impact portfolios with larger BRL or MXN exposures. For MXN, the impact to liquidity add-on is approx. 5-10% for portfolios with aggregated DV01 above 100M+ DV01 in local currency. For BRL, the impact to liquidity add-on is 30%+ for portfolios with aggregated DV01 above 10M+ in local currency. Based on current exposures, CME Clearing expects that there will be no impact to existing portfolios at this time. These changes will be available for testing in our New Release environment April 29, 2020, with a production date of May 4, 2020.

Click here for the full text of the advisory

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German translation of the BIS press release about the BIS Quarterly Review, December 2017

Un año después de la victoria en las elecciones de la Unión Nacional Africana de Zimbabue- Frente Patriótico (ZANU-PF, en sus siglas en inglés) y de la formación de un nuevo gobierno, la política y la economía de Zimbabue son cada vez más precarias. Las perspectivas inmediatas de una recuperación sostenida siguen siendo malas, empeoradas por el alarmante declive económico, los fracasos endémicos en materia de gobernanza y la tensión generada por la sucesión en el partido en el poder.

One major goal of integrative and comparative biology is to understand and explain the interaction between the performance and behavior of animals in their natural environment. The Caviomorph, Octodon degu, is a native rodent species from Chile, and represents a unique model to study physiological and behavioral traits, including cognitive and sensory abilities. Degus live in colonies and have a well-structured social organization, with a mostly diurnal–crepuscular circadian activity pattern. More notable is the fact that in captivity, they reproduce and live between 5 and 7 yr and show hallmarks of neurodegenerative diseases (including Alzheimer's disease), diabetes, and cancer.

Miraculous healing from sudden paralysis gives an OM worker opportunity to preach the gospel in a community.

CNA Staff, May 8, 2020 / 10:25 am (CNA).- Archbishop Carlo Maria Viganò has accused a Vatican cardinal of causing him “serious harm” in a bitter war of words over a controversial open letter regarding the coronavirus crisis.

In a statement published May 8, the archbishop criticized Cardinal Robert Sarah’s decision to distance himself from the letter, titled “Appeal for the Church and the World,” which argues that the coronavirus pandemic has been exploited in order to create a one-world government.

The statement details Vigano’s account of his interactions with Sarah beginning May 4. Viganò claims that on the evening of May 7, the prefect of the Vatican's Congregation for Divine Worship and Sacraments asked him to remove him from the list of signatories to the letter, which had by that time already been published.

“With surprise and deep regret,” he wrote, “I then learned that His Eminence had used his Twitter account, without giving me any notice, to make statements that cause serious harm to the truth and to my person.”

Viganò was referring to a series of three May 7 tweets from Sarah, which said: “A Cardinal Prefect, member of the Roman Curia has to observe a certain restriction  on political matters. He shouldn't sign petitions in such aereas [sic].”

“Therefore this morning I explicitely [sic] asked the authors of the petition titled ‘For the Church and for the world’ not to mention my name.”

“From a personal point of view, I may share some questions or preoccupations raised regarding restrictions on fundamental freedom but I didn't sign that petition,” Sarah added.

Viganò’s statement continued: “I am very sorry that this matter, which is due to human weakness, and for which I bear no resentment towards the person who caused it, has distracted our attention from what must seriously concern us at this dramatic moment.”

After Viganò issued his rebuke, Sarah tweeted May 8: “I will not speak to this petition, which today seems to occupy a lot of people. I leave to their conscience those who want to exploit it in one way or another. I decided not to sign this text. I fully accept my choice.”

In his statement, Viganò said he had chosen to publicize his private conversations with Sarah because he had a duty to tell the truth, and “also for the sake of fraternal correction.”

Vigano said Sarah had initially told him: “Yes, I agree to put my name to it, because this is a fight we must engage in together, not only for the Catholic Church but for all mankind.”

He confirmed that Sarah’s signature has now been removed from the open letter.

Vigano, a former papal nuncio made headlines in August 2018, for a letter that alleged Vatican officials had ignored warnings about the sexual abuse of disgraced former cardinal Theodore McCarrick. Since that time, Vigano has released numerous letters expressing his viewpoints on matters in the Church, which include criticisms of Pope Francis and other curial officials.

The appeal argued that as a result of the pandemic centuries of Christian civilization could be “erased under the pretext of a virus” and an “odious technological tyranny” established in its place.

It said: “We have reason to believe, on the basis of official data on the incidence of the epidemic as related to the number of deaths, that there are powers interested in creating panic among the world’s population with the sole aim of permanently imposing unacceptable forms of restriction on freedoms, of controlling people and of tracking their movements. The imposition of these illiberal measures is a disturbing prelude to the realization of a World Government beyond all control.”

Several bishops and cardinals are alleged to have signed the letter. Bishop Joseph Strickland of Tyler, Texas told CNA May 7 that he had signed it.

A press release on the appeal’s website May 8 claimed that Robert Kennedy Jr, son of the slain US. Presidential candidate Sen. Robert Kennedy, had signed the letter.

To date, nearly 4 million people have tested positive for the coronavirus, and at least 272,000 have died.