Multisensory and Motor Representations in Rat Oral Somatosensory Cortex

Abstract In mammals, a complex array of oral sensors assess the taste, temperature and haptic properties of food. Although the representation of taste has been extensively studied in the gustatory cortex, it is unclear how the somatosensory cortex encodes information about the properties of oral stimuli. Moreover, it is poorly understood how different oral sensory modalities are integrated and how sensory responses are translated into oral motor actions. To investigate whether oral somatosensory cortex processes food-related sensations and movements, we performed in vivo whole-cell recordings and motor mapping experiments in rats. Neurons in oral somatosensory cortex showed robust post-synaptic and sparse action potential responses to air puffs. Membrane potential showed that cold water evoked larger responses than room temperature or hot water. Most neurons showed no clear tuning of responses to bitter, sweet and neutral gustatory stimuli. Finally, motor mapping experiments with histological verification revealed an initiation of movements related to food consumption behavior, such as jaw opening and tongue protrusions. We conclude that somatosensory cortex: (i) provides a representation of the temperature of oral stimuli, (ii) does not systematically encode taste information and (iii) influences orofacial movements related to food consummatory behavior

Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain

SummaryBackgroundChronic established pain, especially that following nerve injury, is difficult to treat and represents a largely unmet therapeutic need. New insights are urgently required, and we reasoned that endogenous processes such as cooling-induced analgesia may point the way to novel strategies for intervention. Molecular receptors for cooling have been identified in sensory nerves, and we demonstrate here how activation of one of these, TRPM8, produces profound, mechanistically novel analgesia in chronic pain states.ResultsWe show that activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of specific pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, thereby inhibiting the characteristic sensitization of dorsal-horn neurons and behavioral-reflex facilitation. TRPM8 expression was increased in a subset of sensory neurons after nerve injury. The essential role of TRPM8 in suppression of sensitized pain responses was corroborated by specific knockdown of its expression after intrathecal application of an antisense oligonucleotide. We further show that the analgesic effect of TRPM8 activation is centrally mediated and relies on Group II/III metabotropic glutamate receptors (mGluRs), but not opioid receptors. We propose a scheme in which Group II/III mGluRs would respond to glutamate released from TRPM8-containing afferents to exert an inhibitory gate control over nociceptive inputs.ConclusionsTRPM8 and its central downstream mediators, as elements of endogenous-cooling-induced analgesia, represent a novel analgesic axis that can be exploited in chronic sensitized pain states

工時有幾長？貧窮新一代的就業與貧窮報告

近年，社會出現有關年輕人「躺平」的討論，指年輕新一代不願找工作、不願勤奮加班、不規構未來。教育局局長楊潤雄亦曾在網誌撰文表示憂慮，批評「躺平這種消極的人生心態，長遠會窒礙社會的進步」。 不過，根據香港政府統計處2021年收入及工時按年統計調查報告， 2021年5月至6月，15至24歲及25至34歲受訪者每周的工作時數中位數分別為44.3及42小時，比亞洲其他國家要高；而2022年4至6月，20至24歲及25至29歲的勞動人口參與率分別為53.5%及87%，後者更是所有年齡組別中第二高（僅次於30至34歲年齡組別），反映年輕人並沒有不願意長時間工作和就業，與成年人無異。 另外，根據中大亞太研究所於本年四月進行的一項調查，超過半數受訪者認為香港社會並沒有足夠機會與年輕一代向上流動，更有六成半受訪者認為，現時香港向上流動的機會比過去10年要少。 在是次研究中，發現有不少手持大學文憑的畢業生甫踏入社會，便從事三行、保安、飲食業等藍領工種，以體力勞動換取更高薪酬。文職的工作機會雖不算難找，但對於畢業生來說，待遇多不及前者；初入職場的年輕人便要忍受長工時以換取較可觀的薪金，更因長期體力勞動及工作環境惡劣，導致工傷或患上職業病，造成不可逆轉的傷害；選擇白領工作的年輕人則花空餘時間研究創業路向，望有天可擺脫低工資、長OT的工作常態。 年輕人是社會重要的群體，促進社會不同面向的發展和進步。勞工議題，正正就是影響年輕人最深遠的問題。不過，社會一般會把青年遇到的問題視為過渡性現象，隨著他們成長而消失。坊間少有深入討論，以致一般年輕人以為工作的沉重是理所當然，對自身的勞工權益鮮有認識。 上述所提及的年輕人工時長的狀況，窒礙他們在成長階段的探索，因長工時影響反心健康、無法進修、交結朋友、和家人相處及了解自我。工時長等問題在港是老生常談，卻是待解決的重要議題。香港人多年來一直受長工時的困擾，回顧香港的工時政策，卻未見突破。由勞顧會於2018年宣布推出「11個行業工時指引」，距今已4年，仍未見進展。更何況，指引的條文亦不適用於大部份長工時的打工仔女，例如只保障月薪不超過1.1萬元作為界定工資較低的基層僱員的工資線等規定。可見，像過往一樣，政府及商界等對標準工時並不持開放態度。 誠然，參考不同地區及國家的工時政策，香港則顯得相當落後。中國、日本、台灣、韓國及新加坡均有明確法例規管工時，如超時工作的補水機制、每天工作8小時作為標準工時等。如香港政策要推行工時相關的政策，大有參考例子。本報告亦整合及分析了上述地區的工時政策，有助了解其他地區的勞工法例。 是次研究探討了現行的工時政策下香港年輕僱員的工作現況。透過深入訪談及問卷調查，發現長工時與生理、心理、社交及家庭關係的影響，以及就研究結果提倡相應的政策改革，讓社會大眾及年輕人自身了解他們的勞動現況，剖析處境並提出有效的改善方針。https://commons.ln.edu.hk/ccrd_report/1002/thumbnail.jp

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis

TRPV3 is a thermosensitive channel that is robustly expressed in skin keratinocytes and activated by innocuous thermal heating, membrane depolarization, and chemical agonists such as 2-aminoethyoxy diphenylborinate, carvacrol, and camphor. TRPV3 modulates sensory thermotransduction, hair growth, and susceptibility to dermatitis in rodents, but the molecular mechanisms responsible for controlling TRPV3 channel activity in keratinocytes remain elusive. We show here that receptor-mediated breakdown of the membrane lipid phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) regulates the activity of both native TRPV3 channels in primary human skin keratinocytes and expressed TRPV3 in a HEK-293–derived cell line stably expressing muscarinic M1-type acetylcholine receptors. Stimulation of PI(4,5)P2 hydrolysis or pharmacological inhibition of PI 4 kinase to block PI(4,5)P2 synthesis potentiates TRPV3 currents by causing a negative shift in the voltage dependence of channel opening, increasing the proportion of voltage-independent current and causing thermal activation to occur at cooler temperatures. The activity of single TRPV3 channels in excised patches is potentiated by PI(4,5)P2 depletion and selectively decreased by PI(4,5)P2 compared with related phosphatidylinositol phosphates. Neutralizing mutations of basic residues in the TRP domain abrogate the effect of PI(4,5)P2 on channel function, suggesting that PI(4,5)P2 directly interacts with a specific protein motif to reduce TRPV3 channel open probability. PI(4,5)P2-dependent modulation of TRPV3 activity represents an attractive mechanism for acute regulation of keratinocyte signaling cascades that control cell proliferation and the release of autocrine and paracrine factors

最低工資有幾低? 貧窮新一代的就業困境報告

為了解香港青年對就業、貧窮、體面生活、相關政策的看法，以及他們收入和支出的情況，嶺南大學政策研究院、文化研究及發展中心聯合進行一項題為《最低工資有幾低？貧窮新一代的就業困境報告》的調查。結果發現，四成接受深度訪談的青年自認貧窮，而絕大部分已有全職工作的受訪青年認為，最低工資調整幅度太低，自己未能受惠。 嶺大研究團隊從2022年5月至12月，先後透過兩輪深度訪談，訪問了67位18至29歲、收入低於2萬元、有工作經驗的青年。另外，團隊亦透過兩輪問卷調查，分別收集到164份及253份有效回覆。 調查結果發現，絕大部分年輕人覺得自己的工資太低，待遇與工作不相稱。受訪青年的收入來源包括全職工作、兼職工作。深度訪談年輕人的收入中位數為15,200元，而問卷調查的收入中位數結果則是6,000至9,999元。一方面，大部分有全職工作的青年認為自己工時長、部分行業長期低薪，比不上任職其他行業的同輩，而覺得不滿。壓力同時來自高昂的生活成本和遙不可及的人生目標，包括置業。 大約四成接受第二輪深度訪談的青年自認是貧窮，他們對於貧窮有多元化的理解。有青年認為三餐不繼才算得上貧窮，有些人覺得人工未達到港人月入中位數就算是貧窮，亦有人認很多目標未能達成，導致「精神貧窮」。其餘自覺不貧窮的青年部分歸因於家庭支援，可以滿足基本需求以外的消費，例如購物和旅遊。 絕大部分已有全職工作的受訪青年覺得最低工資調整幅度太低，自己未能受惠。無論認為自己屬於中產或基層的受訪者，均有共識，認為即使法定最低工資水平提升至40元依然是太低，與市場脫節，調整幅度不合理。不少人往往將最低工資時薪和「一餐飯」的開支掛鉤，認為最低工資水平要吃得起「一餐飯」才合理。受訪者認為最低工資如有合理升幅及政策檢討，對基層家庭及兼職工作者有很大幫助。 問卷調查結果推算，受訪青年要滿足現時的生活開支水平，時薪應該要達到71.6元。問卷調查的結果顯示青年的個人月均生活支出為16,789元，扣除教育開支，平均每月支出約14,894元，按一個月工作26日，每日8小時計算出時薪水平為71.6元，與目前最低工資水平相距很遠。 研究團隊建議，政府應從多方面著手解決此迫切的社會問題。首先，當局應檢討最低工資政策的定位，使它與其他扶貧政策互相配合，以保障不同需要的群體；第二，當局應透明化最低工資的調整過程，改為「一年一檢」；第三，團隊建議重啟標準工時立法程序，訂明標準工時應為每周40小時，加班工資應為正常工資的1.5倍，每月亦應設有加班和總工時上限，並以此為基礎制定「過勞死」的法律定義，把過勞死定為僱主須按《僱員補償條例》（第282章）作出補償的事故。最後，團隊建議政府主動開展設立失業保障制度的工作，包括探討供款式失業保險、檢討現行失業綜援、遣散費／長期服務金，並重視年輕人對相關政策的意見。https://commons.ln.edu.hk/ccrd_report/1003/thumbnail.jp

The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons

The diversity of neurons in sympathetic ganglia and dorsal root ganglia (DRG) provides intriguing systems for the analysis of neuronal differentiation. Cell surface receptors for the GDNF family ligands (GFLs) glial cell-line-derived neurotrophic factor (GDNF), neurturin and artemin, are expressed in subpopulations of these neurons prompting the question regarding their involvement in neuronal subtype specification. Mutational analysis in mice has demonstrated the requirement for GFL signalling during embryonic development of cholinergic sympathetic neurons as shown by the loss of expression from the cholinergic gene locus in ganglia from mice deficient for ret, the signal transducing subunit of the GFL receptor complex. Analysis in mutant animals and transgenic mice overexpressing GFLs demonstrates an effect on sensitivity to thermal and mechanical stimuli in DRG neurons correlating at least partially with the altered expression of transient receptor potential ion channels and acid-sensitive cation channels. Persistence of targeted cells in mutant ganglia suggests that the alterations are caused by differentiation effects and not by cell loss. Because of the massive effect of GFLs on neurite outgrowth, it remains to be determined whether GFL signalling acts directly on neuronal specification or indirectly via altered target innervation and access to other growth factors. The data show that GFL signalling is required for the specification of subpopulations of sensory and autonomic neurons. In order to comprehend this process fully, the role of individual GFLs, the transduction of the GFL signals, and the interplay of GFL signalling with other regulatory pathways need to be deciphered

A Mouse Model of the Human Fragile X Syndrome I304N Mutation

The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA–binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5′UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA–binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1–null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder